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Distal Myopathies Curr Neurol Neurosci Rep (2014) 14:434 DOI 10.1007/s11910-013-0434-4 NERVE AND MUSCLE (L WEIMER, SECTION EDITOR) Distal Myopathies Bjarne Udd Published online: 30 January 2014 # Springer Science+Business Media New York 2014 Abstract Advanced molecular genetic possibilities have myopathy to chromosome 14 in an Australian family [1]. The made it possible to clarify and delineate an ever growing history before molecular genetics includes clinical descrip- number of distinct new disease entities in the group of distal tions of four different distal myopathies occurring in multiple myopathies. These diseases share the clinical features of pref- families: autosomal dominant Welander distal myopathy erential muscle weakness in the feet and/or hands, and as they (WDM) [2], recessive Miyoshi myopathy [3, 4], recessive are genetic disorders that lead to progressive loss of muscle distal myopathy with rimmed vacuoles (Nonaka, DMRV) tissue they can also be called distal muscular dystrophies. [5], and dominant tibial muscular dystrophy (Udd, TMD) More than 20 entities are currently identified and many are [6]. In addition to these, a few disorders described later in still waiting for genetic characterisation. No final diagnosis single families also proved to represent separate entities by can be made on other grounds than by the molecular genetic molecular genetics: early adult-onset dominant distal myopa- defect. Besides the usual investigations, including electromy- thy [7] and late-onset dominant distal myopathy [8] (Table 1). ography and muscle biopsy, muscle imaging is very important All these entities currently have their causative gene iden- in defining the precise pattern of muscle involvement. Based tified: dysferlinfor MM in 1998 [9, 10], desminin the Milhorat on the combination of age at onset, mode of inheritance, family 1998 [11], C-terminal mutations in M-line titin as the pathology and muscle imaging, the list of possible underlying cause of TMD in 2002 [12, 13], mutations in GNE for DMRV genes can be tracked down to minimal number allowing for the same year [14, 15], mutations in slow myosin MYH7 for specific genetic testing. Laing myopathy in 2004 [16], ZASP mutations responsible for Markesbery–Griggs myopathy in 2007 [17] and TIA1 muta- Keywords Distal myopathy . Distal muscular dystrophy . tion in WDM in 2013 [18, 19••]. Classification . Molecular genetics . Pathogenesis . Recent developments have increased the number of sepa- Diagnostics . MRI . Muscle pathology rate diseases identified by molecular genetics to more than 20 different entities [20••]. For clinicians, this means more de- manding diagnostic challenges requiring an updated classifi- cation and differential diagnostic algorithms to increase the Introduction possibilities of reaching a final genetic diagnosis for the patient. Moreover, distal muscle weakness and atrophy fre- In the distal myopathies the molecular genetic era started in quently occurs in other disorders, which needs to be consid- 1995 with linkage of an early-onset autosomal dominant distal ered in the differential diagnostic work-up (Table 2). This article is part of the Topical Collection on Nerve and Muscle B. Udd (*) Neuromuscular Research Center, Tampere University and University Clinical Classification Hospital, Tampere, Finland e-mail: [email protected] Late Onset Autosomal Dominant Distal Myopathies B. Udd Folkhalsan Institute of Genetics, Department of Medical Genetics WDM and Haartman Institute, University of Helsinki, Helsinki, Finland B. Udd Index finger extension weakness is usually the first symptom Department of Neurology, Vasa Central Hospital, Vasa, Finland and sign, followed by extension deficit in the other fingers. 434, Page 2 of 9 Curr Neurol Neurosci Rep (2014) 14:434 Table 1 Distal myopathies with identified genetic cause Gene Protein 1. Late adult-onset autosomal dominant forms a. Welander distal myopathy TIA1 TIA1 b. Tibial muscular dystrophy (Udd myopathy) TTN Titin c. Distal myotilinopathy TTID Myotilin d. ZASPopathy (Markesbery–Griggs) LDB3 ZASP e. Matrin3 distal myopathy (VCPDM, MPD2) MATR3 Matrin3 f. VCP-mutated distal myopathy VCP VCP g. Alpha-B crystallin-mutated distal myopathy CRYAB αB-crystallin 2. Adult-onset autosomal dominant forms a. Desminopathy DESM desmin b. Distal ABD-filaminopathy FLNC Filamin-C 3. Early-onset autosomal dominant forms a. Laing distal myopathy (MPD1) MYH7 beta-MyHC b. KLHL9 mutated distal myopathy KLHL9 KLHL9 —————————————————————————— 4. Early onset autosomal recessive forms a. Distal nebulin myopathy NEB Nebulin 5. Early adult-onset autosomal recessive forms a. Miyoshi myopathy DYSF Dysferlin b. Distal anoctaminopathy ANO5 Anoctamin-5 c. Distal myopathy with rimmed vacuoles (GNE-myopathy) GNE GNE ABD actin binding domain Wrist flexor weakness, atrophy of hand muscles, and weak- upper limbs, but in the lower leg muscles with later involve- ness in toe and ankle extensors are usually the next steps in the ment of the hands. Neuropathic sensory involvement has been disease evolution. Most patients have onset of weakness in the suggested, but definite neuropathy has not been confirmed by fifth–sixth decade, but there are also earlier or later onsets. A electrophysiology measurements [21]. Disease progression is minority of patients do not have onset of weakness in the very slow; patients remain ambulatory and have a normal life span. The main disability relates to hand weakness and foot Table 2 Other muscle diseases that may present with a distal phenotype drop. Electromyography (EMG) reveals myopathic changes in the target muscles and creatine kinase (CK) levels are 1. FSHD normal or slightly elevated. Muscle biopsy taken from a target 2. Nemaline myopathy muscle, such as tibialis anterior, shows rimmed vacuoles with 3. DNM2-mutated centronuclear myopathy degenerated atrophic fibres. Muscle imaging of lower limbs 4. HMERF titinopathy by magnetic resonance imaging (MRI) is useful and shows 5. DNAJB6-mutated LGMD1D advanced fatty degenerative changes in the anterior compart- 6. Myotonic dystrophy type 1 ment of the lower legs, but also marked involvement of 7. Metabolic myopathies posterior calf muscles, despite good plantar flexion [22]. a. Branching glycogenosis b. Debrancher glycogenosis Molecular Pathology The genetic defect causing WDM has c. Phosphorylase b kinase deficiency recently been identified as a missense mutation in the TIA1 d. PNPLA2 lipidosis gene [19••]. As expected from previous linkage studies [18] 8. Caveolinopathy there is one single founder mutation accounting for the disease 9. Telethoninopathy in the Scandinavian families linked to chromosome 2p13. One 10. Sporadic inclusion body myositis UK family proved to have the same mutation on the same 11. Scapuloperoneal syndromes haplotype, suggesting remote ancestry [19••]. TIA1 is an 12. Nephropathic cystinosis RNA binding protein involved in regulation of translation via 13. Amyloid myopathy (myeloma-induced) splicing machinery and protein complexes called stress gran- 14. POLG1 mitochondrial myopathy ules capable of halting transcripts from translation; the mutation FSHD facioscapulohumeral muscular dystrophy causes alteration of the stress granule dynamics [19••]. Curr Neurol Neurosci Rep (2014) 14:434 Page 3 of 9, 434 Epidemiology The numbers of the patients in Sweden and Epidemiology TMD is a very common muscle disease in Finland are in the hundreds, but so far molecularly diagnosed Finland with a prevalence of 20/100,000, whereas only rare patients outside Sweden and Finland are very rare. families are known in other countries [20••, 26–29]. TMD (Udd Myopathy) ZASPopathy (Markesbery–Griggs Late-Onset Distal Myopathy) In contrast to WDM this disease does not involve the upper limbs. There is insidious onset of decreased ankle dorsiflexion The disease has a late onset, with ankle weakness after the age typically after the age of 35–40 years. Later onset after the age of 40–50 years. The slow progression later involves weakness of 60 years may occur and in so far exceptionally rare reces- of finger and wrist extensors, with moderate muscle atrophy. sive forms the onset may be earlier, after the age of 20 years, Proximal limb muscle weakness is a late feature and may cause but childhood onset forms are not known. Asymmetric weak- loss of walking capacity after 15 or 20 years’ disease duration in ness for many years is not unusual. In the typical patient severe cases. CK levels are usually slightly elevated. moderate proximal weakness of lower limbs, mainly in the Cardiomyopathy and heart block have been reported late in hamstring muscles, occurs after the age of 65–70 years, and the disease course and may require a pacemaker [8]. Muscle patients remain ambulant. Extensor digitorum brevis and hand MRI reveals early fatty degenerative changes in medial gastroc- muscles are spared [6]. Variations of the phenotype are ob- nemius and soleus. Later on, all lower leg muscles are severely served even within a family [22, 23]. Muscle MRI is very involved, while proximal lower limb muscles show mild or helpful with highly selective fatty degeneration in the anterior moderate involvement. Muscle biopsy shows extensive myofi- compartment muscles of the lower legs starting in tibialis brillar abnormalities with dark and hyaline structures in anterior (Fig. 1). Hamstring and gluteus minimus muscles trichrome stain. These correspond to myofibrillar disintegration are involved later, and focal changes can be observed in other on EM and protein aggregations on immunohistochemistry,
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