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)

Two infants with lethargy, vomiting, convulsions, coma and marked metabolic acidosis were found to have very high concentrations of methylmalonic acid in their serum and urine. In vitro studies of fibroblasts demonstrated that the infants had different variants of methylmalonic acidemia.Vitamin B(12) was given in two different forms at 1 month of age and at 12 months of age. Each trial continued for 4 months but neither infant showed a clinical or biochemical response.In both infants hyperglycinemia, neutropenia and thrombocytopenia developed during acute metabolic crises only. Hypoglycemia was found in patient 2. Hyperammonemia was severe in patient 2 during acute crises but never appeared in patient 1. When clinically well, both infants continued to excrete abnormal amounts of methylmalonic acid in the urine and both had persistent compensated metabolic acidosis.Marked hyperuricemia developed in patient 1 at 18 months of age and led to progressive renal failure. Allopurinol therapy was necessary to keep the uric acid concentration within the normal range. Renal function returned to normal, as indicated by a marked increase in the renal clearance of creatinine and uric acid.Patient 1 is physically and mentally retarded, and has moderate hypotonia, hepatomegaly and persistent vomiting. Patient 2 has developed normally.The urine concentrations of methylmalonic acid in the four parents were normal.
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PMID:Methylmalonic acidemia: 6 years' clinical experience with two variants unresponsive to vitamin B12 therapy. 3 17

Congenital methylmalonic aciduria (MMA) is a metabolic disorder inherited by an autosomal recessive trait. The metabolic block is located in the catabolic pathway of propionyl-CoA to succinyl-CoA. Biochemically, four enzymatic defects have been recognized, i.e.: 1. Methylmalonyl-CoA racemase. 2. Methylmalonyl-CoA mutase apoenzyme. 3. Synthesis of desoxyadenosyl-cobalamine. 4. Disturbance at an earlier level of cobalamine metabolism which causes defective synthesis of both vitamin B12-coenzymes. These four enzymatic defects express themselves in three ways: non-vitamin B12-dependent MMA (defects 1 and 2); vitamin B12-dependent MMA (defect 3); MMA associated with homocystinuria (defect 4). The various forms of MMA cannot be distinguished clinically from one another. The disorder manifests itself during the first few days to weeks of life. Principal symptoms and signs are: anorexia, vomiting, muscular hypotonia and metabolic acidosis. The diagnosis is established by determination of methylmalonic acid in plasma, cerebrospinal fluid and urine, as well as by assay of enzyme activities in leukocytes, liver tissue or cultured fibroblasts (from biopsied skin). A prenatal diagnosis is feasible by the examination of cultured amnion cells, amniotic fluid and maternal urine. Therapy of non vitamin B12-dependent MMA calls for reduction of protein intake, particularly that of precursors of methylmalonic acid, such as methionine, threonine, isoleucine and valine. The treatment of vitamin B12-dependent forms is accomplished by i.m. injection of high doses of vitamin B12. No definite statement can be made as yet with regard to long-term prognosis and normalcy of mental development in treated children.
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PMID:[Methylmalonic aciduria. Classification, diagnosis and therapy (author's transl)]. 31 93

The clinical and morphologic findings of three patients with metabolic acidosis, methylmalonic aciduria, and homocystinuria are presented. The clinical evolution of the patients was similar and was characterized in the first weeks of life by failure to thrive, hypotonia, and lethargy associated with pancytopenia and hepatic dysfunction, eventually progressing to severe respiratory insufficiency and renal failure consistent with a hemolytic-uremic syndrome. The patients died at 40, 45, and 75 days of age. Biochemical analyses and complementation studies revealed a congenital anomaly of vitamin B12 metabolism (cobalamin C disease). Postmortem morphologic findings in all three cases were dominated by a thrombotic microangiopathy of the kidneys and lungs, diffuse hepatic steatosis, and megaloblastic changes in the bone marrow. A severe gastritis with striking cystic dysplastic mucosal changes and total absence of parietal and chief cells was a consistent finding in all three cases, the rest of the gastrointestinal tract appearing essentially normal. Cobalamin C disease is an intracellular defect of cobalamin metabolism with possible recessive inheritance that can result in multiorgan failure early in life, with a thrombotic microangiopathy and unusual changes in the gastric mucosa.
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PMID:A congenital anomaly of vitamin B12 metabolism: a study of three cases. 156 46

Functional methionine synthase deficiency is generally characterized by homocystinuria and hypomethioninemia in the absence of methylmalonic aciduria. Patients are divided into two classes, cblE and cblG, on the basis of complementation analysis. Presentation has usually been in the first 2 years of life, but one patient came to medical attention at age 21 years with symptoms initially diagnosed as multiple sclerosis. Common findings among 11 patients (4 with cblE and 7 with cblG) have included megaloblastic anemia (all patients) and various neurological deficits including developmental retardation (10 patients), cerebral atrophy (8 patients), hypotonia (7 patients), EEG abnormalities (6 patients), and nystagmus (5 patients). Hypertonia, seizures, blindness, and ataxia were less frequent. All patients have responded to therapy with cobalamin with resolution of anemia and biochemical abnormalities; neurological deficits resolved more slowly and in some cases incompletely. Hydroxycobalamin has been more effective than cyanocobalamin. Fibroblasts from patients with cblE (5 patients) and cblG (6 patients) all showed decreased intracellular levels of methylcobalamin (MeCbl) and decreased incorporation of label from 5-methyltetrahydrofolate into macromolecules, suggesting decreased activity of the MeCbl-dependent enzyme methionine synthase. Methionine synthase specific activity in extracts of all cblE fibroblasts was normal or near-normal under standard reducing conditions; synthase specific activity in extracts of 5 cblG patients was low but was high in a 6th patient measured in another laboratory. Thus, there is heterogeneity among patients with functional methionine synthase deficiency both in clinical presentation and in the results of biochemical studies of cultured cells.
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PMID:Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity. 268 21

Methylmalonic acidemia is a recessively inherited inborn error of metabolism presenting with metabolic acidosis, vomiting, lethargy, anorexia, and hypotonia. The disease may either begin in the neonatal period with acute, life-threatening episodes, or manifest itself with a milder clinical course and a more favorable outcome depending on the location and the severity of enzyme block. Enzymatic abnormalities, clinical features, diagnostic approach with regard to differential diagnosis and the possible treatment are discussed. Genetic counseling and prenatal diagnosis are also stressed.
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PMID:[Methylmalonic acidemia: classification, diagnosis and therapy]. 636 67

The clbC form of methylmalonic acidaemia is a rare and poorly understood condition which results from impaired biosynthesis of methylcobalamin and adenosylcobalamin. The consequent functional deficiencies of methylmalonyl-CoA mutase and methionine synthase produce both methylmalonic aciduria and homocystinuria. Systemic symptoms and neurological decompensation comprise the clinical phenotype. In an effort to clarify the phenotype and prognosis, we obtained clinical information on 50 patients with methylmalonic acidaemia whose cells had been assigned to the cblC complementation group. We identified two distinct phenotypes; they differed in age of onset, presence of systemic symptoms, type of neurological symptoms, and outcome after diagnosis and treatment. Forty-four patients presented in the first year of life. Feeding difficulties, neurological dysfunction (hypotonia, seizures, developmental delay), and ophthalmological and haematological abnormalities characterized their clinical picture. About one-quarter of those patients died. Survival was associated with neurological impairment; only one infant was neurologically intact at follow-up. Onset in childhood, in contrast, was associated with less severe haematological abnormalities, largely involving the red cell series. Extrapyramidal signs, dementia, delirium or psychosis characterized the neurological findings. Survival, with mild to moderate disability in some, was typical in patients with later onset. Treatment in both groups included hydroxycobalamin, betaine and carnitine; complete normalization of biochemical parameters was rare.
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PMID:Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). 926 89

We report on a patient with methylmalonic acidemia (MMA). He experienced a metabolic acidosis attack at 3 weeks of age. He immediately received peritoneal dialysis and exchange transfusion, and recovered from the attack. His MMA phenotype was mut0. Dietary therapy (strict protein restriction) was found to be effective in preventing further attacks, and he had mild hypotonia and impaired psychomotor development. At 9 months of age, he developed brief tonic seizures, which showed polyspike bursts under EEG. His psychomotor development continued to deteriorate. However, intravenous administration of immunoglobulin (200 mg/kg/day for 5 consecutive days) had a dramatic effect; his seizures disappeared and his psychomotor development improved.
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PMID:Effective immunoglobulin therapy for brief tonic seizures in methylmalonic acidemia. 940 1

We performed serial electroencephalograms (EEG) in a newborn with methylmalonic aciduria and homocystinuria to assess the effects of hydroxycobalamin (OHcbl) therapy on the CNS. Diagnosis was made at 22 days of age: she had torpor, failure to thrive and hypotonia of the limbs, and intermittent opisthotonus. The first EEG, performed on the first day of therapy, showed abnormal and immature transients, low voltage and very long flat periods in the discontinuous part of the tracing. These features quickly improved during therapy. After 13 days of OHcbl therapy, the EEG tracing became normal for conceptional age and showed normal sleep phases with only minor anomalies; only mild hypotonia still remained and biochemical parameters normalized. The decrease in blood homocysteine (index of blood detoxification) was statistically correlated to the reduction of the length of flat periods in EEG (p < 0.01). In conclusion, changes in neonatal EEG, particularly the length of interburst periods in the intermittent part of the tracing, appeared to be a reliable index for evaluating drug effectiveness in methylmalonic aciduria and homocystinuria.
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PMID:EEG in assessing hydroxycobalamin therapy in neonatal methylmalonic aciduria with homocystinuria. 1109 15

Methylmalonic acidemia (MMA) is an inborn error of organic acid metabolism that occurs in infancy with hypotonia, vomiting, dehydration, lethargy and failure to thrive and is biochemically characterized by metabolic ketoacidosis, hyperammonemia and sometimes hyperglycinemia. It results from deficiency of methylmalonyl-CoA mutase activity due to a defect in the mutase apoenzyme or to deficient function of one of the enzymes required for metabolism of its cofactor vitamin B12. Tubulointerstitial nephritis with progressive impairment of renal function is one of the most frequent long-term complications. We describe a case of a 17-year-old girl with methylmalonic acidemia unresponsive to vitamin B12 therapy. The clinical symptoms appeared at 4 months of life. She progressed into end stage renal disease and in January 1996 she started on hemodialytic treatment. In November 1996 we performed a kidney transplant. At present, urinary excretion of methylmalonic acid is normal and the renal function of the transplanted kidney is normal without any rejection episodes. We think that a kidney transplant could be a good therapeutic choice for the metabolic alterations in MMA with end stage renal disease. Indeed it would seem that the small methylmalonyl-CoA mutase activity present in the transplanted kidney could be sufficient to ensure normal metabolism of organic acids. Otherwise, the therapeutic goal can be achieved with a protein-restricted diet.
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PMID:Kidney transplantation in a girl with methylmalonic acidemia and end stage renal failure. 1168 86

Methylmalonic aciduria and homocystinuria is a very rare inborn error of cellular cobalamin (Cbl) metabolism. We describe the biochemical evolution and clinical course of a boy with neonatal onset CblC mutant defect.Born after a normal pregnancy, the patient developed general hypotonia and severe feeding difficulties at 5 days of life. Diagnosis of methylmalonic aciduria and homocystinuria was established by amino-acid and organic acid analysis and was confirmed by enzyme and genetic studies. The patient was initially treated with parenteral hydroxocobalamin (1 mg/day), oral carnitine (100 mg/kg/day) and a restricted protein diet. This treatment returned methylmalonic acid levels to normal. Despite the parenteral hydroxocobalamin therapy, the patient showed no improvement in neurological dysfunction, hypotonia or developmental delay. Oral betaine supplementation (3 g/day) from months 3-15 reduced plasma total homocysteine and homocystinuria. The patient showed clinical improvement in neurological and growth development. We conclude that early betaine therapy was safe and effective in our patient with neonatal onset methylmalonic aciduria and homocystinuria type CblC.
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PMID:[Neonatal onset methylmalonic aciduria and homocystinuria:Biochemical and clinical improvement with betaine therapy]. 1192 78


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