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Abstract

To better define the pathophysiologic mechanisms underlying the development of the novel facial-onset sensory and motor neuronopathy (FOSMN) syndrome and, in particular, to determine whether neurodegenerative processes, mediated by excitotoxicity, or autoimmune mechanisms contribute to the development of FOSMN syndrome. Clinical, laboratory, neurophysiologic, and pathologic assessments were undertaken for 5 patients with FOSMN syndrome (3 male and 2 female), the largest cohort of FOSMN syndrome reported to date. In addition to conventional neurophysiologic studies, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were undertaken to assess for the presence of cortical excitability. Clinically, all patients exhibited the typical FOSMN syndrome phenotype, heralded by facial-onset sensory deficits with subsequent development of motor deficits evolving in a rostral-caudal direction. Pathologic studies, including an autopsy, disclosed widespread degeneration of sensory and motor neurons with no evidence of inflammation, amyloid deposition, or intraneuronal inclusions, such as TDP-43, Bunina bodies, or ubiquitin inclusions. Conventional neurophysiologic studies revealed abnormalities of blink reflexes, along with features of motor and sensory neuronopathy. Threshold tracking TMS disclosed normal cortical excitability in patients with FOSMN syndrome, with preserved short-interval intracortical inhibition, resting motor threshold, motor evoked potential amplitude, and cortical silent period duration. Patients with FOSMN syndrome failed to respond to immunomodulatory approaches. Findings from the present study suggest that FOSMN syndrome is a primary neurodegenerative disorder of sensory and motor neurons, with distinct pathophysiologic mechanisms.

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... patients who presented with facial sensory deficits, followed by motor deficits, evolving rostro-caudally (Vucic et al., 2006b). Over the intervening 15 years, a range of individual cases and small case series have been reported (Barca et al., 2012;Bélénotti et al. 2010;de Boer et al., 2021;Broad and Leigh, 2015;Cruccu et al., 2014;Dalla Bella et al., 2016, 2014Dobrev et al., 2012;Fluchere et al., 2011;Hokonohara et al., 2008;Isoardo and Troni, 2008;Karakis et al., 2014;Knopp et al., 2013;Lange et al., 2020;Ohashi et al., 2020;Olney et al., 2018;Pinto et al., 2019;Rossor et al., 2019;Sonoda et al., 2013;Truini et al., 2015;Vázquez-Costa et al., 2019;Vucic et al., 2012;Watanabe et al., 2018;Zhang et al., 2019;Ziso et al., 2015). Clinical, genetic and neuropathological data strongly suggest that FOSMN is a rare phenotype of motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS) (Dalla Bella et al., 2014;Pinto et al., 2019;Rossor et al., 2019;Sonoda et al., 2013;Vázquez-Costa et al., 2019;Vucic, 2014;Zhang et al., 2019;Ziso et al., 2015). ...
... Threshold tracking transcranial magnetic stimulation (ttTMS) was used to measure cortical excitability on the Sydney cohort according to a previously published technique (Vucic et al., 2012(Vucic et al., , 2006a. The motor cortex was stimulated by a 90 mm circular coil with MEPs recorded over APB. ...
... Threshold tracking TMS was performed on 4 previously reported patients (Vucic et al., 2012), referred to as historical patients, and two new patients from the Sydney cohort (Patients 7 and 10 in this series). Cortical function was normal in 4 (66.7%) of the assessed patients as indicated by mean SICI (interstimulus interval 1-7 ms) of 7.1 ± 1.8% (normal > 5.2%, Fig. 5C), and mean ICF (interstimulus interval 10-30 ms) of À2.3 ± 2.5% (normal ! ...
Article
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Objective To determine the electrodiagnostic characteristics of facial onset sensory and motor neuronopathy (FOSMN). Methods Electrophysiological data from 10 FOSMN patients in Newcastle-upon-Tyne and Sydney were reviewed. Relevant literature was reviewed. Results Findings on standard electrophysiological assessment were in broad agreement with those published: blink reflexes were abnormal in all but one patient; sensory nerve action potentials were reduced but compound muscle action potentials preserved; mixed acute and chronic neurogenic change was identified on needle electromyography in bulbar and cervico-thoracic muscles in approximately 50% of patients. Upper limb somatosensory evoked potential (SEP) central conduction times were increased (n=4) and progressed on repeat testing (n=3). Upper motor neuron dysfunction was revealed by several measures [ipsilateral motor evoked potentials (MEPs) (n=1); reduced short interval intra-cortical inhibition on threshold-tracking transcranial magnetic stimulation (n=2); absent beta-band intermuscular coherence (n=3)]. Conclusions Electrodiagnostic investigation of FOSMN should include blink reflex testing, SEPs and tests of upper motor neuron function. The combination of progressive lower motor neuron disease and upper motor neuron disease on neurophysiological investigation provides further support for the contention that FOSMN is a rare variant of motor neuron disease. Significance These findings will aid the neurologist and neurophysiologist in making a confident diagnosis of FOSMN, thus expediting appropriate care.
... 2 In general, only the lower motor neuron system is involved, although upper motor neuron signs have been reported in a few cases. [3][4][5][6][7][8][9][10][11] Pathogenesis is uncertain. Initial indications suggested an autoimmune basis since autoantibodies have been reported as well as a partial and subjective response to immunotherapy. ...
... Our literature search yielded 26 full-text articles reporting on a total of 64 patients with FOSMN, of which 29 were not described in a review before. 1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][18][19][20][21][22][23][24] We further identified 7 abstracts/posters/ supplements reporting on 11 potential cases and 2 articles mentioning 10 FOSMN cases without further patient characteristics. 25,26 After reaching out to the corresponding authors, we received a detailed poster on 7 patients with FOSMN. ...
... Upper motor neuron signs, such as brisk reflexes, Babinski sign, and clonus, were reported in 27 cases. [3][4][5][6][7][8][9][10][11]14 Natural history The mean age at onset is approximately 55 years (range 7-78 years). The rate of progression is highly variable, and survival ranges from 14 months to over 46 years. ...
Article
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Purpose of review To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). Recent findings We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. Summary FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis–FTD spectrum.
... Most cases present with an insidious clinical course between the fifth and seventh decades of life (despite rare childhood-onset cases) [71][72][73][74][75][76][77] and a slowly progressive natural history, commonly stereotyped, usually with paresthesia or numbness in the face with an asymmetrical pattern with trigeminal distribution (often unilateral), eventually with motor involvement and variable amyotrophy in ipsilateral masseteric and temporal muscle groups [73][74][75][76][77]. At this stage, symptoms and signs of bulbar involvement are often reported with slowly progressive dysphagia and dysarthria [77][78][79]. ...
... There is slow progression of cranial symptoms over months to years evolving with abnormal protopathic and pain sensitivity in the upper limbs with a symmetrical syringomyelic-like pattern [77][78][79]. There is typically a LMNpredominant involvement without early signs of UMN compromise and only lately with motor involvement of the lower limbs. ...
... Elevation of serum creatine kinase is common, generally at levels below 1000 IU/L (upper normal limit < 250 IU/L). It is exceptionally rare to find mildly raised levels of cerebrospinal fluid protein and IgG levels, as well as the presence of hypergammaglobulinemia, gammopathies, and positive serum anti-MAG (myelin-associated glycoprotein) and antigangliosides (IgG anti-sulphatides and anti-GD1b) antibodies [75][76][77][78][79]. There are no specific brain neuroimaging findings in FOSMN syndrome. ...
Article
Motor Neuron disease (MND) representes a wide and heterogeneous expanding group of disorders involving the upper or lower motor neurons, mainly represented by Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis, Progressive Muscular Atrophy and Progressive Bulbar Palsy. Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Despite its well-known natural history, pathophysiological and clinical characteristics for the most common MND, atypical clinical presentation and neurodegenerative mechanisms are commonly observed in rare clinical entities, so-called atypical variants of MND-ALS, including flail-leg syndrome, flail-arm syndrome, facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus (FEWDON-MND) and long-lasting and juvenile MND-ALS. Herein, we provide a review article presenting clinical, genetic, pathophysiological and neuroimaging findings of atypical variants of MND-ALS in clinical practice.
... Initial reports described the presence of anti-ganglioside antibodies and response to immunotherapy, 5 whereas others have described a progressive and terminal decline, resistant to immunotherapy and suggestive of bulbar-onset amyotrophic lateral sclerosis (ALS). 3,[6][7][8] Two of 3 postmortem studies of patients with FOSMN have revealed the presence of TAR DNA-binding protein (TDP) 43 inclusions in the brainstem nuclei and cervical motor neurons. 3,7,8 In this article, we describe a patient with FOSMN and behavioral change in whom postmortem examination revealed frequent pathologic TDP43 inclusions in the deep cerebral nuclei, brainstem, and spinal cord and rarely in the medial temporal lobe, frontal cortex, and dorsal root ganglia (DRG). ...
... 3,[6][7][8] Two of 3 postmortem studies of patients with FOSMN have revealed the presence of TAR DNA-binding protein (TDP) 43 inclusions in the brainstem nuclei and cervical motor neurons. 3,7,8 In this article, we describe a patient with FOSMN and behavioral change in whom postmortem examination revealed frequent pathologic TDP43 inclusions in the deep cerebral nuclei, brainstem, and spinal cord and rarely in the medial temporal lobe, frontal cortex, and dorsal root ganglia (DRG). ...
... Our findings corroborate the findings of 2 of 3 previous postmortem examinations of patients with FOSMN in which TDP43 inclusions were identified in the brainstem. 3,7,8 This report provides further evidence that FOSMN may be considered a forme fruste of bulbar-onset ALS, a notion further supported by the behavioral change and TDP43 inclusions in the frontal cortex. We were unable to measure β-amyloid 42 and tau in the CSF because this assay was not available 15 year ago at the time of the patient's illness. ...
Article
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Objective: To describe the histopathologic features of a case of facial-onset sensory and motor neuronopathy (FOSMN). Methods: We describe a postmortem examination performed on a 54-year-old man with FOSMN associated with personality change. Results: Postmortem examination revealed TAR DNA-binding protein (TDP) 43 proteinopathy with widespread distribution. TDP43 pathology was seen in the neurons and glial cells and was most pronounced in the subthalamic nucleus followed by the spinal cord, including dorsal root ganglia, brainstem, and other deep cerebral nuclei. In the medial temporal lobe, neocortex and subcortical hemispheric white matter TDP43 pathologic inclusions were very rare. In contrast to TDP43 pathologies associated with typical amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD)-TDP, in this case, there were more frequent TDP43-positive oligodendroglial, coiled body-like cytoplasmic inclusions than neuronal inclusions. Neuronal cytoplasmic TDP43 inclusions with globular and skein-like morphology were seen in both anterior horn cells and dorsal root ganglia. No β-amyloid, α-synuclein, or significant hyperphosphorylated tau pathology was seen. Conclusion: This case provides further evidence that FOSMN is a neurodegenerative disease characterized by TDP43 pathology. Despite minimal cortical TDP43 pathology, the clinical features of the behavioral variant of FTD in this patient suggest that FOSMN may fall within or overlap with the FTD-ALS spectrum.
... Yet, despite this classic clinical picture, atypical presentations have been described, while the main pathophysiological basis and the possible genetic mechanisms involved are still poorly understood, as they have been only scantily evaluated in previous studies [9,11,12]. For this reason, the present report is a description of 10 new cases of Brazilian patients, with definite clinical and neurophysiological diagnoses of FOSMN syndrome, aiming to provide a definitive new neurogenetic basis in some cases to expand the spectrum of known pathogenetic mechanisms. ...
... Elevated serum CK is common in FOSMN syndrome, although generally with levels <1000 IU/L. It is exceptionally unusual to find only mildly raised levels of CSF protein and immunoglobulin G (IgG) levels, and the presence of hypergammaglobulinemia, gammopathies, and positive serum anti-MAG and anti-ganglioside (anti-sulfatide IgG, anti-GD1b) antibodies [8,10,11]. None of our patients presented with sustained high levels of serum CK or positivity for serum autoantibodies, thereby suggesting that these biomarkers may perhaps be non-specific and not clinically obligatory for a definitive diagnosis. Also, there are no specific brain neuroimaging findings in FOSMN syndrome: cervical and thoracic segments of the spinal cord have never shown abnormalities indicative of the syringomyelic clinical pattern of sensory abnormalities, despite the previously reported rare findings of atrophy of the middle segment of the cervical spinal cord [10]. ...
... In fact, as detected in the present series, SNAPs may also have had reduced amplitudes, especially in the upper limbs during NCS. Also, although not performed in the present study, transcranial magnetic stimulation (TMS) studies have failed to detect cortical hyperexcitability in FOSMN syndrome, but did reveal higher motor thresholds during resting states, reduced amplitudes of evoked motor potentials and no marked loss of intracortical inhibition on short-term paired-pulse stimulation, a finding frequently reported in patients with ALS [8,10,11,23,27]. ...
Article
Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.
... Its cardinal features are initial asymmetrical facial paresthesia and/or sensory deficits followed by bulbar symptoms and spreading of sensory and motor deficits from the face to the scalp, neck, upper trunk, and upper extremities in a rostral-caudal direction. FOSMN is a rare disorder, with only 40-50 reported cases; the exact number of patients is unclear because some reported cases may be overlapping (Barca et al., 2013;Broad & Leigh, 2015;Cruccu et al., 2014;Dalla Bella et al., 2014Dobrev et al., 2012;Fluchere et al., 2011;Hokonohara et al., 2008;Isoardo & Troni, 2008;Karakis, Vucic, & Srinivasan, 2014;Knopp, Vaghela, Shanmugam, & Rajabally, 2013;Sonoda et al., 2013;Truini et al., 2015;Vucic et al., 2006Vucic et al., , 2012Ziso et al., 2015). FOSMN is regarded as a neurodegenerative condition with close links to amyotrophic lateral sclerosis (ALS) (Zheng, Chu, Tan, & Zhang, 2016). ...
... Some patients with FOSMN have a rapidly progressive course (Barca et al., 2013;Broad & Leigh, 2015;Fluchere et al., 2011;Sonoda et al., 2013) , similar to bulbar-onset ALS (Chiò, Calvo, Moglia, Mazzini, & Mora, 2011). Others have a relatively long course (Cruccu et al., 2014;Dalla Bella et al., 2016;Isoardo & Troni, 2008;Karakis et al., 2014;Vucic et al., 2006Vucic et al., , 2012Ziso et al., 2015), which is unusual for ALS (Haverkamp, Appel, & Appel, 1995). Partly because of the rarity of this disease, long-term prognostic factors have not been established. ...
... Partly because of the rarity of this disease, long-term prognostic factors have not been established. Bulbar involvement is frequently observed in this condition (Barca et al., 2013;Broad & Leigh, 2015;Cruccu et al., 2014;Dalla Bella et al., 2014Dobrev et al., 2012;Fluchere et al., 2011;Hokonohara et al., 2008;Isoardo & Troni, 2008;Karakis et al., 2014;Knopp et al., 2013;Sonoda et al., 2013;Truini et al., 2015;Vucic et al., 2006Vucic et al., , 2012Ziso et al., 2015) and could be a prognostic factor. However, bulbar manifestations in FOSMN have not been thoroughly described. ...
Article
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Introduction Facial onset motor and sensory neuronopathy (FOSMN) is a rare disease whose cardinal features are initial asymmetrical facial sensory deficits followed by bulbar symptoms and spreading of sensory and motor deficits from face to scalp, neck, upper trunk, and upper extremities in a rostral–caudal direction. Although bulbar involvement is frequently observed in FOSMN, dysphagia in these patients has not been fully described. In this study, we aimed to characterize dysphagia as a prognostic factor in FOSMN by investigating our institutional case series. Methods We retrospectively reviewed the medical records, including swallowing function tests, of six patients with FOSMN (three men and three women) who were thoroughly examined at Kyushu University Hospital between 1 January 2005 and 30 November 2017. Results Average age at onset was 58.5 years; average disease duration was 5.7 years. All patients developed bulbar dysfunction and dysphagia (at an average of 1.8 and 2.6 years from onset, respectively), resulting in choking episodes in three patients, percutaneous endoscopic gastrostomy placement in three, and recurrent aspiration pneumonia in one. Four of five patients evaluated with videofluoroscopic swallowing studies had poor oral retention, leading to bolus flowing into the pharynx before swallowing; the fifth patient showed poor lingual transfer. Fiberoptic endoscopic evaluation of swallowing revealed leakage of blue‐dyed water from the mouth to the pharynx in three patients because of poor oral retention, but only mild pharyngeal phase dysphagia in all four cases evaluated. Conclusions Oral phase dysphagia predominates in the early stage of FOSMN.
... Facial onset sensory and motor neuronopathy (FOSMN) is a slowly progressive disorder characterised by facial sensory deficits which may spread to affect the neck, the upper trunk and the limbs, with the development later in the course of the disease of bulbar symptoms such as dysarthria and dysphagia, muscle weakness, cramps and fasciculation [1]. Because of these latter features, parallels between FOSMN and motor neurone disease (MND) have been drawn, although sensory features are not a feature of MND and the onset and progression of FOSMN appear to be slower than those of MND [2]. ...
... The pathogenesis of FOSMN is uncertain. Based on the limited currently available clinical and investigative evidence [1][2][3][4][5][6][7][8][9][10][11][12] and the lack of therapeutic response to immunosuppressive agents in most (but not all) [4] cases, an underlying neurodegenerative process has been suggested in FOSMN, although cases with neuropathological examinations are very few [2,6,9]. We report 3 further cases of FOSMN, one with a post-mortem examination, suggesting that at least some of these cases fall within the spectrum of the transactive response DNA binding protein 43 (TDP-43) proteinopathies. ...
... The pathogenesis of FOSMN is uncertain. Based on the limited currently available clinical and investigative evidence [1][2][3][4][5][6][7][8][9][10][11][12] and the lack of therapeutic response to immunosuppressive agents in most (but not all) [4] cases, an underlying neurodegenerative process has been suggested in FOSMN, although cases with neuropathological examinations are very few [2,6,9]. We report 3 further cases of FOSMN, one with a post-mortem examination, suggesting that at least some of these cases fall within the spectrum of the transactive response DNA binding protein 43 (TDP-43) proteinopathies. ...
Article
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Three patients with the clinical and investigation features of facial onset sensory and motor neuronopathy (FOSMN) syndrome are presented, one of whom came to a post-mortem examination. This showed TDP-43-positive inclusions in the bulbar and spinal motor neurones as well as in the trigeminal nerve nuclei, consistent with a neurodegenerative pathogenesis. These data support the idea that at least some FOSMN cases fall within the spectrum of the TDP-43 proteinopathies, and represent a focal form of this pathology.
... Facial onset sensory and motor neuronopathy is a rare, slowly progressive neurodegenerative disorder clinically characterized by numbness and paresthesias initially in a trigeminal nerve distribution followed by spreading to the scalp, neck, upper trunk, and upper limbs. [101] Later in the course, patients develop muscle cramps, fasciculations, muscle weakness and wasting, dysphagia, and dysarthria. [101] Nerve conduction studies reveal a caudally descending sensorimotor neuropathy. ...
... [101] Later in the course, patients develop muscle cramps, fasciculations, muscle weakness and wasting, dysphagia, and dysarthria. [101] Nerve conduction studies reveal a caudally descending sensorimotor neuropathy. [101] An autopsy may show loss of motoneurons in the hypoglossal nucleus and cervical anterior horns. ...
... [101] Nerve conduction studies reveal a caudally descending sensorimotor neuropathy. [101] An autopsy may show loss of motoneurons in the hypoglossal nucleus and cervical anterior horns. ...
Article
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Lesions of the lower cranial nerves (LCN) are due to numerous causes, which need to be differentiated to optimize management and outcome. This review aims at summarizing and discussing diseases affecting LCN. Review of publications dealing with disorders of the LCN in humans. Affection of multiple LCN is much more frequent than the affection of a single LCN. LCN may be affected solely or together with more proximal cranial nerves, with central nervous system disease, or with nonneurological disorders. LCN lesions have to be suspected if there are typical symptoms or signs attributable to a LCN. Causes of LCN lesions can be classified as genetic, vascular, traumatic, iatrogenic, infectious, immunologic, metabolic, nutritional, degenerative, or neoplastic. Treatment of LCN lesions depends on the underlying cause. An effective treatment is available in the majority of the cases, but a prerequisite for complete recovery is the prompt and correct diagnosis. LCN lesions need to be considered in case of disturbed speech, swallowing, coughing, deglutition, sensory functions, taste, or autonomic functions, neuralgic pain, dysphagia, head, pharyngeal, or neck pain, cardiac or gastrointestinal compromise, or weakness of the trapezius, sternocleidomastoid, or the tongue muscles. To correctly assess manifestations of LCN lesions, precise knowledge of the anatomy and physiology of the area is required.
... This neurodegenerative disorder has a slowly progressive course. Probably for this reason, transcranial magnetic stimulation (TMS) resting motor threshold, motor evoked potential amplitude, cortical silent period duration and threshold tracking TMS were found unaffected in these patients (Vucic et al., 2012). In spite of the apparent male predominance, Dobrev et al. (2012) reported 3 affected woman, one with neurogenic changes in lower limb muscles. ...
... Nowadays, more than 100 cases of this rare disorder have been reported. Disease progression is variable (survival from 1 to 46 years) but is generally slow, in a rostro-caudal direction, the mean age at onset is approximately 55 years (de Boer et al., 2021), and upper motor neuron signs are generally absent, in agreement with normal TMS studies (Fluchere et al., 2011;Vucic et al., 2012) and no abnormal neuropathological findings in the motor cortex (Sonoda et al., 2013;Rossor et al., 2019). In this volume of Clinical Neurophysiology, De Oliveira et al. report longitudinal neurophysiological findings from 10 patients with FOSMN followed in Newcastle-upon-Tyne and Sydney, although not all patients underwent the same tests (De Oliveira et al., 2022). ...
... Facial-onset sensory and motor neuronopathy (FOSMN) is a rare clinical syndrome characterized by trigeminal involvement and bulbar palsy that may progress to the limbs [1]. Onset of FOSMN is usually after the fourth decade, and the prognosis is variable, from months to decades. ...
... Her slow evolution is also classical both for FOSMN and HD, but the severity of corneal ulcer leading to blindness is unusual. Conversely, the clinical progression of the FOSMN syndrome in this patient well correspond to what is described in the literature, with progressive paralysis of the upper and then lower limb [1][2][3][4]. Psychiatric and cognitive involvement was late and preceded of a few months the occurrence of Chorea. Pathogenesis of the FOSMN syndrome remains unclear, but in several cases, gene mutations undoubtedly implicated in hereditary ALS pathogenesis, have been reported [4][5][6]. ...
Article
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Objectives: To describe a patient with facial-onset sensory-motor neuronopathy (FOSMN) that later developed Huntington’s disease (HD). Case report: A 62-year-old woman complained of progressive dysphagia 8 years before referral. At initial evaluation, there was excessive salivation, dysphagia, and sensory-motor trigeminal impairment. Denervation was noted on the upper limbs and the tongue. Blink reflexes were abolished. Genetic study of amyotrophic lateral sclerosis (ALS)-related genes was normal. She was diagnosed with FOSMN syndrome. Her clinical state progressively worsened with corneal anesthesia, severe denutrition, right arm and axial weakness. Seven years after referral, she was unable walk and developed generalized chorea. Abnormal huntingtin gene repeat expansion confirmed the diagnosis of HD. She died 16 years after onset of dysphagia. Conclusion: Cases with both HD and ALS have already been reported but not FOSMN and HD, to our knowledge. Some FOSMN cases have been linked to ALS-related gene mutations and HD phenocopies have been associated with C9ORF72 repeat expansions. Recently, huntingtin repeat expansions were described in the ALS population. Although a chance association cannot be excluded, data from the literature are in favor of a pathogenic relationship between FOSMN and HD in this particular case. We suggest that huntingtin gene be more systematically studied in patients with FOSMN.
... Our patient had a transient mild albuminocytologic dissociation which was potentially caused by recent lumbar disc herniations. Corroborating previous reports, our patient did not improve after immunotherapy [4,5]. Thus, we did not find evidence for an inflammatory etiology of FOSMN. ...
... To date, FOSMN pathophysiology remains unclear. The hypothesis of neurodegenerative disease has been supported by neuronal loss in the nuclei of affected cranial nerves, anterior horn cells, and dorsal root ganglia in one patient [5]. Several studies found features supporting common pathophysiology of MND and FOSMN, namely proof of heterozygous D90A-SOD1 mutation in one patient [6] and widespread TDP-43 inclusions in postmortem studies another patient [4]. ...
... The distinct spinal cord pathology of amyotrophic lateral sclerosis (ALS) was first described by Charcot over 100 years ago [1,2]. ALS is now considered part of a larger heterogeneous spectrum of motor neuron diseases (MND) [3], that includes (but is not limited to): ALS, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), ALS and frontotemporal dementia (ALS-FTD), and facial-onset sensory and motor neuronopathy (FOSMN) [3][4][5]. These four MND phenotypes have recently been associated with TDP-43 (transactive response DNAbinding protein 43) neuropathology found on autopsy, and it has been posited that they are linked as TDP-43 proteinopathies [2,5]. ...
... Ten patients with a diagnosis within the MND spectrum [3,4] were recruited from the UCSF ALS clinic for PSIR imaging between December 2016 and August 2017. MND had been diagnosed by clinical and electrophysiological examination at the discretion of the treating physician at the UCSF ALS clinic. ...
Article
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Background The spectrum of motor neuron disease (MND) includes numerous phenotypes with various life expectancies. The degree of upper and lower motor neuron involvement can impact prognosis. Phase sensitive inversion recovery (PSIR) imaging has been shown to detect in vivo gray matter (GM) and white matter (WM) atrophy in the spinal cord of other patient populations but has not been explored in MND. Methods In this study, total cord, WM and GM areas of ten patients with a diagnosis within the MND spectrum were compared to those of ten healthy controls (HC). Patients’ diagnosis included amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, primary muscular atrophy, facial onset sensory and motor neuronopathy and ALS-Frontotemporal dementia. Axial 2D PSIR images were acquired at four cervical disc levels (C2-C3, C3-C4, C5-C6 and C7-T1) with a short acquisition time (2 minutes) protocol. Total cross-sectional areas (TCA), GM and WM areas were measured using a combination of highly reliable manual and semi-automated methods. Cord areas in MND patients were compared with HC using linear regression analyses adjusted for age and sex. Correlation of WM and GM areas in MND patients was explored to gain insights into underlying atrophy patterns. Results MND patients as a group had significantly smaller cervical cord GM area compared to HC at all four levels (C2-C3: p = .009; C3-C4: p = .001; C5-C6: p = .006; C7-T1: p = .002). WM area at C5-C6 level was significantly smaller (p = .001). TCA was significantly smaller at C3-C4 (p = .018) and C5-C6 (p = .002). No significant GM and WM atrophy was detected in the two patients with predominantly bulbar phenotype. Concomitant GM and WM atrophy was detected in solely upper or lower motor neuron level phenotypes. There was a significant correlation between GM and WM areas at all four levels in this diverse population of MND. Conclusion Spinal cord GM and WM atrophy can be detected in vivo in patients within the MND spectrum using a short acquisition time 2D PSIR imaging protocol. PSIR imaging shows promise as a method for quantifying spinal cord involvement and thus may be useful for diagnosis, prognosis and for monitoring disease progression.
... Amongst them, six patients met the diagnosis of facial onset sensory and motor neuronopathy (FOSMN) according to published criteria [9]. Table 1 details demographics and clinical characteristics of all patients. ...
... Our case series includes patients diagnosed with FOSMN, a condition recently recognized and characterized by predominantly bulbar and upper limb progressive amyotrophy associated with large sensory nerve fiber dysfunction mainly involving the trigeminal territory [11]. Despite possible peculiar pathogenic mechanisms and, more frequently, longer course [9], FOSMN can be considered a variant of the ALS phenotype. Indeed, its presentation is very similar to bulbar ALS from which, in clinical practice, it can be distinguished by the lack of corneal reflex. ...
Article
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Our aim was to address the correlation between small fiber loss and amyotrophic lateral sclerosis (ALS) for disease onset, phenotype, genotype, duration, severity and sensory findings. Consecutive patients referred for suspected ALS were screened. Exclusion criteria were possible ALS and previous diagnosis or known risk factors for small fiber neuropathies. A sural nerve conduction study (NCS) was bilaterally recorded. The ALS functional rating scale revised was administered and loss of functions were calculated using the Milano−Torino staging (MITOS) system. Sensory symptoms and signs were recorded. Genetic analysis was performed by the next-generation sequencing approach. Skin biopsy was performed at the distal leg and intraepidermal nerve fiber (IENF) density was quantified in three non-consecutive sections following published guidelines. Findings were referred to age- and sex-adjusted normative values. Fifty-seven patients including six with facial onset sensory and motor neuronopathy (FOSMN) were enrolled. Eight (15.7%) pure ALS patients and five (83%) FOSMN patients complained of sensory disturbances with different distributions. Sural NCS was normal in all except two patients. IENF density was reduced in 75.4% of pure ALS and 50% of FOSMN patients, without correlation with any disease features. IENF density was similarly reduced in bulbar (78.5%), flail limb (87.5%), pyramidal (100%), and spinal (68.2%) onset, as well as in genetic (83.3%) and sporadic (82%) ALS. There was no correlation with genotype, disease duration and severity. Intraepidermal nerve fiber loss is a feature of most ALS patients. It does not correlate with onset, phenotype, course and severity of the disease, and cannot be considered a clinical or prognostic biomarker.
... In past reports, temporary response to intravenous immunoglobulin (IVIG) or plasmapheresis (PE) in some patients suggested an inflammatory pathogenesis [2, 3]. More recently, pathologic studies indicated a neurodegenerative mechanism [4]. We describe a rapidly progressive case of FOSMN mimicking amyotrophic lateral sclerosis (ALS). ...
... Contrary to previously reported patients, with a slowly progressive clinical course, our presented rapid progression. Although the pathophysiologic association between FOSMN and ALS has been criticized [2, 4], in our patient, TMS evidenced upper motor neuron (UMN) involvement; in addition, the lack of response to any immunomodulating therapy led to support the hypotehesis of the neurodegenerative nature of FOSMN, rather than an immunomediated inflammatory mechanism. Even though mild sensory abnormalities have been previously described both in FOSMN and ALS [5], our patient experienced intense and drug resistant pain never reported before. ...
... Facial onset sensory and motor neuronopathy (FOSMN) is a rare disease characterized by sensory disturbance and weakness of the face followed by muscle weakness in the limbs [10][11][12]. FOSMN might be a variant of ALS resulting from an irreversible disease progression with a lack of response to immunotherapies as well as deposition of TAR DNA-binding protein 43 (TDP-43) in the nervous systems [13][14][15]. However, the clinical pictures and pathophysiology of FOSMN have not been well established. ...
Article
Full-text available
Background: Taste disorder is a common symptom in the general population. Several studies have shown that patients with neurological disorders, such as amyotrophic lateral sclerosis and Parkinson's disease, develop taste disturbance. Facial onset sensory and motor neuronopathy (FOSMN) is a rare disease characterized by sensory disturbance and weakness spreading from the face to the limbs caudally. We describe a patient with FOSMN who showed taste disorder as the sole initial symptom. Case presentation: A 49-year-old man who smoked cigarettes developed taste disturbance. Despite using zinc supplements, an herbal medication, and an ointment, his taste disorder worsened. 4 years later, a tingling feeling emerged at the tip of his tongue and gradually spread to his entire lips. At 55 years of age, he showed difficulty in swallowing, followed by facial paresthesia, muscle atrophy, and weakness in the face and upper limbs without apparent upper motor neuron sign. Cessation of smoking did not improve his taste disturbance, and he was unable to discriminate different tastes on the entire tongue. In an electrogustometric study, electrical stimulation did not induce any type of taste sensation. Blink reflex showed delayed or diminished R2 responses. Needle electromyography revealed severe chronic neurogenic changes in the tongue and masseter muscles. Mild chronic neurogenic changes were also observed in the limbs. In the thoracic paraspinal muscles, active neurogenic changes were detected. Findings of hematological and cerebrospinal fluid analyses, and magnetic resonance images of the brain and spinal cord were unremarkable. One cycle of intravenous immunoglobulin therapy did not improve his symptoms. We diagnosed him as having FOSMN with the sole initial symptom of taste disorder. Nine years after the onset of taste disorder, he developed impaired sensation of touch in the right upper limb and required tube feeding and ventilator support. Conclusion: Taste disorder can be the initial manifestation of FOSMN and might involve the solitary nucleus.
... later, Lecky and colleagues described 13 patients with idiopathic sensory disorders limited to the trigeminal region and referred to this condition as "idiopathic trigeminal sensory neuropathy" [5]. Recently, Vucic and colleagues indicated that in patients with bilateral trigeminal neuropathy a severe motor involvement may develop [2,6]. The treatment for this rare disease has stayed controversial. ...
... The disease course is relentlessly progressive, although the progression's rate widely varies between individuals. The steadily progression together with the lack of a compelling response to immunomodulatory treatments (1)(2)(3)(4) suggest a neurodegenerative origin. However, whether this condition is part of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) spectrum or a different entity is still debated, with evidence for and against this relationship (1). ...
Article
Objective: To describe a patient with facial onset sensory and motor neuronopathy (FOSMN) carrying heterozygous mutations in both TARDBP and SQSTM1 genes. Methods: The patient underwent neurological, neuropsychological, and neurophysiological examinations. Brain magnetic resonance imaging (MRI) and extensive genetic analysis were also performed. Results: The neurological examination showed dysphonia, left trigeminal hypesthesia, and left masseter and temporalis muscle atrophy. Mild cognitive impairment, affecting predominantly executive functions and social cognition, was appreciable in the neuropsychological examination. The electrophysiological studies revealed: left abnormal blink reflex; neurogenic changes in bulbar and cervical muscles; normal motor evoked potential amplitude, central motor conduction time and cortical silent period. Brain MRI showed right-predominant frontotemporal atrophy. Genetic analysis showed a heterozygous mutation in TARDBP (p.A390S) and in SQSTM1 (p.P392L), both previously described as causing amyotrophic lateral sclerosis. The SQSTM1, but not the TARDBP, mutation was found in both healthy siblings. Conclusions: Our data provide new clinical, neuroimaging, and genetic evidence that FOSMN is a neurodegenerative disease of the motor neuron disease and frontotemporal dementia spectrum, with a possible oligogenic origin. Multicentric efforts focusing on cognitive and genetic studies are necessary to confirm this hypothesis and to determine if ALS genes should be systematically screened in these patients.
... The early pathology exhibited by the thoracic cord sensory neurons might result in secondary abnormal function of the MNs that they innervate and thereby be involved in the early stages of intercostal muscle atrophy (Ausborn et al., 2009; Mentis et al., 2011). Similarly, sensory impairment precedes motor dysfunction in other neuromuscular disorders (Vucic et al., 2012). ...
Article
Canine degenerative myelopathy (CDM) represents a unique naturally occurring animal model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs, neuropathologic findings, and involvement of the superoxide dismutase 1 (SOD1) mutation. A definitive diagnosis can only be made postmortem through microscopic detection of axonal degeneration, demyelination and astroglial proliferation, which is more severe in the dorsal columns of the thoracic spinal cord and in the dorsal portion of the lateral funiculus. Interestingly, the muscle acetylcholine receptor complexes are intact in CDM prior to functional impairment, thus suggesting that muscle atrophy in CDM does not result from physical denervation. Moreover, since sensory involvement seems to play an important role in CDM progression, a more careful investigation of the sensory pathology in ALS is also warranted. The importance of SOD1 expression remains unclear, while oxidative stress and denatured ubiquinated proteins appear to play a crucial role in the pathogenesis of CDM. In this updated narrative review we performed a systematic search of the published studies on CDM that may shed light on the pathophysiological mechanisms of human ALS. A better understanding of the factors that determine the disease progression in CDM may be beneficial for the development of effective treatments for ALS.
... Facial onset sensory motor neuronopathy (FOSMN) is a recently described under-recognized, rare, slowly progressive bulbar onset motor and sensory neuronopathy [Vucic et al 2012]. Although there are marked similarities to classic bulbar-onset motor neuron disease, FOSMN differs clinically by the striking facial-onset sensory deficits with subsequent development of motor deficits, slow evolution in a rostral-caudal direction, and a much better prognosis. ...
Article
Riboflavin transporter deficiency neuronopathy is characterized by motor neuronopathy (manifest as proximal and distal limb weakness, often with severe distal wasting and breathing problems due to paralysis of the diaphragm), sensory neuronopathy (manifest as gait ataxia), and cranial neuronopathy (manifest as optic atrophy, sensorineural deafness, and bulbar palsy). Onset is usually in infancy or in childhood before age eight years; however, on occasion individuals with genetically proven disease present in the third decade. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first years of life. In the majority of affected individuals the initial finding is sensorineural deafness, which is usually progressive and severe. The time between the onset of deafness and the development of other manifestations varies but is usually one to two years. In some individuals an inter-current event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings. The diagnosis of riboflavin transporter deficiency neuronopathy is based on clinical, neurophysiologic, neuroimaging, and laboratory findings as well as the identification of biallelic pathogenic variants in either SLC52A2 or SLC52A3 on molecular genetic testing. Treatment of manifestations: High-dose oral supplementation of riboflavin between 10 mg and 50 mg/kg/day improves symptoms and signs on clinical examination, improves objective testing (vital capacity, brain stem evoked potentials, nerve conduction studies), and normalizes acylcarnitine levels. The optimal dose is as yet unknown. Because oral riboflavin supplementation is effective (and possibly life saving), it should begin as soon as a riboflavin transporter deficiency neuronopathy is suspected and continued lifelong unless the diagnosis is excluded by molecular genetic testing. Supportive care includes: respiratory support; physiotherapy to avoid contractures; occupational therapy to support activities of daily living; orthotics for limb and trunk bracing; speech and language therapy to avoid choking and respiratory problems; wheel chair as needed; low vision aids as needed; routine management of scoliosis to avoid long-term respiratory problems; and routine management of depression. Surveillance: At three months and six months after initiation of riboflavin supplementation: follow-up physical and neurologic examinations, and measurement of blood riboflavin/FAD/FMN and acylcarnitine analysis. Thereafter, follow up should be biannual in older individuals and more frequent in younger children. Agents/circumstances to avoid: Dietary restriction of riboflavin. Evaluation of relatives at risk: When the SLC52A2 or SLC52A3 pathogenic variants in the family are known, it is appropriate to perform molecular genetic testing on the older and younger sibs of an affected individual to identify as early as possible those who would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder. Pregnancy management: Females who have riboflavin transporter neuronopathy or are heterozygous for a pathogenic variant in SLC52A2 or SLC52A3 should have riboflavin supplements before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the baby. Riboflavin transporter deficiency neuronopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (carrier), and a 25% chance of being unaffected and not a carrier. Heterozygote (carrier) testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the SLC52A2 or SLC52A3 pathogenic variants in the family are known. Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.
... Facial-onset sensory-motor neuronopathy (FOSMN) first manifests with trigeminal sensory loss and pain, then spreads to bulbopontine and spinal motoneurons, sometimes with a fatal outcome. 1,2 Although a previous study assessed infraorbital nerve pathology in one patient, 2 no studies have directly aimed at investigating trigeminal nerve fiber damage in patients with FOSMN and assessing the involvement of the different sensory nerve fiber populations in this disease. Having this information might help understand the pathophysiology of FOSMN and thus guide its clinical management. ...
Article
Facial-onset sensory-motor neuronopathy (FOSMN) first manifests with trigeminal sensory loss and pain, then spreads to bulbopontine and spinal motoneurons, sometimes with a fatal outcome.(1,2)
... Facial-onset sensory and motor neuronopathy hallmarks are the development of sensory symptoms within the face followed by evolution of sensory deficits and signs of LMN degeneration of bulbar and upper limb muscles, such as fasciculations, cramps, muscle weakness and wasting. The hypothesis of a neurodegenerative pathogenesis has also been proposed (Vucic et al., 2012). However, the notion that FOSMN syndrome represents an unusual ALS phenotype is still object of debate (Vucic, 2014). ...
Article
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Although subclinical involvement of sensory neurons in amyotrophic lateral sclerosis (ALS) has been previously demonstrated, corneal small fiber sensory neuropathy has not been reported to-date. We examined a group of sporadic ALS patients with corneal confocal microscopy, a recently developed imaging technique allowing in vivo observation of corneal small sensory fibers. Corneal confocal microscopy (CCM) examination revealed a reduction of corneal small fiber sensory nerve number and branching in ALS patients. Quantitative analysis demonstrated an increase in tortuosity and reduction in length and fractal dimension of ALS patients' corneal nerve fibers compared to age-matched controls. Moreover, bulbar function disability scores were significantly related to measures of corneal nerve fibers anatomical damage. Our study demonstrates for the first time a corneal small fiber sensory neuropathy in ALS patients. This finding further suggests a link between sporadic ALS and facial-onset sensory and motor neuronopathy (FOSMN) syndrome, a rare condition characterized by early sensory symptoms (with trigeminal nerve distribution), followed by wasting and weakness of bulbar and upper limb muscles. In addition, the finding supports a model of neurodegeneration in ALS as a focally advancing process.
... 'Facial-onset sensorimotor neuropathy', a novel neurodegenerative neuropathy, is also possible; however, the clinical course is usually indolent and progresses to involve other limbs. 1 A postinfective immune phenomenon would be an alternative. ...
... It is possible that the early pathology exhibited by the thoracic cord sensory neurons results in secondary abnormal function of the motor neurons they innervate and thereby is involved in the early stages of intercostal muscle atrophy (Ausborn et al. 2009;Mentis et al. 2011). Indeed, in some neuromuscular disorders, sensory impairment precedes motor dysfunction (Vucic et al. 2012). In diseases like DM and ALS deficits in sensory functions that are subconscious, such as those involved in regulating respiration, would be difficult to detect. ...
Article
Canine degenerative myelopathy (DM) is a progressive, adult-onset, multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced-stage DM. To determine whether other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MNs) and dorsal root ganglia (DRG) and in motor and sensory nerve root axons from DM-affected boxers and Pembroke Welsh corgis (PWCs). No alterations in MNs or motor root axons were observed in either breed. However, advanced-stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, nor of their axons. Axonal loss in thoracic sensory roots and sensory neuron death suggest that sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS. © 2013 Wiley Periodicals, Inc.
Book
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The second edition of a book on inflammatory, endocrine, intensive care unit myopathies, polyneuropathies, Guillain-Barrè syndrome, and paraneoplastic neuropathies with Covid-19 related conditions. Several international Authors contributed to the up-to-date edition.
Chapter
Immune-mediated neuropathies are a heterogeneous group of disorders affecting the peripheral nerves. The first immune-mediated neuropathy was reported in France during the First World War in 1916 when Guillain, Barré, and Strohl described two patients with acute onset weakness that was progressive and predominantly motor, both of which recovered spontaneously. Though similar cases were previously described in 1859 by Landry [1], Guillain and colleagues were the first to demonstrate the presence of areflexia and albuminocytological dissociation in the cerebrospinal fluid (CSF). The disease was subsequently named Guillain-Barré syndrome (GBS).
Chapter
Chronic immune-mediated neuropathies are a rather heterogeneous group of disorders of the peripheral nervous system deemed to be caused by an autoimmune attack against peripheral nerves. They include idiopathic disorders where the disease only involves peripheral nerve such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) or may be the consequence of other disease that causes the production of antibodies against nerve such as neuropathies associated with monoclonal gammopathy or paraneoplastic neuropathies. The spreading interest on these neuropathies is derived from the fact that most affected patients can be treated successfully with immune therapies that differ however from disease to disease highlighting the need for a correct diagnosis. We will here review the clinical, pathogenetic, and therapeutic aspects of the two main forms of idiopathic immune-mediated neuropathies, CIDP and MMN.
Article
Objectives: Facial onset sensory and motor neuronopathy syndrome (FOSMN) is a rare motor neuron disorder characterized by facial sensory and motor aberrations that progress to the upper limbs. We present a case of FOSMN-like syndrome that has characteristics of FOSMN but is confined to the craniofacial region. Methods: Retrospective chart review and review of the literature. Results: A 70-year-old woman presented with a 1-month history of progressive bilateral facial sensory loss and weakness affecting the trigeminal and hypoglossal nerves. Within 12 months, she developed debilitating weakness affecting her lower and midface bilaterally. After an extensive workup, a diagnosis of FOSMN-like syndrome was made, as symptoms failed to progress to the upper extremities. Conclusions: This case demonstrates a unique presentation of FOSMN that we classify as FOSMN-like syndrome. Clinicians must maintain a high index of suspicion when a patient presents with clinical features characteristic of FOSMN syndrome without progression of symptoms distal to the craniofacial region because it may represent a FOSMN-like syndrome.
Article
A 19-year-old man presented with 4 years of facial numbness and 3 years of progressive dysarthria and dysphagia. Additionally, 18 months prior to presentation, he also developed arm weakness and hand atrophy followed by leg weakness 1 year later.
Article
A 59-year-old woman presented with a 7-year history of facial numbness on the left side, and gradual worsening of symptoms. Over several years, facial muscle weakness, dysarthria, tongue atrophy and fasciculation had progressed. Then, she developed cerebellar ataxia affecting the left extremities, in addition to earlier symptoms. Brain MRI revealed cerebellar atrophy, and 99mTc-SPECT depicted cerebellar hypoperfusion. A repetitive nerve stimulation test (RNS) indicated abnormal decrement in the nasalis and trapezius muscles on the left side. Facial-onset sensory and motor neuronopathy (FOSMN) was diagnosed. Administration of intravenous immunoglobulin resulted in improvement of some symptoms. Although cerebellar ataxia is not a common symptom of FOSMN, a case showing TDP-43-positive glial cytoplasmic inclusions in cerebellar white matter has been reported. Therefore, it is possible that FOSMN may cause cerebellum impairment in some patients. Furthermore, RNS positive rate in the trapezius muscle is known to be high in amyotrophic lateral sclerosis (ALS) patients. It is speculated that RNS of the affected muscles in FOSMN may show abnormal decrement by the same mechanisms as ALS.
Article
Objectives Slow-onset peripheral facial palsy is far less common than acute-onset peripheral facial palsy and necessitates diagnostic evaluation for a benign or malignant tumors, or other less common etiologies. In the rare scenario when no clarifying etiology is discovered following long-term evaluation (no radiographic or hematologic abnormalities and an otherwise unremarkable evaluation), a diagnostic and management dilemma occurs. We present a series of patients with this possible new clinical entity: f acial palsy, r adiographic and o ther w orkup n egative (FROWN), and propose a management strategy for this diagnosis of exclusion. Methods A series of 3,849 patients presenting with facial palsy to a tertiary Facial Nerve Center was retrospectively assessed to identify those with progressive loss of facial function over at least 1 month. Exclusion criteria included history, physical or hematologic findings indicative of known diseases associated with facial palsy, and radiographic studies demonstrating a benign or malignant tumor. Results Patients with slow-onset facial palsy constituted 5% (190 patients) of the cohort and were ultimately diagnosed with either a benign or malignant neoplasm or other facial nerve pathology. Fourteen patients with slow-onset facial palsy remained without a diagnosis following long-term evaluation and serial imaging. Eleven patients underwent dynamic facial reanimation surgery and facial nerve and muscle biopsy, with no clear histopathologic diagnosis. Conclusion Patients with slow-onset facial palsy with negative radiographic and medical evaluations over several years may be characterized as having FROWN, an idiopathic and as yet poorly understood condition, which appears to be amenable to facial reanimation, but which requires further investigation as to its pathophysiology.
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Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding ( TARDBP ) and unrelated genes (eg, C9orf72 ). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.
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A Representative Collection of Previously Published Articles
Article
Introduction: Facial onset sensory and motor neuronopathy (FOSMN) syndrome was a rare and slowly progressive neurodegenerative disorder, which heralded by sensory symptoms within the face, and followed by evolution of sensory and motor deficits in the face and limbs. The underlying pathogenesis of FOSMN remains to be fully elucidated. Case report: A 40-year-old man was admitted to our hospital with facial sensory deficits spreading in a rostral-caudal manner. He then developed diffuse fasciculation, bulbar signs, atrophy and weakness of facial, neck, and limb muscles progressively, a process resembling amyotrophic lateral sclerosis. Neurophysiological studies demonstrated abnormal blink reflexes and some denervation-reinnervation changes in electromyogram. He was diagnosed with FOSMN syndrome clinically. A novel heterozygous Gly386Glu mutation in the transactive response DNA-binding protein (TARDBP) gene was found. The patient had no response to immunologic treatment and finally died of respiratory failure. Conclusions: This is the first time that a novel mutation in TARDBP gene was identified in a patient with FOSMN syndrome, which further suggested a link between FOSMN and amyotrophic lateral sclerosis. Our findings widen the spectrum of TARDBP-related motor neuron diseases.
Thesis
Les neuronopathies sensitives ou ganglionopathies sont des pathologies du système nerveux périphérique et englobent un groupe de pathologies dysimmunitaires, paranéoplasiques, toxiques, métaboliques, infectieuses, héréditaires et idiopathiques qui touchent le ganglion rachidien postérieur. Camdessanché et al. ont récemment proposé des critères cliniques et électrophysiologiques pour le diagnostic des ganglionopathies. Nous avons appliqué les critères diagnostiques de Camdessanché sur une cohorte de patients avec un diagnostic de ganglionopathie comparée à une cohorte de patients classés neuropathie sensitive pure afin d’évaluer notre pratique. Le recueil des données a été réalisé sur une cohorte de 101 patients. 66 patients étaient codés « ganglionopathie » après l’ENMG et 44 patients étaient codés « neuropathie sensitive pure » après l’ENMG. A partir des éléments cliniques et électrophysiologiques recueillis, nous avons ensuite appliqué les critères de Camdessanché. Les examens complémentaires réalisés ainsi que l’étiologie retenue étaient également recueillis. Sur les 66 patients codés « ganglionopathie », seuls 37 patients (56%) étaient classés «ganglionopathie possible». D’après les critères, 13 patients sur ces 37 (35,1%) pouvaient être ensuite classés « ganglionopathie probable » grâce à l’item traitement par cisplatine/cancer actuel. Parmi les 35 patients (34,6%) codés « neuropathie sensitive pure », quatre patients étaient classés « ganglionopathie possible » dont deux obtenaient le classement « ganglionopathie probable » par l’item cancer actuel. Au total, 26 patients étaient classés « ganglionopathie possible » (25,7%) et 15 patients étaient classés « ganglionopathie probable » (14,8%). Dans le groupe « ganglionopathie » 41,5% des patients présentaient des douleurs au début de la maladie versus 20% dans le groupe « neuropathie sensitive » (p=0,02) alors que l’ataxie au début de la maladie n’était pas significativement différente entre les groupes. Au développement maximal de la maladie, les items cliniques des critères de Camdessanché (ataxie, asymétrie des symptômes et anomalies sensitives non limitées aux membres inférieurs) étaient significativement plus fréquent dans le groupe « ganglionopathie ». 97,6% des patients du groupe « ganglionopathie » avaient un potentiel moteur anormal maximum à l’ENMG versus 36,7% dans le groupe « neuropathie sensitive » (p=4,9*10-11). De même, 97,6% des patients du groupe « ganglionopathie » avaient un potentiel sensitif aboli aux membres supérieurs ou au moins 3 potentiels sensitifs inférieurs ou égaux à 30% de la limite inférieure normale aux membres supérieurs versus 58,3% des patients du groupe « neuropathie sensitive ». En ce qui concerne les étiologies, seule la cause carentielle était significativement plus fréquente dans le groupe « ganglionopathie » : 21,9% versus 3,3% dans le groupe « neuropathie sensitive » (p=0,006). L’application des critères diagnostiques de Camdessanché permet de poser un diagnostic plus spécifique de ganglionopathie en prenant en compte les données cliniques et paracliniques et en utilisant des critères électrophysiologiques plus précis. Un examen clinique et un ENMG minimum sont nécessaires à leur application.
Article
Facial onset sensory and motor neuronopathy (FOSMN) is a recently defined slowly progressive motor neuron disorder. It is characterized by facial onset sensory abnormalities which may spread to the scalp, neck, upper trunk and extremities, followed by lower motor neuron deficits. Bulbar symptoms, such as dysarthria and dysphagia, muscle weakness, cramps and fasciculations, can present later in the course of the disease. We search the PubMed database for articles published in English from 2006 to 2016 using the term of “Facial onset sensory and motor neuronopathy”. Reference lists of the identified articles were selected and reviewed. Only 38 cases of FOSMN have been reported in the Pubmed database since it was first reported in 2006. Typically, FOSMN present with slowly evolving numbness of the face followed by neck and arm weakness. Reduced or absent of corneal reflexes and blink reflex is the main pathognomonic features of FOSMN. In this review, we summarize the epidemiology, clinical presentation, auxiliary examination, and treatment of all the reported cases of FOSMN. Moreover, we discuss the pathogenesis of this rare disorder. In addition, we propose diagnostic criteria for FOSMN.
Article
The sensory neuronopathies (or ganglionopathies) are a small subcategory of neuropathies that are characterized by primary degeneration of the dorsal root ganglia and trigeminal ganglion sensory neurons resulting in a distinctive clinical presentation. Patients typically have subacute onset of asymmetric, non-length dependent sensory impairment and early ataxia. The etiologies of acquired sensory neuronopathies are rather limited, and early identification is imperative, as they may herald an underlying malignancy or an autoimmune condition such as Sjögren syndrome. This review will discuss the various causes of acquired sensory neuronopathies, the recommended diagnostic approach, and treatment options. Finally, I will briefly discuss a select few hereditary and degenerative sensory neuronopathies which, in contrast to the acquired disorders, are slowly progressive and are usually associated with additional neurological symptoms. This article is protected by copyright. All rights reserved.
Article
Facial onset sensory and motor neuronopathy (FOSMN) was first described in 2006 as an apparently sporadic neurodegenerative disease. Thirty cases have been reported to date. We summarise six new cases, highlighting the key clinical aspects of FOSMN and how to differentiate it from motor neurone disease (amyotrophic lateral sclerosis). Typically, patients present with slowly evolving numbness of the face followed by bulbar and proximal (neck and arm) weakness. However, one of our patients presented with a motor syndrome and his abnormal blink reflex studies provided a useful diagnostic clue. This extends the spectrum of the syndrome and emphasises that FOSMN should be considered in the differential diagnosis of motor neurone disease. We discuss the pathophysiology, diagnosis, prognosis and management considerations of FOSMN. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Article
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Background Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms.Methods Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain.ResultsThe disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex.Conclusions Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms.
Article
Although the pathophysiological mechanisms underlying the development of amyotrophic lateral sclerosis (ALS) remain to be fully elucidated, there have been significant advances in the understanding of ALS pathogenesis, with evidence emerging of a complex interaction between genetic factors and dysfunction of vital molecular pathways. Glutamate-mediated excitoxicity is an important pathophysiological pathway in ALS, and was identified as an important therapeutic biomarker leading to development of the only pharmacologically based disease-modifying treatment currently available for ALS. More recently, a putative role of voltage-gated persistent Na+ channels in ALS pathogenesis has been suggested and underscored by neuroprotective effects of Na+ channel blocking agents in animal models. In addition, advances in ALS genetics have lead to identification of novel pathophysiological processes that could potentially serve as therapeutic targets in ALS. Genetic therapies, including antisense oligonucleotide approaches have been shown to exert neuroprotective effects in animal models of ALS, and Phase I human trial have been completed demonstrating the feasibility of such a therapeutic approach. The present review summarises the advances in ALS pathogenesis, emphasising the importance of these processes as potential targets for drug development in ALS.
Article
Introduction: Recessive mutations in the anoctamin-5 gene (ANO5) cause a spectrum of clinical phenotypes, including limb-girdle muscular dystrophy (LGMD 2L), distal myopathy, and asymptomatic hyperCKemia. Methods: In this report we describe our clinical, electrophysiological, pathological, and molecular findings in a subject with anoctaminopathy-5. Results: A 49-year-old Arabic man from a consanguineous family presented with a 5-year history of myalgias, hyperCKemia and an episode of unprovoked rhabdomyolysis. Muscle biopsy showed mild myopathic changes and interstitial amyloid deposition. ANO5 analysis detected a novel homozygous deletion of approximately 11.9 kb encompassing exons 13-17, predicted to be pathogenic. Conclusions: Anoctaminopathy-5 can manifest with a phenotype reminiscent of metabolic myopathy and should be considered as a potential cause of myalgia and myoglobinuria. Amyloid deposition in the muscle biopsy is helpful for the diagnosis. A novel homozygous ANO5 deletion was identified, suggesting that screening for common mutations may have low yield in non-European subjects. Muscle Nerve 50: 610-613, 2014
Article
Facial onset sensory and motor neuronopathy (FOSMN) syndrome may represent an amyotrophic lateral sclerosis phenotype as indicated by associated with the heterozygous D90A superoxide dismutase-1 (SOD-1) gene mutation.
Article
To describe a patient with facial onset sensory motor neuronopathy (FOSMN) syndrome associated with a heterozygous D90A mutation in superoxide dismutase (SOD1) gene. The patient underwent neurological and neurophysiologic examinations, including blink and jaw reflexes, sural nerve and skin biopsies, and analysis of TARDBP, FUS and C9ORF72 genes. Neurological examination showed diffuse fasciculations, bulbar signs, hypotrophy and weakness of facial, neck, shoulder girdle and first interosseus muscles, and absent corneal reflex. Neurophysiologic studies demonstrated abnormal blink and jaw reflexes and reduced sensory nerve action potentials at upper limbs. Sural nerve and skin biopsies revealed mild loss of large and small nerve fibres. Genetic analysis demonstrated a heterozygous D90A-SOD1 mutation. FOSMN syndrome has been recently described in patients with slowly progressive bulbar and upper limb amyotrophy. Sensory symptoms, mainly involving the trigeminal territory, typically precede the onset of motor weakness by months or years. The pathogenesis of FOSMN syndrome is unknown and possible immune-mediated mechanisms have been claimed. Our findings support the hypothesis that FOSMN syndrome is a primary degenerative disorder that widens the spectrum of motor neuron diseases.
Article
Bulbospinal muscular atrophy (BSMA) is an X-linked late-onset neuroendocrine disorder dominated by signs of lower motor neuron loss but characterized by a phenotypic heterogeneity. We describe two cases in order to illustrate this clinical heterogeneity and summarize current knowledge and recent advances. The first patient presented progressive muscle weakness, signs of lower motor neuron loss and a sensorial peripheral neuropathy with chronic denervation. The second patient developed a sensorial disorder attributed to chronic axonal polyneuropathy, postural tremor and hyper-CK-emia. Muscle fasciculation was present in both cases. PCR testing showed an expansion of CAG with 44 ± 1 repeats, confirming Kennedy disease. BSMA may be suspected in patients presenting an atypical lower motor neuron loss or muscular disease. Early diagnosis is important to propose appropriate treatment and genetic counseling.
Article
We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.
Article
Facial onset sensory motor neuronopathy (FOSMN) is a recently identified condition characterized initially by trigeminal sensory involvement followed by sensory propagation and motor neuronopathy. Few cases have been reported, and latest evidence points toward a neurodegenerative cause. We describe a 59-year-old female who presented a typical clinical picture of FOSMN over 10 years. Immunological investigations showed positive antinuclear antibodies and antibodies to extractable nuclear antigens (anti-Ro antibodies). A mild inflammatory infiltrate was found on salivary gland biopsy. Intravenous immunoglobulin therapy was effective in improving and then stabilizing this patient's condition. The pathophysiology of FOSMN remains uncertain, and this condition may be heterogeneous. An immune basis cannot be discounted in any given case, and suspected cases merit a trial of immunotherapy.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.
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We assessed the clinicopathological features of 92 patients with primary Sjögren's syndrome-associated neuropathy (76 women, 16 men, 54.7 years, age at onset). The majority of patients (93%) were diagnosed with Sjögren's syndrome after neuropathic symptoms appeared. We classified these patients into seven forms of neuropathy: sensory ataxic neuropathy (n = 36), painful sensory neuropathy without sensory ataxia (n = 18), multiple mononeuropathy (n = 11), multiple cranial neuropathy (n = 5), trigeminal neuropathy (n = 15), autonomic neuropathy (n = 3) and radiculoneuropathy (n = 4), based on the predominant neuropathic symptoms. Acute or subacute onset was seen more frequently in multiple mononeuropathy and multiple cranial neuropathy, whereas chronic progression was predominant in other forms of neuropathy. Sensory symptoms without substantial motor involvement were seen predominantly in sensory ataxic, painful sensory, trigeminal and autonomic neuropathy, although the affected sensory modalities and distribution pattern varied. In contrast, motor weakness and muscle atrophy were observed in multiple mononeuropathy, multiple cranial neuropathy and radiculoneuropathy. Autonomic symptoms were often seen in all forms of neuropathy. Abnormal pupils and orthostatic hypotension were particularly frequent in sensory ataxic, painful, trigeminal and autonomic neuropathy. Unelicited somatosensory evoked potentials and spinal cord posterior column abnormalities in MRI were observed in sensory ataxic, painful and autonomic neuropathy. Sural nerve biopsy specimens (n = 55) revealed variable degrees of axon loss. Predominantly large fibre loss was observed in sensory ataxic neuropathy, whereas predominantly small fibre loss occurred in painful sensory neuropathy. Angiitis and perivascular cell invasion were seen most frequently in multiple mononeuropathy, followed by sensory ataxic neuropathy. The autopsy findings of one patient with sensory ataxic neuropathy showed severe large sensory neuron loss paralleling to dorsal root and posterior column involvement of the spinal cord, and severe sympathetic neuron loss. Degrees of neuron loss in the dorsal and sympathetic ganglion corresponded to segmental distribution of sensory and sweating impairment. Multifocal T-cell invasion was seen in the dorsal root and sympathetic ganglion, perineurial space and vessel walls in the nerve trunks. Differential therapeutic responses for corticosteroids and IVIg were seen among the neuropathic forms. These clinicopathological observations suggest that sensory ataxic, painful and perhaps trigeminal neuropathy are related to ganglioneuronopathic process, whereas multiple mononeuropathy and multiple cranial neuropathy would be more closely associated with vasculitic process.
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The dying forward hypothesis of motor neuron disease (MND) suggests that corticomotoneurons induce excitotoxic anterior horn cell death, with involvement of the glutamatergic neurotransmitter system. The aim of the present study was to apply novel threshold tracking transcranial magnetic stimulation (TMS) techniques in conjunction with peripheral nerve excitability studies in MND patients to further investigate the dying forward hypothesis and possibly determine the site of disease onset. Studies were undertaken in 23 MND patients using a 90-mm circular coil connected to a BiStim magnetic stimulator for cortical studies and electrical stimulation for peripheral nerve excitability studies. Motor-evoked potentials and compound muscle action potentials (CMAPs) were recorded from the right abductor pollicis brevis in the same setting. Measures of cortical and peripheral nerve excitability were correlated with clinical and neurophysiological parameters of disease severity. Short-interval intracortical inhibition (SICI) was significantly reduced in MND patients compared with controls (MND group = 3.6 +/- 0.8%; controls = 8.5 +/- 1.0%, P < 0.001), most prominently in MND patients with limb-onset disease. Changes in intracortical inhibition were accompanied by alterations in the magnetic stimulus-response curve, cortical silent period duration and resting motor threshold, all indicative of cortical hyperexcitability. Although the reduction in SICI was more pronounced in MND patients with less severe disease, as assessed by the CMAP amplitude, it remained evident even in MND patients with advanced disease. Measures of peripheral disease burden, namely the CMAP amplitude (r = -0.6) and neurophysiological index (r = -0.6), correlated with cortical hyperexcitability changes, as did the strength-duration time constant (r = -0.6), a peripheral marker of axonal excitability. Simultaneous assessment of central and peripheral nerve excitability has established the presence of co-existent upper and lower motor neuron dysfunction, with cortical hyperexcitability an early feature in MND.
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A 'syringomyelia-like' syndrome has been infrequently reported in neurological disorders such as Tangiers disease and lepromatous leprosy. This study reports a novel 'syringomyelia-like' syndrome in four adult male patients, which we have termed facial onset sensory and motor neuronopathy, or FOSMN syndrome, that appears to have a neurodegenerative aetiology. Clinical, neurophysiological and pathological data of four patients were reviewed, including the autopsy in one patient. Four male patients (mean age at onset 43), initially developed paraesthesiae and numbness in a trigeminal nerve distribution, which slowly progressed to involve the scalp, neck, upper trunk and upper limbs in sequential order. Motor manifestations, including cramps, fasciculations, dysphagia, dysarthria, muscle weakness and atrophy developed later in the course of the illness. Neurophysiological findings revealed a generalized sensory motor neuronopathy of caudally decreasing severity in all four patients. Autopsy in one patient disclosed loss of motoneurons in the hypoglossal nucleus and cervical anterior horns, along with loss of sensory neurons in the main trigeminal sensory nucleus and dorsal root ganglia. FOSMN syndrome appears to be a slowly progressive neurodegenerative disorder, whose pathogenesis remains to be determined.
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Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. OPMD is caused by a small expansion of a short polyalanine tract in the poly (A) binding protein nuclear 1 protein (PABPN1). The mechanism by which the polyalanine expansion mutation in PABPN1 causes disease is unclear. PABPN1 is a nuclear multi-functional protein which is involved in pre-mRNA polyadenylation, transcription regulation, and mRNA nucleocytoplasmic transport. The distinct pathological hallmark of OPMD is the presence of filamentous intranuclear inclusions (INIs) in patient's skeletal muscle cells. The exact relationship between mutant PABPN1 intranuclear aggregates and pathology is not clear. OPMD is a unique disease sharing common pathogenic features with other polyalanine disorders, as well as with polyglutamine and dystrophic disorders. This chapter aims to review the rapidly growing body of knowledge concerning OPMD. First, we outline the background of OPMD. Second, we compare OPMD with other trinucleotide repeat disorders. Third, we discuss the recent advances in the understanding of the molecular mechanisms underlying OPMD pathogenesis. Finally, we review recent therapeutic strategies for OPMD.
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Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10-15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (-1.2 +/- 0.6%) and sporadic ALS patients (-0.7 +/- 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 +/- 1.5%, P<0.00001) and normal controls (8.5 +/- 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, -3.2%; patients 2, -1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.
Article
Summary Tangier disease is a rare autosomal recessive disorder caused by mutations in the recently identified ATPbinding cassette transporter 1 gene (ABC1). A typical clinical manifestation of Tangier disease is peripheral neuropathy. Former studies differentiated between two manifestations: the more frequent mono- or polyneuropathic form and a syringomyelia-like type. It is unknown whether specific mutations in the ABC1 gene or a particular genetic background are responsible for either of these forms. A family is presented comprising a case with a severe syringomyelia-like phenotype of Tangier disease and absence of cardiovascular disease. Sequencing analysis of the ABC1 gene was performed. A new homozygous CfiT transition in exon 18 was found in the index patient. This mutation results in a stop codon at position 909 (R909X) leading to premature termination of translation. Her clinically asymptomatic daughters, her sister and one of her nieces were heterozygous. Sural nerve biopsies were studied in the index patient at the age of 45 and 54 years; both revealed a severe neuropathy, characterized by a subtotal and finally complete loss of nerve fibres. The entire loss of Schwann cells resulted in an extraordinary form of endoneurial sclerosis. Only rare capillaries, lipid-laden macrophages and fibroblasts had survived in the endoneurium. This case appears to be unique in respect to the underlying novel mutation in the ABC1 gene and its association with complete endoneurial sclerosis of all fascicles in the sural nerve and absence of cardiovascular disease.
Article
AMYOTROPHIC lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord1,2. Its cause is unknown and it is uniformly fatal, typically within five years3. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade4,5. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar4,6,7. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders11, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.
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本研究の目的は, 筋萎縮性側索硬化症患者の病いを意味づけるプロセスを明らかにすることである. Franklの提唱する理論を基盤に, ALS患者の病いの意味づけを, 意味への意志という視点から捉える. 質的帰納的手法としてグラウンデッド・セオリー法を用いた. 対象者は, 在宅療養中のA聡患者6名であった. データの収集は, 参加観察と半構成的面接を用い, 継続的比較分析を行った.分析の結果, ALS患者の病いを意味づけるプロセスには,〈戦略的補完行為〉〈鏡像行為〉〈新しい生への超越行為〉の3つの位相カテゴリーが見出された.それぞれの位相は4つのサブカテゴリーを含んでいた. 各位相間には, 一定の時間的順次性が認められ, 病いを意味づけるプロセスは発展的変化を示した. 最初患者は, 病いの状況が補われれば病気前と変わらず完全であることを自他に示そうとするが, やがて病いを自己の現実として直視するようになり, そして, 病いに積極的な意味を与え, 新しい生き方を切り拓くようになる. つまりALS患者は,生きる意味に向かって3位相の価値転換をしていた.以上より, ALS患者にとって極限状況とも思える進行体験は, 主体的努力によって乗り越えられることが明確になった. 看護ケアの提供において, ALS患者の病いを意味づける能力を高めることの重要性が示唆された.
Article
The diagnosis of amyotrophic lateral sclerosis (ALS) relies on stringent clinical criteria, resulting in diagnostic delay and inevitably the institution of appropriate therapy. Cortical hyperexcitability, as assessed by the novel threshold tracking transcranial magnetic stimulation (TTTMS) technique, appears as an early feature of ALS. Consequently, the present study assessed the diagnostic utility of threshold tracking TMS and developed algorithms to aid the diagnosis of ALS. Prospective studies were undertaken on a cohort of 156 consecutive patients with neuromuscular symptoms (104 ALS and 52 lower motor neuron syndrome, non-ALS syndrome, NALS) and 62 healthy controls. Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (2.4 ± 0.9%) compared to NALS (8.7 ± 0.8%, P<0.0001) and controls (10.6 ± 0.8%, P < 0.0001). The MEP amplitude and intracortical facilitation were increased, while the cortical silent period duration was reduced in ALS, all indicative of cortical hyperexcitability. Analysis of receiver operating characteristic curves suggested that threshold tracking TMS distinguished ALS from NALS, with averaged (area under curve 0.76, P < 0.0001) and peak SICI 3 ms (area under curve 0.73, P<0.0001) being the most robust diagnostic markers. The presence of cortical hyperexcitability distinguishes ALS from mimic disorders. The threshold tracking TMS techniques may prove useful as a diagnostic investigation for ALS.
Article
Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.
Article
In this study we report three patients with facial-onset sensory and motor neuronopathy (FOSMN), including the first female to be described. A fourth rather atypical case of a pyramidal syndrome with a fast rate of progression is also described. These cases raise the question as to whether upper motor neuron impairment is involved in FOSMN and whether there is a link between this syndrome and amyotrophic lateral sclerosis. The existence of this syndrome suggests that it may be wise to monitor all patients with isolated idiopathic trigeminal sensory neuropathy to ensure that this type of motor neuron disease is not overlooked.
Article
Hereditary amyloidosis of the Finnish type (HAF, or familial amyloid polyneuropathy type IV) is an autosomal dominant disease that has been described most commonly in the Finnish population but has also been found in some other countries. Herein we report the first German family whose members suffer from this condition. There are no known Finnish ancestors. We performed clinical and electrophysiological examinations in 22 members of this family. All symptomatic family members suffered from facial palsy, and most of them had peripheral neuropathy. One patient had confirmed corneal lattice dystrophy. Additional symptoms were hypoglossal nerve involvement in 5 patients and oculomotor nerve palsy in 1 patient. The lips of all older patients appeared thickened. The causative G654A mutation in the gelsolin gene was found in all affected family members.
Article
We report the first non-Caucasian case of facial onset sensory and motor neuronopathy (FOSMN) syndrome partially responding to various immunotherapies. A 55-year-old man had first felt paresthesia on his right cheek at age 45. This gradually extended to the scalp. Paresthesia of bilateral fingers and dysphagia appeared 6 years later. On admission, facial sensory impairment and bulbar palsy were found. There were no sensory or motor deficits evident in any limb, except for decreased deep tendon reflex and vibratory sensation. Videofluorography (VF) revealed decreased pharyngeal clearance. The sensory nerve action potential (SNAP) amplitudes of median and ulnar nerves were decreased. Intravenous immunoglobulin therapy and plasma exchange ameliorated his dysesthesia and dysphagia after several weeks, and resulted in improvements in VF and SNAP abnormalities. These observations suggest that FOSMN syndrome maybe, in part, immune-mediated.
Article
A 67-year-old woman, with the typical biochemical features of Tangier disease, had a syringomyelia-like syndrome which has now been observed in several patients with symptomatic onset in adult life. She developed progressive facial diplegia, bilateral wasting of hand muscles and loss of sensation over cranial, cervical and brachial dermatomes over 17 years. Nociception alone was first affected, then nociception and thermal discrimination and finally all modalities of sensation. Quantified tests of cutaneous sensation confirmed that sensation was normal in lower limbs but markedly abnormal in upper limbs. Biopsied fascicles of cutaneous nerves from clinically affected (forearm) and from clinically unaffected (leg) regions permitted a comparison of well-advanced and early pathologic lesions, respectively. The selective vulnerability of unmyelinated and small myelinated fibers in affected regions in this disorder has been confirmed. The earliest morphologic abnormalities of myelinated fibers, but seen infrequently, were mitochondrial enlargement and structural abnormality, aggregation of mitochondria and dense bodies and clusters of neurofilaments. Increased numbers of sudanophilic lipid droplets did not seem to form in Schwann cell cytoplasm prior to fiber degeneration. On the contrary, for myelinated fibers there appeared to be an altered process of axonal degeneration from that seen in Wallerian degeneration and in other axonal degenerations. Distinctive linear bands of closely-packed, minute, osmiophilic and clear lipid droplets formed and their further degradation appeared delayed. Although less clearly demonstrated, lipid droplets in Schwann cells of unmyelinated fibers also appeared to form following their degeneration. We would propose that in Tangier disease, the degradation of myelin ovoids to neutral lipid in Schwann cells does not appear to be delayed. However, further degradation of neutral lipid or its transport away from Schwann cells appears to be retarded.
Supramaximal percutaneous electrical stimuli applied over the human cervical vertebral column produce maximal compound muscle action potentials (CMAPs) in abductor digiti minimi. It is important to know which neural elements are excited by these stimuli and experiments were performed to answer this question. With stimulating electrodes placed progressively lateral to the midline, submaximal CMAPs with the same latency are produced. With shocks over the cervical vertebrae in the midline, the threshold for excitation of arm muscles is much lower than for excitation of leg muscles. Comparison of conduction time from the cervical column to more distal sites on the ulnar nerve by direct measurement and by F wave latency determination shows that the latter exceeds the former by 1.6 msec. Collision experiments in which paired shocks were given at the wrist and Erb's point or the wrist and cervical column showed that recovery from blocking as interstimulus interval lengthened was similar for the two sites, and that it was possible to detect F waves from the proximal stimulus. The latency of CMAPs evoked from midline surface stimuli was identical to that from a needle stimulus near the C8 root. It is concluded that electrical stimuli applied over the cervical vertebrae in the midline excite the motor roots at their exit from the spinal canal. This finding has implications for clinical studies of pyramidal tract and proximal peripheral nerve conduction.
Article
We investigated 14 patients with amyotrophic lateral sclerosis (ALS) by paired conditioning-test transcranial magnetic stimulation to test the hypothesis that the motor cortex is hyperexcitable in ALS. Intracortical (corticocortical) inhibition was significantly less in the ALS group than in an age-matched healthy control group (85.3 +/- 27.0% versus 45.2 +/- 15.5%, respectively; p < 0.0001). In contrast, intracortical facilitation, motor threshold, and cortical silent period duration in the ALS patients were not different from the control group. We suggest that the selective abnormality of intracortical inhibition is best compatible with an impaired function of inhibitory interneuronal circuits in the motor cortex that in turn renders the corticomotoneuron hyperexcitable.
Article
We have analysed how the behaviour of a voluntarily activated motor unit changes when subjected to 100-150 threshold cortical stimuli using peristimulus time histograms (PSTHs). This is a measure of the integrity of the corticomotoneuronal core innervating a single anterior horn cell. One hundred and thirty units in 29 patients with ALS and 35 units in eight age-matched normal controls were studied. PSTHs were constructed using 1-ms bins of stimulus triggered sweeps with a total analysis time of 250 ms (50 ms before and 200 ms after the stimulus). In ALS the primary peak of the PSTH was delayed in onset and prolonged in duration. The primary peak was further analysed by finer 0.2-ms bins, which showed in ALS there were more sub-components than normally occur. Additional sub-components in the PSTH primary peak implies a hyper-excitable corticomotoneuron that fires excessively. Excitability could be glutamate induced and/or due to failure of GABA inhibitory mechanisms. Some glutamate antagonsits may be therapeutic in ALS because of their anticonvulsant or GABergic properties rather than their anti-glutamate properties. GABA(B) agonists might have a role in future therapeutic combined therapies for ALS.
Article
Intracortical inhibition was investigated in normal human volunteers by paired-pulse transcranial magnetic stimulation, using a new, computer-assisted threshold-tracking method. Motor threshold was defined as the stimulus amplitude required to evoke a motor evoked potential of 0.2 mV (peak-to-peak) in abductor pollicis brevis, and inhibition was measured as the percentage increase in threshold, when the test stimulus was preceded by a subthreshold conditioning stimulus. This method was used to investigate the dependence of intracortical inhibition on conditioning stimulus parameters and on voluntary activity. Interstimulus interval (ISI) was first stepped from 1 to 4.5 ms, as inhibition was measured using conditioning stimuli of fixed amplitude (50-90% resting motor threshold). Maximal inhibition was produced at ISIs of 1 and 2.5 ms. The effect of conditioning stimulus intensity was then assessed at these ISIs. Inhibition occurred at significantly lower conditioning stimulus intensities with ISI=1 ms than with ISI=2.5 ms. Voluntary activity reduced inhibition at both ISIs, but had a much greater effect on inhibition at ISI=2.5 ms. Inhibition during voluntary activity was also examined for single motor units in first dorsal interosseous by generating poststimulus time histograms. Inhibition, indicated by a reduction in the later peaks of increased firing, was observed with ISI=1 ms, but not with ISI=2.5 ms. We conclude that there are two distinct phases of inhibition, occurring at ISI=1 ms and ISI=2.5 ms, differing both in thresholds and susceptibility to voluntary activity.
Article
This paper reviews the clinical diagnostic approach to hereditary neuropathies in adults by analysing: elements that point to a neuropathy of inherited origin, different modalities of presentation, laboratory and instrumental diagnostic tests, including molecular tests, symptoms and signs of involvement of other organs. Different phenotypes may be identified according to: disease course; involvement of motor, sensory, autonomic fibres; site of lesion (neuropathy versus neuronopathy); calibre of involved fibres (small-fibre versus large-fibre neuropathy); presence of distinctive symptoms (neuropathic pain); involvement of other organs or apparatus. Charcot-Marie-Tooth disease, Familial Amyloid Polyneuropathy, Hereditary Sensory and Autonomic Neuropathy, Fabry disease, Tangier disease, Porphyric Neuropathies, Refsum disease, Hereditary Neuropathy with liability to Pressure Palsies, Hereditary Neuralgic Amyotrophy, and other rare disorders involving the peripheral nervous system are reviewed.
Article
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder caused by a (GCG)n trinucleotide repeat expansion in the poly(A) binding protein nuclear-1 (PABPN1) gene, which in turn leads to an expanded polyalanine tract in the protein. We generated transgenic mice expressing either the wild type or the expanded form of human PABPN1, and transgenic animals with the expanded form showed clear signs of abnormal limb clasping, muscle weakness, coordination deficits, and peripheral nerves alterations. Analysis of mitotic and postmitotic tissues in those transgenic animals revealed ubiquitinated PABPN1-positive intranuclear inclusions (INIs) in neuronal cells. This latter observation led us to test and confirm the presence of similar INIs in postmortem brain sections from an OPMD patient. Our results indicate that expanded PABPN1, presumably via the toxic effects of its polyalanine tract, can lead to inclusion formation and neurodegeneration in both the mouse and the human.
Article
Conventional paired-pulse transcranial magnetic stimulation (TMS) techniques of assessing cortical excitability are limited by fluctuations in the motor evoked potential (MEP) amplitude. The aim of the present study was to determine the feasibility of threshold tracking TMS for assessing cortical excitability in a clinical setting and to establish normative data. Studies were undertaken in 26 healthy controls, tracking the MEP response from abductor pollicis brevis. Short-interval intracortical inhibition (SICI) occurred up to an interstimulus interval (ISI) of 7-10 ms, with two distinct peaks evident, at ISIs of < or =1 and 3 ms, followed by intracortical facilitation to an ISI of 30 ms. Long-interval intracortical inhibition (LICI) occurred at ISIs of 50-300 ms, peaking at 150 ms. The present study has confirmed the effectiveness of the threshold tracking TMS technique in reliably and reproducibly measuring cortical excitability. Simultaneous assessment of upper and lower motor neuronal function with threshold tracking techniques may help to determine the site of disease onset and patterns of progression in neurodegenerative diseases.
Article
The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.
Article
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
Article
We report a case of idiopathic severe facial-onset sensorimotor neuropathy with no evidence of Kennedy's disease, familial amyotrophic lateral sclerosis, amyloidosis, Tangier disease, sarcoidosis, chronic basilar meningitis, or Sjögren's syndrome. Clinical and neurophysiological features of this patient resemble those of four recently reported patients who were affected with facial-onset sensorimotor neuropathy (FOSMN), a probably novel disease. The present report provides information about a further patient with FOSMN in order to better characterize the clinical and laboratory features of this disease.