engleski

Possible Mechanims Responsible for great Inter and Intra Familial Phenotypic Heterogeneity in FSHD

Presenting: Nina Canki-Klain, M.D., Ph.D. Canki-Klain N.1, 2, Zagar M.2, Lannoy N.3, Verellen-Dumoulin C3 1 Croatian Institute for Brain Research, Zagreb University Medical School 2 Department of Neurology, Zagreb University Hospital Center, Croatia 3 Unité de Génétique Médicale, UCL, Bruxelles, Belgique BACKGROUND FSHD is caused by deletions within a tandem array of D4Z4 repeats on chromosome 4q35. A correlation between repeat contraction and clinical severity is well known. However, a remarkable phenotypic variability of clinical expression between and even within the same family is observed. This can be explained by several known and still hypothetic mechanisms. As illustration we present two unrelated Croatian families. CASE REPORTS The first family consisted in three differently affected members: the proband had infantile onset of muscular weakness, but he was still ambulant at age of 17 years. He was intelligent, very tall (190cm) and thin (51 kg) adolescent with extremely hypotrophic facial, shoulder girdle, upper arm and upper leg muscles, scoliosis, pectus excavatum, pronounced lumbar hyperlordosis, and end-stage Coats disease in the blind right eye since the age of 2 years. His 11-year-old brother had facial weakness since early infancy, showed mild scapular winging and slight lumbar lordosis. He was active in sport and clinically in good condition. Minimally affected 40- year- old mother has facial asymmetry with right side muscular hypotrophy and slight frontal muscle weakness. In both sons, EMG pattern was myopathic, CK was twice normal. There was no hearing loss detected by audiogram. Fluorescein angiography of retina was normal in younger brother. The proband’ s angiogram showed only left eye with very prolonged interval arm-retina (25 sec) and was not adequate for assessment. DNA analysis of both sons and parents were done by Southern blotting using EcoRI and EcoRI/BlnI digested DNA and hybridization with p13E-11. The results have discovered that both sons and their mother have one short EcoRI/BlnI fragment of 12, 0 kb. The second family was presented by a 49- year- old proband from a four generation family in which at least thirteen individuals in three generations were affected. He had moderate sensorineuronal hearing loss, a slowly progressive, late onset weakness of facial, shoulder and pelvic girdle muscles and he was ambulant. His all three children: 25-year-old daughter, 21-year-old son and 10- year- old daughter had very mild symptoms without functional impairment. Proband's 53- year-old brother had classical but slowly progressive form of FSHD. His 25-year-old daughter showed only mild facial weakness and his 21-year-old son (not examined) would have some moderate muscular weakness. In proband’ s both parents families hearing loss was noticed. Southern blot analysis using probe p13E-11 showed in probands and his 53-year-old brother two shortened fragments of 35 kb and 32 kb. Proband’ s 25- year-old daughter as well as his 21-year-old son had a fragment of 32 kb and one normal fragment. The 10- year-old daughter was not tested even she had mild disease’ s symptoms. Very mildly affected daughter of older brother had one normal allele and the other with short fragment of 35 kb. DISCUSSION To explain the observed inter and intra familial heterogeneity in presented families different genetic and epigenetic mechanisms can be raised: A correlation between repeat contracture and clinical severity is well known. Possible maternal mosaicism in first family, which was not excluded by pulse field electrophoresis. In addition maternal family history seems negative for FSHD. To explain severe infantile form in older brother and relatively mild form at age of 11 in younger (follow up was not available) could be explained by hypothetical modifier genes and epigenetic disease mechanism (S.M. van der Maarel, 13th WMS, 2008) explained by compound heterozygous patients for short deleted alleles and their progeny with only one short deleted allele. Although such families seem to be very rare, accurate molecular study are needed to confirm this hypothesis. It is interesting to mention that the size and number of D4Z4 alleles play a role in FSHD phenotype (G.Faabri et al., 13th WMS, 2008) who hypothesizes that the more severe clinical expression of the disease observed in compound heterozygotes might be related to transcriptional depression of genes at 4q35 occurring at both deleted D4Z4 alleles, supporting the current model for FSHD.

Facioscapulohumeral muscular dystrophy (FSHD); possible mechanims; phenotypic heterogeneity

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