SHORT REPORT ABSTRACT: Dysferlinopathies exhibit marked heterogeneity in the initialdistribution of muscle involvement at the onset of the disease. We describea Japanese patient with dysferlinopathy who exhibited distal anterior com-partment myopathy (DACM) with early contractures of the ankle, whosepedigree included patients with two other types of dysferlinopathy. Theexistence of three phenotypes of dysferlinopathy in one pedigree is reported,indicating the involvement of molecules other than dysferlin in the patho-genesis.

Muscle Nerve 36: 525–527, 2007

DISTAL ANTERIOR COMPARTMENT MYOPATHYWITH EARLY ANKLE CONTRACTURES

HIROSHI SAITO, MD,1 NAOKI SUZUKI, MD,2 HIDEAKI ISHIGURO, MD,1 KOICHI HIROTA, MD,1

YASUTO ITOYAMA, MD,2 TOSHIAKI TAKAHASHI, MD,2,3 and MASASHI AOKI, MD2

1 Department of Neurology, Akita Red Cross Hospital, Akita, Japan2 Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi,

Aoba-ku, Sendai 980-8574, Japan3 Department of Neurology, Nishitaga National Hospital, Sendai, Japan

Accepted 4 May 2007

Dysferlinopathies exhibit marked heterogeneity inthe initial distribution of muscle involvement at theonset of the disease. Because dysferlinopathies in-clude Miyoshi myopathy (MM) and limb-girdle mus-cular dystrophy type 2B (LGMD2B), both of whichhave been observed within the same family, someadditional factors distinct from dysferlin are likely tobe involved in the pathogenesis.15,16 Distal anteriorcompartment myopathy (DACM) is a relatively newphenotype of autosomal-recessive muscular dystro-phy caused by a dysferlin mutation first described byIlla and colleagues.8 We describe a Japanese patientwho exhibited the clinical features of DACM andwhose pedigree included two other types of dysferli-nopathy.

CASE REPORTS

A 42-year-old man (Fig. 1, IV-9, arrow), who hadbeen noted to stumble frequently at 15 years of age,subsequently developed a gait disturbance with tran-sient swelling of the muscles in the lower legs. By 18years of age, lower-limb weakness had progressed

and he could only walk on tip-toes due to an ankledeformity. He also had difficulty in extending hisfingers. At age 29 years, he could not extend hiswrists and fingers fully nor stand without support.His grip strength was about 10 kg. The weakness ofthe lower limbs was pronounced in the anteriortibial muscles, and motor testing revealed grade 2strength in the anterior tibial muscles on the Medi-cal Research Council (MRC) scale, whereas the ili-opsoas, gluteus, quadriceps, hamstrings, and plantarflexors showed moderate weakness (MRC 3). Severemuscle atrophy was present in the peroneal areas ofboth legs. His serum creatine kinase level was 950–1400 U/L. He lost the ability to walk at 34 years ofage. At age 42, all the muscles in the lower extrem-ities (MRC 1–2) and the deltoid, biceps, triceps, andwrist and finger extensors were severely affected(MRC 2), whereas wrist and finger flexors weremildly affected (MRC 4). Tendon reflexes were ab-sent. There was no facial, bulbar, or cardiac muscleinvolvement.

His first cousin (Fig. 1, IV-2) and older sister (Fig.1, IV-5) exhibited the typical features of Miyoshimyopathy, characterized by predominant involve-ment of the posterior compartment of the legs, withonset in the late teens.15 His cousin’s father (Fig. 1,III-1) and cousin’s aunt (Fig. 1, III-3) presented withfeatures of limb-girdle muscular dystrophy with juve-nile-onset pelvic-femoral weakness.12,17 They alsopresented with congenital amblyopia, which was notobserved in other members of the pedigree. This

Abbreviations: DACM, distal anterior compartment myopathy; LGMD, limb-girdle muscular dystrophy; MM, Miyoshi myopathy; MRC, Medical ResearchCouncilKey words: ankle contracture; distal anterior compartment myopathy; dys-ferlin; dysferlinopathy; limb-girdle muscular dystrophy; Miyoshi myopathyCorrespondence to: M. Aoki; e-mail: aokim@mail.tains.tohoku.ac.jp

© 2007 Wiley Periodicals, Inc.Published online 5 July 2007 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20836

Short Reports MUSCLE & NERVE October 2007 525

patient’s older brother (Fig. 1, IV-6) exhibited my-opathy affecting the distal part of the lower limbs.We found degenerative and regenerative changeswithout rimmed vacuoles or myofibrillar formationsin biopsied muscles of IV-2 and III-1. Sensory func-tion was intact in all four patients (III-1, IV-2, IV-5,and IV-9). All ancestors of the family members orig-inated from the same small village. Affected mem-bers of the family (III-1, IV-2, IV-5, and IV-9) wereexamined by the same physician (S.H., T.T., orA.M.).

We tested for the presence of the dysferlin mu-tation in the patients using the single-strand confor-mation polymorphism technique and automatedDNA sequencing15 for each of 55 exons of the gene.2Gene analysis confirmed that all four patients sharedthe same homozygous dysferlin 4870delT mutationpredicted to lead to a stop codon by causing a frame-shift.

DISCUSSION

In the present case, both the site of onset in thetibialis anterior muscle and the rapid progression ofthe lower-limb weakness were similar to the findingsin the DACM cases described by Illa and colleagues.8However, our case had weakness of the wrist andfinger extensor rather than flexor muscles, and earlycontractures of the ankle deformities were a promi-nent and unique feature. In cases presenting earlyankle contracture, DACM should be considered inaddition to X-linked Emery–Dreifuss muscular dys-trophy.4,7 Muscular dystrophy due to the dysferlinmutation has been shown to have at least threedistinct phenotypes (MM, LGMD2B, and DACM)16;

the family studied in this report included all thephenotypes in one pedigree, which further empha-sizes the clinical heterogeneity of dysferlinopathies.We are unaware of other cases of DACM in a non-European ethnic group.

Identical mutations in the dysferlin gene canproduce different myopathy phenotypes even in thesame pedigree as described in the present and otherreports.9,10,12,14,15,17 Why can different phenotypes beproduced from the same mutation and in the samefamily? Dysferlin has a role in membrane repairduring muscle damage.3,6,11 Many molecules areknown to interact with dysferlin.1,5,11,13 We speculatethat the expression levels of these molecules maymodify the severity and distribution of diseaseprogress in dysferlinopathy. The pedigree describedherein may provide clues in elucidating the causes ofthe heterogeneity of dysferlinopathy.

This work was supported by Research Grant (17A-10) for Nervousand Mental Disorders from the Ministry of Health, Labour andWelfare of Japan, and a Grant-in-Aid for Scientific Research(17590857) from the Japanese Society for the Promotion of Sci-ence. The authors thank Professor R. H. Brown, Jr. for usefuldiscussions. We also thank Brent Bell for reading the manuscript.

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FIGURE 1. Pedigree of a Japanese kindred with six patients (3 males and 3 females) affected by muscular dystrophy in the AkitaPrefecture in Japan. Squares: males; circles: females; symbols with diagonals: deceased individuals; solid symbols: members withmuscular dystrophy. A consanguineous marriage was identified between III-6 and III-17. All ancestors of the members originated from thesame small village. The case indicated by the arrow represents the present case of DACM. The patient’s first cousin (IV-2) and older sister(IV-5) exhibited typical features of Miyoshi myopathy, and his cousin’s father (III-1) and his cousin’s aunt (III-3) presented with the featuresof limb-girdle muscular dystrophy. His older brother (IV-6) exhibited distal-dominant myopathy.

526 Short Reports MUSCLE & NERVE October 2007

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