Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia.

Progressive myoclonic ataxia (PMA) is a clinical syndrome defined as progressive ataxia and myoclonus and infrequent seizures in the absence of progressive dementia. Due to the extremely heterogeneous nature of PMA, a large proportion of PMA cases remain molecularly undiagnosed. The aim of this study was to clarify the molecular etiology of PMA. The patient was a 52-year-old female from consanguineous parents. She developed a jerking neck movement at age 9, which gradually expanded to her entire body. On physical examination at age 47, she exhibited generalized, spontaneous myoclonus that occurred continuously. She also presented with mild limb and truncal ataxia. An electroencephalogram revealed no abnormalities. A brain MRI displayed no atrophy of the cerebellum. Electrophysiological studies suggested myoclonus of a subcortical origin. For further evaluation, we performed exome sequencing, and we identified a novel homozygous missense mutation in the MRE11 gene (NM_005590:c.140C>T:p.A47V). Subsequently, we analyzed the expression of MRE11 and related proteins (RAD50 and NBS1) via Western blot, and they were markedly decreased compared to a healthy control. Mutations in the MRE11 gene have been known to cause an ataxia-telangiectasia-like (ATLD) disorder. Accumulating evidence has indicated that its wide phenotypic variations in ATLD correspond to genotypic differences. Interestingly, our case exhibited a relatively mild decrease in NBS1 compared to previously reported cases of a homozygous missense mutation, which may account for the milder phenotype in this patient. Moreover, together with a recently reported case of an MRE11 mutation, it is suggested that MRE11 mutations can present as PMA.

Cerebellar atrophy in essential tremor using an automated segmentation method.

BACKGROUND AND PURPOSE: Essential tremor (ET) is a slowly progressive disorder characterized by postural and kinetic tremors most commonly affecting the forearms and hands. Several lines of evidence from physiologic and neuroimaging studies point toward a major role of the cerebellum in this disease. Recently, voxel-based morphometry (VBM) has been proposed to quantify cerebellar atrophy in ET. However, VBM was not originally designed to study subcortical structures, and the complicated anatomy of the cerebellum may hamper the automatic processing of VBM. The aim of this study was to determine the efficacy and utility of using automated subcortical segmentation to identify atrophy of the cerebellum and other subcortical structures in patients with ET. MATERIALS AND METHODS: We used a recently developed automated volumetric method (FreeSurfer) to quantify subcortical atrophy in ET by comparing results obtained with this method with those provided by previous evidence. The study included T1-weighted MR images of 46 patients with ET grouped into those having arm ET (n = 27, a-ET) or head ET (n = 19, h-ET) and 28 healthy controls. RESULTS: Results revealed the expected reduction of cerebellar volume in patients with h-ET with respect to healthy controls after controlling for intracranial volume. No significant difference was detected in any other subcortical area. CONCLUSIONS: Volumetric data obtained with automated segmentation of subcortical and cerebellar structures approximate data from a previous study based on VBM. The current findings extend the literature by providing initial validation for using fully automated segmentation to derive cerebellar volumetric information from patients with ET.

Clinical and imaging characterization of a patient with idiopathic progressive ataxia and palatal tremor.

We describe clinical and imaging features of a patient with sporadic progressive ataxia and palatal tremor (PAPT) of unknown etiology. There was hypertrophy of bilateral inferior olivary nuclei with hyperintense T2-weighted signal and mild cerebellar atrophy at brain magnetic resonance imaging. 18F-fluoro-2-desoxy-d-glucose positron emission tomography scanning (FDG-PET) showed hypometabolism in the red nucleus, external globus pallidus and precuneus while FP-CIT-SPECT imaging revealed mild and progressive loss of striatal dopaminergic terminals. Our findings suggest that in idiopathic PAPT involvement of the dentato-rubro-olivary pathway occurs along with some dopaminergic dysfunction.

Acyclovir responsive brain stem disease after the Ramsay Hunt syndrome.

We report an immunocompetent patient with the Ramsay Hunt syndrome (RHS) followed days later by brainstem disease. Extensive virological studies proved that varicella zoster virus (VZV) was the causative agent. Treatment with intravenous acyclovir resulted in prompt resolution of all neurological deficits except peripheral facial palsy. This case demonstrates that after geniculate zoster, brainstem disease may develop even in an immunocompetent individual and effective antiviral therapy can be curative.

DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation.

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease with variable clinical phenotypes. Progressive ataxia, choreoathetosis, and dementia are the main clinical features of adult-onset cases, whereas the main feature in juvenile-onset DRPLA is progressive myoclonus epilepsy. Earlier onset is apparent in successive generations (anticipation). The molecular abnormality underlying DRPLA is an expanded, unstable CAG trinucleotide repeat on chromosome 12p. We analyzed 71 DNA samples obtained from 12 Japanese DRPLA pedigrees that included 38 affected individuals. Normal alleles had 7 to 23 repeats, DRPLA alleles 53 to 88 repeats. DRPLA alleles also were detected in five asymptomatic family members. Patients with juvenile onset had significantly larger repeats than did those with adult onset, and there was a significant negative correlation between CAG repeat length and age at onset. In 80% of the paternal transmissions, there was an increase of more than five repeats, whereas all the maternal transmissions showed either a decrease or an increase of fewer than five repeats. There was a significant correlation between father-child differences in repeat length and differences in age at onset. The analysis of CAG repeat length is a reliable diagnostic test for DRPLA and is of value for the presymptomatic detection of individuals at risk. The expansion of CAG repeats is important in phenotypic variation and anticipation. In addition, the sex of the transmitting parent has a significant effect on the molecular mechanism of anticipation.

Ramsay Hunt syndrome: progressive mental deterioration in association with unusual cerebral white matter change.

An autopsied case of Ramsay Hunt syndrome with progressive dementia was reported. The clinical symptoms included progressive intellectual decline, myoclonus, generalized convulsive seizure, cerebellar ataxia and positive pyramidal signs. Neuropathological examination disclosed cerebral white matter demyelination marked in the frontal lobe and fibrillary gliosis predominantly in the subcortical U-fibers, grumose degeneration in the dentate nucleus and inferior olivary nucleus lesion. The skeletal muscle showed no ragged-red fiber. The present case can be included in Ramsay Hunt syndrome because of the absence of pathological hallmark of mitochondrial encephalomyopathy and of the presence of the degenerative lesions in the olivary and dentate nucleus without cerebellar Purkinje cell loss. The intellectual decline is a result of extensive frontal white matter change, and myoclonus and ataxia are closely associated with dentate grumose degeneration. The cerebral white matter change is an unusual finding and the present case might be a variant in Ramsay Hunt syndrome.

Progressive myoclonus epilepsies: an electroclinical, biochemical, morphological and molecular genetic study of 17 cases.

Electroclinical, morphological, biochemical and molecular genetic data from 17 patients affected by progressive myoclonus epilepsies (PME) are reported. Twelve patients were characterized by prominent action myoclonus, sporadic seizures, mild ataxia, lack of dementia and persistence of normal EEG background activity; three patients showed a more rapid worsening of symptomatology, characterized by early mental impairment, massive and action myoclonus, cerebellar signs and tonic clonic seizures; in these patients EEG background activity was slow, even in early stages of the disease. In two patients, previously classified as cryptogenetic PME, a mitochondrial aetiology was recognized by the presence of ragged red fibers in muscle biopsy and by a reduction of the respiratory chains enzymes. Molecular genetical investigation of mtDNA demonstrated the reported heteroplasmic point mutation at nt 8344 of mtDNA in the two MERRF patients, while it was negative in all of the others.

Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome): a condition unrelated to mitochondrial encephalomyopathies.

Thirteen patients with dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome) had full clinical and neurophysiological study as well as muscle biopsy. The patients had action myoclonus, generalised epileptic seizures, and mild cerebellar syndrome. The disease was inherited in an autosomal recessive pattern in five patients, and occurred as isolated cases in the remaining eight patients. The age at onset of symptoms ranged from 6 to 15 years (mean, 10.4 years). The EEG and polygraphic findings included normal background activity in most patients, spontaneous fast generalised spike-and-wave discharges, photosensitivity, no activation during slow sleep, and vertex and rolandic spikes in REM sleep. Results of muscle biopsy, performed an average of 14 years after onset of the disease, were normal and showed no mitochondrial abnormalities. These findings suggest that Ramsay Hunt syndrome is a condition with distinctive clinical and neurophysiological features and unrelated to mitochondrial encephalomyopathies.

Normal muscle mitochondrial function in Ramsay-Hunt syndrome.

Mitochondrial encephalomyopathies may display clinical features similar to Ramsay-Hunt syndrome (RHS). We studied muscles mitochondrial function in 2 patients with RHS. Histochemical and ultrastructural studies of muscle biopsies and biochemical analysis of muscle mitochondrial enzymes were normal. There is no evidence for a disturbance of muscle mitochondrial function in RHS.

Cerebellar efferent fibers around the dentate nucleus. Pathological anatomy in olivo-ponto-cerebellar and dentato-pallido-luysian atrophy.

In patients with olivo-ponto-cerebellar atrophy (OPCA), the deep cerebellar white matter showed evidence of severe degeneration and gliosis. However, the circumferential white matter enclosing the dentate nucleus was less involved. In addition, the Holzer stain verified the presence of mild gliosis inside the wrinkled band of the dentate gray matter. In contrast, dentato-rubro-pallido-luysian atrophy (DRPLA) affected the mantle layer covering the dentate nucleus. The fibers encircling the dentate nucleus, which degenerate in DRPLA and are spared in OPCA, are anatomically noticeable to be dentatofugal pathways. Moreover, the afferent fibers from the cerebellar cortex and other systems may reach the dentate nucleus partly from the medial aspect via the hilus, as was noted in cases of OPCA.

[Myoclonic cerebellar dyssynergia (Ramsay-Hunt syndrome) and cerebellar telangiectasia]. / Dyssynergie cérébelleuse myoclonique (syndrome de Ramsay-Hunt) et télangiectasies cérébelleuses.

A 8 year-old girl presented with generalized epileptic seizures followed by the progressive onset of myoclonic jerks, sometimes associated with willed movements, and a static and kinetic cerebellar syndrome without conspicuous intellectual impairment. Death occurred 10 years after the onset of the disorders. There was no family history. Neuropathological studies showed lesions confined to the cerebellum. Diffuse and bilateral telangiectases were present in the cerebellar white matter. They were associated with patchy cortical alterations of the distal parts of some folia involving mainly the granule-cells ans sparing the Purkinje cells. No Lafora bodies and no abnormal lipofuscin storage were observed. The dentate nuclei, superior cerebellar peduncles and red nuclei were normal as were the inferior olives and inferior cerebellar peduncles. The spino-cerebellar tracts were unaffected. This case confirms the hypothesis that dyssynergia cerebellaris myoclonica corresponds only to a clinical entity. It may be encountered in various degenerative or metabolic disorders involving the cerebellum and/or its pathways. To our knowledge the association of a Ramsay Hunt syndrome with a vascular malformation has not been previously reported.

Ramsay Hunt syndrome in dentatorubral-pallidoluysian atrophy.

We report a case of Ramsay Hunt syndrome which was clinically characterized by myoclonus epilepsy, cerebellar ataxia, convulsions, and dementia. Major necropsy findings were dentatorubral-pallidoluysian atrophy. Dentatorubral-pallidoluysian atrophy may be associated with a variety of clinical symptoms, amongst which Ramsay Hunt syndrome can be included.