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Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.

ABSTRACT: UNLABELLED: In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. METHODS: X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. RESULTS: We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1-12.7) and 24.7 (19.8-29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. CONCLUSIONS: This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

SUBMITTER: Pereira Fdos S

PROVIDER: S-EPMC3315551 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.

Pereira Fernanda dos Santos Fdos S Matte Ursula U Habekost Clarissa Troller CT de Castilhos Raphael Machado RM El Husny Antonette Souto AS Lourenço Charles Marques CM Vianna-Morgante Angela M AM Giuliani Liane L Galera Marcial Francis MF Honjo Rachel R Kim Chong Ae CA Politei Juan J Vargas Carmen Regla CR Jardim Laura Bannach LB

PloS one 20120329 3

<h4>Unlabelled</h4>In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics.<h4>Methods</h4>X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the gen ...[more]

PMID: 22479560

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Project description:X-linked adrenoleukodystrophy (X-ALD) is the most frequent type of inherited demyelinating peroxisomal disease caused by mutations in the ATP binding cassette subfamily D member 1 (ABCD1) gene. The rate of early recognition and genetic diagnosis of X-ALD remains low due to its variable clinical manifestations. The present study summarized the clinical features Chinese X-ALD patients and performed a follow-up study to further precisely characterize this disease. A total of 10 patients diagnosed with X-ALD between 1994 and 2016 at Shandong Provincial Hospital Affiliated to Shandong University (Jinan, China) were included in the present study. Through reviewing their medical records and performing telephone follow-ups, the clinical features, biochemical laboratory data, brain images, treatments and long-term outcomes were retrospectively summarized. Mutation analysis of the ABCD1 gene was performed in certain patients. Most of the patients (8/10) had the childhood cerebral form of X-ALD. One patient presented with the olivo-ponto-cerebellar form, the rarest form of X-ALD. In all patients, brain magnetic resonance images revealed abnormalities with typical T2-weighted hyperintensity. Analysis of very long chain fatty acid revealed high plasma levels of hexacosanoic acid in all patients. Increased adrenocorticotropic hormone, decreased cortisol and neurophysiological manifestations were also observed. Three different mutations of the ABCD1 gene were identified in the 3 patients subjected to genotyping. During the follow-ups, most patients took neurotrophic drugs and received hydrocortisone replacement when required. One patient received a hematopoietic stem cell transplantation, but died 1 year following the transplantation. Chronic myelopathy and peripheral neuropathy progressed with time, gradually leading to a vegetative state or paralysis within several years of clinical symptom onset. In conclusion, male patients with adrenocortical insufficiency should be further investigated for X-ALD. Early detection is critical to prevent the progression of X-ALD with mutation analysis of ABCD1 the most accurate method to confirm diagnosis.

Project description:Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype-phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35-40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.

Project description:PURPOSE: To determine clinical phenotypes, examine the age dependency of X-linked juvenile retinoschisis (XLRS), and identify mutations in the retinoschisis1 gene (RS1) in 13 Hungarian (Caucasian) families with this disease. METHODS: This study included 72 members in 13 families. Complete ophthalmological examinations, including optical coherence tomography (OCT) and full-field and multifocal electroretinography (ERG), were performed on 20 affected males, 13 female carriers, and 27 healthy controls. The patients were divided into two age groups (Group I <25 years and Group II >25 years), retrospectively, to assess the possible effects of age. Correlations among genotype, age, best corrected visual acuity (BCVA), OCT, and ERG results were analyzed. A modified classification scheme was done to identify the different phenotypes of the disease. In each of the 72 family members and 100 age-matched male controls, all exons and introns of RS1 were amplified by polymerase chain reaction (PCR) and directly sequenced. RESULTS: Foveal retinoschisis was detected in 25 eyes (62.5%) of patients by funduscopy, and in 29 eyes (72.5%) by OCT, while macular lamellar schisis was recognizable only by OCT in 30 eyes (75%) of patients. Foveal thickness (FT) and total macular volume were significantly increased in younger (Group I) patients only. For patients younger than 26 years, large inner nuclear central cysts were observable by OCT, while after 26 years, foveas were atrophic. White flecks and dots, which were like that seen in fundus albipunctatus, were detected in both eyes of one patient. In both patient groups, characteristically decreased b-waves of standard combined ERG were recorded without any significant difference between the patient groups. The BCVA and ERG parameters of all patients and the OCT of younger patients were significantly worse (p<0.05) than those of age-matched controls. A significant difference between the two age groups was found in case FT, total macular volume, and amplitudes of rod b-wave only. Moderate negative correlation (r=-0.54, p<0.001) was detected between age and FT, while only low negative correlation (r=-0.33, p<0.05) was detected between age and standard combined b-wave amplitudes of full-field ERG. BCVA LogMAR did not show any obvious correlation with age (r=-0.14, p=0.39) or with the type of mutation. Nine different mutations were identified in 25 male patients and 31 female carriers of 13 families: six known and one novel missense mutation (c.575C>T, p.Pro192Leu), one insertion mutation (c.579dupC, p.Ile194Hisfs29ext43), and one frameshift, causing splice site mutation (c.78+1G>C) were detected. These mutations were absent in the 100 age-matched male control samples. CONCLUSIONS: Foveal cystic schisis was found more often by OCT than by funduscopy (+10%), while flat macular lamellar schisis was recognizable only by OCT. Advancing age inversely influenced the size of cavities (FT), and standard combined b-wave amplitudes of full-field ERG, while BCVA, response density, and implicit times of multifocal electroretinography did not show any obvious correlation with age. The atrophic stage of the disease was observable after 26 years of age. The lesions that appeared to be indicative of fundus albipunctatus were proven to be palisades between the splitted retinal layers. Our modified classification scheme was helpful in assessing the prevalence of disease types. In these Hungarian patients, one novel and eight known mutations were detected. The distribution of mutations in RS1 was different to that reported in the literature, because the greatest number of different mutations was in exon 6 instead of exon 4. Two mutation hot spots were found: between c.418-422 in exon 5 and between c.574-579 in exon 6. Genotype-phenotype correlation was not demonstrable.

Dataset Information

Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.

Publications

Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.

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