Spinal muscular atrophy among the Roma (Gypsies) in Bulgaria and Hungary

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Abstract

Spinal muscular atrophy is one of the most common autosomal recessive disorders, classified into three major clinical forms. It is caused mainly by deletions or gene conversions of the telomeric survival motor neuron gene (SMN1) on human chromosome 5. We have conducted molecular studies of the disorder in genetically isolated Romani (Gypsy) communities in Bulgaria and Hungary, where spinal muscular atrophy appears to have different prevalence and both mild and severe spinal muscular atrophy phenotypes have been diagnosed. We have observed three distinct genetic defects which, in different combinations, lead to different forms of the disease. The similar chromosomal background on which the different mutations occur suggests a common origin and founder effect, with rearrangements of a single ancestral chromosome resulting in a diversity of molecular defects.

Introduction

Spinal muscular atrophy (SMA) is a severe autosomal recessive disorder of motor neurons, neuropathologically characterized by death of the anterior horn cells [1], [2]. The disease is classified into three major clinical forms: severe (SMA type I), intermediate (SMA type II) and mild (with onset in childhood – SMA type III or in adolescence – SMA type IV) [3], all mapping to chromosome 5q13.1 [4], [5], [6], [7]. The SMA gene is located in an unstable genomic region with a large inverted duplication, which contains several multicopy microsatellites and at least four genes (H4F5, SMN, NAIP and BTF2p44) [8], [9], [10], [11], [12]. The survival motor neuron (SMN) gene usually exists in two copies, SMN1 (telomeric copy) and SMN2 (centromeric copy), which are identical except for five silent nucleotide substitutions [9]. A causal role of SMN1 as the major gene involved in the pathogenesis of SMA is supported by the findings of homozygous deletions or disruptions in more than 95% of SMA patients, and by several different mutations identified in non-deleted SMA chromosomes (see references in [13]). While SMN1 is the major causal factor in the development of the disease, clinical observations [9], [14], [15], [16], [17], [18] and recent studies of a knock-out mouse model [19], [20] have demonstrated a correlation between phenotype severity, the nature of the molecular defect (deletions versus gene conversions), and the number of SMN2 copies present on SMA chromosomes.

Deletions eliminate the whole SMN1 gene [21], [22] and are usually found in patients with the most severe SMA phenotype [14], [15], [22], [23], [24]. In gene conversions, implicated mainly in the milder forms of the disease [14], [21], [22], [24], [25], [26], part of the SMN2 gene is copied into SMN1, whereby the donor gene remains unaffected whereas the acceptor becomes a hybrid SMN1/2 gene [21]. The prevalent genotype/phenotype model predicts that type I patients carry two ‘severe’ alleles with gene deletions, type II patients are compound heterozygotes for a ‘mild’ and a ‘severe’ SMN allele, and type III patients have two ‘mild’- type alleles generated by gene conversions [15], [16], [22], [24], [26]. Epigenetic effects have also been proposed to explain the observed variations in SMA phenotypes [27], [28], [29], [30]

Studies of genetically isolated populations can contribute to understanding the genetic mechanisms and genotype–phenotype correlation in hereditary disorders. In the case of SMA, two such studies report a striking increase in the incidence of the disorder. While the global frequency is estimated at about 1 in 10, 000 live births [31], SMA type I affects 1 in 400 among the Egyptian Karaites [32] and 1 in 1263 in the European population of the Reunion Island [33]. No molecular data have been reported on either population.

Here we present the characterization of spinal muscular atrophy among the Roma (Gypsies) in Bulgaria and Hungary, where both mild and severe SMA phenotypes occur. The common chromosomal background shared by the different gene defects points to their common origin and further diversification of the ancestral SMA allele. Genotype/phenotype correlations are made possible by the genetic homogeneity of this patient population.

Section snippets

Subjects and methods

The affected families were referred by neurological departments and genetic counselling units across Bulgaria and Hungary. The phenotypic findings in all Bulgarian cases were independently reviewed by four clinicians from the team of the Medical University in Sofia, while the Hungarian patients were scored by A.H. Phenotype assignment followed the diagnostic criteria proposed by the International SMA Consortium [3].

The study included a total of 32 Romani families, 24 from Bulgaria and 8 from

Genetic analysis

The analysis of polymorphic markers in the SMA region revealed the existence of three distinct but related disease haplotypes (Table 1) that were associated with different gene defects.

Population genetics

This study is not based on complete ascertainment of all SMA cases in either Bulgaria or Hungary, moreover complete ascertainment is unlikely in the case of affected Romani families, where marginalisation by health care systems can be expected to result in lack of accurate diagnosis of the early severe forms (SMA type I) and low referral rates for the milder cases (types III and IV).

Based on the number of cases included in this study relative to the overall Romani population of each of the two

Acknowledgments

We are grateful to all Romani SMA families for their kind cooperation. We thank Dr Nadja Bogdanova, Institut für Humangenetik, Münster, for providing us with primers and controls for markers C212 and C272. We appreciate the assistance of Dr V. Gergelcheva, Dr S. Tomov, Dr T. Ivanova, Dr D. Konstantinova, Dr M. Veleva, Dr Peteva and Dr I. Ivanov, who referred Gypsy patients for genetic testing. We are also grateful to the Hungarian neurologists Dr A. Lang and Dr E. Halics who referred patients

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