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High Frequency of Atypical Phenotypes

Karine Nguyen, MD; Guillaume Bassez, MD; Martin Krahn, MD; Rafaelle Bernard, MD; Pascal Laforêt, MD; Véronique Labelle, BSc; Jon Andoni Urtizberea, MD; Dominique Figarella-Branger, MD, PhD; Norma Romero, MD; Shahram Attarian, MD; France Leturcq, PhD; Jean Pouget, MD; Nicolas Lévy, MD, PhD; Bruno Eymard, MD, PhD

Arch Neurol. 2007;64(8):1176-1182.

Objective  To describe the phenotypic spectrum of dysferlin (DYSF) gene mutations (which cause dysferlinopathies, autosomal recessive muscular dystrophies) in patients with a dysferlin protein deficiency.

Design  Clinical, biological, and pathological data from 40 patients were reviewed. The diagnosis of dysferlinopathy was based on the absence or strong reduction of dysferlin in muscle, and confirmed by mutational screening of the DYSF gene.

Setting  Two French neuromuscular diseases centers (in Paris and Marseilles).

Results  Two main dysferlinopathy phenotypes are well recognized: Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. Typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B were found in 20 (50%) patients only. Unusual phenotypes included a mixed phenotype, referred to as "proximodistal," combining distal and proximal onset in 14 (35%) patients, pseudometabolic myopathy in 4 (10%), and asymptomatic hyperCKemia (an increased serum creatine kinase level) in 2 (5%). The disease may worsen rapidly, and 10 (25%) patients were initially misdiagnosed as having polymyositis. We suggest a relationship between proximodistal phenotype, inflammation, and severity.

Conclusion  In addition to typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B, dysferlinopathies are a clinically heterogeneous group of disorders ranging from asymptomatism to severe functional disability.

Author Affiliations: Département de Génétique Médicale (Drs Nguyen, Krahn, Bernard, and Lévy and Ms Labelle), Laboratoire d’Anatomopathologie (Dr Figarella-Branger), and Service de Neurologie et Maladies Neuromusculaires (Drs Attarian and Pouget), Assistance Publique–Hôpitaux de Marseille, Hôpital Timone, Marseille; Institut de Myologie, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris (Drs Bassez, Laforêt, Romero, and Eymard); Consultation Neuromusculaire, Assistance Publique–Hôpitaux de Paris, Hôpital Henri Mondor, Créteil (Dr Bassez); Consultation Neuromusculaire, Assistance Publique– Hôpitaux de Paris, Hôpital Marin, Hendaye (Dr Urtizberea); Laboratoire de Biochimie et Génétique, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris (Dr Leturcq); and INSERM U491: "Génétique Médicale et Développement," Faculté de Médecine Timone, Marseille (Dr Lévy), France.

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