Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD)

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Abstract

Facioscapulohumeral muscular dystrophy is an autosomal dominant muscle disorder, mapped to 4q35. It is characterized by remarkable inter- and intrafamilial clinical variability ranging from severe phenotype to asymptomatic carriers. The aim of the present study was to assess the size of the Eco RI fragment in a large sample of asymptomatic or minimally affected carriers as well as symptomatic patients, comparing both sexes, in order to verify if asymptomatic carriers are randomly distributed or concentrated in some particular families and if there is preferential parental transmission (maternal or paternal) resulting in non-penetrant carriers. We have analysed a total of 506 individuals from 106 unrelated families with at least one affected facioscapulohumeral muscular dystrophy proband. In all patients the molecular diagnosis was confirmed following double digestion (Eco RI/Bln I fragment <35 kb). About 20% among probands' relatives who were found to carry the small fragment were asymptomatic or minimally affected, without preferential parental transmission, but with a significantly higher proportion of females (n=37) than males (n=14). Although asymptomatic carriers were found in about 30% of the families, some genealogies seem to concentrate more non-penetrant cases. A significant correlation between the size of the Eco RI fragment and severity of the phenotype was observed in the total sample but surprisingly this correlation is significant only among affected females. The gender difference in clinical manifestation as well as the observation that asymptomatic carriers are not rare should be taken into consideration in genetic counseling of affected patients or ‘at-risk’ relatives.

Introduction

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder, mapped to 4q35 [1]. In most patients, probe p13E-11 (D4F104S1) detects a polymorphic Eco RI fragment smaller than 35 kb, which has 35–300 kb in normal individuals, and consists of multiple copies of a tandemly repeated 3.3 kb Kpn I unit. This unit has been termed D4Z4. The 4q35 region is highly homologous to the subtelomeric region of chromosome 10 (10q26) and molecular diagnosis is confirmed through the use of the restriction enzyme Bln I, which cleaves only the 10q26 units into small, non-detectable fragments [2]. The molecular mechanism that causes FSHD has been investigated for a long time. It had been suggested that deletions of integral number of the chromosome 4 units might affect nearby genes by altering the chromosomal structure, inducing position effect variegation. Recently, Gabellini et al. [3] reported an overexpression of genes upstream of D4Z4 in FSHD patients, which would be caused by the inappropriate transcriptional derepression of 4q35 genes inversely to deletion size. A polymorphic segment, distal to D4Z4, has also been found by Lemmers et al. [4], with two alleles: 4qA and 4qB. These authors observed that while in control individuals both alleles are equally present, only the 4qA allele is associated with FSHD. Clinically, FSHD is characterized by progressive weakness of facial, shoulder girdle and upper arm musculature. Lower limb involvement is not rare but there is a remarkable inter and intrafamilial variable expression ranging from asymptomatic carriers to severely affected cases.

Understanding the clinical variability in FSHD remains a great challenge. A correlation between the size of the Eco RI fragment and clinical course has been observed in several studies with severe phenotypes being often associated with the smallest fragments [5], [6], [7], [8].

On the other hand, the existence of abortive or partially affected cases as well as the gender difference in clinical manifestation has been recognized a long time ago [9], [10]. However, we are not aware of any publication focusing mainly on asymptomatic or minimally affected carriers or gender differences in patients characterized at the molecular level. We have previously observed in Brazilian FSHD families a significantly greater proportion of females than males who remain asymptomatic or who are minimally affected [11]. Understanding the molecular mechanism, which protects some individuals who carry the FSHD fragment from clinical manifestation, is of utmost interest.

Therefore the aim of the present study was to: (a) assess the size of the Eco RI fragment in a large sample of asymptomatic or minimally affected carriers from FSHD families as well as symptomatic patients, comparing both sexes; (b) to verify if asymptomatic carriers are randomly distributed or concentrated in some particular families; (c) to verify if there is a preferential parental transmission (maternal or paternal) resulting in non-penetrant carriers.

In order to address these issues we have analysed and measured the size of the Eco RI fragment in a large sample of FSHD patients with a variable phenotype ranging from severely affected to asymptomatic.

Section snippets

Patients and methods

Patients from 106 unrelated families with at least one affected FSHD proband, referred to the Human Genome Research Center at the University of São Paulo, were analysed. The probands and the at-risk relatives were clinically and neurologically examined by the same team, who have been working in our center for more than one decade. FSHD diagnosis was confirmed in all of them through molecular analysis. The clinical classification in the three clinical groups was done before the results of the

Results

A total of 506 individuals from 106 unrelated families with at least one affected FSHD proband were analysed. Molecular analysis revealed that 238 individuals carried a small Eco RI/Bln I fragment, with no gender differences (113 males and 125 females, χ2=0.61; P>0.05; 1 d.f.). Among these 238 individuals 7 (1 male and 6 females) were mosaic and classified in group 1. As seen in Table 1, the majority of the patients (n=145; 61%) had the classical phenotype. Although in this group there were more

Eco RI fragment size and clinical course

The significant correlation between the mean sizes of the Eco RI fragment and clinical severity in the total sample observed in the present study is in accordance with previous data [5], [6], [7], [8], [11]. However, surprisingly, when both sexes were analysed separately, the correlation was significant only for females.

It is noteworthy that a highly significant correlation between the deletion size and the severity of the phenotype was also observed only for females in spinal muscular

Acknowledgements

The collaboration of the following persons is gratefully acknowledged: Dr Rune Frants and Richard Lemmers who kindly provided the P13E-11 probe and Dr Silvere van der Maarel, from the University of Leiden; Agnes Nishimura, Flavia de Paula, Kikue Abe and Constancia Urbani. Special thanks to all patients who collaborated in this study. This work is supported by grants from FAPESP-CEPID, CNPq, PRONEX, CAPES.

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