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Neuromuscular Disorders 22 (2012) 5–12 www.elsevier.com/locate/nmd Review Distal myopathies – New genetic entities expand diagnostic challenge

Bjarne Udd ⇑

Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland Folkhalsan Institute of Genetics, Department of Medical Genetics and Haartman Institute, University of Helsinki, Finland Department of Neurology, Vasa Central Hospital, Vasa, Finland

Received 19 August 2011; received in revised form 2 October 2011; accepted 4 October 2011

Abstract

Distal myopathies are a group of muscle diseases which share the clinical pattern of predominant weakness in the feet and/or hands. Rapid advance in the understanding of underlying gene defects have to date separated more than 20 distinct disorders and many are yet without genetic characterisation. No definite diagnosis can be made on other grounds than identification of the final molecular genetic defect. Besides usual investigations including EMG and muscle biopsy, muscle imaging is very important in defining the precise pattern of muscle involvement. Based on the combination of age at onset, mode of inheritance, pathology and muscle imag- ing, the number of underlying candidate genes for a certain disease can be significantly reduced, which is of help for the molecular genetic approach. Ó 2011 Elsevier B.V. All rights reserved.

Keywords: Distal myopathy; Muscular dystrophy; MRI; Molecular genetics

1. Introduction soon followed: MM [9], DMRV [10], TMD [11], and WDM [12]. Subsequently the responsible genes and Four different distal myopathies had been clinically mutations in encoded proteins were identified: dysferlin described before the new era of molecular genetics: autoso- for MM in 1998 [13], desmin in the Milhorat family mal dominant Welander distal myopathy (WDM) [1], 1998 [14], C-terminal mutations in M-line titin as the recessive Miyoshi myopathy (MM) [2,3], recessive Distal cause of TMD in 2002 [15], mutations in GNE for myopathy with rimmed vacuoles (Nonaka, DMRV) [4], DMRV the same year [16], mutations in slow myosin and dominant Tibial muscular dystrophy (Udd, TMD) MYH7 for Laing myopathy 2004 [17], and ZASP muta- [5]. Comprehensive descriptions of a few single families tions responsible for Markesbery–Griggs myopathy 2007 also represented different entities: early adult onset domi- [18]. nant distal myopathy (Milhorat and Wolff) [6], late onset New distal myopathies have expanded the list of dominant distal myopathy (Markesbery–Griggs) [7]. separate diseases by molecular genetics to more than 20 dif- Molecular genetics has proved these all being caused by ferent entities. The extensive developments prompt for an different genes (Table 1). updated classification of the distal myopathies and for dif- The advance in molecular genetics started in the 1990s ferential diagnostic algorithms to help the clinician identify with linkage in an Australian family with early-onset the genetically determined forms (Figs. 2A and 2B). In autosomal dominant distal myopathy (MPD1) [8]. Others addition, distal muscle weakness and atrophy is frequently the presenting symptom and sign in other disorders, char- acterized and classified on other ground by different terms, ⇑ Address: Department of Neurology, Vasa Central Hospital, Vasa, Finland. Tel.: +358 3 31169169; fax: +358 6 3232888. which need to be considered in the differential diagnostic E-mail address: Bjarne.udd@netikka.fi approach (Table 2).

0960-8966/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2011.10.003 6 B. Udd / Neuromuscular Disorders 22 (2012) 5–12

Table 1 Genetically determined distal myopathies. Gene Protein Ref. 1. Late adult onset autosomal dominant forms a. Welander distal myopathy nd nd Welander [1] b. Tibial muscular dystrophy (TMD, Udd myopathy) TTN Titin Udd et al. [5] c. Distal myotilinopathy TTID Myotilin Penisson-Besnier et al. [30] d. ZASPopathy (Markesbery–Griggs) LDB3 ZASP Griggs et al. [18] e. Matrin3 distal myopathy (VCPDM, MPD2) MATR3 Matrin3 Senderek et al. [35] f. VCP-mutated distal myopathy VCP VCP Palmio et al. [36] g. Alpha-B crystallin mutated distal myopathy CRYAB aB-crystallin Reichlich et al. [38] 2. Adult onset autosomal dominant forms a. Desminopathy DES Desmin Sjo¨berg et al. [14] b. Distal ABD-filaminopathy FLNC Filamin-C Duff et al. [42] c. Finnish-MPD3 nd nd Mahjneh et al. [57] d. Italian 19p13-linked distal myopathy nd nd Servidei et al. [55] e. US-Polish family nd nd Felice et al. [56] f. Oculopharyngeal distal myopathy, OPDM nd nd Durmus et al. [54] 3. Early onset autosomal dominant forms a. Laing distal myopathy (MPD1) MYH7 Beta-MyHHC Laing et al. [8] b. KLHL9 mutated distal myopathy KLHL9 KLHL9 Cirak et al. [46] 4. Early onset autosomal recessive forms a. Distal nebulin myopathy NEB Nebulin Wallgren-Pettersson al. [47] 5. Early adult onset autosomal recessive forms a. Miyoshi myopathy (MM) DYSF Dysferlin Miyoshi et al. [2] b. Distal Anoctaminopathy ANO5 Anoctamin-5 Bolduc et al. [52] c. Distal myopathy with rimmed vacuoles (DMRV) GNE GNE Nonaka et al. [4] d. Oculopharyngeal distal myopathy, OPDM nd nd Durmus et al. [54] 6. Adult onset autosomal recessive form a. Calf myopathy non-DYSF/ANO5 nd nd Linssen et al. [59]

2. Disease manifestations and findings useful in clinical 2.1.1.2. Molecular genetics. Welander distal myopathy is practice linked to chromosome 2p13 [12]. The locus is close to, but outside of the dysferlin gene. So far no mutations have 2.1. Late onset autosomal dominant distal myopathies been reported. In Scandinavian patients, a common founder haplotype can be identified over the linked locus, 2.1.1. Welander distal myopathy which to some extent can be used for molecular genetic Weakness typically starts in index finger and wrist exten- diagnostics. sors usually in the fifth–sixth decade, followed by atrophy of thenar and intrinsic hand muscles. Finger and wrist flex- 2.1.2. Tibial muscular dystrophy (TMD, Udd myopathy) ors and weakness in toe and ankle extensors may develop Weakness starts with decreased ankle dorsiflexion usu- after several years, although some patients have onset of ally typically after age 35–40, but late onset after age 60 weakness in the lower leg muscles. Some sensory involve- may occur. Weakness can be asymmetric for years. Some ment because patients may complain of cold fingers have proximal weakness in lower limbs is present in the eight been suggested but neuropathy has not been confirmed decade; most patients remain ambulant. Extensor digito- [19]. The progression is slow and patients have a normal rum brevis and hand muscles are spared [21]. As with other life expectancy, while losing their fine motor hand skills. dominant diseases variations are observed even within the CK levels are slightly elevated. Muscle pathology is family [22]. CK is slightly elevated. Muscle MRI shows rimmed vacuolar with degenerated fibers leading to end- highly selective fatty degeneration in lower leg anterior stage loss of muscle fibers in affected muscles. Muscle compartment muscles starting in tibialis anterior MRI is informative, with considerable involvement of pos- (Fig. 1A). Later, hamstring and gluteus minimus muscles terior calf muscles besides fatty degenerative changes in the are involved and focal changes may occur in soleus and anterior compartment (Fig. 1C) [20]. medial gastrocnemius [23]. Muscle biopsy in the target muscle tibialis anterior muscle show rimmed vacuolated 2.1.1.1. Epidemiology. So far definitely diagnosed patients and rare necrotic fibers progressing over time to total end- were identified only in Sweden and Finland. stage pathology. B. Udd / Neuromuscular Disorders 22 (2012) 5–12 7

Fig. 1B. MR/CT imaging of fatty degenerative change in lower leg muscles. Genes causing predominant involvement of posterior compart- ment calf muscles: gastrocnemius medialis, gastrocnemius lateralis and soleus.

Fig. 1A. MR/CT imaging of fatty degenerative change in lower leg muscles. Genes causing predominant involvement of anterior compart- ment muscles: tibialis anterior, extensor hallucis longus and extensor digitorum longus.

2.1.2.1. Epidemiology. TMD is the most common muscle disease in Finland with a prevalence of 20/100,000 and patients with Finnish ancestry found in several other coun- tries. TMD families without Finnish background have been identified in France, Belgium, Spain, Italy and Switzerland ([24–27], and unpublished data).

2.1.2.2. Molecular genetics. Mutations causing this pheno- Fig. 1C. MR/CT imaging of fatty degenerative change in lower leg type are located in the C-terminus of the giant sarcomeric muscles. Genes causing involvement of both anterior, lateral and posterior compartment muscles are the C-terminal Filamin-C mutations causing protein titin. The Finnish founder mutation (FINmaj) is myofibrillar myopathy and alphaB-crystallin, but also the established a complex 11 bp insertion–deletion mutation exchanging distal myopathies Welander disease and the MPD3 [58] without yet four amino acids [15]. Point mutations were identified in identified genes this pattern is common. 8 B. Udd / Neuromuscular Disorders 22 (2012) 5–12 unrelated French and Belgian TMD families [24,25], 2.1.4. Distal myotilinopathy truncating mutations in the last and second to last exons Weakness of ankle plantar- or dorsiflexion starts late, of titin in Spanish and French families [26], and recently between age 50 and 60 [28]. Despite the very late onset dis- point mutations in the last exon in an Italian TMD family ease progression can be very disabling. Upper limbs and [27] and one Swiss patient as reported here. Sequencing the proximal leg muscle weakness with loss of ambulation last three titin exons is the diagnostic method of choice in may occur after 10 years [29,30]. CK levels vary from nor- new families without Finnish ancestry. mal to slight increase. Muscle MRI show fatty degenerative changes first in calf muscles followed by all lower leg mus- 2.1.3. ZASPopathy (Markesbery–Griggs late onset distal cles and much milder involvement of proximal lower limb myopathy) muscles (Fig. 1B). Muscle pathology is myofibrillar and Symptoms start after age 40–50 years with ankle weak- similar to that of ZASPopathy, including ultrastructure ness, progressing slowly to involve finger and wrist [31], and may contain pathologically defined spheroid extensors. Mild-moderate proximal weakness occurs very bodies [32]. late, but in the severe case walking is lost 15 or 20 years after onset. Very late cardiomyopathy and heart block 2.1.4.1. Molecular genetics. Myotilin mutations were first requiring a pacemaker has been reported [7]. CK levels described in two families with dominant limb-girdle pheno- are normal or mildly elevated and muscle MRI shows early type (LGMD1A). However, our and other experience sug- degenerative changes in medial gastrocnemius and soleus gest that most myotilinopathy patients present with late (Fig. 1B). At the late stage all lower leg muscles are onset distal myopathy [29,33]. Almost all myotilin replaced while proximal lower limb muscles show mild mutations are located within the second exon, coding for changes. Myofibrillar abnormalities with rimmed and a serine-rich domain of the Z-disk protein. non-rimmed vacuoles are shown on muscle biopsy with dark and hyaline structures in trichrome stain correspond- 2.1.5. Vocal cord and pharyngeal distal myopathy ing to myofibrillar disintegration on EM. Protein aggrega- (VCPDM, MPD2) tions contain ectopic dystrophin, desmin, myotilin, alphaB- Late onset distal upper and lower extremity weakness crystallin, among others [18]. combined with symptoms of vocal cord and pharyngeal weakness characterize this disease. Distal weakness may 2.1.3.1. Epidemiology. So far, all reported families are of start either in ankle and toe extensors or in finger extensors. Central European descent. Serum CK levels reported to be normal or up to eightfold increased and muscle biopsy findings consist of rimmed 2.1.3.2. Molecular genetics. Mutations in ZASP (Z-disk vacuolated fibers [34]. Muscle imaging has not been alternatively spliced PDZ-domain containing protein, also reported. termed LDB3 gene) are responsible with two ancient Euro- pean founder mutations, A165V and A147T, being most 2.1.5.1. Molecular genetics and epidemiology. The disease is prevalent [18]. so far known only in two families, one US family and one

MORPHOLOGICAL CRITERIA

Rimmed vacuoles

YES

MFM

YES NO NO Muscle imaging findings in the lower legs Muscle imaging findings in the lower legs

Lateral> mixed Posterior anterior Mixed anterior mixed posterior anterior >anterior ant/post DES FLNC MYOT GNE WDM MYH7 DYSF DYSF CRYAB ZASP TITIN MPD3 NEB KLHL9 ANO5 FLNC MATR3 ABD- VCP FLNC DNM2

Fig. 2A. Flow chart algorithm for diagnostic purpose aiming at reducing the number of genes qualified for possible molecular genetic testing, using morphological data as the starting point. (adapted from Udd: 165th ENMC International Workshop: Distal myopathies) [60]. B. Udd / Neuromuscular Disorders 22 (2012) 5–12 9

WDM CLINICAL CRITERIA Age of onset hands Childhood to Teens to early adulthood age 40 yrs Late

hands AD/spor AR/spor AD AR/spor AD/spor AR/spor Muscle imaging findings in the lower legs Muscle imaging findings in the lower legs

Ant > post Ant > Ant> mixed post Ant> mixed post Ant> Post post post post post post post >ant

MYH7 DNM2 NEB DES MFM- ABD-FLNCGNE DYSF DYSF MYOT KLHL9 CRYAB FLNC ANO5 hands ZASP MPD3

YES NO Non-DYSF WDM TITIN Non-ANO5 MATR3 VCP VCP

Fig. 2B. Flow chart algorithm for diagnostic purpose aiming at reducing the number of genes qualified for possible molecular genetic testing, using clinical data as the starting point. (adapted from Udd: 165th ENMC International Workshop: Distal myopathies) [60].

Table 2 level were slightly elevated, muscle biopsy showed rimmed Distal phenotypes occurring with other diseases. vacuolation with ring fibers and muscle CT/MRI anterior 1. FSHD compartment fatty degeneration in lower legs (Fig. 1A). 2. Myotonic dystrophy type 1 3. DNM2 mutated centronuclear myopathy 2.1.7. Alpha-B crystalline-mutated distal myopathy 4. Metabolic myopathies a. Branching glycogenosis Distinct late onset distal myopathy without cardiomy- b. Debrancher glycogenosis opathy, respiratory dysfunction or significant cataracts c. Phosphorylase b kinase deficiency may occur with CRYAB mutations [38]. CRYAB d. PNPLA2 lipidosis mutations have previously been associated with distal 5. Caveolinopathy and proximal muscle weakness combined with cataracts 6. Telethoninopathy 7. Nemaline myopathy and dilated cardiomyopathy [39]. Muscle biopsy showed 8. Sporadic inclusion body myositis s-IBM rimmed vacuolar pathology. 9. Scapuloperoneal syndromes 10. Distal spinal muscular atrophy 2.2. Adult onset dominant distal myopathies 11. Focal motor neuron disease (e.g., Hirayama) 2.2.1. Desminopathy Bulgarian family. Both unrelated families were shown to Juvenile or early adult onset distal leg weakness, especially have the same missense mutation in a protein of the nuclear when combined with cardiomyopathy and/or respiratory fail- matrix, Matrin3 [35]. ure should alert the clinician to consider desmin gene, CK levels are moderately elevated and muscle biopsy findings are usually consistent with myofibrillar myopathy. However, typical myo- 2.1.6. VCP-mutated distal myopathy pathology may be inconsistent as shown in the scapulo- VCP mutation may cause a late onset distal myopathy peroneal syndrome of Kaeser reported first to be a neurogenic clinically indistinguishable from WDM or TMD [36], even disease [40]. Muscle MRI displays earliest changes in the if proximal or scapuloperoneal myopathy with Paget, and anterior compartment of lower legs with progression to other frontotemporal dementia (IBMPFD) is more common distal and proximal muscles (Fig. 1A). [37]. In the reported distal family Paget disease was not present, the myopathy was slowly progressive but remained 2.2.1.1. Molecular genetics. Mutations are located over distal, and rapidly progressive lethal frontotemporal large parts of the gene with no certain genotype-phenotype dementia appeared very late, 20–25 years after onset. CK correlation. 10 B. Udd / Neuromuscular Disorders 22 (2012) 5–12

2.2.2. Distal ABD-filaminopathy 2.4. Early onset recessive distal myopathies This is one of the newcomers with a distinct clinical onset of weakness first of the handgrip in early adulthood 2.4.1. Distal nebulin myopathy followed by thenar atrophy and calf muscle weakness in the Onset of ankle dorsiflexion is usually in childhood with 40’s. [41]. CK is normal or slightly elevated. Muscle biopsy weakness of extensors of fingers and hands. Neck flexor shows non-specific pathology, unlike the myofibrillar and weakness is less marked than in Laing myopathy. The pro- rimmed vacuolated pathology described with FLNC muta- gression is slow and patients remain ambulant [47]. EMG is tions causing generalized myofibrillar myopathy. Muscle myopathic or shows mixed findings. CK is normal or CT/MRI on lower limbs reveals replacement in all poster- mildly elevated. Selective fatty degeneration in the lower ior calf muscles while anterior and lateral compartments leg anterior compartment muscles is typically present on are spared (Fig. 1B). muscle CT/MRI (Fig. 1A). Muscle biopsy findings are problematic and may show scattered and grouped atrophic 2.2.2.1. Molecular genetics and epridemiology. Mutations in fibers mimicking neurogenic changes without nemaline the N-terminal actin binding domain (ABD) of muscle spe- rods on light microscopy. On EM rare small rod structures cific Filamin C are the underlying cause of this particular may be encountered [47]. type of distal myopathy, whereas in the clinically and path- ologically different myofibrillar myopathy mutations are 2.4.1.1. Molecular genetics. This mild distal myopathy is located in the central or C-terminal part [42]. Currently caused by two missense mutations in nebulin [47], while one Australian and two Italian families are known. disruptive recessive mutations cause the more severe con- genital nemaline myopathy. 2.3. Early onset dominant distal myopathies 2.5. Early adult-onset distal myopathies 2.3.1. Laing distal myopathy (MPD1) 2.5.1. GNE-myopathy (Nonaka myopathy, Distal myopathy Weakness of ankle dorsiflexion, neck flexors and a hanging with rimmed vacuoles) big toe usually appear in early childhood (see also MRI find- The disease, first described in Japanese patients, presents ings in Fig. 1A). Progression is slow, most patients remain with weakness of ankle dorsiflexors and toe extensors in the ambulant, and weakness of finger extensors, shoulder muscles, second or third decade, followed by foot drop and a step- scoliosis and milder proximal weakness may occur [8].Muscle page gait (see also CT findings in Fig. 1A). Proximal weak- biopsy shows findings compatible with congenital fiber type ness with relative sparing of quadriceps muscles are the disproportion. Rimmed vacuoles are exceptional with some next stages and patients may become wheelchair-dependent mutations. CK levels are normal or mildly elevated [43]. 10 to 15 years after onset [4]. EMG is myopathic with spon- taneous activity and CK is moderately increased (3–4-fold). 2.3.1.1. Epidemiology. Families and sporadic de novo- On muscle pathology abundant rimmed vacuoles are found mutated patients are known in very many populations, also in proximal muscle. and based on experience from Finland, Spain and Norway the prevalence is >1/million [44,45]. 2.5.1.1. Epidemiology. Founder mutations account for higher frequency in Japanese and Middle Eastern popula- 2.3.1.2. Molecular genetics. MYH7 gene encoding slow beta tions, whereas the general stochastic frequency of muta- myosin heavy chain protein is the main myosin isoform in tions indicates a prevalence of less than 1/million. type 1 slow muscle fibers and in the heart. Cardiomyopathy is only occasionally part of the phenotype in Laing distal 2.5.1.2. Molecular genetics. The gene responsible for disease myopathy. All mutations causing this phenotype are is UDP-N-acetylglucosamine 2 epimerase/N-acetyl manno- located in the tail region of the MYH7 heavy chain, with samine kinase (GNE) and was first identified in patients in hot-spots and many occurring de novo [17,45]. Middle East described as having quadriceps sparing myopa- thy (HIBM) [48]. Later the same gene was confirmed in Non- 2.3.2. KHLH9-mutated distal myopathy aka myopathy [16]. GNE is the rate limiting enzyme for sialic Weakness of ankle dorsiflexion in the so far only known acid and hyposialylation is proposed as one pathomechanis- one German family starts in early childhood. Later patients tic feature currently targeted for therapeutic approach. have atrophy of intrinsic hand muscles and proximal limb weakness [46]. 2.5.2. Miyoshi myopathy (MM) EMG is myopathic and muscle biopsy findings are myo- Calf muscles are first affected with weakness and atrophy pathic without rimmed vacuoles. CK levels are mildly- between 15 and 25 years [2,3] (see also MRI findings moderately elevated. Fig. 1B). Proximal limb muscles are always involved later, and the two phenotypes of dysferlinopathy, Miyoshi myop- 2.3.2.1. Molecular genetics. KHLH9 gene encodes a kelch- athy and LGMD2B, converge by time [49,50]. Rarely, the like homologue protein [46]. anterior lower leg muscles are affected at onset [51]. Charac- B. Udd / Neuromuscular Disorders 22 (2012) 5–12 11 teristic for the disease are very high CK levels ranging from 3. Management 20 to 150 fold normal values. EMG shows myopathic changes with spontaneous activity due to fiber necrosis seen The final genetic diagnosis is necessary to avoid wrong on muscle pathology together with other dystrophic treatments due to erroneous diagnosis (Figs. 2A and 2B). changes. Gold standard for diagnosis relies on absent In desminopathy associated cardiomyopathy and respira- dysferlin on immunohistochemical staining of muscle sec- tory muscle involvement needs correct monitoring. In the tions or on Western blotting tissue of muscle or monocytes. case of VCP mutated distal myopathy Paget disease cannot be excluded even if it was not present in the primary distal 2.5.2.1. Epidemiology. Patients were first described in myopathy family, and late dementia is a lethal complica- Japan. Later experience show that patients exist in many tion. In the milder late onset forms orthoses are commonly populations with an overall frequency of dysferlinopathies used for stabilization of wrists, fingers, ankles and toes. In of around 1/million. cases of early severe foot drop tibialis posterior tendon reposition has been used in both TMD and VCP mutated 2.5.2.2. Molecular genetics. Mutations in the dysferlin gene distal myopathy patients with good outcome for many cause both distal Miyoshi myopathy and proximal onset years. However, validated studies of the benefit of these LGMD2B [13]. Dysferlin has been implicated to be impor- measures are not available. tant for sarcolemmal repair mechanisms. References 2.5.3. Distal anoctaminopathy Anoctaminopathy may present with various pheno- [1] Welander L. Myopathia distalis tarda hereditaria. Acta Med Scand types, one of them being early adult onset distal myopathy 1951;141:1–124. with asymmetric calf involvement, starting with pain and [2] Miyoshi K, Iwasa M, Kawai H. 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