Phenotypic variability in a family with x-linked adrenoleukodystrophy caused by the p.Trp132Ter mutation

Abstract

SUMMARYX-linked adrenoleukodystrophy (X-ALD) is an inherited disease with clinical heterogeneity varying from presymptomatic individuals to rapidly progressive cerebral ALD forms. This disease is characterized by increased concentration of very long chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues. Affected individuals can be classified in different clinical settings, according to phenotypic expression and age at onset of initial symptoms. Molecular defects in X-ALD individuals usually result from ABCD1 gene mutations. In the present report we describe clinical data and the ABCD1 gene study in two boys affected with the childhood cerebral form that presented with different symptomatic manifestations at diagnosis. In addition, their maternal grandfather had been diagnosed with Addison's disease indicating phenotypic variation for X-ALD within this family. The mutation p.Trp132Ter was identified in both male patients; additionally, three females, out of eleven family members, were found to be heterozygous after screening for this mutation. In the present report, the molecular analysis was especially important since one of the heterozygous females was in first stages of pregnancy. Therefore, depending on the fetus outcome, if male and p.Trp132Ter carrier, storage of the umbilical cord blood should be recommended as hematopoietic stem cell transplantation could be considered as an option for treatment in the future. Arq Bras Endocrinol Metab. 2010;54(8):738-43 SUMÁRIO A adrenoleucodistrofia é uma doença genética com padrão de herança ligado ao X (X-ALD) que apresenta heterogeneidade clínica e varia desde a forma infantil cerebral severa até casos de indivíduos pré-sintomáticos. Essa doença é caracterizada pelo acúmulo de ácidos graxos de cadeia muito longa (VLCFA) no plasma, nas adrenais, nos testículos e no sistema nervoso. Indivíduos afetados podem apresentar diferentes formas clínicas, as quais são classificadas de acordo com a expressão fenotípica e a idade de aparecimento dos sintomas iniciais. Alterações moleculares em indivíduos com X-ALD são geralmente mutações no gene ABCD1. No presente trabalho, descrevemos os dados clínicos e a investigação molecular do gene ABCD1 em uma família com duas crianças do sexo masculino afetadas com a forma infantil cerebral, que apresentaram diferenças nas primeiras manifestações sintomáticas para o diagnóstico. Além disso, houve referência ao avô materno diagnosticado com doença de Addison's, indicando a variabilidade fenotípica da X-ALD nessa família. A análise molecular indicou a mutação p.Trp132Ter nos dois pacientes masculinos, e três indivíduos do sexo feminino, entre os onze estudados, mostraram-se heterozigotos para mutação. O conhecimento molecular descrito no presente relato adquiriu maior importância uma vez que uma das portadoras da mutação apresentou-se nos primeiros estágios de gestação. Assim, poderá ser oferecida a possibilidade de armazenamento de sangue de cordão umbilical para que se possa considerar, no futuro, o transplan...

Clinical and Genetic Aspects in Twelve Korean Patients with Adrenomyeloneuropathy

“…Additionally, patient 10 reported interfamilial clinical differences. This was compatible with previous results for a lack of correlation between genotype and phenotype 17,18. Furthermore, the presence of mutational hotspots and the predominance of missense variants were similar to previous reports 5,6…”

“…Nevertheless, neuropathologic study has revealed a fundamental difference between AMN and cerebral ALD 16. Additionally, studies have shown that the clinical phenotypes thereof are not correlated with genotype, even in members of the same family with the same mutation 17,18. This suggests that beyond mutations in the ABCD1 gene, other genetic, epigenetic or environmental factors might be associated with the clinical presentation of ALD.…”

Exome sequencing identifies mutations in ABCD1 and DACH2in two brothers with a distinct phenotype

“…To date, several clinical forms have been reported in male patients (Table 5) [3,4,10-12]. The cerebral forms, including childhood cerebral, adolescent cerebral and adult cerebral, are associated with an inflammatory reaction in the cerebral white matter and progressive neurological damage with rapid evolution, leading to a vegetative state within 6 months to 2 years after onset of symptoms, followed by death at variable ages [13,14]. In contrast, AMN mainly involves the spinal cord and peripheral nerves, the inflammatory response is absent or mild, and its progression is slower.…”

Exome sequencing identifies mutations in ABCD1 and DACH2 in two brothers with a distinct phenotype

“…To date, several clinical forms have been reported in male patients (Table 5) [3,4,[10][11][12]. The cerebral forms, including childhood cerebral, adolescent cerebral and adult cerebral, are associated with an inflammatory reaction in the cerebral white matter and progressive neurological damage with rapid evolution, leading to a vegetative state within 6 months to 2 years after onset of symptoms, followed by death at variable ages [13,14]. In contrast, AMN mainly involves the spinal cord and peripheral nerves, the inflammatory response is absent or mild, and its progression is slower.…”