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)

Mutations in 12 different PEX genes can cause a generalized peroxisomal biogenesis disorder with clinical phenotypes ranging from Zellweger syndrome to infantile Refsum disease. To identify the specific PEX gene to be sequenced, complementation analysis is first performed in fibroblasts using catalase immunofluorescence. A patient with a relatively mild phenotype of infantile cholestasis, hypotonia and motor delay had elevated plasma very long-chain fatty acids and bile acid precursors, but fibroblast studies revealed normal or only mildly abnormal peroxisomal parameters and mosaic catalase immunofluorescence. This mosaicism persisted even when the incubation temperature was increased from 37 degrees C to 40 degrees C, a maneuver previously shown to abolish mosaicism by exacerbating peroxisomal dysfunction. As mosaicism precludes complementation analysis, a candidate gene approach was employed. After PEX1 sequencing was unrewarding, PEX12 sequencing revealed homozygosity for a novel c.102A>T (p.R34S) missense mutation affecting a partially conserved residue in the N-terminal region important for localization to peroxisomes. Transfection of patient fibroblasts with wild-type PEX12 cDNA confirmed that a PEX12 defect was the basis for the PBD. Homozygosity for c.102A>T was identified in a second patient of similar ethnic origin also presenting with a mild phenotype. PEX12 is a highly probable candidate gene for direct sequencing in the context of a mild clinical phenotype with mosaicism and minimally abnormal peroxisomal parameters in fibroblasts.
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PMID:A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C. 1753 73

Peroxisomal biogenesis disorders (PBD) are groups of inherited neurometabolic disorders caused by defects in PEX genes. We report on a female infant, born to a consanguineous parents (first degree cousins), who presented with inactivity, poor sucking, and hypotonia early in the neonatal period. She had subtle dysmorphic features. Liver function tests were impaired with raised liver enzymes, conjugated and unconjugated hyperbilirubinemia. CT of the brain showed diffuse bilateral changes. She developed seizures with an abnormal EEG. Plasma very long chain fatty acid analysis showed high C26:0 levels and increasedC26:0/C22:0 and C24:0/C22:0 ratios, which is consistent with a PBD. Studies in fibroblasts including plasmalogen biosynthesis, peroxisomal fatty acid alfa and beta oxidation confirmed the diagnosis of PBD. Immunofluoresence microscopy revealed the absence of peroxisomes in fibroblasts. The patient was assigned to the PEX19 complementation group. Subsequent mutation analysis of the PEX19 gene revealed homozygosity for a c.320delA frameshift mutation. The patient had a stormy course with multiple admissions to the pediatric intensive care unit with pneumonia, liver impairment, sepsis, and epilepsy. At 1 year of age she developed metabolic acidosis with normal anion gap, proteinuria, aminoaciduria, and glucosuria consistent with a renal tubular defect. Abdominal ultrasound showed multiple gallstones. Other causes of gallstones like haemoglobinopathy were excluded. So far, only two siblings had been reported with mutations in the PEX19 gene. Our patient showed a previously unrecognized association of gallstones and a renal tubular defect with a PBD.
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PMID:A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder. 2068 89

Zellweger syndrome is a peroxisomal disorder resulting from the mutations in PEX genes generally presenting in the neonatal period with profound hypotonia seizures, inability to feed, liver cysts with hepatic dysfunction, chondrodysplasia punctata. Kabuki make-up syndrome is a multiple congenital anomalies and mental retardation syndrome with characteristic facial appearance, skeletal abnormalities, dermatoglyphic abnormalities, mental retardation and short stature. Abnormal liver functions and some atypical findings were also reported in some patients with Kabuki syndrome. In this report a case with late onset Zellweger syndrome who had some phenotypical findings which are also seen in Kabuki Syndrome will be presented. The inclusion of Zellweger syndrome into the differential diagnosis of the patients with Kabuki-like phenotype in addition to abnormal liver functions is emphasized.
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PMID:An infantile case of Zellweger syndrome presented with Kabuki-like phenotype. 2184 15

Zellweger syndrome (ZS) is the severest variety of peroxisomal biogenesis disorder (PBD). This is a fatal hereditary, autosomal recessive disorder. It is characterized by the absence of peroxisomes in the cells which are essential for many metabolic functions especially beta oxidation of very long chain fatty acids (VLCFAs). We report the case of a female Saudi toddler. She presented with dysmorphism, profound hypotonia, psychomotor retardation, seizures, and loss of hearing and vision with findings of optic atrophy. Biochemical study revealed significantly elevated level of VLCFAs, cerotic acid and phytanic acid. She also had periventricular leukomalacia and abnormal electroencephalography results and a PEX 1 gene mutation. The clinical data and investigations were consistent with ZS. As it is fatal in early life, genetic counseling and prenatal diagnosis are thus crucial.
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PMID:Zellweger syndrome - a lethal peroxisome biogenesis disorder. 2332 10

Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondroplasia punctata. Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities. In patients with ZS, a mutation in one of the PEX genes coding for a peroxin (a peroxisome assembly protein) creates functionally incompetent organelles causing an accumulation of very long chain fatty acids (VLCFA), among other complications. Despite an absence of treatment options, prompt diagnosis of ZS is important for providing appropriate symptomatic care, definitive genetic testing, and counseling regarding family planning.
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PMID:Child neurology: Zellweger syndrome. 2367 47

Zellweger syndrome, one of the peroxisome biogenesis disorders, is an autosomal recessive disease caused by mutations in PEX genes. It is characterized by severe hypotonia, failure to thrive, psychomotor retardation, liver dysfunction, and sensorineural hearing impairment. Most of the patients with this disease die before the age of 1 year. PEX14 is the 13th PEX gene responsible for peroxisome biogenesis disorders. Thus far, only two patients with PEX14 deficiency have been reported. Here, we report the first case of a Japanese patient with a PEX14 mutation who showed severe hypotonia, psychomotor retardation, demyelination, and developed rickets at the age of 5 months. An increased excretion of 3,6-epoxydicarboxylic acids leads to the diagnosis of Zellweger syndrome and a mutation analysis of PEX14 revealed a homozygous mutation of c.538C>T (p.Q180X). The patient survived for a prolonged period of time but died of liver failure at the age of 46 months.
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PMID:First Japanese case of Zellweger syndrome with a mutation in PEX14. 2662 64

Peroxisome biogenesis disorders (PBDs) represent a spectrum of human genetic disorders that are characterized by damaged peroxisome assembly. In the newborn period, the characteristics of affected patients include dysmorphic facial features, neonatal hypotonia, seizures, ocular abnormalities, poor feeding, liver cysts with hepatic dysfunction and skeletal defects. These can be caused by a defect in at least 14 different PEX genes. In this study, whole-exome sequencing (WES) was performed on samples from two Chinese newborns with clinical features of Zellweger syndrome. WES identified two novel mutations (c.2416+1G>T and c.2489delT) in patient 1 and another two novel mutations (c.1483+1G>A and c.1727dupG) in patient 2 in the PEX1 gene. All four mutations have a serious influence on the protein function, which also highlights the power of WES, particularly in clinically challenging cases.
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PMID:Novel compound heterozygous mutations in the PEX1 gene in two Chinese newborns with Zellweger syndrome based on whole exome sequencing. 2843 12

Background Peroxisomal biogenesis disorders (PBDs) include a miscellaneous group of diseases which cause serious multisystem disease. Mutations of 13 different PEX genes lead to PBDs including Zellweger syndrome (ZS). Different types of mutations of PEX1 and PEX10 genes are correlated with broad-range phenotypes of PBDs. Case presentation Patient 1 is a 4-month-old boy who was affected by myoclonic seizures, poor oral feeding since birth. The patient was hypotonic and had hepatosplenomegaly. Patient 2 is a 2-month-old boy who presented with decreased movement, severe hypotonia and failure to thrive. The laboratory studies of the patients revealed increased plasma very-long-chain fatty acids (VLCFAs). The genetic analyses of patient 1 demonstrated the first homozygous missense mutation in the PEX10 gene. A novel homozygous missense mutation was found in the PEX1 gene in patient 2. Conclusions This report highlights that the detected homozygous missense mutations of PEX10 and PEX1 genes and the substitutions of specific amino acids lead to the severe form of PBDs.
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PMID:Two different missense mutations of PEX genes in two similar patients with severe Zellweger syndrome: an argument on the genotype-phenotype correlation. 3206 32

At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.
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PMID:A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder. 3312 25