Dysferlinopathy in Iran: Clinical and genetic report

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Highlights

  • •

    This work may help shed some light on the pattern of dysferlinopathy in Iran.

  • •

    Seven patients had distal type, 6 patients proximal type and 2 proximo-distal type.

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    Some patients were previously erroneously diagnosed as polymyositis.

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    The rate of consanguinity was high in this study (7/9 families).

  • •

    We found homozygous mutation of dysferlin gene in 9 probands, 5 of which were new.

Abstract

Background

Dysferlinopathy is caused by a very wide range of autosomal recessively inherited mutations of the Dysferlin gene. It causes a spectrum of muscle diseases including limb-girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy (MM). We describe the clinical course and mutational analyses of 15 Iranian patients with dysferlinopathy from 9 different families.

Methods

Genomic DNA was extracted from peripheral blood and 55 exons and flanking intronic boundaries of the dysferlin gene (DYSF; NM_003494.2) were screened for mutations and analyzed.

Results

From 15 studied patients in 9 families, 5 patients were male. Seven families had consanguineous marriage. Median age of onset was 16.8; and the median age of diagnosis was 26.6. The onset was clearly distal in 7 patients, and proximal in 6 patients. Three patients had partial biceps atrophy and 13 showed prominent calf muscle wasting. Foot plantar flexors, deep finger flexors and hip adductors were predominantly involved. Genetic testing showed homozygous mutation of dysferlin gene in 9 probands, 5 of which were not previously reported.

Conclusion

This work, in fact, may help shed some light on the pattern of this morbidity in Iran, an effort that may have not been attempted so far.

Introduction

Mutations in the gene encoding dysferlin (DYSF; Online Mendelian Inheritance in Man [OMIM] gene number 603009, 2p13, GenBank NM_003494.2) lead to dysferlinopathies which are autosomal recessive muscular dystrophies [1] including limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, and distal anterior compartment myopathy [2], [3]. LGMD2B patients usually vary for pattern of muscle involvement at beginning (distal in Miyoshi dystrophy or proximal in LGMD); but they usually have a rather homogeneous age at onset in the second decade; on the other hand, the rate of disease progression seems to be similar [4]. Initially, nearly one-third of patients present with a diverse clinical manifestation which merges both proximal and distal forms of the lower limbs. It is noticeable that, in every patient, by advanced stages of the disease, all muscles of limb-girdle are involved [1], [5].

The previous reports of hereditary myopathies from Persian population dates back to 1984 for autosomal recessive forms of hereditary inclusion body myopathy type 2 (hIBM2) [6] and afterwards, some other reports have confirmed the high prevalence of this form of distal myopathy among Iranians especially Iranian Jews [7], [8], [9], [10].

Herein, we describe the clinical course and mutational analyses of 15 Iranian patients with dysferlinopathy from 9 different families. To the best of our knowledge, it is seemingly the first report from Iran.

Section snippets

Phenotypical diagnosis

Fifteen patients from 9 families originating from the Iranian descent with the clinical diagnosis of limb girdle muscular dystrophy were recruited. The patients were examined by neurologists in Shariati Hospital affiliated to Tehran University of Medical Sciences.

The clinical diagnosis of dysferlinopathy was made when the patient had muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles which had started in young adulthood and

Results

The clinical and paraclinical findings of the patients as well as genetic mutation are depicted in Table 1. Ten patients (66%) were female; in 12 patients (80%), the first symptom was weakness, in 2 patients it was muscle swelling and in 1 patient pain. The median age of onset in patients was 17 years and the median age of diagnosis was 25 years.

The rate of consanguinity was high in this study (7/9 families) and 5 families had more than one involved cases. Median age of onset was 16.8; and the

Discussion

Dysferlinopathy is a ubiquitous disease seen under every sky and in all ethnicities but found with a higher prevalence in endogamic populations. Like many other autosomal recessive forms of muscular dystrophy, this condition has already been reported in the Middle-East (Palestine, Turkey and Israel), in the Indian subcontinent (India) [12], [13] but not in Iran so far.

In our cohort, we found 5 families with novel mutations; it is significant that the previously reported mutations were from

Acknowledgments

A part of this research was supported by a grant from the Campus France in the program Gundishapur and Center for International Scientific Studies & Collaboration (CISSC) (9303) in Iran. In addition, we thank Mr. Pierre-André Lhôte for his support.

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