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)

The peroxisomal disorders belong to a group of inborn errors of metabolism due to malformation or malfunction of these subcellular organelles. Their clinical features vary with age. However, the commonest form presents in the syndrome of Zellweger with severe hypotonia, craniofacial dysmorphism, stippled calcifications, renal cortical cysts and liver dysfunction. By means of complementation very long tests 17 different genotypes have been identified and in 15 of these there were neurological changes. Diagnosis requires recognition of the clinical features, raised levels of very long chain fatty acids, and radiological and neuroimaging studies.
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PMID:[Clinical features of the peroxisomal disorders]. 973 63

Clinical and laboratory findings of Zellweger syndrome (ZS) patients diagnosed at King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia over a period of 10 years are presented in this report. Eleven patients (nine females and two males) from 2 to 4 months old were referred to KFSH & RC for evaluation of hypotonia, seizures, and dysmorphic features. The common clinical findings included high forehead, large fontanelle, shallow orbit ridges, micrognathia, upslanting palebral fissures, epicanthal folds, severe hypotonia, hyporeflexia, pigmentary retinopathy, optic nerve atrophy, complete or partial agenesis of corpus callusum, and failure to thrive. We did not observe any Brushfield spots, any renal and brain cysts, or adrenal insufficiency. Some unique clinical findings were the presence of gallstones, club feet, or bilateral knee or hip dislocation in some patients. All patients had markedly elevated plasma levels of very long chain fatty acids (VLCFA). Electron microscopy performed on liver biopsies of two patients revealed absence of peroxisomes. Biochemical studies of dermal fibroblasts from three patients showed deficient beta-oxidation of lignoceric acid and dihydroxyacetone phosphate acyltransferase (DHAPATase) activity. The tribal living in Saudi Arabia and our observation that 10 of the 11 parents in this study were first-degree relatives and, except for families 1 and 3, each family had at least another baby who died of the same disease. This suggests that the incidence of ZS in Saudi Arabia may actually be higher than our experience at KFSH & RC.
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PMID:Zellweger syndrome in Saudi Arabia and its distinct features. 1004 40

A term infant with hydrops fetalis presented with hypotonia, massive splenomegaly, renal failure, and severe hyperferritinemia. Multiple organ failure, myoclonus, and opisthotonus ensued and she died at 15 days of age. High rounded forehead, large open fontanel, and a small recessed chin led to initial premortem diagnosis of Zellweger syndrome, but her plasma profile of long chain fatty acid was normal. Her subsequent clinical course and findings of postmortem examinations were consistent with perinatal lethal form of Gaucher's disease (PLGD). The diagnosis was confirmed by deficiency of enzyme beta-glucocerebrosidase in white blood cells and in cultured fibroblasts. In addition to the crossover features of Zellweger phenotype, this infant exhibited a number of unusual features including, severe hyperferritinemia, rapid progression of splenomegaly, and absence of icthyosis.
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PMID:Perinatal lethal form of Gaucher's disease presenting with hemosiderosis. 1104 42

Zellweger syndrome is a fatal autosomal-recessive hereditary disease characterized by the absence of peroxisomes in liver and kidneys. The absence of peroxisomes results in impairment of many metabolic pathways, especially beta-oxidation of very long chain fatty acids (VLCFAs). We report a case of a three-month-old male infant with facial dysmorphism, hypotonia, psychomotor retardation, and hepatomegaly. He had an elder brother with the same facial features and hypotonia who died of hepatic failure at four months of age. Biochemical studies revealed elevation of blood pipecolic acid and VLCFAs, compatible with peroxisomal disorder. Electron microscopy of liver biopsy revealed absence of peroxisomes. Zellweger syndrome was diagnosed. Because this syndrome is usually fatal in early life, genetic counseling and prenatal diagnosis are crucial.
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PMID:Zellweger syndrome: report of one case. 1127 Jan 89

Peroxisome biogenesis disorders (PBDs) are severe autosomal recessive neurological diseases caused by a defect of peroxisomal assembly factors. Zellweger syndrome, the most severe phenotype, is characterized by hypotonia, psychomotor retardation and neuronal migration disorder. Neonatal adrenoleukodystrophy and infantile Refsum disease are milder phenotypes of this disease. Thirteen complementation groups have been established since the genetic heterogeneity of PBDs was elucidated in 1988. Eleven genes for PBDs have been identified either by a functional complementation cloning or by EST homology searches. In 1992, the first gene for PBDs, PEX2, was identified. It encodes peroxisomal integral membrane protein with a RING finger domain. PEX5 and PEX7 are the genes for peroxisomal targeting signal (PTS)-1 and -2 receptors, respectively. PEX3, PEX16 and PEX19 are considered to be required for the early stage of peroxisome biogenesis. PEX13 protein has an SH3 docking site that binds to the PTS-1 receptor. PEX1 and PEX6 encode ABC protein, and PEX10 and PEX12 also encode integral membrane protein, with RING finger. Temperature-sensitivity, whereby peroxisomal biogenesis and metabolic dysfunctions are restored at 30 degrees C in cells from mild phenotypes, is a useful event for predicting the clinical severity and for elucidation of peroxisome biogenesis. Investigations using knockout mice are expected to facilitate understanding of migration disorders.
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PMID:Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders. 1140 37

Zellweger syndrome is a lethal neurological disorder characterized by severe defects in peroxisomal protein import. The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the other Zellweger syndrome phenotypes, including neuronal migration defects, hypotonia, a developmental delay, and neonatal lethality. These phenotypes are also manifested in mouse models of Zellweger syndrome generated by disruption of the PEX5 or PEX2 gene. Here we show that mice lacking peroxisomal membrane protein PEX11 beta display several pathologic features shared by these mouse models of Zellweger syndrome, including neuronal migration defects, enhanced neuronal apoptosis, a developmental delay, hypotonia, and neonatal lethality. However, PEX11 beta deficiency differs significantly from Zellweger syndrome and Zellweger syndrome mice in that it is not characterized by a detectable defect in peroxisomal protein import and displays only mild defects in peroxisomal fatty acid beta-oxidation and peroxisomal ether lipid biosynthesis. These results demonstrate that the neurological pathologic features of Zellweger syndrome can occur without peroxisomal enzyme mislocalization and challenge current models of Zellweger syndrome pathogenesis.
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PMID:PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function. 1202 45

Causes of hypotonia in the newborn can be broadly categorized into two classifications. Hypotonia with a supraspinal origin may be seen with systemic disease, hypoxic ischemic encephalopathy, cerebral malformations, syndromes (for example: Down, Prader-Willi, Lowe, Zellweger, Smith-Lemli-Opitz), and c-spine injury. Disorders of the motor unit that present with hypotonia in the newborn period include SMA, congenital myotonic dystrophy, congenital myasthenia gravis, and congenital myopathies. Central core disease is one of the classic congenital myopathies that can be differentiated based on characteristic histologic findings. Muscle fiber samples from patients with central core disease possess distinct morphology that can be diagnostic. Many infants may not exhibit muscle weakness in the newborn period, although there have been rare cases of profound hypotonia and respiratory failure. Clearly, muscle biopsy is the gold standard and is indicated for any infant with marked hypotonia that is not thought to be supraspinal in origin.
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PMID:The hypotonic infant: case study of central core disease. 1259 91

A son and daughter of consanguineous Ashkenazi Jewish parents presented with phenotypic features that are typically seen in Zellweger syndrome: high forehead, broad nasal bridge, epicanthal fold, upslanting palpebral fissures, and micrognathia. In addition to the physical anomalies, they also have severe psychomotor retardation and hypotonia. However, results of peroxisomal studies including very long chain fatty acids and plasmalogen functions, were normal. There was partial deficiency of respiratory chain complexes. We suggest that this is a new autosomal recessive syndrome that could be due to a nuclear-encoded mitochondrial defect.
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PMID:A new autosomal recessive syndrome with Zellweger-like manifestations. 1278 4

Zellweger syndrome is the archetypical peroxisome biogenesis disorder and is characterized by defective import of proteins into the peroxisome, leading to peroxisomal metabolic dysfunction and widespread tissue pathology. In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype. To develop mouse models for this disorder, we have generated a targeted mouse with a loxP-modified Pex13 gene to enable conditional Cre recombinase-mediated inactivation of Pex13. In the studies reported here, we crossed these mice with transgenic mice that express Cre recombinase in all cells to generate progeny with ubiquitous disruption of Pex13. The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death. These animals lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type 1 or type 2 targeting signals. Biochemical analyses of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis. The brains of these animals showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect. Thus, Pex13(-/-) mice reproduce many of the features of Zellweger syndrome and PEX13 deficiency in humans.
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PMID:Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype. 1289 63

During the past 10 years, several Pex genes have been knocked out in the mouse with the purpose to generate models to study the pathogenesis of peroxisome biogenesis disorders and/or to investigate the physiological importance of the Pex proteins. More recently, mice with selective inactivation of a Pex gene in particular cell types were created. The metabolic abnormalities in peroxisome deficient mice paralleled to a large extent those of Zellweger patients. Several but not all of the clinical and histological features reported in patients also occurred in peroxisome deficient mice as for example hypotonia, cortical and cerebellar malformations, endochondral ossification defects, hepatomegaly, liver fibrosis and ultrastructural abnormalities of mitochondria in hepatocytes. Although the molecular origins of the observed pathologies have not yet been resolved, several new insights on the importance of peroxisomes in different tissues have emerged.
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PMID:Generalised and conditional inactivation of Pex genes in mice. 1700 45


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