Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007758 (cerebellar ataxia)
 3,609 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the correlations of deletions of mitochondrial DNA in skeletal muscle with clinical manifestations of mitochondrial myopathies, a group of disorders defined either by biochemical abnormalities of mitochondria or by morphologic changes causing a ragged red appearance of the muscle fibers histochemically. We performed genomic Southern blot analysis of muscle mitochondrial DNA from 123 patients with different mitochondrial myopathies or encephalomyopathies. Deletions were found in the mitochondrial DNA of 32 patients, all of whom had progressive external ophthalmoplegia. Some patients had only ocular myopathy, whereas others had Kearns-Sayre syndrome, a multisystem disorder characterized by ophthalmoplegia, pigmentary retinopathy, heart block, and cerebellar ataxia. The deletions ranged in size from 1.3 to 7.6 kilobases and were mapped to different sites in the mitochondrial DNA, but an identical 4.9-kilobase deletion was found in the same location in 11 patients. Biochemical analysis showed decreased activities of NADH dehydrogenase, rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase, four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA. We conclude that deletions of muscle mitochondrial DNA are associated with ophthalmoplegia and may result in impaired mitochondrial function. However, the precise relation between clinical and biochemical phenotypes and deletions remains to be defined.
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PMID:Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. 230

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.
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PMID:Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation. 772 55

We report four sporadic cases of cerebellar ataxia associated with hypogonadism. All patients were female. The neurological symptoms appeared in the first three decades. Apart from ataxia, the most frequent features were nystagmus, dysarthria, mental impairment, brisk tendon reflexes, skeletal deformities, peripheral neuropathy, and tremor. Neuroimaging studies showed constant cerebellar atrophy, in some instances associated with involvement of either grey or white cerebral matter. Neurophysiological studies demonstrated an axonal neuropathy. Endocrine evaluation showed heterogeneity of the hypogonadism, which was hypogonadotrophic in one patient and hypergonadotrophic in the other three. One patient had partial deficiency of muscle cytochrome c oxidase. The syndrome appears to be a heterogeneous multisystem disorder and in some cases a mitochondrial metabolism deficiency could be suspected.
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PMID:Heterogeneous findings in four cases of cerebellar ataxia associated with hypogonadism (Holmes' type ataxia). 845 11

A large Swedish family with members affected by progressive external ophthalmoplegia with hypogonadism were followed-up and reviewed. Hypogonadism included delayed sexual maturation, primary amenorrhea, early menopause, and testicular atrophy. Cataracts, cerebellar ataxia, neuropathy, hypoacusia, pes cavus, tremor, parkinsonism, depression, and mental retardation were other features observed in this family. Muscle biopsy samples of advanced cases showed ragged-red fibers, focal cytochrome c oxidase deficiency, and multiple mtDNA deletions by Southern blot analysis. An autosomal dominant mode of inheritance was evident with anticipation in successive generations. Linkage analysis excluded the chromosome 10q23.3-q24.3 region reported as being linked to the disease in a Finnish family with autosomal dominant progressive external ophthalmoplegia. We report for the first time clinical evidence for anticipation in a family with autosomal dominant progressive external ophthalmoplegia. We hypothesize that the nuclear gene causing this enigmatic disorder may be directly influenced by an expansion of an unstable DNA sequence and that the resulting phenotype is caused by a concerted action with multiple deletions of mtDNA.
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PMID:Anticipation of autosomal dominant progressive external ophthalmoplegia with hypogonadism. 894 Dec 70

We report a 56-year old female with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), presenting with protein-losing gastroenteropathy and serum copper deficiency. There was no neuromuscular disease in her family members. Three years prior to admission, she developed severe gastrointestinal symptoms including diarrhea, nausea, vomiting and ascites, and was diagnosed as having protein-losing gastroenteropathy based on alpha(1)-antitrypsin clearance and other tests. She was referred to our department when neurological symptoms were apparent. Neurological examinations revealed bilateral ptosis, ophthalmoplegia, hearing loss, facial and limb muscle weakness, mild sensory deficit of vibration on her feet and hypoactive deep tendon reflexes. Pigmentary retinopathy, cerebellar ataxia and heart block were not seen. Serum copper level was decreased to 45 micrograms/dl (normal: 83-155). Chronic intestinal pseudo-obstruction was proven by X-ray studies, and diffuse leukoencephalopathy demonstrated on brain MRI. On EMG, motor nerve conduction velocities were prolonged with temporal dispersion. Her muscle biopsy from biceps brachii muscle showed both neuropathic and myopathic changes, scattered ragged-red fibers and focal cytochrome c oxidase deficiency. Southern blot and polymerase chain reaction analysis on mitochondrial DNA showed no deletions nor point mutations. The clinical and pathologic findings of the present patient fulfilled the diagnostic criteria of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) proposed by Hirano et al. There are few reported patients with MNGIE in Japan, but none presented with protein-losing gastroenteropathy and serum copper deficiency. Since the copper is a cofactor of cytochrome c oxidase, decreased serum copper level may aggravate the respiratory chain enzyme metabolism in mitochondria. Therefore, treatment for gastrointestinal tract disturbance and copper administration may be necessary to prevent disease progression.
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PMID:[Mitochondrial neurogastrointestinal encephalomyopathy presenting with protein-losing gastroenteropathy and serum copper deficiency: a case report]. 949 Sep 4

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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PMID:Neuropathological and histochemical changes in a multiple mitochondrial DNA deletion disorder. 1090 Dec 34

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNA(Phe) gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.
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PMID:A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy. 2142 49

We report the case of a 19-year-old Chinese female harboring the m.3291T>C mutation in the MT-TL1 gene encoding the mitochondrial transfer RNA for leucine. She presented with a complex phenotype characterized by progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, and elevated resting lactate blood level. It is known that the myoclonus epilepsy with ragged-red fibers (MERRF) is characterized by cerebellar ataxia and myoclonus epilepsy, while that the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by recurrent stroke-like episodes, migraine-like headaches, and elevated resting lactate blood level. So the patient's clinical manifestations suggest the presence of a MERRF/MELAS overlap syndrome. Muscle biopsy of the patient showed the presence of numerous scattered ragged-red fibers, some cytochrome c oxidase-deficient fibers, and several strongly succinate dehygrogenase-reactive vessels, suggestive of a mitochondrial disorder. Direct sequencing of the complete mitochondrial genome of the proband revealed no mutations other than the T-to-C transition at nucleotide position 3291. Restriction fragment length polymorphism analysis of the proband and her family revealed maternal inheritance of the mutation in a heteroplasmic manner. The analysis of aerobic respiration and glycolysis demonstrated that the fibroblasts from the patient had mitochondrial dysfunction. Our results suggest that the m.3291T>C is pathogenic. This study is the first to describe the m.3291T>C mutation in association with the MERRF/MELAS overlap syndrome.
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PMID:MERRF/MELAS overlap syndrome due to the m.3291T>C mutation. 2433 29

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.
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PMID:A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. 2671 83

Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. Clinical features of MERRF are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALys gene of the DNAmt, mainly A8344G, are responsible for almost 90% of MERRF cases. Morphological changes seen upon muscle biopsy in MERRF include a substantive proportion of RRF, muscle fibers showing a deficient activity of cytochrome c oxidase (COX) and the presence of vessels with a strong reaction for succinate dehydrogenase and COX deficiency. In this review, we discuss mainly clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings as well as some differential diagnoses and treatments.
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PMID:When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis? 2533 34


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