Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes?

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Abstract

We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed in medical records. Molecular examination of genomic DNA showed no expansion of the unstable (CTG)n trinucleotide repeat on chromosome 19q13.3 associated with myotonic dystrophy (DM). Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel (CLCN1) gene, and the muscle sodium channel (SCN4A) gene, was assessed and excluded. The clinical findings differ from those described in proximal myotonic myopathy (PROMM), in terms of the more severe muscle involvement with atrophy of affected muscles and the hearing loss. These findings suggest phenotypic and probably genetic heterogeneity among the proximal myotonic syndromes.

Introduction

Myotonic dystrophy (DM) is an autosomal dominant (AD) multi-systemic disease characterised primarily by the combination of myotonia and progressive dystrophy of the distal skeletal muscles [1]. The mutation underlying DM has been identified as an unstable (CTG)n trinucleotide repeat in the 3′ untranslated region of a gene encoding a protein kinase, designated as DM protein kinase (DMPK) 2, 3, 4. The vast majority of patients (≥98%) with the classical manifestations of DM show an abnormal expansion of this repeat on chromosome 19q13.3. The size of the expansion generally increases through successive generations and correlates to a reasonable degree with the observed anticipation of the clinical phenotype in a given family [5].

Recently, an increasing number of syndromic myotonic myopathy patients with proximal rather than distal muscle involvement, previously usually considered atypical DM cases, have been reported to have no (CTG)n expansion 6, 7, 8, 9, 10, 11, 12. For one such group of patients, proximal myotonic myopathy (PROMM), has been considered a separate entity 10, 13. The underlying genetic defect(s) is still unknown. Disorders with a phenotype similar to DM, but without (CTG)n expansion may exist as well [12].

The patients in the family we present here show many features similar to those found in PROMM, including proximal muscle weakness, cataracts, and electrophysiologically detectable myotonia. Unlike PROMM patients, however, they do not report myalgias, symptomatic myotonia, or muscle stiffness. Instead they present traits not present in PROMM, such as pronounced dystrophic-atrophic changes in the proximal muscles and late-onset progressive deafness. The patients usually die of cardiovascular, atherosclerotic disease. These findings suggest that myotonic syndromes with proximal muscle weakness may in fact be a set of heterogeneous disorders.

Section snippets

Patients and methods

The family presented originates from Björkö Island in the Gulf of Bothnia off the west coast of mid-Finland (Fig. 1, inlet). The family history was obtained from the patients and their examined relatives. Archival medical records of 12 deceased family members were assessed. Four patients and all seven available first-degree and seven other close relatives were clinically examined by one of the authors (BU) (Fig. 1, pedigree). Otological consultation in four patients and 13 relatives included an

Patient III-1

The patient was referred to the hospital for examinations of glaucoma at age 47. Two years later, examinations were continued in the neurological department because of muscle weakness he had experienced for some years already. At age 45 he had suffered a transient right sciatic radiculopathy problem. Clinically his gait was unaffected with well preserved walking, both tip-toe and on his heels. All tendon reflexes were present, but rising from low chairs and neck flexion were impaired. He also

Discussion

The patients in this family had proximal muscular dystrophy with onset of muscle weakness around age 30. Myotonic bursts were recorded at electrophysiological examinations, despite the absence of clinical myotonia. The muscle weakness was non-fluctuant and progressive over time, leading to major disability after the age of 55–60 years. At age 40–45, patients also developed progressive DM-like cataracts and hearing loss, which required surgical removal and hearing aids, respectively.

Acknowledgements

Continuous support by Professor Albert de la Chapelle, Department of Medical Genetics, University of Helsinki, is gratefully acknowledged. Dr Matti Raivio, Dr Outi Strömsholm, Dr Leo Keski-Nisula, Dr Markku Nieminen, and Dr Risto Niemi, all from Vasa Central Hospital, are acknowledged for their advanced help in performing the audiological, ophthalmological, radiological/imaging, electrophysiological and physiological studies, respectively. Technical assistance by Riitta Lehtinen, and friendly

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