Elsevier

Neuromuscular Disorders

Volume 12, Issue 6, August 2002, Pages 554-557
Neuromuscular Disorders

Facioscapulohumeral (FSHD1) and other forms of muscular dystrophy in the same family: is there more in muscular dystrophy than meets the eye?

https://doi.org/10.1016/S0960-8966(02)00014-7Get rights and content

Abstract

We report on two unrelated Brazilian families with members affected by two different forms of muscular dystrophy. In the first one, the 35-year-old male proband has limb-girdle muscular dystrophy with proximal weakness, elevated creatine kinase and a myopathic muscle biopsy. All the proteins known to be associated with limb-girdle muscular dystrophy were normal. Two of his sisters also complained of muscle weakness. The oldest sister showed clinical signs consistent with facioscapulohumeral muscular dystrophy, confirmed through molecular analysis. She presented a 30 kb EcoRI/BlnI fragment which was found in another six relatives, but surprisingly not in the affected proband or the other sister. In the second family, a 57-year-old male with a typical facioscapulohumeral muscular dystrophy phenotype has a 17 kb EcoRI/BlnI fragment, which was also present in other affected relatives. However in a 14-year-old severely affected male cousin, confined to a wheelchair since age 12, but without facial weakness, the small fragment was absent. These families illustrate the importance of testing all affected individuals in a family.

Introduction

Facioscapulohumeral muscular dystrophy (FSHD1) is an autosomal dominant muscle disorder, mapped to 4q35 [1]. In most patients, probe p13E-11 (D4F104S1) detects a polymorphic EcoRI 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 KpnI unit. It has been suggested that deletions of integral number of these units might affect nearby genes by altering the chromosomal structure, inducing position effect variegation [2]. Since the subtelomeric region of chromosome 10 (10q26) is highly homologous to 4q35, molecular diagnosis is confirmed through the use of the restriction enzyme BlnI, which cleaves only the 10q26 units into small, non-detectable fragments [3]. Clinically, FSHD1 is characterized by progressive weakness of facial, shoulder girdle and upper arm musculature, with occasional lower limb involvement and a remarkable inter and intrafamilial variable expression ranging from asymptomatic carriers to severely affected children.

Limb-girdle muscular dystrophy (LGMD) is also a clinically and genetically heterogeneous disorder, characterized by proximal weakness, ranging from severe childhood to milder adult forms. Fifteen genes, six autosomal dominant (AD), LGMD1A (5q22), LGMD1B (1q11), LGMD1C (3p25), LGMD1D (6q23), LGMD1E (7q) and LGMD1F (5q31) and 9 autosomal recessive (AR), LGMD2A (15q15), LGMD2B (2p13), LGMD2C (13q12), LGMD2D (17q12), LGMD2E (4q12), LGMD2F (5q33), LGMD2G (17q11), LGMD2H (9q31) and LGMD2I (19q13) responsible for LGMD have already been mapped and/or identified [4], [5]. Linkage analysis in Brazilian affected families has shown that there is still further genetic heterogeneity for both AD as well as AR forms [6].

Section snippets

Family 1

The proband (III-12), a 35-year-old Brazilian male was referred to our Center in 1997, with a clinical course suggestive of LGMD. He had progressive weakness of the upper and lower limbs with onset in childhood, diminished reflexes but no facial involvement. He could walk on his toes and heels but had some difficulty in climbing stairs. His family (Fig. 1) comprises seven sisters and five brothers, and his healthy parents (mother aged 69 and father aged 72), are non-consanguineous. His

Discussion

The present families illustrate complicated situations that may occur in the diagnosis and genetic counseling of neuromuscular disorders.

In family 1, individual III-1 although mildly affected, has a clinical course characteristic of FSHD1. If she would be the proband, the diagnosis of FSHD1 would be established and her brother III-12 would be probably classified as having the same disorder. Although he has no facial weakness, FSHD1 4q35 has been reported recently in patients, mostly males,

Acknowledgements

We would like to thank the researchers Rune Frants and Richard Lemmers, who kindly provided the P13E-11 probe. The collaboration of Agnes Nishimura, Andrea Bernardino, Flavia de Paula, Elisangela Quedas and Constancia Urbani are also greatly appreciated. This work is supported by grants from FAPESP-CEPID, CNPq, PRONEx and ABDIM

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