Autosomal dominant palatal myoclonus and spinal cord atrophy

Third Department of Internal Medicine, Kagoshima University Faculty of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Kagoshima City, Japan.
Journal of the Neurological Sciences (Impact Factor: 2.47). 04/2002; 195(1):71-6. DOI: 10.1016/S0022-510X(01)00687-6
Source: PubMed


We report a new family with palatal myoclonus, pyramidal tract signs, cerebellar signs, marked atrophy of the medulla oblongata and spinal cord, and autosomal dominant inheritance. These findings were almost identical with those in patients previously reported to have histopathologically confirmed adult-onset Alexander disease. Recently, heterozygous point mutations in the coding region of glial fibrillary acidic protein (GFAP) in patients with an infantile form of Alexander disease have been reported. We found a new heterozygous amino acid substitution, Val87Gly in exon 1 of GFAP, in the affected individuals in this family but not in 100 spinocerebellar ataxia (SCA) patients and 100 controls. Therefore, this family might have new clinical entities related to adult-onset Alexander disease and GFAP mutation.

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    • "Following identification of the GFAP gene as responsible for ALX [8], the adult form has been increasingly reported [10,11,15-36]. However, only a few cases have been pathologically proven [11,16,17,21,28]; the rest were diagnosed as having ALX only by molecular testing. "
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    ABSTRACT: Alexander disease (ALX) is a rare neurological disorder characterized by white matter degeneration and cytoplasmic inclusions in astrocytes called Rosenthal fibers, labeled by antibodies against glial fibrillary acidic protein (GFAP). Three subtypes are distinguished according to age at onset: infantile (under age 2), juvenile (age 2 to 12) and adult (over age 12). Following the identification of heterozygous mutations in GFAP that cause this disease, cases of adult-onset ALX have been increasingly reported. We present a 60-year-old Japanese man with an unremarkable past and no family history of ALX. After head trauma in a traffic accident at the age of 46, his character changed, and dementia and dysarthria developed, but he remained independent. Spastic paresis and dysphagia were observed at age 57 and 59, respectively, and worsened progressively. Neurological examination at the age of 60 revealed dementia, pseudobulbar palsy, left-side predominant spastic tetraparesis, axial rigidity, bradykinesia and gaze-evoked nystagmus. Brain MRI showed tadpole-like atrophy of the brainstem, caused by marked atrophy of the medulla oblongata, cervical spinal cord and midbrain tegmentum, with an intact pontine base. Analysis of the GFAP gene revealed a heterozygous missense mutation, c.827G>T, p.R276L, which was already shown to be pathogenic in a case of pathologically proven hereditary adult-onset ALX. The typical tadpole-like appearance of the brainstem is strongly suggestive of adult-onset ALX, and should lead to a genetic investigation of the GFAP gene. The unusual feature of this patient is the symmetrical involvement of the basal ganglia, which is rarely observed in the adult form of the disease. More patients must be examined to confirm, clinically and neuroradiologically, extrapyramidal involvement of the basal ganglia in adult-onset ALX.
    Full-text · Article · Apr 2010 · BMC Neurology
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    • "At the other end of the disease spectrum, two of our patients had no symptoms definitely attributable to AOAD, and were diagnosed by chance on MRI performed for possibly unrelated clinical problems; one further asymptomatic mutation carrier was uncovered during genetic family investigation. Four other asymptomatic patients with GFAP mutations have been reported in the literature (Okamoto et al., 2002; Stumpf et al., 2003; Shiihara et al., 2004; Balbi et al., 2008). It is impossible to predict when they will develop the disease, if ever. "
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    ABSTRACT: Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibre accumulation. Following the identification of glial fibrillary acidic protein (GFAP) gene as the causative gene, cases of adult-onset AD (AOAD) are being described with increasing frequency. AOAD has a different clinical and neuroradiological presentation with respect to early-onset AD, as abnormalities are mainly concentrated in the brainstem-spinal cord junction. We report detailed clinical and genetic data of 11 cases of AOAD, observed over a 4-year period, and a review of the previously reported 25 cases of genetically confirmed AOAD. In our series, onset occurred as late as age 62, and up to 71 in an affected deceased relative. Most cases appeared sporadic, but family history may be misleading. The most frequent symptoms were related to bulbar dysfunction-with dysarthria, dysphagia, dysphonia (seven patients)-, pyramidal involvement (seven patients) and cerebellar ataxia (seven patients). Four patients had palatal myoclonus. Sleep disorders were also observed (four cases). Bulbar symptoms, however, were infrequent at onset and two symptomatic patients had an almost pure pyramidal involvement. Two subjects were asymptomatic. Misdiagnosis at presentation was frequent and MRI was instrumental in suggesting the correct diagnosis by showing, in all cases, mild to severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord. In ten patients, molecular studies revealed six novel missense mutations and three previously reported changes in GFAP. The last typical patient carried no definitely pathogenic mutation, but a missense variant (p.D157N), supposedly a rare polymorphism. Revision of the literature and the present series indicate that the clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive. Pyramidal involvement, cerebellar ataxia and urinary disturbances are common. Less frequent findings include sleep disorders and dysautonomia. Fluctuations may occur. The course is variable, usually slowly progressive and less severe than the AD forms with earlier onset. AOAD is more common than previously thought and might even be the most common form of AD. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis.
    Full-text · Article · Oct 2008 · Brain
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    • "Clinically, Alexander disease is classified into three subtypes: infantile, juvenile, and adult forms, based on the age at disease onset. Recently, GFAP mutations have been reported in various forms of Alexander disease (Brenner et al. 2001; Aoki et al. 2001; Rodriguez et al. 2001; Shiroma et al. 2001; Gorospe et al. 2002; Li et al. 2002; Meins et al. 2002; Namekawa et al. 2002; Probst et al. 2003; Sawaishi et al. 2002; Shiihara et al. 2002; Shiroma et al. 2003; Suzuki et al. 2004) and we have identified juvenile and adult forms of Alexander disease with three different GFAP mutations: V87G (Okamoto et al. 2002), R88C (Nobuhara et al. 2004) and R416W (Kinoshita et al. 2003). To date, there had been few reports investigating the properties of mutant GFAP (Li et al. 2005; Hsiao et al. 2005; Perng et al. 2006). "
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    ABSTRACT: To clarify the functional effects of mutant glial fibrillary acidic protein (GFAP), we examined the expression patterns of mutant GFAPs (V87G, R88C, and R416W) in astrocytoma-derived cells and performed migration assay. The morphological change was found in mutant GFAP cells, although the number of changes was small. On migration assay, the migration rate in cells with the V87G or R88C mutation, which are located in the helical rod domain in GFAP, was significantly higher than those of wild-type and R416W. These findings suggest that the functional abnormalities of astrocytes might be induced prior to aggregation of GFAP in Alexander disease and that the functional alteration depends on the location of the domain.
    Full-text · Article · Feb 2007 · Journal of Human Genetics
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