[Clinical and molecular diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) in 2012.]
ABSTRACT Diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) is supported by a suggestive clinical presentation and associated with a heterozygous contraction of the D4Z4 repeat array on chromosome 4q35.
The FSHD1 phenotype has a widely variable course with great inter- and intrafamilial heterogeneity. Three clinical forms can be distinguished: the classical phenotype associated with four to seven repeat units (RU) and a variable course, a severe infantile form with one to three RU, and a mild phenotype associated with borderline UR (8 to 10 RU). At the molecular level, for D4Z4 contraction to be pathogenic, it needs to occur on a specific chromosomal background, namely on the 4qA allelic variant of chromosome 4. In most cases, once FSHD is clinically suspected, the diagnosis can be genetically confirmed with a DNA test using Southern Blotting and hybridization to a set of probes. However, diagnosis of FSHD1 remains challenging. Firstly, some patients may present with an atypical phenotype with highly focal or unusual symptoms. Secondly, there are potential pitfalls in the genetic diagnosis of FSHD resulting in false positive or false negative results. In the absence of genetic confirmation, other investigations, mainly EMG and muscle biopsy, are needed to rule out another diagnosis. In cases with no clear diagnosis and a permissive chromosome without contraction, FSHD2 may be suspected.
Molecular combing is a new technique which permits visualization and sizing of the D4Z4 repeat array on its genetic background on stretched single DNA fibers by fluorescence microscopy. This tool will improve genetic diagnosis in FSHD patients.
Diagnosis of FSHD1 is mainly supported by clinical features. Clinicians need to be aware of unusual presentations of this disease. The wide spectrum of intrafamilial variability and the lack of good correlation between genotype and phenotype present challenges for genetic counseling and prognostication. More studies are needed concerning penetrance and genotype-phenotype correlation.
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ABSTRACT: Because of occasional reports of exudative retinal detachment with facioscapulohumeral muscular dystrophy (FSH) and deafness, we sought to determine by fluorescein angiography whether there is any general relationship between FSH muscular dystrophy and retinal vascular disease. Peripheral retinal capillary abnormalities, comprising telangiectasis, closure, leakage and microaneurysm formation, were demonstrated by angiography in 56 out of 75 individuals with clinical or genetic evidence of FSH. Only 3 patients had relevant ophthalmoscopic abnormalities of the posterior pole and in only 1 was there consequent visual loss. This study included one FSH family in which the propositus was treated for exudative retinopathy and 13 other subjects had telangiectasis, and 8 cases (including 3 parents of apparently 'sporadic' FSH cases) in which fluorescein angiography confirmed the abnormal genotype, even though clinical examination of skeletal muscle revealed no clear abnormality. There was no correlation between the severity of the muscle disease and the extent of the retinal vascular abnormality. Visual complications of telangiectasis, although rare, may present early in life and before there is overt evidence of muscle disease. Since visual loss may be preventable, ophthalmic examination should be undertaken on infants at risk of having the abnormal gene. The findings support the hypothesis that retinal capillary abnormalities are an integral part of the FSH muscular dystrophy syndrome and raise the question as to whether analogous capillary abnormalities could be implicated in the pathogenesis of FSH muscle disease.Brain 07/1987; 110 ( Pt 3):631-48. DOI:10.1093/brain/110.3.631 · 10.23 Impact Factor
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ABSTRACT: Acid maltase deficiency (AMD) is a rare cause of muscle disease in adult patients. The present report of 2 sibs and review of 36 previously reported cases illustrates the vast clinical variability in adult-onset AMD. This is 1 of only 3 reports to document tongue weakness and enlargement in an adult with AMD. The presenting signs and symptoms usually include progressive limb weakness, restrictive lung disease, or both. Consistent supportive abnormalities include a modest elevation in serum CK, a reduction in the forced vital capacity, and abnormal spontaneous activity (that is, myotonic discharges or fibrillations) in resting muscles during needle electromyography. The clinical spectrum is also extended to include distal limb weakness, scapular winging, asymmetric muscle weakness, and tongue involvement.Medicine 06/1995; 74(3):131-5. · 4.87 Impact Factor
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ABSTRACT: In facioscapulohumeral muscular dystrophy (FSHD), the wide range of clinical severity observed both within and between families has obscured past attempts to identify any phenotypic differences between families from which phenotype-genotype correlation could proposed, although it is noted that age at onset is youngest and severity greatest in isolated cases. From 14/16 large 4q35-linked FSHD families, and 25/34 isolated cases exhibiting a de novo D4F104S1 DNA fragment, we find a significant correlation between proband age at onset and FSHD-associated D4F104S1 fragment size (r = 0.56; p < 0.001), with the smallest fragments occurring in isolated cases. A similar correlation (r = 0.70; p < 0.01) with fragment size is observed for age to loss of ambulation in 16 subjects using a wheelchair. We find also that age at onset appears younger with successive generations in the 4q35 families. We propose that fragment size at D4F104S1, together with a possible generational effect, accounts for a significant part of the wide phenotypic variation in FSHD. Our results predict a more limited range for severity within families, and in one family with a 4q35-linked 38kb fragment support scapulohumeral presentation without facial involvement as a late onset variant of FSHD. We propose that in FSHD, quantitative variation in a uniform mutation mechanism influences age at onset, but by deletion rather than expansion of DNA.Human Molecular Genetics 06/1995; 4(5):951-8. DOI:10.1093/hmg/4.5.951 · 6.68 Impact Factor