Autosomal dominant palatal myoclonus and spinal cord atrophy
Introduction
Palatal myoclonus is a rhythmic involuntary movement associated with brain stem lesions caused by several disorders including neurodegenerative disorders [1]. The incidence of palatal myoclonus associated with neurodegenerative disorders has been estimated to be 2% [1] and familial palatal myoclonus has been rarely reported [2], [3], [4], [5]. Only a few familial cases of palatal myoclonus of suspected autosomal dominant inheritance have been reported and show pathological findings consistent with Alexander disease (OMIM #203450). Recently, Brenner et al. [6] reported that Alexander disease was associated with glial fibrillary acidic protein (GFAP) gene mutations. Although most of the cases studied by Brenner et al. were infantile forms, one case had the age of onset at 10 years and subsequently expired at 48 years old. Therefore, we speculated that adult-onset Alexander disease may be caused by these GFAP mutations. We then attempted to screen the GFAP in our cases suspected to have adult-onset Alexander disease. Here, we report familial cases of palatal myoclonus with marked atrophy of the medulla oblongata and spinal cord, and a new GFAP substitution and discuss the relation between adult-onset Alexander disease and our familial cases.
Section snippets
Patients and methods
Patient 1, a 58-year-old woman (Fig. 1, II-2), noted unsteady gait and muscle weakness in the lower limbs at age 53. One year later, she had episodes of falling to the floor. She had dysarthria at age 56, and developed progressive dysphagia and dysphonia. At age 58, she noted frequent intermittent episodes of diplopia. She noted gradual progression of the dysphagia and muscle weakness with pollakiuria, incontinence, and constipation. She had acute pneumonia and respiratory failure requiring
Brain and spinal cord MRI findings
MRI findings showed marked atrophy of the medulla oblongata and spinal cord in all three patients (Fig. 2A–I). Periventricular hyperintensities in T2-weighted images were detected in Patients 1 and 2, but not in Patient 3 (Fig. 3A–C). Periventricular hyperintensities in FLAIR image, however, were detected in Patient 3 (Fig. 3D). The cerebellum and corpus callosum were mildly affected in the three Patients. Hypertrophy of the inferior olivary nucleus was seen in Patient 1 (Fig. 2D). Mild pontine
Genetic analysis
After informed consent was obtained from the patients and the spouse of Patient 1, genomic DNA was extracted from the peripheral blood (it was not possible to obtain an informed consent from the youngest son (Fig. 1, III-3) who was living abroad) [7]. Using the genomic DNA, we screened the genes responsible for spinocerebellar ataxia (SCA) 1, 2, 6, 7, 8, Friedrich ataxia, and Machado–Joseph disease (MJD) using polymerase chain reaction (PCR) with the primers as described in previous reports [8]
Results
Direct sequencing of GFAP showed a heterozygous point substitution; i.e. a transversion involving a change from T to G at nucleotide position 274 [11]. This alternation produced a glycine for valine 87 in exon 1 in the three patients (Fig. 4A and B). We made a mismatch primer (5′-GCGCCTTGTTTTGCTGTTCCAGGAAGTGA-3′), that produces a new recognition site for Tsp45I in the mutant allele (Fig. 4C), to confirm the substitution detected by the direct sequencing. Using this mismatch primer, we confirmed
Discussion
Here, we describe a family characterized by palatal myoclonus, spastic paraparesis, mild cerebellar dysfunction, severe atrophy of the medulla oblongata and spinal cord, suspected autosomal dominant inheritance, and Val87Gly substitution in GFAP exon 1, which was not detected in 100 SCA patients and 100 controls. Patient 3 in this family showed severe atrophy of the medulla oblongata and spinal cord, and the GFAP substitution, although the clinical symptoms were only bilateral Babinski sign.
Acknowledgments
The authors are grateful to Dr. A. R. Ng of Kagoshima University Faculty of Medicine for critical review. The authors also thank Ms. S. Taniguchi of Kagoshima University Faculty of Medicine for her excellent technical assistance. This work was supported in part by a Research Grant (10B-4) for Nervous and Mental Disorders and a Research Grant (6-2A) for Central Nervous System Degenerative Disorders from the Ministry of Health, Labour and Welfare of Japan.
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2021, Principles and Practice of Movement DisordersFamilial adult-onset Alexander disease with a novel mutation (D78N) in the glial fibrillary acidic protein gene with unusual bilateral basal ganglia involvement
2013, Journal of the Neurological SciencesCitation Excerpt :Patient 3 in our study was asymptomatic and his MRI findings showed mild atrophy of the medulla oblongata and upper cervical cord, without abnormal hyperintensity signals and contrast enhancement. To date, only four cases of asymptomatic adult-onset Alexander disease, detected from MR images of the brain, have been reported [the two patients reported in refs. [3] and [5] are referred to as Patients 5 and 9 in both papers, respectively, Patient II.3 in ref. [12], and Patient 3 in ref. [17]]. Only the patient of Okamoto et al. [17] showed severe atrophy of the medulla oblongata and spinal cord without abnormal hyperintensity signals on T2-weighted MR images, as in our Patient 3.
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2012, Handbook of Clinical NeurologyGenetic demyelinating diseases
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These authors contributed equally to this work.