Characterization of two common 5' polymorphisms in PEX1 and correlation to survival in PEX1 peroxisome biogenesis disorder patients.

BACKGROUND: Mutations in PEX1 are the most common primary cause of Zellweger syndrome. In addition to exonic mutations, deletions and splice site mutations two 5' polymorphisms at c.-137 and c.-53 with a potential influence on PEX1 protein levels have been described in the 5' untranslated region (UTR) of the PEX1 gene. METHODS: We used RACE and in silico promoter prediction analysis to study the 5' UTR of PEX1. We determined the distribution of PEX1 5' polymorphisms in a cohort of 30 Zellweger syndrome patients by standard DNA sequencing. 5' polymorphisms were analysed in relation to the two most common mutations in PEX1 and were incorporated into a novel genotype-phenotype analysis by correlation of three classes of PEX1 mutations with patient survival. RESULTS: We provide evidence that the polymorphism 137 bp upstream of the ATG codon is not part of the UTR, rendering it a promoter polymorphism. We show that the first, but not the second most common PEX1 mutation arose independently of a specific upstream polymorphic constellation. By genotype-phenotype analysis we identified patients with identical exonic mutation and identical 5' polymorphisms, but strongly differing survival. CONCLUSIONS: Our study suggests that two different types of PEX1 5' polymorphisms have to be distinguished: a 5' UTR polymorphism at position c.-53 and a promoter polymorphism 137 bp upstream of the PEX1 start codon. Our results indicate that the exonic PEX1 mutation correlates with patient survival, but the two 5' polymorphisms analysed in this study do not have to be considered for diagnostic and/or prognostic purposes.

Cerebral MRI as a valuable diagnostic tool in Zellweger spectrum patients.

Patients with defects in the biogenesis of peroxisomes include those with Zellweger syndrome spectrum (ZSS), a developmental and progressive metabolic disease with a distinct dysmorphic phenotype and varying severity. The diagnosis of ZSS relies on the clinical presentation and the biochemical evaluation of peroxisomal metabolites. Mutation detection in one out of twelve genes coding for proteins involved in the biogenesis of peroxisomes confirms the diagnosis. In the absence of pronounced clinical features of ZSS, neuroradiological findings may lead the way to the diagnosis. Cerebral magnetic resonance imaging (cMRI) pathology in ZSS consists of abnormal gyration pattern including polymicrogyria and pachygyria, leukencephalopathy, germinolytic cysts and heterotopias as reported by previous systematic studies including cMRI of a total of 34 ZSS patients, only five of whom had a severe phenotype. The present study evaluated the cMRI results of additional 18 patients, 6 with a severe and 12 with a milder ZSS phenotype. It confirms and extends knowledge of the characteristic cMRI pattern in ZSS patients. Besides an abnormal gyration pattern and delayed myelination or leukencephalopathy, brain atrophy was a common finding. Polymicrogyria and pachygyria were more common in patients with severe ZSS, while leukencephalopathy increases with age in patients with longer survival. Nevertheless, an abnormal gyration pattern might be more frequent in patients with a mild ZSS than deduced from previous studies. In addition, we discuss the differential diagnosis of the ZSS cMRI pattern and review investigations on the pathogenesis of the ZSS cerebral phenotype in mouse models of the disease.

Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival.

OBJECTIVE: To define neuroimaging characteristics of peroxisome biogenesis disorders (PBD) with prolonged survival belonging to the Zellweger spectrum (ZeS). METHODS: The authors studied MR images of 25 patients surviving the first year. Neuroimages were compared to neurologic profiles, PBD-ZeS specific compound developmental scores, and two common PEX1 mutations. RESULTS: Three groups are defined based on normal findings, developmental anomalies, and regressive changes. Regressive changes consisting of leukoencephalopathy were identified in patients who had either stable clinical course or progressive deterioration. Concomitant neocortical atrophy was encountered in a minority. Leukoencephalopathy with stable clinical course represents the largest subgroup (48%). The authors found the central cerebellar white matter a focus for early changes in both asymptomatic and symptomatic leukoencephalopathy. A relationship between white matter involvement in clinically stable leukoencephalopathy and degree of developmental failure could not be established. The common homozygous PEX1 G843D mutation is represented in the three main outcome groups. This result points to variable phenotypic expression of the most common PEX1 mutation. CONCLUSIONS: MR findings in ZeS patients surviving the first year differ from Zellweger syndrome in predominance of regressive over developmental changes. Distribution pattern suggests identical pathomechanisms for symptomatic and asymptomatic leukoencephalopathy.

Biochemical markers predicting survival in peroxisome biogenesis disorders.

OBJECTIVE: To identify prognostic markers reflecting the extent of peroxisome dysfunction in primary skin fibroblasts from patients with peroxisome biogenesis disorders (PBD). BACKGROUND: PBD are a genetically heterogeneous group of disorders due to defects in at least 11 distinct genes. Zellweger syndrome is the prototype of this group of disorders, with neonatal adrenoleukodystrophy and infantile Refsum disease as milder variants. Common to these three disorders are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness. Because genotype-phenotype studies are complicated by the genetic heterogeneity among patients with PBD, the authors evaluated a series of biochemical markers as a measure of peroxisome dysfunction in skin fibroblasts. METHODS: Multiple peroxisomal functions including de novo plasmalogen synthesis, dihydroxyacetonephosphate acyltransferase (DHAPAT) activity, C26:0/C22:0 ratio, C26:0 and pristanic acid beta-oxidation, and phytanic acid alpha-oxidation were analyzed in fibroblasts from a series of patients with defined clinical phenotypes. RESULTS: A poor correlation with age at death was found for de novo plasmalogen synthesis, C26:0/C22:0 ratio, and phytanic acid alpha-oxidation. A fairly good correlation was found for pristanic acid beta-oxidation, but the best correlation was found for DHAPAT activity and C26:0 beta-oxidation. A mathematic combination of DHAPAT activity and C26:0 beta-oxidation showed an even better correlation. CONCLUSIONS: DHAPAT activity and C26:0 beta-oxidation are the best markers in predicting life expectancy of patients with PBD. Combination of both markers gives an even better prediction. These results contribute to the management of patients with PBD.

Síndrome e de Zellweger: descripción de un caso de supervivencia prolongada / Zellweger syndrome: report of a case of long-term suviral

El síndrome de Zellweger es una rara enfermedad metabólica producida por una hipofunción marcada de los peroxisomas a causa de la disminución de su número. Se afecta el metabolismo lipídico, sobre todo el perfil de ácidos grasos de cadena muy larga (AGCML) en sangre y en botón celular. Clínicamente debuta en el periodo neonatal con convulsiones, hipotonía generalizada, alteraciones oculares, hepáticas y renales. Las complicaciones son muy incapacitantes y provocan la muerte en los primeros meses. Presentamos un caso típico en el que se ensayó un aporte exógeno de AGCML durante 6 meses sin que se observara ninguna mejoría clínica ni cambios del perfil de AGCML. Nuestra paciente falleció a los 2 años y 8 meses por sobreinfección respiratoria (AU)

Additional congenital defects in anorectal malformations.

UNLABELLED: From 1974 until 1995 a total of 264 (141 male, 123 female) patients born with an anorectal malformation (ARM) were referred to the University Hospital Nijmegen in the Netherlands. All additional congenital defects (ACDs) were registered. Special attention was paid to whether the ACDs take part in associations, syndromes, or sequences. One or more ACDs were observed in 67% of the patients. In decreasing order the defects concerned the uro-genital tract (43%), skeleton (38%), gastrointestinal tract (24%), circulation (21%), extremities (16%), face (16%), central nervous system (15%), respiratory tract (5%), and remaining defects (5%). Associations were observed in 49% of the patients mostly (in 44%) the Vertebral, Anorectal, Cardial, Tracheo-Esophageal, Renal and Limb association. In 5% of the patients syndromes were recognized. Sequences were seen in 2% of the patients. Remarkable is the combination of trisomy 21 and ARM without a fistula. The combination of ARM and the Zellweger syndrome has not been reported before. CONCLUSION: Almost all combinations of ARM and ACDs can be classified as an association, syndrome or sequence. ARM-causing agents affect males and females in equal numbers but lead to different expression in the sexes. The origin of the Omphalocele, Extrophia of the bladder, Imperforate anus, Sacral anomalies complex probably differs from that of other forms of ARM.