Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0026827 (hypotonia)
5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a novel inborn error of metabolism identified in a child with an unusual neurodegenerative disease. The male patient was born at term and recovered well from a postnatal episode of metabolic decompensation and lactic acidosis. Psychomotor development in the first year of life was only moderately delayed. After 14 mo of age, there was progressive loss of mental and motor skills; at 2 years of age, he was severely retarded with marked restlessness, choreoathetoid movements, absence of directed hand movements, marked hypotonia and little reaction to external stimuli. Notable laboratory findings included marked elevations of urinary 2-methyl-3-hydroxybutyrate and tiglylglycine without elevation of 2-methylacetoacetate, mild elevations of lactate in CSF and blood, and a slightly abnormal acylcarnitine profile. These abnormalities became more apparent after isoleucine challenge. Enzyme studies showed absent activity of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) in the mitochondrial oxidation of 2-methyl branched-chain fatty acids and isoleucine. Under dietary isoleucine restriction, neurologic symptoms stabilized over the next 7 months.
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PMID:Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. 1110 58

Leigh syndrome (LS) affects 1/40,000 newborn infants in the worldwide population and is characterized by the presence of developmental delay and lactic acidosis and by a mean life expectancy variously estimated at 3-5 years. Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. We studied DNA samples from 14 patients with LSFC and from their parents, representing a total of 13 families. Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation. We therefore performed a genomewide screen for LD, using 290 autosomal microsatellite markers. A single marker, D2S1356, located on 2p16, showed significant (P < 10(-5)) genomewide LD. Using high-resolution genetic mapping with additional markers and four additional families with LSFC, we were able to identify a common ancestral haplotype and to limit the critical region to approximately 2 cM between D2S119 and D2S2174. COX7AR, a gene encoding a COX7a-related protein, had previously been mapped to this region. We determined the genomic structure and resequenced this gene in patients with LSFC and in controls but found no functional mutations. Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population.
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PMID:A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16. 1115 35

Leigh syndrome is an encephalomyelopathy that results from a heterogeneous group of mitochondrial disorders characterized by symmetric brainstem spongioform lesions. An infant born with hypotonia and lactic acidosis was found to have symmetric brainstem lesions on T(2)-weighted magnetic resonance imaging consistent with Leigh syndrome. Muscle biopsy failed to reveal ragged-red fibers or cells devoid of cytochrome C oxidase or succinate dehyrogenase. Southern blot analysis of mitochondrial DNA isolated from the patient's quadriceps muscle indicated severe mitochondrial DNA depletion, which was suggested as the cause for the Leigh syndrome seen in this patient. Consideration of mitochondrial DNA depletion as an etiology when evaluating the patient with Leigh syndrome is encouraged.
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PMID:Leigh syndrome in an infant resulting from mitochondrial DNA depletion. 1118 83

The first girl of an unrelated couple was noted to have failure to thrive since age 3 months, generalized hypotonia and weakness, hepatomegaly, hypoglycemia, and lactic acidosis at 4 months. She was found to have severe mitochondrial DNA (mtDNA) depletion and respiratory chain complex IV deficiency in both skeletal muscle and liver but without other common mtDNA mutations. Her younger brother developed vomiting at age 3 weeks and was diagnosed as having pyloric stenosis. His skeletal muscle and liver also showed severe mtDNA depletion. He developed generalized weakness and hypotonia, hepatomegaly, and lactic acidosis at age 3 months. Both siblings died of hepatic failure and hemorrhagic complication before 6 months of age. The brother also had chemical pancreatitis, which had not been reported before in mtDNA depletion in children. Severe mtDNA depletion may present with nonspecific symptoms such as vomiting, failure to thrive, and developmental delay; multiorgan involvement such as hepatomegaly, pancreatitis, and myopathy occurs later. Mitochondrial DNA depletion should be considered in the differential diagnosis in children with developmental delay or failure to thrive of unknown etiology.
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PMID:Mitochondrial DNA depletion in children. 1119 1

Mitochondrial disorders are multisystem diseases with very heterogeneous clinical manifestations. Common cardiac features include cardiomyopathy and conduction defects. We report a five-year-old boy who presented with signs of congestive cardiac failure and was diagnosed to have dilated cardiomyopathy. Six months later, he developed progressively worsening ataxia, hypotonia, other cerebellar signs, hearing loss, severe sensory peripheral neuropathy and lactic acidosis. Electronmicroscopy of skeletal muscle biopsy was consistent with mitochondrial myopathy.
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PMID:Mitochondrial myopathy presenting as ataxia with dilated cardiomyopathy. 1137 Apr 43

Three cases of Leigh disease are described. In all three, symptoms began in the first months of life, with muscle hypotonia, lactic acidosis, and psychomotor delay. The diagnosis was made on the basis of the clinical characteristics, biochemical abnormalities, and typical brain magnetic resonance imaging with symmetric lesions suggesting bilateral necrosis at the level of the basal ganglia and of the midbrain. Cytochrome c oxidase (complex IV of the mitochondrial respiratory chain) deficiency was demonstrated in muscle tissue in all patients and confirmed in skin fibroblasts in patient 3. A genetic heterogeneity was present in these patients since only one had a SURF-1 gene mutation. The clinical, biochemical, and neuroradiologic aspects are discussed. Finally, the finding of facial dysmorphisms in the cytochrome c oxidase deficiency observed in one of the described cases is of extreme interest; to our knowledge, this association has never been reported in the literature.
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PMID:Leigh disease: clinical, neuroradiologic, and biochemical study of three new cases with cytochrome c oxidase deficiency. 1151 Sep 37

Mitochondrial DNA (mtDNA) disorders are clinically very heterogeneous, ranging from single organ involvement to severe multisystem disease. One of the most frequently observed mtDNA mutations is the A-to-G transition at position 3243 of the tRNA(Leu (UUR)) gene. This mutation is often related to MELAS syndrome. However, not all patients with the A3243G mutation share the same clinical disease expression and, on the contrary, patients clinically exhibiting MELAS syndrome may have other mtDNA mutations. Here we describe two patients with a very early infantile presentation of disease associated with the A3243G mutation. Patient 1 presented with hypotonia, feeding difficulties and failure to thrive (FTT) at the age of 3 months. Laboratory investigations showed persistent hyperlactic acidemia, elevated lactate/pyruvate ratios and elevated alanine concentrations in blood. Developmental delay was progressive and he developed cardiomyopathy and seizures. Death occurred at the age of 3.5 years. Patient 2 was born prematurely and had persistent, severe lactic acidosis from birth on. Moderate biventricular hypertrophy was seen on ultrasound studies of the heart and, suffering from progressive lactic acidosis, he died at the age of 13 days. Because of the rarity of this very early presentation, we searched the literature for other infantile cases associated with the A3243G mutation and found 8 additional ones. In infants presenting with lactic acidosis/hyperlactic acidemia, failure to thrive, hypotonia, seizures and/or cardiomyopathy, mtDNA mutational analysis, also for the disease entities, usually only observed in juveniles or adults is warranted.
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PMID:Infantile presentation of the mtDNA A3243G tRNA(Leu (UUR)) mutation. 1157 98

We report three children, each of whom seemed to have a primary mitochondrial disorder at presentation but was eventually diagnosed with an extramitochondrial inherited metabolic disease. The first patient presented at 6 months with developmental delay. Magnetic resonance imaging showed an abnormal signal in the white matter, and magnetic resonance spectroscopy showed elevated lactate peaks. A muscle biopsy showed complex IV deficiency, but leukocyte measurement of galactosylceramide beta-galactosidase activity was markedly diminished, consistent with Krabbe's disease. The second patient presented at birth with seizures and later had developmental delays. There was brain atrophy on neuroimaging. Serum and cerebrospinal fluid lactate levels were elevated. She had persistently elevated urine thiosulfate, which was diagnostic for molybdenum cofactor deficiency. The third child presented at 2 months with seizures and hypotonia. Magnetic resonance imaging showed an abnormal signal in the basal ganglia and surrounding white matter, whereas magnetic resonance spectroscopy showed elevated lactate peaks. A brain biopsy was diagnostic for Alexander's disease. These cases and others in the literature suggest that lactic acid elevation in the central nervous system can be found in a number of extramitochondrial neurologic diseases. Such diseases would constitute a third category of lactic acidosis.
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PMID:Lactic acid elevation in extramitochondrial childhood neurodegenerative diseases. 1157 6

Mitochondrial cytopathies are caused by genetic alterations of nuclear- or mitochondrial-encoded genes involved in the synthesis of subunits of the electron transport chain. Mutations of mitochondrial DNA are associated with a wide range of clinical presentations [1-4]. The ubiquitous nature of mitochondria and the role of the mitochondria in cellular metabolism result in the potential for any tissue in the body to be affected [5-7,8..,9]. Although some children with mitochondrial disease present with life-threatening lactic acidosis in the newborn period, the majority of children come to clinical attention for nonspecific problems, including failure to thrive, developmental delay, seizures, hypotonia, and loss of developmental milestones. The diagnosis of these disorders is made through careful clinical evaluation, coupled with biochemical, morphologic, and molecular biologic techniques. Genetic counseling is difficult due to unique aspects of mitochondrial genetics. Despite advances in our understanding of mitochondrial biochemistry and genetics, treatment options remain limited.
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PMID:Diagnosis and treatment of childhood mitochondrial diseases. 1189 15

A boy presented with lactic acidosis, hepatomegaly, hypoglycemia, generalised icterus, and muscle hypotonia in the first weeks of life. At the age of 2 months, neonatal giant cell hepatitis was diagnosed by light microscopy. Electron microscopy of the liver revealed an accumulation of abnormal mitochondria and steatosis. Skeletal muscle was normal on both light and electron microscopy. At the age of 5 months, the patient died of liver failure. Biochemical studies of the respiratory chain enzymes in muscle showed that cytochrome-c oxidase (complex IV) and succinate-cytochrome-c oxidoreductase (complex II + III) activities were (just) below the control range. When related to citrate synthase activity, however, complex IV and complex II + III activities were normal. Complex I activity was within the control range. The content of mitochondrial DNA (mtDNA) was severely reduced in the liver (17% to 18% of control values). Ultracytochemistry and immunocytochemistry of cytochrome-c oxidase demonstrated a mosaic pattern of normal and defective liver cells. In defective cells, a reduced amount of the mtDNA-encoded subunits II-III and the nuclear DNA-encoded subunits Vab was found. Cells of the biliary system were spared. Immunohistochemistry of mtDNA replication factors revealed normal expression of DNA polymerase gamma. The mitochondrial single-stranded binding protein (mtSSB) was absent in some abnormal hepatocytes, whereas the mitochondrial transcription factor A (mtTFA) was deficient in all abnormal hepatocytes. In conclusion, depletion of mtDNA may present as giant cell hepatitis. mtTFA and to a lesser degree mtSSB are reduced in mtDNA depletion of the liver and may, therefore, be of pathogenetic importance. The primary defect, however, is still unknown.
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PMID:Depletion of mitochondrial DNA in the liver of an infant with neonatal giant cell hepatitis. 1195 53


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