Publications (58)187.66 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating neuropathy. It presents as infancy or early childhood-onset neuropathy associated with FGD4 mutations. Clinically it causes predominantly distal muscle weakness. On nerve biopsy examination, myelin outfoldings are seen. The previous case reports have been from regions bordering the Mediterranean, as well as a family from Northern Ireland. This paper presents the detailed clinical course of the first reported case of CMT4H in a Japanese woman. The patient showed mild weakness without scoliosis and a severe sensory disturbance; her functional impairment was less severe than the previously published cases. In addition, a novel homozygous FGD4 c.837-1G>A mutation was identified in this patient.
- [Show abstract] [Hide abstract] ABSTRACT: Acute disseminated encephalomyelitis has an acute onset followed by improvement over several weeks. However, some cases require more time for a definitive diagnosis after protracted psychiatric or nonspecific symptoms. The authors investigated the time from onset to definitive diagnosis, subsequent course of treatment, and outcomes in 7 children with acute disseminated encephalomyelitis treated at the authors' hospital. The mean duration of illness before definitive diagnosis was 20.7 days (range: 2-50 days). Steroid pulse therapy was performed in all cases, and rapid improvements were observed; the mean duration from treatment initiation to hospital discharge was 8.6 days (range: 4-14 days). None of the cases showed neurological sequelae. Although this study investigated a small number of patients, its results suggest that time to diagnosis is often longer in children than in adults, and even in cases of delayed treatment, response to steroid pulse therapy is good and outcomes may not necessarily be affected.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Detection of 14-3-3 proteins in cerebrospinal fluid (CSF) is a powerful tool for elucidating the mechanisms of neurological disorders. There have been useful studies on 14-3-3 CSF protein detection in Creutzfeldt-Jakob disease and other neurological disorders, but none on cerebellar diseases. Objective: To elucidate whether 14-3-3 CSF proteins are a sensitive biomarker of cerebellar disruption in children. Materials and Methods: We examined 14-3-3 CSF proteins by immunoblotting in seven patients with cerebellar disorders: two with acute cerebellitis, two with acute cerebellar ataxia, and three with cerebellar atrophy. We also investigated 14-3-3 CSF proteins in four cases of febrile seizure and three of influenza-related encephalopathy. Isoforms of 14-3-3 proteins were also identified using isoform-specific antibodies. Results: 14-3-3 proteins were detected in CSF of six patients with cerebellar disorders, the exception being one with acute cerebellar ataxia caused by viral infection. Interestingly, only the 14-3-3 ε isoform was detected in two tested patients with cerebellar involvement. Moreover, longitudinal analysis of 14-3-3 CSF proteins in one patient with infantile neuroaxonal dystrophy showed that the 14-3-3 band density proportionally decreased when the cerebellar atrophy gradually progressed. Another CSF derived from a case of febrile seizure showed no 14-3-3 proteins, whereas all those derived from influenza-related encephalopathy demonstrated 14-3-3 CSF proteins with six isoforms. Conclusions: This is the first report on 14-3-3 CSF proteins as a significant biomarker of cerebellar disruption, as well as other brain diseases. Since 14-3-3 ε is localized in the molecular layer of cerebellum, the unique detection of 14-3-3 ε may indicate cerebellar involvement in the brain.
- [Show abstract] [Hide abstract] ABSTRACT: A female patient presented with horizontal gaze nystagmus, mild cerebellar ataxia, recurrent headache and hemiplegia since childhood with cerebellar atrophy on magnetic resonance imaging. Genetic analysis revealed a CACNA1A gene mutation, leading to a diagnosis of familial hemiplegic migraine (FHM1). FHM is very rare, but should be considered as a differential diagnosis for childhood cerebellar symptoms and/or cerebellar atrophy. To avoid missing FHM1, a detailed clinical history including headache or hemiplegia is essential. Oral acetazolamide during the aura phase, comprising mild headache and abnormal leg sensation, relieved these symptoms in this patient, suggesting that acetazolamide could represent a first line of treatment.
- [Show abstract] [Hide abstract] ABSTRACT: A 5-year-old girl presented with flushing and sweating on the left arm with coldness on the left palm that had persisted for approximately 24 hours. She had a fever and chicken pox-like exanthemas on her skin. She had no weakness, sensory disturbance or other autonomic dysfunction, such as orthostatic hypotension. Physical, neurological, blood and cerebrospinal fluid findings, including those of a viral study, were normal. A spinal MRI revealed no abnormal signals. Motor nerve conduction velocity, compound muscle action potential and sensory nerve conduction velocity in both medial nerves were normal, although compound sensory nerve action potential was low in the left medial nerve. F waves were absent in both medial nerves. The amplitude of the sympathetic skin response was low in the left palm. The cold-induced vasodilatation test showed bilateral sympathetic nerve dysfunction, especially on the left side. The coefficient of variation of RR intervals was low. Aciclovir was administered until chicken pox was ruled out. Subsequently, her symptoms improved. However, a sympathetic skin response and cold-induced vasodilatation findings 9 months later revealed sympathetic nerve dysfunction. These findings suggested autonomic neuropathy with local sympathetic dysfunction and a mild sensory nerve disturbance.
- [Show abstract] [Hide abstract] ABSTRACT: We report, for the first time, on a female Becker muscular dystrophy (BMD) patient with homozygous dystrophin deletion. The 14-year-old patient, product of consanguineous parents, presented with a 7-year history of exercise intolerance and recurrent myoglobinuria. Although CK was elevated to 1,800 U/L, no muscle weakness, atrophy, or hypertrophy was seen on examination. Muscle pathology demonstrated a minimal dystrophic change and faint dystrophin staining pattern. Semi-quantitative PCR of dystrophin revealed a homozygous dystrophin deletion of exons 45-55, which is predicted to remove 593 amino acids without frame shifting. Western blot analysis of skeletal muscle for dystrophin showed a 306 kDa band; thus, we made a diagnosis of female BMD. We confirmed identical deletion in both father and mother, in hemizygous and heterozygous modes, respectively. Neither female Duchenne muscular dystrophy (DMD) nor BMD due to homozygous dystrophin mutation has ever been identified although female DMD has been found in patients with Turner syndrome or unilateral parental disomy for X chromosome. Our results indicate that dystrophinopathy can also be caused in females by homozygosity, albeit rare.
- [Show abstract] [Hide abstract] ABSTRACT: We recently evaluated a patient with ADEM after a mycoplasma infection who initially presented with psychiatric symptoms, including hyperkinesis, irritability, and emotional outbursts. Psychiatric symptoms in ADEM are rare and usually suggest some underlying psychiatric or psychogenic disorder. This case illustrates that in children who initially present with psychiatric symptoms, even in the absence of typical neurologic symptoms associated with encephalitis such as disturbance of consciousness or seizures, ADEM should be considered in the differential diagnosis. Recent history of infections or vaccinations should also be considered.
- [Show abstract] [Hide abstract] ABSTRACT: The fukutin gene (FKTN) is the causative gene for Fukuyama-type congenital muscular dystrophy, characterized by rather homogeneous clinical features of severe muscle wasting and hypotonia from early infancy with mental retardation. In contrast with the severe dystrophic involvement of skeletal muscle, cardiac insufficiency is quite rare. Fukuyama-type congenital muscular dystrophy is one of the disorders associated with glycosylation defects of alpha-dystroglycan, an indispensable molecule for intra-extra cell membrane linkage. Protein and functional analyses of alpha-dystroglycan and mutation screening of FKTN and other associated genes were performed. Surprisingly, we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation. One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old. Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability. One cardiac muscle that underwent biopsy showed altered glycosylation of alpha-dystroglycan similar to that observed in a Fukuyama-type congenital muscular dystrophy patient. FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy.
- [Show abstract] [Hide abstract] ABSTRACT: Influenza-associated encephalopathy is characterized by high fever, convulsions, and loss of consciousness associated with influenza infection in children, but its pathophysiology remains to be clarified. We examined 14-3-3 proteins, which are acidic brain proteins, in cerebrospinal fluid by immunoblotting in four patients with influenza-associated encephalopathy, four patients with influenza without encephalopathy, and four patients with another encephalopathy. Interestingly, we detected 14-3-3 proteins in all four patients with influenza-associated encephalopathy (100%) but not in any of the other patients. 14-3-3 isoforms, including beta, gamma, epsilon, xi, and theta, were found in the cerebrospinal fluid of the patients with influenza-associated encephalopathy, suggesting extensive damage to the brain. We conclude that 14-3-3 proteins in cerebrospinal fluid are highly detectable in influenza-associated encephalopathy and thus can be used as a rapid diagnostic marker.
Conference Paper: Fukutin (FKTN) mutations can cause cardiomyopahty
- [Show abstract] [Hide abstract] ABSTRACT: Guillain-Barré syndrome (GBS) is classified into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN), but little is known about the incidence of the subtypes and the prognosis of childhood GBS. To elucidate the features and long-term prognosis, clinical and electrophysiological data for 31 Japanese GBS children were reviewed. By electrodiagnostic criteria, children were classified as having AIDP (35%) or AMAN (48%), or were unclassified (16%). The AMAN children invariably had normal sensory nerve potentials. Between the two groups, age, sex, and clinical disability did not differ significantly, but the AIDP children more frequently had cranial and sensory nerve involvement, and the AMAN children more frequently had preceding gastroenteritis. By 6 months after onset, all the AIDP and 80% of the AMAN children had regained the ability to walk; by 2 years, all but one of the AMAN children could walk. In Japanese childhood GBS, the proportion of AIDP and AMAN appears to be similar. Recovery is generally favorable in both subtypes, but some of the AMAN children experienced delayed recovery.
- [Show abstract] [Hide abstract] ABSTRACT: Patients with encephalopathy heralded by a prolonged seizure as the initial symptom often have abnormal subcortical white matter on diffusion-weighted MRI (DWI). To determine if these patients share other common features. Patients with encephalopathy heralded by a prolonged seizure and followed by the identification of abnormal subcortical white matter on MRI were collected retrospectively. Their clinical, laboratory, and radiologic data were reviewed. Seventeen patients were identified, ages 10 months to 4 years. All had a prolonged febrile seizure (longer than 1 hour in 12 patients) as their initial symptom. Subsequent seizures, most often in clusters of complex partial seizures, were seen 4 to 6 days after the initial seizure in 16 patients. Outcome ranged from almost normal to severe mental retardation. MRI performed within 2 days of presentation showed no abnormality. Subcortical white matter lesions were observed on DWI between 3 and 9 days in all 17 patients. T2-weighted images showed linear high intensity of subcortical U fibers in 13 patients. The lesions were predominantly frontal or frontoparietal in location with sparing of the perirolandic region. The diffusion abnormality disappeared between days 9 and 25, and cerebral atrophy was detected later than 2 weeks. Three patients having only frontal lesions had relatively good clinical outcome. Although the pathophysiologic mechanism remains unknown, these patients seem to have a distinctive encephalopathy syndrome. MRI is helpful in establishing the diagnosis of this encephalopathy.
- [Show abstract] [Hide abstract] ABSTRACT: We describe a 13-year-old boy with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) who experienced a stroke-like episode resulting in severe mental regression and quadriplegia. We tested 14-3-3 protein in the cerebrospinal fluid (CSF) of the patient four times around a stroke-like episode in a magnetic resonance imaging (MRI) study. Detection of the protein in the CSF was well correlated with the clinical course and range of damage of the brain lesion on MRI. Interestingly, 14-3-3 CSF protein was detected at the beginning of mitochondrial encephalopathy without new MRI abnormalities, suggesting that it is a sensitive brain marker. We conclude that 14-3-3 CSF protein is a useful biological marker of brain disruption in MELAS as well as other neurological disorders.
- [Show abstract] [Hide abstract] ABSTRACT: To elucidate autonomic function in spinal muscular atrophy, we evaluated finger cold-induced vasodilatation, sympathetic skin response, and R-R interval variation in 10 patients with spinal muscular atrophy: 7 of type 1, 2 of type 2, and 1 of type 3. Results of finger cold-induced vasodilatation, sympathetic skin response, and R-R interval variation were compared with those of healthy children. Finger cold-induced vasodilatation was abnormal in 6 of 10 patients with spinal muscular atrophy; it was normal in the healthy children. The mean sympathetic skin response latency and amplitude did not differ significantly from those of the healthy children. Amplitudes of sympathetic skin response to sound stimulation were absent or low in all six patients with spinal muscular atrophy. No significant difference was found in the mean R-R interval variation of patients with spinal muscular atrophy and healthy children. Results show that some patients with spinal muscular atrophy have autonomic dysfunction, especially sympathetic nerve hyperactivity, that resembles dysfunction observed in amyotrophic lateral sclerosis.
- [Show abstract] [Hide abstract] ABSTRACT: Various organ involvements and endocrinologic abnormalities associated with electrolyte imbalance, including hyponatremia, are seen in patients with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS); however, the clinical significance of hyponatremia in these patients is rarely reported. We analyzed the serum sodium concentration profiles and clinical and laboratory data of seven patients with MELAS. We found that hyponatremia occurred episodically in four of the seven patients from an early stage of the disease. We identified excessive sodium loss in urine to be associated with the hyponatremic episodes and the causes of hyponatremia in two patients as relative adrenal insufficiency, acute renal failure, and serious paralytic ileus. However, even extensive examinations failed to reveal the cause in other patients. Because severe hyponatremia can cause serious complications, clinicians should pay attention to serum sodium levels and maintain them properly in patients with MELAS.
- [Show abstract] [Hide abstract] ABSTRACT: Based on the hypothesis that mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) are caused by impaired vasodilation in an intracerebral artery, the authors evaluated the effects of administering l-arginine, a nitric oxide precursor. Patients were administered L-arginine intravenously at the acute phase or orally at the interictal phase. L-arginine infusions significantly improved all strokelike symptoms, suggesting that oral administration within 30 minutes of a stroke significantly decreased frequency and severity of strokelike episodes.
- [Show abstract] [Hide abstract] ABSTRACT: We present 2 cases of narcolepsy with prepubertal onset. Although excessive daytime sleepiness and cataplexy had appeared early in both patients, the presence of sleep-onset rapid eye movement periods was detected several months after the onset of hypersomnia. The levels of hypocretin in the cerebrospinal fluid were reduced when measured 3 weeks (Patient 1) and 2 months (Patient 2) after the appearance of hypersomnia, before the presence of sleep-onset rapid eye movement periods was confirmed. Because the symptoms of narcolepsy in children are often obscure and easily mistaken as other diseases, and the electrophysiologic studies may not be specific in the early stage, the definite diagnosis tends to be delayed. Measurement of hypocretin-1 levels in the cerebrospinal fluid is useful for the early diagnosis of narcolepsy with prepubertal onset.
Chiba Children's HospitalTiba, Chiba, Japan