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)

Six patients are described in whom a deficiency of cytochrome oxidase in muscle tissue was found. Four patients suffered from the syndrome of 'floppy babies' with profound hypotonia, muscle weakness and failure to thrive. They died within the first 6 months of life. Two patients suffered from Leigh's and Alpers' syndrome, respectively. In all patients lactate level was elevated in one or more body fluids, whereas in 4 patients a generalized amino-aciduria was found. With electronmicroscopy structurally abnormal mitochondria were seen in the muscle of 5 out of the 6 patients.
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PMID:[Mitochondrial myopathy associated with cytochrome oxidase deficiency]. 609 82

Two newborn female siblings fell ill with apathy, failure of suckling and a generalized progressive muscular hypotonia. Death occured at the age of 7 weeks, obviously caused by impairment of respiratory musculature. Biochemical studies in one child revealed carnitine deficiency especially in skeletal muscle; hepatic encephalopathy was absent. Both children had a generalized hyperaminoaciduria, an unusual finding in primary carnitine deficiency. Besides fatty metamorphosis of the liver, bilateral hydroureters and tubular calcifications of both kidneys, morphological studies showed a generalized lipid storage myopathy which predominated in Type-I-fibres and was accentuated in the muscles of the neck. Enzymehistochemical electron microscopy in longterm frozen muscle demonstrated that cytochrome-c-oxidase activity was absent not only in myopathic but also in most of the morphological unchanged muscle fibres. Only some fibres and endothelial cells displayed normal activity of mitochondria. Biochemically no cytochrome aa3 (cytochrome-c-oxidase) could be found in skeletal muscle; cytochrome b was almost undetectable. --In newborns with fatal lipid storage myopathy and carnitine deficiency it seems necessary to look for additional defects in the respiratory chain. Enzyme histochemical electron microscopy is a sensitive method in identifying cytochrome-c-oxidase even after a 12 months period of storage.
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PMID:Fatal lipid storage myopathy with deficiency of cytochrome-c-oxidase and carnitine. A contribution to the combined cytochemical-finestructural identification of cytochrome-c-oxidase in longterm frozen muscle. 629 99

A case of cytochrome c oxidase deficiency primarily affecting skeletal muscle is described. The child was admitted at 4 weeks due to failure to thrive and examination at that time revealed weakness and hypotonia. His condition deteriorated until at 11 weeks respiratory arrest necessitated artificial ventilation and death occurred at 14 weeks. Biochemical investigation showed lactic acidaemia and generalised aminoaciduria. Histochemical examination of muscle obtained at biopsy showed strong reactions for some oxidative enzymes, but by contrast cytochrome c oxidase could not be detected. Cytochrome c oxidase activity was less than 5% of control values in an extract of fresh muscle. The reduced-minus oxidised absorption spectra of muscle mitochondrial fractions prepared from post-mortem tissue showed an absence of cytochrome aa3 and a partial deficiency of cytochrome b. Ultra-structural examination showed abnormal mitochondria with loss of cristae and an abnormal granular matrix. The family history suggests autosomal recessive inheritance.
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PMID:Fatal infantile mitochondrial myopathy due to cytochrome c oxidase deficiency. 631 67

In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.
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PMID:Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria. 769 3

Disruption of early or late fetal brain development resulting in structural abnormalities may be associated with inborn errors of mitochondrial metabolism. It is common in patients with deficiency of pyruvate dehydrogenase activity and it has sporadically been described in patients with dysfunction of the tricarboxylic acid cycle. Mitochondrial respiratory chain disorders are not commonly known to interfere with early brain development. We describe here a girl with an encephalomyopathy likely to be due to a novel type of deficiency of cytochrome c oxidase (complex IV) activity that presented with severe hypotonia, myoclonic seizures, optic atrophy and elevated lactate concentration in cerebrospinal fluid shortly after birth. Cranial magnetic resonance imaging revealed hypoplasia of the cerebellum with rudimentary cerebellar hemispheres and relative sparing of the vermis. This case suggests that deficiency of cytochrome c oxidase and possibly respiratory chain disorders in general have to be considered in the differential diagnosis of cerebellar hypoplasia.
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PMID:Cerebellar hypoplasia in respiratory chain dysfunction. 889 74

A boy was born at 39 weeks gestation with severe weakness and hypotonia, fractured femurs, poor suck and swallow, and absent deep tendon reflexes. Electrodiagnostic studies revealed marked slowing of motor nerve conduction velocities and normal muscle electrical activity with no evidence of acute denervation. Muscle biopsy showed mild type 2 fiber predominance, and sural nerve biopsy revealed large axons without myelin, and axons with insufficient amount of myelin for their diameter. There was no evidence of inflammation or demyelination. Gradual clinical improvement in tone and strength occurred in a cephalocaudal direction. By 4 months, motor nerve conduction velocities and clinical examination were normal apart from absent deep tendon reflexes. On review at 19 months, motor development and neurological examination were completely normal. Pathogenesis of this reversible pathologically documented case of congenital hypomyelinating neuropathy is unclear. No evidence was found for an inflammatory, toxic, metabolic, or demyelinating cause. Abnormal expression of a developmental gene, as in reversible cytochrome oxidase deficiency, may be a cause of this neuropathy.
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PMID:Congenital hypomyelinating neuropathy: a reversible case. 904 8

By studying a large series of 157 patients, we found that complex I (33%), complex IV (28%), and complex I+IV (28%) deficiencies were the most common causes of respiratory chain (RC) defects in childhood. Truncal hypotonia (36%), antenatal (20%) and postnatal (31%) growth retardation, cardiomyopathy (24%), encephalopathy (20%), and liver failure (20%) were the main clinical features in our series. No correlation between the type of RC defect and the clinical presentation was noted, but complex I and complex I+IV deficiencies were significantly more frequent in cases of cardiomyopathy (P<.01) and hepatic failure (P<.05), respectively. The sex ratio (male/female) in our entire series was mostly balanced but was skewed toward males being affected with complex I deficiency (sex ratio R=1.68). Interestingly, a high rate of parental consanguinity was observed in complex IV (20%) and complex I+IV (28%) deficiencies. When parental consanguinity was related to geographic origin, an even higher rate of inbreeding was observed in North African families (76%, P<.01). This study gives strong support to the view that an autosomal recessive mode of inheritance is involved in most cases of mitochondrial disorders in childhood, a feature that is particularly relevant to genetic counseling for this devastating condition.
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PMID:A high rate (20%-30%) of parental consanguinity in cytochrome-oxidase deficiency. 968 89

The primary presentations of neuromuscular disease in the newborn period are hypotonia and weakness. Although metabolic myopathies are inherited disorders that present from birth and may present with subtle to marked neonatal hypotonia, a number of these defects are diagnosed classically in childhood, adolescence, or adulthood. Disorders of glycogen, lipid, or mitochondrial metabolism may cause three main clinical syndromes in muscle, namely, (1) progressive weakness with hypotonia (e.g., acid maltase, debrancher enzyme, and brancher enzyme deficiencies among the glycogenoses; carnitine uptake and carnitine acylcarnitine translocase defects among the fatty acid oxidation (FAO) defects; and cytochrome oxidase deficiency among the mitochondrial disorders) or (2) acute, recurrent, reversible muscle dysfunction with exercise intolerance and acute muscle breakdown or myoglobinuria (with or without cramps), e.g., phosphorylase, phosphofructokinase, and phosphoglycerate kinase among the glycogenoses and carnitine palmitoyltransferase II deficiency among the disorders of FAO or (3) both (e.g., long-chain or very long-chain acyl coenzyme A (CoA) dehydrogenase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and trifunctional protein deficiencies among the FAO defects). Episodes of exercise-induced myoglobinuria tend to present in later childhood or adolescence; however, myoglobinuria in the first year of life may occur in FAO disorders during catabolic crises precipitated by fasting or infection. The following is a survey of genetic disorders of glycogen and lipid metabolism resulting in myopathy, focusing primarily on those defects, to date, that have presented in the neonatal or early infancy period. Disorders of mitochondrial metabolism are discussed in another chapter.
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PMID:Neonatal metabolic myopathies. 1033 65

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

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


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