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1/15. Infantile and juvenile presentations of Alexander's disease: a report of two cases.

    We describe 2 new cases of Alexander's disease, the first to be reported in belgium. The first patient, a 4-year-old girl, presented with progressive megalencephaly, mental retardation, spastic tetraparesis, ataxia and epilepsy: post-mortem examination showed widespread myelin loss with Rosenthal fibers (RFs) accumulation throughout the neuraxis. She was the third of heterozygotic twins, the 2 others having developed normally and being alive at age 5 years. The second patient developed at age 10 years and over a decade spastic paraparesis, palatal myoclonus, nystagmus, thoracic hyperkyphosis and thoraco-lumbar scoliosis with radiological findings of bilateral anterior leukoencephalopathy. Brain stereotactic biopsy at age 16 years demonstrated numerous RFs. With these 2 cases, we review the literature on the various clinico-pathological conditions reported as Alexander's disease. We discuss the nosology of this entity and the pathogeny of RFs formation and dysmyelination. Clues to the diagnosis of this encephalopathy in the living patient are briefly described.
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ranking = 1
keywords = ataxia
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2/15. Palatal tremor, progressive multiple cranial nerve palsies, and cerebellar ataxia: a case report and review of literature of palatal tremors in neurodegenerative disease.

    We describe a patient with an unusual clinical presentation of progressive multiple cranial nerve palsies, cerebellar ataxia, and palatal tremor (PT) resulting from an unknown etiology. magnetic resonance imaging showed evidence of hypertrophy of the inferior olivary nuclei, brain stem atrophy, and marked cerebellar atrophy. This combination of progressive multiple cranial nerve palsies, cerebellar ataxia, and PT has never been reported in the literature. We have also reviewed the literature of PT secondary to neurodegenerative causes. In a total of 23 patients, the common causes are sporadic olivopontocerebellar atrophy (OPCA; 22%), Alexander's disease (22%), unknown etiology (43.4%), and occasionally progressive supranuclear palsy (4.3%) and spinocerebellar degeneration (4.3%). Most patients present with progressive cerebellar ataxia and approximately two thirds of them have rhythmic tremors elsewhere. ear clicks are observed in 13% and evidence of hypertrophy of the inferior olivary nucleus in 25% of the patients. The common neurodegenerative causes of PT are OPCA/multiple system atrophy, Alexander's disease, and, in most of them, the result of an unknown cause.
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ranking = 27.867758978123
keywords = cerebellar ataxia, ataxia
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3/15. Neuropathological and histochemical changes in a multiple mitochondrial dna deletion disorder.

    The identification of cytochrome c oxidase (COX)-deficient/succinate dehydrogenase (SDH)- positive cells using sequential histochemistry has proved important in the identification of cells with high mitochondrial dna (mtDNA) mutant load. We demonstrate large numbers of COX-deficient/SDH-positive neurons in a mosaic pattern throughout the CNS of a patient with a multiple mtDNA deletion disorder. This patient had prominent central and peripheral nervous system involvement with marked cerebellar ataxia, a parkinsonian extra-pyramidal movement disorder, external ophthalmoplegia, dysphagia, and a severe peripheral neuropathy. There was degeneration of myelin tracts in the cerebellum and dorsal spinal columns, diffuse astrocytosis, and selective neuronal degeneration particularly in the midbrain and cerebral microvacuolation. The proportional distribution of the COX-deficient neurons did not always correlate directly with the degree of neuropathological damage with regions of high neuronal loss having relatively low proportions of these cells. Other clinically affected CNS regions have high levels of COX-deficient neurons without significant cell loss. The role of these COX-deficient neurons in causing neuronal degeneration and clinical symptoms is discussed.
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ranking = 3.9811084254462
keywords = cerebellar ataxia, ataxia
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4/15. Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology.

    Neurodegeneration with brain iron accumulation, type 1 (NBIA 1), or Hallervorden-Spatz syndrome, is a rare neurodegenerative disorder characterized clinically by Parkinsonism, cognitive impairment, pseudobulbar features, as well as cerebellar ataxia, and neuropathologically by neuronal loss, gliosis, and iron deposition in the globus pallidus, red nucleus, and substantia nigra. The hallmark pathological lesions of NBIA 1 are axonal spheroids, but Lewy body (LB)-like intraneuronal inclusions, glial inclusions, and rare neurofibrillary tangles also occur. Here we show that there is an accumulation of alpha-synuclein (alphaS) in LB-like inclusions, glial inclusions, and spheroids in the brains of three NBIA 1 patients. Further, beta-synuclein (betaS) and gamma-synuclein (gammaS) immunoreactivity was detected in spheroids but not in LB-like or glial inclusions. Western blot analysis demonstrated high-molecular weight alphaS aggregates in the high-salt-soluble and Triton X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1 brain. Significantly, the levels of alphaS were markedly reduced in the Triton X-100-soluble fractions compared to control brain, and unlike other synucleinopathies, insoluble alphaS did not accumulate in the formic acid-soluble fraction. These findings expand the concept of neurodegenerative synucleinopathies by implicating alphaS, betaS, and gammaS in the pathogenesis of NBIA 1.
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ranking = 3.9811084254462
keywords = cerebellar ataxia, ataxia
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5/15. Japanese family with an autosomal dominant chromosome instability syndrome: a new neurodegenerative disease?

    We report on a Japanese family having an autosomal dominant neurodegenerative disease with chromosomal instability and radiosensitivity. Clinical manifestations of affected members included short stature, osteoporosis, severe dental caries, and various neurological abnormalities, such as mental retardation, depression, dysarthria, hyperreflexia, and ataxic gait. MRI demonstrated a markedly atrophic spinal cord and degeneration of the white matter. Cytogenetic examination showed spontaneous chromosome rearrangements at 14q11.2 and hypersensitivity to radiation and bleomycin. The degree of these cytogenetic abnormalities was significantly higher in the patients than in normal controls but lower than in patients with ataxia telangiectasia or nijmegen breakage syndrome. Moreover, genetic anticipation was observed in this family: the age of disease onset became earlier, MRI abnormalities more extensive, and the chromosome hypersensitivity to radiation increased in successive generations. We speculate that a basic defect in this family is a mutation in the gene that is responsible for dna double-strand breakage repair.
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ranking = 1
keywords = ataxia
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6/15. Leucoencephalopathy after heroin inhalation. A case with partial regression of MRI lesions.

    We report the case of a 41 year old patient who developed a severe cerebellar ataxia. MRI findings were suggestive of myelin damage with symmetrical involvement of the cerebellar hemispheres and, to a lesser extent, the decussation of the superior cerebellar peduncles, the corticospinal tracts and the centrum semiovale. He had been inhaling heroin for the last 5 years. Two years after stopping heroin, he showed clinical improvement with partial regression of the MRI lesions. MRI findings of leucoencephalopathy after heroin inhalation are well described in the literature, however longitudinal studies are rare. It is the purpose of this report to show that clinical and MRI features can be characteristic of this leucoencephalopathy and that regression of white matter lesions can be seen after heroin withdrawal.
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ranking = 3.9811084254462
keywords = cerebellar ataxia, ataxia
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7/15. SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease.

    Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by progressive ataxia and neuronal nuclear inclusions (NIs), similar to the inclusions found in expanded CAG repeat diseases. NIID may be familial or sporadic. The cause of familial NIID is poorly understood, as no CAG expansion has been detected. We examined three cases, from two unrelated families, who had autosomal dominant NIID but normal CAG repeats in genes involved in polyglutamine neurodegenerative diseases. We found that NIs in all three cases were intensely immunopositive for SUMO-1, a protein which covalently conjugates to other proteins and targets them to the nuclear regions (nuclear bodies) responsible for nuclear proteasomal degradation. Electron microscopy demonstrated that SUMO-1 was located on the 10-nm fibrils of NIs. In cultured pc12 cells, we found that inhibition of proteasome function by specific inhibitors resulted in the appearance of SUMO-1-immunopositive nuclear inclusions. Our study suggests that recruitment of SUMO-1 modified proteins into insoluble nuclear inclusions and proteasomal dysfunction may be involved in the pathogenesis of NIs in familial NIID cases.
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ranking = 1
keywords = ataxia
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8/15. Progressive neurodegenerative disease in presumed spinal cord injury: case report of a patient with prion disease.

    BACKGROUND: prion diseases or transmissible spongiform encephalopathies (TSEs) are neurodegenerative syndromes caused by proteinaceous infectious particles (or "prions"), are fatally progressive, and affect humans and animals. Human prion disease may be familial, sporadic, or due to iatrogenic causes. The signs and symptoms include dementia, ataxia, myoclonus, dysautonomia, pyramidal and extrapyramidal tract signs, and akinesia. The incubation period of iatrogenic TSE ranges from 15 months to 30 years, and clinical presentations may be atypical. DESIGN: Case report. FINDINGS: This article presents the case study of a 39-year-old man who fell at work and subsequently complained of subjective lower extremity weakness, followed by onset of ataxia, bowel and bladder incontinence, and progressive decline in ambulation over 6 months. In the absence of a unifying diagnosis, the patient was presumed to have had a spinal cord injury (SCI). Because neuro-axis imaging studies failed to explain his symptoms, the patient's complaints were thought to have a large psychologic component. The patient then developed neurologic abnormalities proximal to the presumed SCI. Somatosensory evoked potentials were suggestive of a thoracic or lumbar cord myelopathy and cerebrospinal fluid analysis was suggestive of prion disease. family members eventually revealed that the patient had had injections of growth hormones derived from cadaveric human pituitary glands as a child. Postmortem brain examination later revealed definitive Creutzfeldt-Jakob disease.
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ranking = 2
keywords = ataxia
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9/15. Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene.

    Abnormal accumulation of ferritin was found to be associated with an autosomal dominant slowly progressing neurodegenerative disease clinically characterized by tremor, cerebellar ataxia, parkinsonism and pyramidal signs, behavioral disturbances, and cognitive decline. These symptoms may appear sequentially over a period of 4 decades. Pathologically, intranuclear and intracytoplasmic bodies were found in glia and subsets of neurons in the central nervous system as well as in extraneural tissue. Biochemical analyses of these bodies isolated from the striatum and cerebellar cortex revealed that ferritin light polypeptide (FTL) and ferritin heavy polypeptide (FTH1) were the main constituents. Molecular genetic studies revealed a 2-bp insertion mutation in exon 4 of the FTL gene. The resulting mutant polypeptide is predicted to have a carboxy terminus that is altered in amino-acid sequence and length. In tissue sections, the bodies were immunolabeled by anti-ferritin and anti-ubiquitin antibodies and were stained by Perls' method for ferric iron. Synthetic peptides homologous to the altered and wild-type carboxy termini were used to raise polyclonal antibodies. These novel antibodies as well as an antibody recognizing FTH1 immunolabeled the bodies. This study of this disorder has provided additional knowledge and insights in the growing area of ferritin-related neurodegeneration.
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ranking = 3.9811084254462
keywords = cerebellar ataxia, ataxia
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10/15. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.

    OBJECTIVE: To identify POLG mutations in patients with sensory ataxia and CNS features. methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors conducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analyzed muscle mitochondrial dna (mtDNA), including Southern blot analysis and long-range PCR. RESULTS: Ataxia occurred in combination with various CNS features, including myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions on MRI, and neuronal loss in discrete gray nuclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate-induced hepatotoxicity occurred less frequently. Two patients died without preceding signs of progressive external ophthalmoplegia. In muscle, typical findings of mitochondrial disease, such as ragged red fibers and Southern blot mtDNA abnormalities, were absent. POLG mutations were present in eight patients, including two isolated cases, and one Finnish and two unrelated Belgian families contained in total six patients. All POLG mutations were recessive, occurring in a homozygous state in seven patients and in a compound heterozygous state in one patient. The novel W748S mutation was identified in five patients from three unrelated families. CONCLUSIONS: The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial dna also are not mandatory features associated with POLG mutations.
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ranking = 5
keywords = ataxia
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