The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies Review Article

December 2016 The dawn of molecular genetics in the resulted in a fundamental change inthese how disorders arediagnosed, defined, and identified, managed. Forin example, the traditionalopsies approach, were muscle performed bi- routinelysentially on all es- patients withof LGMD the as part characterizationprocess. and However, the diagnostic lack of specificity tities (eg, Emery-Dreifuss musculartrophy) dys- and with entities notpresenting necessarily in aweakness (eg, limb-girdle dysferlinopathies). pattern of 1990s and, moreapplication recently, of the increasing next-generationparallel-sequencing massive technologies have The classic approach to identifying and accurately diagnosing limb- In recent years, the advent of next-generation sequencing has heralded The LGMDs are a heterogeneous group of hereditary, progressive, and Stanley Jones P. Iyadurai, MSc, PhD, MD; John T. Kissel, MD, FAAN Summary: degenerative neuromuscular disorders thatgirdle present and pelvic with girdle weakness. primary Although a symptoms combinationevaluations of of clinical and may shoulder molecular genetic becontribution sufficient of imaging for andnecessary, accurate histopathologic component of correlations diagnosis evaluation still in of some remains cases. a LGMDs critical, in if notContinuum many (Minneap a Minn) 2016;22(6):1954–1977. cases, the girdle muscular dystrophies (LGMDs)ancillary studies relied including muscle heavily biopsy. Because on ofmethodologies, rapid phenotypic several advances in characterization additional genetic and LGMDs sequencing havediagnostic been approach molecularly to characterized, these andepidemiology, disorders clinical the features, has and genetic been defects simplified. underlyingRecent the This Findings: LGMDs. article summarizes the an era of molecular diagnosisthis in process conjunction has with also led physical to characterization. the Inadvertently, significance ‘‘next-generation aftermath,’’ are whereby variants identified of unknown in mostment patients. Similar guidelines to for the Duchenne publishedhave muscular diagnostic recently dystrophy, and been diagnostic treat- published and for treatmentexon-skipping LGMDs. guidelines strategy) In for addition, treatment thedystrophy first of has medication been patients recently (based approved with on by the a the US subset Food and of Drug Duchenne Administration (FDA). muscular ABSTRACT Purpose of Review: tem has sometimes generated confusion in regard to more traditionally named en- (LGMDs) are a heterogeneousgenetic group disorders of generally characterized by weakness of the shoulder andgirdle the muscles. pelvic Based on thepatterns, inheritance autosomaltype dominant 1), (LGMD autosomaltype recessive 2), and (LGMD have been X-linked described. Successive letters of formsthealphabethavebeenusedtonamethe of LGMD LGMDs according to theidentification of chronology the of genetic locus.straightforward While and convenient, this sys- INTRODUCTION The limb-girdle muscular dystrophies The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies Review Article . Muscle Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is www.ContinuumJournal.com ; and as a consultant 2016 American Academy HTML, PDF, and appof this versions article; the URLs arevided pro- in the print version. Video legends begin on page 1976. Videos accompanying this article are citedSupplemental in the Digital textVideos Content. as mayclicking be on links accessed provided in by the Supplemental digital content: University Press. Unlabeled Use of Products/Investigational Use Disclosure: Drs Iyadurai and Kissel discuss the unlabeled/ investigational use of corticosteroids to treat Duchenne muscular dystrophy. * of Neurology. Cytokinetics, Inc; Ionis Pharmaceuticals; and Quintiles, Inc; and receives publishing royalties from Oxford compensation for serving on a consulting board ofInc; AveXis, as journal editor of & Nerve for Novartis AG. Drreceived Kissel research/grant has funding as principal investigator of a study from theInstitutes National of Health and has received funding for clinical trials from AveXis, Inc; AxelaCare Health Solutions, LLC; BioMarin; CSL Behring; serving on the advisory boards of Allergan; Alnylam Pharmaceuticals, Inc; CSL Behring; and Pfizer, Inc.Kissel Dr has received personal Address correspondence to Dr Stanley Jones P.Ohio Iyadurai, State University, Wexner Medical Center, Department of Neurology, 395 WAve, 12th Columbus, OH 43210, [email protected] Relationship Disclosure: Dr Iyadurai has received personal compensation for 1954

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and invariably leads to testing of genes disorders, different allelic alterations re- irrelevant to the presenting phenotype sult in different phenotypic expressions and, worse yet, identification of unexpected/ from defects in the same gene. For exam- irrelevant variants of unknown significance ple, LGMD2B (dysferlinopathy) can pres- in other unwanted genes in the panel. ent as a classic LGMD phenotype or a Therefore, the selection of the most distal-predominant myopathy (ie, Miyoshi appropriate gene panel from the many myopathy). The following discussion high- available must be based on precise phe- lights the characteristics of the various notypic and laboratory characterization LGMDs based on the standard alphanu- and the best guess as to the most likely meric nomenclature followed in paren- diagnosis. theses by the involved protein. Even with multigene panel testing, a significant proportion of LGMD cases Limb-Girdle Muscular (up to 25% in some instances) may re- Dystrophy Type 1 (Dominant main undiagnosed.1 In such cases, whole- Forms of Limb-Girdle exome sequencing may be performed, a Muscular Dystrophy) process that typically involves sequencing To date, eight LGMD1 loci with domi- of all known exons in a given individual, nant inheritance have been described with variants called based on comparisons based on clinical and genetic criteria; made to standard sequences. Although other dominant LGMDs will certainly be evidence suggests that whole-exome se- identified in the future. Sporadic forms quencing of the trio (the patient and the of LGMD1 are often encountered since biological mother and father) increases de novo dominant mutations can present the diagnostic hit rate,2 it is important with the disease phenotype (with an to bear in mind that exome sequencing obvious lack of family history). At times, does not provide complete coverage of the lack of penetrance and expressivity all coding exons and typically does not and broad range of clinical variability detect deletions and duplications. In ad- precludes the identification of the phe- dition, genetic diagnosis via multigene notype in the carrier parent. The LGMD1 panel testing and whole-exome sequenc- disorders are usually adult onset and in ing may be limited by insurance cover- general have a milder phenotype than age, requires technical expertise, and is the LGMD2 disorders so that affected usually restricted to specialized neuro- patients are usually in good health at muscular centers around the country. The reproductive age. To date, mutations in genetic evaluation of patients with nega- seven genes have been identified as tive results in whole-exome sequencing is causative for LGMD1 disorders, with therefore best pursued only at specialized commercial testing available for most research centers. of the disorders. The LGMD1 subtypes, Genetic and molecular characteriza- characteristic features, clinical features, tions have revealed that the LGMD gene and limited gene information are sum- products are localized to various parts of marized in Table 10-13 and described the muscle fiber (nucleus, cytosol, Golgi briefly in the following sections. apparatus, sarcolemma, sarcoplasmic re- Limb-girdle muscular dystrophy ticulum, extracellular matrix, cytoskeleton type 1A (myotilinopathy). The onset [cytoplasmic structural framework], and of this late-onset disease is variable from contractile cytoskeleton [motor and motor- the midtwenties to midseventies. Weak- associated proteins]) and perform a vari- ness is symmetric and starts in the legs ety of related functions, resulting in a and then progresses to the arms. Distal plethora of clinical phenotypes. In certain weakness is observed with further

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Clinical Information Gene Information Typical Creatine Heart Gene/ Type Onset Progressionb Kinase Level Involvement Locus Protein LGMD1A Adulthood Slow 1Y15X Yes MYOT Myotilin LGMD1B Variable; Slow 1Y6X Yes LMNA Lamin A/C childhood to adulthood

LGMD1C Childhood Slow to 10Y15X Yes CAV3 Caveolin 3 moderate

LGMD1D Adulthood Slow 1Y6X Not usual DNAJB6 HSP40

LGMD1E Adulthood Slow 2Y4X Yes DES Desmin LGMD1F Variable; Rapid Variable; No TNPO3 Transportin 3 infancy to normal to 15X adulthood

LGMD1G Adulthood Slow Variable; No HNRPDL Heterogeneous normal to 10X nuclear ribonucleoprotein DYlike protein LGMD1H Variable; Slow Variable; No 3p23 To be identified childhood to normal to 10X adulthood LGMD = limb-girdle muscular dystrophy. a Modified with permission from Iyadurai SJ, Kassar D, Springer.3 B 2013 Springer Science+Business Media. b Progression of the disease as noted by time frame (arbitrarily assigned) of loss of ambulation: rapid is 2 years from diagnosis; moderate is 5 years from diagnosis; slow is more than 5 years from diagnosis. progression, although some patients may seen in some patients. Muscle biopsy present with footdrop. In the upper reveals a myopathic pattern with signifi- extremities, weakness is noticed in the cant size variability, rounded fibers, wrist extensors, fingers extensors, and rimmed or autophagic vacuoles, hyaline deltoid muscles. Facial and neck extensor inclusions, and spheroid bodies on muscle weakness may occur. Some pa- ATPase staining. Mutations in myotilin tients develop dysarthria (due to palatal gene cause LGMD1A. weakness),4 myalgia, and joint contrac- Limb-girdle muscular dystrophy type tures mainly of the ankles. Tendon re- 1B (laminopathy). LGMD1B usually man- flexes are absent at the knees and the ifests before the age of 20 with symmet- ankles but loss of tendon reflexes may be rical weakness affecting the proximal diffuse. Cardiomyopathy is present in lower extremities (Case 10-1). However, one-half of patients, with onset between a variant of this syndrome (Arg377His mu- ages 60 and 70. Progression of weakness tation of the lamin A/C gene, infra vida) is slow, with loss of ambulation usually may result in early and predominant within 10 years of onset. Serum CK can be quadriceps involvement. Progression is normal to 15-fold elevated. Needle EMG generally slow, with the upper extremities reveals myopathic changes and fibrillation usually involved in the third or fourth de- potentials, and myotonic discharges are cade. Cardiac abnormalities are noted in

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about 60% of patients and are typified by endomysial thickness, and mislocalized cardiomyopathy, atrioventricular conduc- and aggregated lamin. Mutations in the tion block, bradycardia, and sudden car- lamin A/C gene underlie the LGMD1B diac death.5 Specific mutations such as phenotype and also many other pheno- the Arg377His have been associated with types. For example, patients with certain dilated cardiomyopathy. Serum CK may mutations in the lamin A/C gene mani- be either normal or mildly elevated. fest as Emery-Dreifuss muscular dys- Muscle biopsy shows rounded fibers, trophy phenotype characterized by variability in fiber size, increased contractures of the posterior cervical

Case 10-1 This 28-year-old woman with diffuse weakness and atrophy was seen initially as a 16-month-old girl when her mother noted that she had difficulty running and arising from the floor. Muscle biopsy revealed a dystrophic process. On follow-up examination at age 4, the patient used a wheelchair for all mobility. Laboratory evaluation showed a mildly elevated creatine kinase level at that time. On follow-up examination at age 21, generalized atrophy of the appendicular muscles was noted. The cranial, facial, and truncal muscles were spared. Contractures were noted in the hips, ankles, and elbows. Pulmonary function tests showed a vital capacity of 75% predicted. Gene sequencing identified a mutation in the lamin A/C gene compatible with limb-girdle muscular dystrophy type 1B (Figure 10-1).

FIGURE 10-1 Patient in Case 10-1 with limb-girdle muscular dystrophy type 1B. Notice the sparing of cranial musculature and severe atrophy of arm muscles (A). Elbow and knee contractures, scoliosis, and scapular winging are common (B).

Comment. This case demonstrates a classic onset and progression as would be expected in patients with lamin A/C mutations, an autosomal dominant limb-girdle muscular dystrophy. These patients have delayed motor milestones, contractures, scoliosis, elevated creatine kinase levels, and develop pulmonary dysfunction and cardiac abnormalities. Cranial nerves are not usually affected.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT muscles, elbows, and ankles; cardiac in- tients usually experience muscle cramps, h Patients with certain volvement; slowly progressive weakness pain, and stiffness (particularly with exer- mutations in the lamin A/C involving the humeral and peroneal mus- cise), and serum CK is elevated up to 10 gene manifest as cles with some pelvic girdle involvement; times the normal value. Emery-Dreifuss muscular tendon areflexia; and slight elevation in Limb-girdle muscular dystrophy type dystrophy phenotype CK levels. Recently, recessive mutations 1D (HSP40 proteinopathy). LGMD1D characterized by in lamin A/C resulting in the LGMD1B usually presents with onset of weakness contractures of the posterior cervical muscles, phenotype have been described. at 20 to 60 years of age, although most elbows, and ankles; cardiac Limb-girdle muscular dystrophy type patients have weakness, slowness, and involvement; slowly 1C (caveolinopathy and rippling muscle clumsiness of movements as children. Hip progressive weakness disease). LGMD1C is an early-onset dis- girdle weakness and waddling gait are involving the humeral and order with manifestation between 5 years noted first, followed variably by progres- peroneal muscles with of age and adulthood. Proximal weakness sion to the shoulder girdle. Progression is some pelvic girdle in the lower extremities, difficulty walk- gradual, with need for a wheelchair usually involvement; tendon ing, and a positive Gowers sign are usually occurring 20 to 30 years after diagnosis. areflexia; and slight elevation in creatine noted. Patients with LGMD1C may also Dysphagia occurs in about 20% of the pa- kinase levels. experience cramps after exercise. Vari- tients, and dysarthria may occur. Cardiac able clinical manifestations may occur in or respiratory involvement has not been a single family, and the disorder often has observed with LGMD1D. Most patients a benign clinical course. No evidence of have elevated serum CK (up to five times respiratory impairment occurs, and life normal). Mild calf hypertrophy may be expectancy is not reduced. Hypertrophic present. Myopathic changes are noted on cardiomyopathy has been noted in EMG. Muscle biopsy usually shows varied patients, although rarely. EMG may be fiber size, rounded fibers, endomysial normal or reveal myopathic changes. thickening, rimmed vacuoles, eosinophilic Usually, muscle biopsy demonstrates cytoplasmic bodies, and dystrophic fibers. variability in muscle fiber size, fibers Mutations in DNAJB6 underlie LGMD1D with internal nuclei, degenerating and phenotype.6 regenerating fibers, and increased con- Limb-girdle muscular dystrophy type nective tissue. Caveolin 3 mutations un- 1E (desminopathy). LGMD1E is charac- derlie LGMD1C. In muscle biopsies terized by dilated cardiomyopathy, cardiac obtained from patients with LGMD1C, conduction system disease, and adult- caveolin 3 is invariably reduced both onset myopathy.7 Cardiac manifestations by immunohistochemistry and immuno- include arrhythmia, which manifests at blot analysis. 20 to 25 years of age, and congestive Another manifestation of patients with heart failure with four-chamber enlarge- caveolin 3 mutations results in rippling ment during the third to fifth decade. muscle disease phenotype. Rippling mus- Cardiac sudden death has been noted as cle disease is characterized by several a major familial symptomatology.8 Mus- specific behaviors of the muscle: worm- cle biopsy shows significant variability is like movements on the surface of the fiber size, increased endomysial thicken- muscle, percussion-related contraction, ing, cytoplasmic bodies, and eosinophilic and muscle mounding. Muscle hyper- inclusions. Mutations in desmin gene trophy is common in caveolinopathy. At were found to be causative of LGMD1E times, a parent may be a benign carrier phenotype. with muscle hypertrophy but have no Limb-girdle muscular dystrophy other signs or symptoms. The presenting type 1F (transportinopathy). Onset of manifestations are usually fatigue, tiptoe LGMD1F is typically in the third or fourth walking difficulty, and myalgia. The pa- decade but can manifest in infancy. All

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KEY POINT h In most of the limb-girdle affected patients show characteristic pel- slow course. However, atrophy of shoul- muscular dystrophy vic and shoulder girdle proximal weak- der and pelvic girdle muscles is noted. type 2 disorders, the ness. Pelvic girdle impairment precedes Generalized hyporeflexia and calf hyper- creatine kinase is quite the shoulder girdle weakness, and distal trophy are also characteristically noted. elevated. Although weakness often occurs later. Respiratory Serum CK levels are usually elevated but limb-girdle muscular muscles are clinically affected in some can be normal (normal to 10 times the dystrophy type 2 patients with juvenile-onset LGMD1F. normal level). EMG reveals nonirritable disorders are usually Serum CK is normal in 40% of patients myopathic changes. Muscle histology of early childhood onset and quite debilitating, and varies between normal to as high as shows abnormal fiber size and shape adult-onset forms have 15 times the normal levels. EMG of variation and increased presence of en- also been described. proximal muscles shows myopathic domysial and perimysial connective tissue. changes including short-duration, low- Central nuclei are occasionally present. amplitude potentials and polyphasia. No Although the LGMD1H mutation has abnormalities in sensory and motor nerve been linked to 3p23Yp25.1,9 the gene conduction velocities are noted. Muscle defect is unknown. biopsy shows fiber size variability, increased connective tissue (both endo- Limb-Girdle Muscular mysial and perimysial), rimmed vacuoles, Dystrophy Type 2 (Recessive central nuclei, and scattered dystrophic Forms of Limb-Girdle fibers. Gene defects in transportin 3 are Muscular Dystrophy) associated with LGMD1F. Twenty-three distinct LGMD2 loci with Limb-girdle muscular dystrophy recessive inheritance have been de- type 1G (HNRPDL proteinopathy). The scribed. In most of these disorders, the age of onset in LGMD1G is in the third CK is quite elevated. Although LGMD2s or fourth decade. The initial symptoms are usually of early childhood onset and are seen in the proximal lower limbs as- quite debilitating, adult-onset forms sociated with muscle cramps followed have also been described. A variable, by weakness of the upper limbs. Pro- progressive course is typical. Although gressive finger and toe flexion limitation LGMD2I (FKRP deficiency) is the most with decreased range of motion in inter- common form of all LGMDs in northern phalangeal joints also occurs. However, Europe, LGMD2A (calpainopathy) is the intrinsic hand muscles are not usually most prevalent in many other European affected. CK may be normal or elevated countries, as well as in Turkey, Brazil, up to 10 times the upper level of Japan, Russia, and Australia. LGMD2I, normal. Muscle biopsy shows fiber size LGMD2B, and LGMD2A remain the variability, perimysial thickening, rimmed most common autosomal recessive vacuoles, and necrotic fibers. Interest- LGMDs in North America. The LGMD2 ingly, scattered areas of angulated subtypes, characteristic features, clinical fibers may also be noted. Mutations in features, and genetic information are the heterogeneous nuclear ribonucleo- listed in Table 10-2.IndividualLGMD2 protein DYLike protein underlie the subtypes are described in the follow- LGMD1G phenotype. ing sections. Limb-girdle muscular dystrophy Limb-girdle muscular dystrophy type type 1H. LGMD1H is extremely rare and 2A (calpainopathy). LGMD2A is charac- has been described in only 11 members terized by a wide variability in clinical of a single large family. The disease onset features and rates of progression. Although is usually in the fifth decade and manifests the mean age at onset is approximately with proximal weakness in upper and 14 years, a considerable variation in pre- lower extremities and follows a relatively sentation from ages 2 to 40 years has

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Clinical Information Gene Information Creatine Kinase Heart Type Typical Onset Progression Level Involvement Gene Protein LGMD2A 12Y30 years Slow Markedly No CAPN3 Calpain 3 elevated

LGMD2B Adolescence Slow 10X Possible; not DYSF Dysferlin common

LGMD2C Early childhood Moderate to 20Y30X Yes SGCG +-Sarcoglycan rapid

LGMD2D Variable Rapid 20X Yes SGCA !-Sarcoglycan

LGMD2E Early childhood Moderate to 20X Yes SGCB "-Sarcoglycan rapid

LGMD2F Early childhood Rapid 10Y50X Yes SGCD G-Sarcoglycan

LGMD2G Childhood, Moderate 3Y30X Yes, TCAP Telethonin adolescence approximately 50%

LGMD2H Adolescence, Slow 1Y20X No TRIM32 E3 ubiquitin ligase adulthood

LGMD2I Early childhood Rapid to slow 5Y40X Yes FKRP Fukutin-related and late protein adulthood LGMD2J Childhood, Slow 10Y15X No TTN Titin adulthood LGMD2K Childhood Slow 10Y40X No POMT1 Protein O-mannosyltransferase 1 LGMD2L Adulthood Slow 1Y100X No ANO5 Anoctamin 5

LGMD2M Early infancy Slow 50Y100X Possible FKTN Fukutin

LGMD2N Prenatal to infancy Rapid 6Y12X No POMT2 Protein O-mannosyltransferase 2

LGMD2O Late childhood Moderate 2Y10X No POMGNT1 Protein O-linked mannose "1,2-N- acetylglucosaminyltransferase LGMD2P Early childhood Moderate 20X No DAG1 Dystroglycan

LGMD2Q Early childhood Slow 10Y50X No PLEC1 Plectin 1

LGMD2R Childhood to Slow Normal Yes DES Desmin young adulthood

LGMD2S Early childhood Slow 10Y15X No TRAPPC11 Trafficking protein particle complex 11

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a TABLE 10-2 The Subtypes of Limb-Girdle Muscular Dystrophy Type 2 Continued from page 1961

Clinical Information Gene Information Creatine Kinase Heart Type Typical Onset Progression Level Involvement Gene Protein LGMD2T Variable Slow Variable Possible GMPPB GDP-mannose pyrophosphorylase B

LGMD2U Early childhood Rapid to 6Y50X Possible ISPD Isoprenoid synthase moderate domain containing

LGMD2V Variable Usually slow 1Y20X Yes, GAA Acid !-1,4-glucosidase predominantly in infantile-onset cases

LGMD2W Childhood Variable, but Up to 25X Possible LIMS2 LIM zinc finger usually slow domain containing 2 LGMD = limb-girdle muscular dystrophy. a Modified with permission from Iyadurai SJ, Kassar D, Springer.3 B 2013 Springer Science+Business Media.

been described. Ambulation is affected Although no significant cardiac involve- during adolescence but is affected earlier ment occurs, worsening of respiratory in infantile-onset disease. The disorder function may lead to cardiac complica- is characterized by a symmetric, selective tions. Strangely, CK levels may be normal atrophic involvement of limb-girdle and or elevated, even up to 500 times the trunk muscles.10 Muscle weakness usually normal values. With progression of the begins in the pelvic girdle, with difficulty disease, the CK values may begin to drop, running, climbing stairs, or rising from a consistent with worsening atrophy of the chair. The pelvic girdle muscles are the affected muscles. EMG shows an irritable most severely affected, even when the myopathy characterized by increased disease starts in the shoulder girdle. Hip insertional activity, fibrillation potentials, adductors and gluteus maximus are the and positive sharp waves. Muscle biopsy earliest clinically affected muscles and, shows variability of muscle fiber size, en- to a lesser degree, the hip flexors and domysial thickening, necrotic fibers and posterior thigh muscles are also affected. rare regenerating fibers, type 1 predom- The distal leg muscles and proximal hip inance, lobulation of type 1 fibers, and abductors are relatively spared. The weak- inflammation in perivascular or endomysial ness in the upper extremity muscles and areas.11 Eosinophilic infiltrates are char- the shoulder girdle occurs later in the acteristic. Imaging of the thigh muscles disease course. Scapular winging is evi- may show marked atrophy of the ham- dent. Abdominal muscles may also be strings and hip adductors and moderate involved. Early in the disease course, atrophy in quadriceps with sparing of the contractures are seen in the calves, wrists, sartorius. With progression of the disease, elbows, and fingers. As a result, toe other thigh muscles are also affected walking may be noted in early stages. In depending on clinical severity; the adduc- later disease, contractures in the proximal tors and semimembranosus muscles are parts of the body (including the spine) involved in young patients with minimal are noted. functional motor impairment. In patients

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. with restricted ambulation, a diffuse in- cific distal myopathies such as Miyoshi volvement of the posterolateral muscles myopathy (also known as Miyoshi mus- of the thigh and of the vastus intermedius cular dystrophy type 1) and distal myop- is found with relative sparing of the vastus athy with anterior tibial onset. Symptom lateralis, sartorius, and gracilis. Imaging of onset of LGMD2B ranges from adoles- the calf muscles reveals involvement of cence to late adulthood (10 to 40 years of the soleus muscle and the medial head age), with significant variability in pre- of the gastrocnemius with relative sparing sentation between family members and of the lateral head. LGMD2A is caused by different families. Usually, the muscle mutations in the CAPN3 gene, which weakness starts in the pelvic girdle, man- encodes for a muscle-specific proteolytic ifesting as difficulty running and walking enzyme called calpain 3 (Case 10-2). up the stairs. Early difficulty with walking Limb-girdle muscular dystrophy is usually associated with involvement of type 2B (dysferlinopathy). LGMD2B has a the gastrocnemius (specifically the me- wide range of clinical presentations, from dial head). In later stages of the disease, a classic limb-girdle presentation to spe- upper extremity muscles are involved.

Case 10-2 A 50-year-old woman presented with arm and leg weaknessandahistoryofmotordifficultiesthatshe had experienced since childhood. (She stated, ‘‘I was a klutzy kid.’’) However, she had experienced noticeable weakness only at age 30 when she had difficulty going up stairs. Laboratory evaluations showed an elevated creatine kinase level of 1300 IU/L (six times the upper limit of normal). Muscle biopsy demonstrated significant size variability, many small rounded fibers, central nuclei, increased endomysial connective tissue, and necrotic fibers, but no inflammation. Physical examination showed normal cognition, normal cranial nerves, scapular winging, proximal and distal weakness, hyperlordotic posture, generalized atrophy, and normal sensation (Figure 10-2). Gene testing revealed compound heterozygous mutations in the calpain 3 gene, diagnostic of limb-girdle muscular dystrophy (LGMD) type 2A.

FIGURE 10-2 Patient in Case 10-2 with limb-girdle muscular dystrophy type 2A. The patient has notable shoulder abduction weakness (A) and scapular winging (B).

Comment. This case demonstrates common features associated with autosomal recessive LGMDs. Creatine kinase is usually elevated to a higher level (compared to autosomal dominant LGMDs in general). Early-onset motor delay and normal cognition are usually noted. While scapular winging can be variably seen, cranial musculature is usually preserved.

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KEY POINT h Miyoshi and limb-girdle Specifically, biceps are affected approx- veals either a reduction or lack of staining. muscular dystrophy imately 10 years after the onset of lower Mutations in the skeletal muscle protein phenotypes can be extremity weakness. The disease follows dysferlin underlie LGMD2B. present in the same a fairly slow course of progression, and Limb-girdle muscular dystrophy family. The exact reason loss of ambulation is noted at 30 years of types 2C TO 2F (!, ", +,andG sarco- behind the differences in age. However, some patients do not lose glycanopathies). The age of onset and presentation within a ambulation until age 60. Hypertrophy of clinical presentation has a wide inter- and given family is unclear. several muscles (deltoid, biceps, and the intrafamilial variability. The clinical pre- calves) is noted early in the course of the sentation can vary from a Duchenne disease. Classic diamond on quadriceps muscular dystrophy (DMD)Ylike course sign is seen in most patients. This sign to intermediate to a mild Becker mus- represents the characteristic shape ac- cular dystrophy (BMD)Ylike phenotype quired by the anterior compartment in a given family. The onset of the disease muscles of the thigh when the patient is approximately 5 or 6 years of age with attempts to sit down (lower his or her involvement mainly of proximal muscles, torso or back as if sitting in a chair) with although distal involvement may occur. feet firmly and flatly planted on the The inability to walk may occur anywhere ground. In some patients, cramps and between the second and the fourth muscle discomfort may be the only early decade. The glutei, adductors, paraspinal, presenting symptoms. The allelic form abdominal, subscapular, and soleus mus- of Miyoshi distal myopathy may present cles are affected whereas quadriceps is in early adulthood with the inability to spared in some patients.12 Patients may walk on or get up on toes. However, the develop calf and tongue hypertrophy and anterior tibialYonset variant may present deafness. Respiratory failure occurs in with footdrop and steppage gait. In these the third decade of life. Cardiac functions distal-predominant allelic forms, the prox- are fairly spared. Serum CK is noted to be imal muscles and the upper limbs be- extremely high. EMG shows small- come affected later in the disease course. amplitude, short-duration, polyphasic Serum CK levels are considerably motor unit action potentials. Muscle increased. Muscle imaging confirms a biopsy shows fiber size variability, selective involvement of the soleus and rounded fibers, increased endomysial gastrocnemius (medial head) and early thickness, and necrotic fibers. Rarely, muscle edema. Miyoshi and LGMD phe- inflammatory infiltrates are also found. notypes can be present in the same family. The immunoreactivity of the affected The exact reason behind the differences sarcoglycan may be reduced or absent. in presentation within a given family is Secondary reductions in other sarco- unclear. EMG shows typical myopathic glycans may also be noted. Occasionally, changes. Muscle pathology shows inflam- reductions in dystrophin staining may mation, necrosis, and degeneration of mus- also be noted. However, how the second- cle fibers, fiber size variability, and rarely, ary reduction in other sarcoglycan or de- fiber splitting. Endomysial thickening is creased dystrophin staining relate to the also commonly noted. Amyloid deposition phenotype is unclear. The individual sar- at the muscle membrane, endomysium, coglycans and their deficiencies relate to or perivascular spaces are noted in some the specific LGMD type (2C, 2D, 2E, and patients. Given the predominant inflam- 2F). Sarcoglycans appear to play a role in mation seen in the muscle biopsies in maintaining muscle membrane integrity. these patients, a misdiagnosis of polymyo- Limb-girdle muscular dystrophy type sitis is not uncommon. However, in these 2G (telethoninopathy). Patients with patients, dysferlin immunostaining re- LGMD2G usually present at a mean age

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT of onset of 12 years with difficulty walking, veals mild dystrophic changes including h Limb-girdle muscular running, and climbing stairs. Although fiber size variability, endomysial fibrosis, dystrophy type 2I is one this condition spares the gastrocne- and muscle fiber degeneration and regen- of the most common mius (which is affected in LGMD2B/ eration. Fiber splitting and internal nuclei limb-girdle muscular dysferlinopathy), these patients have dif- are observed. dystrophies with a carrier ficulty walking on their heels. The tibialis Another allelic variant of LGMD2H frequency of 1 in 400 in anterior is severely affected, and difficul- is sarcotubular myopathy. As the name the white population. ties with foot dorsiflexion and footdrop implies, distinctive features in muscle ensue. Atrophy of the shoulder girdle biopsy led to the name. Patients with the muscles is prominent. In the lower ex- sarcotubular myopathy allelic variant pres- tremities, the pelvic girdle muscles and ent with exercise-induced fatigue and distal muscles are affected. About 40% of muscle pain. In addition to the weakness patients with LGMD2G become nonam- of pelvic and shoulder girdle muscles, bulatory by the third or fourth decade. neck flexion weakness is also noted. Other Interestingly, calf atrophy or hypertrophy accompanying features include mild facial may be noted as the first sign of disease in weakness, scapular winging, calf hyper- one-half of patients. Serum CK may be trophy, and Gowers sign. In general, the mildly elevated (three times the normal muscle atrophy noted in successive ex- level) or quite highly elevated (30 times aminations is a fair indication of progres- the normal level). Muscle biopsy shows sive weakness. Contractures in the Achilles significant variability in fiber size, in- tendons are noted frequently, and deep creased number of fibers with central tendon reflexes are either normal or nuclei, necrotic and regenerating fibers, depressed. Serum CK levels may be ele- and rimmed vacuoles. In Western blot vated up to 20 times the normal values. analysis, telethonin is absent. LGMD2G is Muscle biopsy shows fiber size variability, most commonly seen in patients with rounded fibers, and in addition, small Brazilian ancestry and is caused by muta- rounded vacuoles in type 2 fibers. Small tions in the gene encoding telethonin.13,14 abnormal spaces are noted in segments Other variant telethonin syndromes in- of many muscle fibers. The gene muta- clude dilated cardiomyopathy 1N and tions underlying LGMD2H involve the congenital muscular dystrophy. gene encoding tripartite motif-containing Limb-girdle muscular dystrophy protein32 (TRIM32). type 2H (TRIM32 proteinopathy/ Limb-girdle muscular dystrophy type sarcotubular myopathy). To date, 2I (fukutin-related proteinopathy). LGMD2H has been described only in the LGMD2I is one of the most common Hutterite population of North America15 LGMDs with a carrier frequency of 1 in and is a mild form of recessive LGMD with 400 in the white population. The combi- a variable clinical presentation. Disease nation of limb-girdle weakness, respiratory onset is usually within the second or third insufficiency, and dilated cardiomyopathy decade of life and progression is slow; is noted in patients with LGMD2I.16 The most patients continue walking into their disease onset may be as early as infancy sixth decade. Quadriceps and pelvic gir- (5 months) or as late as midadulthood dle muscles are primarily involved, and (40 years). Patients with early-onset disease patients show a waddling gait and diffi- symptoms may present with hypotonia and culty rising from the squatting position. display delayed motor milestones. Tongue Cardiac and facial involvement does not hypertrophy is often noted, although occur. The serum CK is high (up to 20 other muscles may also display hypertro- times the normal level), and EMG shows phy. These patients usually lose ambula- myopathic changes. Muscle histology re- tion by their early teens (much like

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patients with DMD). The loss of am- responsible for LGMD2J. However, bulation is usually followed by cardiomy- it should be emphasized that titin is a opathy.17 The patients with adult-onset large protein, and mutations/truncations symptoms usually have a milder form of affecting several distinct domains within the disease and a slow course of pro- the protein may lead to specific pheno- gression. However, hypertrophy of mus- types including selective involvement cles may be noted; the calf, anterior thigh of the cardiac, skeletal, or respiratory muscles, brachioradialis, and tongue may muscles. The details of the genotype- be prominently involved. These patients phenotype correlation are still being may also report nonspecific symptoms worked out. such as cramps and myalgia, especially Limb-girdle muscular dystrophy after exercise. In selected cases, myoglo- type 2L (anoctaminopathy). LGMD2L binuria may occur. Brain MRI and cogni- usually presents as an asymmetric dis- tion are normal.18 Serum CK is elevated order and that involves the muscles of between 10 to 30 times the normal level. the scapula. The onset is usually in adult- Muscle biopsy shows fiber size variation, hood,anywherefrom20yearsto55years. necrosis, and regeneration of muscle Asymmetric atrophy of muscles is com- fibers, increased endomysial connective monly noted in quadriceps femoris, tissue, and type 1 predominance. LGMD2I biceps brachii, and gastrocnemius. In is caused by mutation in Fukutin-related some patients, calf hypertrophy is noted; protein gene (FKRP), which also affects however, calf atrophy ensues with pro- glycosylation of dystroglycans, which is gression of the disease, usually in an discussed in the following section on asymmetric fashion. While proximal LGMD types 2K, 2M, 2N, 2O, and 2P. weakness is prominent in both the shoul- Limb-girdle muscular dystrophy der and the pelvic girdle, distal weakness type 2J (titinopathy/Finnish distal my- is not usually noted. Selected patients opathy). LGMD2J is most prevalent in may develop subtle facial weakness. patients from Finland or of Finnish origin. Myalgia, either due to exertional or non- The onset of symptoms may be variable exertional causes, is a common present- and can occur anywhere from childhood ing symptom in these patients. Serum CK to adulthood (third decade). LGMD2J can have a very wide range, from normal classically presents as a myopathy involv- levels to 80 times the normal level. EMG ing distal muscles, specifically of the leg. shows an irritable myopathy. Muscle The initial manifestation is noted in the biopsy shows rounded fibers, fiber size tibialis anterior muscle, and hence is also variability, increased endomysial connec- known as tibial muscular dystrophy. MRI tive tissue, degenerating fibers, and occa- of the muscles show prominent involve- sionally inflammatory infiltrates and fiber ment of the tibialis anterior and the splitting. Mutations in the anoctamin 5 extensor digitorum longus. In general, (ANO5) gene underlie LGMD2L. Recently, LGMD2J follows a slow course of pro- dominant mutations in ANO5 have gression. Usually patients become been noted to be associated with the nonambulatory about 20 years after LGMD2L phenotype. symptom onset. In these patients, car- Limb-girdle muscular dystrophy diomyopathy is not usually noted. Serum types 2K, 2M, 2N, 2O, 2P. This group CK can be elevated up to 20 times the of LGMD disorders shares a common normal level. Muscle biopsy shows myo- feature in that they all result from hypo- pathic features. Immunohistochemistry glycosylation of !-dystroglycan. The reveals secondary reduction in calpain proteins involved are as follows: type 3.19 Mutations in the titin gene are 2K: POMT1 proteinopathy; type 2M:

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT fukutinopathy; type 2N: POMT2 pro- require cardiac pacemaker placement. h Limb-girdle muscular teinopathy; type 2O: POMGNT1 pro- Muscle pathology is significant for hya- dystrophy types 2K, 2M, teinopathy; and type 2P: dystroglycan 1 line accumulations and amorphous 2N, 2O, and 2P usually proteinopathy. These disorders all usually subsarcolemmal inclusions. Recessive present in early childhood present in early childhood as congenital mutations in desmin underlie LGMD2R. as congenital muscular muscular dystrophies with multiple organs As noted in the previous section, dom- dystrophies with multiple involved (muscle, eye, brain). Variable inant mutations in desmin underlie organs involved (muscle, eye, brain). rates of progression, proximal muscle LGMD1E. weakness, mild pseudohypertrophy, mi- Limb-girdle muscular dystrophy crocephaly, and mild mental retardation type 2S (TRAPPC11 proteinopathy). with an IQ ranging from 50 to 76 is usually Patients with LGMD2S have an early noted. Joint contractures occur in about childhood onset of proximal weakness, one-half of patients.20 The serum CK is 40 scapular winging, and mild myopathic times the normal level. Muscle histology facies. CK is elevated up to 10 times the shows fiber size variability and reduced !- normal values. In addition, global devel- dystroglycan. In LGMD2M, muscle hyper- opmental delay, infantile-onset hyperki- trophy is seen in the posterior leg and, in netic movements (dystonia/chorea), and some patients, the tongue. Spinal rigidity, truncal ataxia are noted. EMG reveals a joint contractures, and cardiomyopathy myopathic picture, and MRI of the brain may occur.21,22 Although brain MRI may may reveal cerebral volume loss. The be normal, vermis hypoplasia and gene defect underlying this LGMD is in polymicrogyria may be seen. the trafficking protein particle complex Limb-girdle muscular dystrophy type 11 gene. 2Q (plectinopathy). Plectinopathy has Limb-girdle muscular dystrophy been reported in Turkish, Indian, English, type 2T (GDP-mannose pyrophos- and Egyptian families/backgrounds. phorylase B proteinopathy). The dis- The disease onset occurs in early child- ease onset is quite variable with onset hood and is usually accompanied by from birth to age 40 and has a fairly slow microcephaly and mental/intellectual progression of proximal weakness. In- disabilities. The CK is elevated up to 20 fants with early-onset LGMD2T have hy- times the normal level. EMG shows potonia at birth and intellectual disabilities, myopathic changes, and muscle biopsy sometimes with concurrent onset of reveals a dystrophic picture, varied seizures. In older patients, enlarged fiber size, internal nuclei, necrosis/ calves, rhabdomyolysis, and cramps are regeneration, and reduced plectin stain- noted. Some patients may have cardiac ing. Mutations in the plectin gene under- involvement. EMG is myopathic and lie LGMD2Q. muscle biopsy reveals a dystrophic pic- Limb-girdle muscular dystrophy ture, internal nuclei, muscle fiber necro- type 2R (desminopathy). Patients with sis, and endomysial thickening. The gene this desmin variant syndrome (as op- defect underlying this LGMD has been posed to LGMD1E) have a recessive localized to the GDP-mannose pyrophos- mode of inheritance. The disease onset phorylase B gene. is usually early (childhood to the second Limb-girdle muscular dystrophy type decade of life) and involves facial weak- 2U (ISPD proteinopathy). The disease ness and respiratory muscle weakness onset is in early childhood with a pro- in addition to the proximal weakness. gressive course of proximal-predominant High-arched palate and scoliosis are weakness. Hypotonia, gait disorder, and also noted. All patients have severe Gowers sign may be noted. Loss of am- atrioventricular conduction defects and bulation occurs early, around 10 to 12 years

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KEY POINTS h Identification of limb-girdle of age. Hypertrophy of muscles may be General Treatment Approach muscular dystrophy type noted. Cardiac involvement with left for the Dominant and 2V (Pompe disease, also ventricular dysfunction may be noted Recessive Forms of Limb-Girdle known as acid maltase as well. MRI of the brain is usually Muscular Dystrophies deficiency) is crucial since normal. CK is usually elevated three to All of the LGMD syndromes cause pro- IV enzyme replacement 50 times the normal level. Muscle biopsy gressive weakness, although the rates therapy is life-saving for shows a dystrophic picture. The gene infants with the disorder of progression vary considerably. Certain defect associated with this disease is in and improves ambulation LGMD syndromes have cardiac involve- and respiratory status in the isoprenoid synthase domain- ment, and affected patients are prone to adults with the disease. containing gene. cardiac conduction system defects, which h Pompe disease can Limb-girdle muscular dystrophy may lead to sudden death. Rarely, respi- have infantile-onset, type 2V (Pompe disease). Preisler and ratory insufficiency may occur, but usually 23 adolescent-onset, and colleagues have suggested that Pompe in late stages of the disease and in pa- adult-onset forms. disease (acid maltase deficiency or !- tients severely affected. In general, later- Respiratory insufficiency 1,4-glucosidase deficiency) should be onset disease predicts a better prognosis. and thigh adductor included as an LGMD because it was Except for LGMD2V (acid maltase defi- weakness is commonly identified in 8% of patients in a group of ciency), where enzyme replacement ther- seen in conjunction with unclassified LGMDs. Pompe disease can proximal weakness. apy is an available treatment option, no have infantile-onset, adolescent-onset, h specific disease-altering treatments cur- For most patients with a and adult-onset forms. Respiratory insuf- limb-girdle muscular rently exist for any of the LGMD1 or ficiency and thigh adductor weakness is dystrophy, physical therapy LGMD2 disorders, although corticoste- and occupational therapy commonly seen in conjunction with prox- roids have been reported helpful in should be encouraged to imal weakness. EMG reveals complex maintaining muscle function in LGMD2I. prevent the formation repetitive discharges and myotonic dis- However, novel therapies and treatment of contractures and to charges, specifically in thoracic paraspinal approaches are being explored in disor- maximize limb use. muscles. Muscle biopsy shows character- ders where inflammatory pathways may h In the subset of patients istic subsarcolemmal periodic acid- play a role (eg, dysferlinopathies). Exon- with a limb-girdle SchiffYpositive inclusions. The gene skipping strategies are also being ex- muscular dystrophy with defect lies in the deficiency of the acid plored in several disorders. heart involvement, serial !-glucosidase enzyme (GAA). Identifica- For most patients, physical therapy ECG and echocardiograms tion of this disorder is crucial since IV are mandatory for and occupational therapy should be en- monitoring cardiac status, enzyme replacement therapy is life-saving couraged to prevent the formation of and cardiac MRI is for infants with the disorder and improves contractures and to maximize limb use. increasingly being used to ambulation and respiratory status in Some patients with LGMD report cramps identify early myocardial adults with the disease. in the muscles, and symptomatic treat- fibrotic changes. Limb-girdle muscular dystrophy type ment may be provided with either baclo- 2W (LIMS2 proteinopathy). LGMD2W fen, tizanidine, or gabapentin. Genetic has onset in childhood with severe weak- counseling may be helpful for the affected ness noted proximally and with fairly slow families and the patients. progression. Cardiac involvement may In the subset of patients with heart happen in the third decade. Macroglossia, involvement (ie, LGMD types 1A, 1B, 1C, calf hypertrophy, and triangular tongue 2C, 2D, 2E), serial ECG and echocardio- are unique features of this condition. CK grams are mandatory for monitoring is elevated up to 25 times the normal cardiac status. In these patients, cardiac level. Muscle biopsy shows variability in MRI is increasingly being used to identify fiber size, internal nuclei, and increased early myocardial fibrotic changes. In these endomysial thickness. Defects in the patients, cardiologic follow-up is crucial LIMS2 gene underlie LGMD2W. for management of cardiomyopathy and

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS placement of intracardiac pacemaker or gene alterations in the X-linked dystro- h Duchenne muscular defibrillators when indicated. Respiratory phin gene (and resultant abnormal dystrophy is caused by involvement is common in most LGMD dystrophin protein), leading to a phe- alterations in the types, especially in those with severe pe- notypic spectrum that includes a milder dystrophin gene, and the ripheral weakness (including Pompe dis- BMD to severe DMD. However, dys- incidence has been ease), and pulmonary function tests are trophinopathies can also manifest as reported to be 1 per useful in identification of respiratory weak- isolated quadriceps myopathy, asymptom- 3500 male live births. ness. Noninvasive or invasive methods atic or symptomatic hyperCKemia, “aches, h Boys with Duchenne of ventilation are helpful in this clinical cramps, and pains” syndrome, rhabdo- muscular dystrophy setting, although which is preferable is myolysis, manifesting female carriers, usually present between ages 2 and 5 years. somewhat controversial. X-linked dilated cardiomyopathy, and disorders of cognition such as develop- X-Linked Limb-Girdle Muscular mental delay, attention deficit hyperactiv- Dystrophy ity disorder, and impaired intelligence. The X-linked LGMDs are summarized Dystrophin gene structure, clinical in Table 10-3. Only the dystrophino- and molecular genetic diagnosis. Muta- pathies will be discussed in this article. tions in the dystrophin gene, located on Dystrophinopathies. Dystrophinopa- the X chromosome, cause DMD/BMD. thies, as the name implies, result from The dystrophin gene is one of the largest

TABLE 10-3 Selected List of X-linked Limb-Girdle Muscular Dystrophiesa

Clinical Phenotype Gene Information Creatine Typical Kinase Condition Onset Progression Level Allelism Gene Protein Duchenne Early Slow to 100Y200X Becker muscular DMD Dystrophin muscular childhood moderate dystrophy dystrophy Becker muscular Late Slow 10Y15X Duchenne muscular DMD Dystrophin dystrophy childhood dystrophy Barth syndrome Infancy Moderate Normal X-linked dilated TAZ Tafazzin cardiomyopathy Emery-Dreifuss Variable; Slow 2Y10X X-linked sinus EMD Emerin muscular teenage node dysfunction dystrophy type 1 years

Emery-Dreifuss Adulthood Slow 2Y10X Hyaline body FHL1 Four-and- muscular myopathy; one-half- dystrophy type 6 X-linked myopa- LIM domains thy with postural 1 muscles atrophy

Danon disease Early Moderate 4Y35X X-linked vacuolar LAMP2 Lysosomal- childhood cardiomyopathy associated and myopathy membrane protein 2 a Modified with permission from Iyadurai SJ, Kassar D, Springer.3 B 2013 Springer Science+Business Media.

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KEY POINT Y h Boys with delayed motor genes in the human genome (by genomic opathy, or limb-girdle type weakness milestones, enlarged size, including large introns), spanning should raise suspicion of the condition. calves, proximal weakness about 2.3 megabases. The extent of Boys with delayed motor milestones, (including Gowers sign), intronic sequences is such that out of enlarged calves, proximal weakness (in- and elevated creatine the whole transcript (preYmessenger RNA), cluding Gowers sign), and elevated CK kinase levels (100 to the 79 exons only make 0.6% of the gene. levels (100 to 200 times the normal level) 200 times the normal level) The dystrophin gene encodes a major should be suspected having of DMD. should be suspected of 3685 amino acid, 427 kD skeletal muscle Diagnosis relies on DNA analysis of the having Duchenne muscular dystrophy. protein. Eight other promoters direct dystrophin gene. Deleterious DNA alter- transcription of seven other transcripts, ations include deletions (50% to 60%; in with expression in skeletal, cardiac, and frame or out of frame), sequence alterations smooth muscle cells and in multiple other (20% to 35%), duplications (5% to 10%), or tissue cell types including the brain. The leading missense and nonsense mutations, dystrophin protein connects the contrac- splice siteYaltering mutations, and cryptic tile apparatus to the extracellular matrix intronic mutations. Deletions and duplica- via the muscle membrane. tions may be detected by multiplex poly- The dystrophinopathies are inherited merase chain reaction (PCR), multiplex in an X-linked recessive fashion; ie, a ligation-dependent probe amplification, male child receives (inherits) the muta- and chromosome microarray techniques; tion from the mother. However, in a sequence alterations may be detected by sizeable minority of cases (20% to 30%), Sanger or next-generation sequencing. the mutation identified in the affected Epidemiology. The incidence of DMD son is not identified in the mother by in live male births is estimated between 1 gene testing. In such cases, the mutation in 3500 and 1 in 5000. BMD is much less is thought to arise de novo or reflect common with a prevalence of 1 in 17,500 germline mosaicism. In a mother who to 1 in 50,000. As expected, the preva- tests negative for the mutation because lence of BMD is higher in comparison to of germline mosaicism, the possibility of that of DMD mainly because of the delivering another affected boy in a shortened survival in the latter group. subsequent pregnancy is not excluded, Clinical features. Boys with DMD and caution should be used in genetic present at a young age, usually between counseling in such cases. Prenatal diag- 2 and 5 years of age with delayed motor nosis or preimplantation genetic testing milestones, falls, and difficulties running is available for mothers who test nega- and jumping. Prominent head lag, calf tive for their son’s mutation or in whom enlargement (often termed pseudo- germline mosaicism is suspected. Female hypertrophy, a partial misnomer as the carriers may exhibit a DMD/BMD-like enlargement results from a combination phenotype (including dilated cardiomy- of fibrotic replacement and true fiber opathy) due to random lyonization of the hypertrophy), and Gowers sign are almost X chromosome (heterochromatinization always seen. Progression is steady, and or inactivation of the X chromosome). If untreated patients typically are in wheel- lyonization occurs to the chromosome chairs by age 12. Clinically, respiratory and containing the wild-type dystrophin, and cardiac issues ensue. By classic conven- the chromosome containing the mutant tion, boys still walking after their 16th dystrophin is expressed, a DMD/BMD- birthday are considered to have BMD, like phenotype may be observed in the and boys who stop walking by age 12 are female patient. considered to have DMD. This distinction A positive family history, in conjunc- is in some ways artificial since corticoste- tion with an elevated CK level, cardiomy- roid therapy may prolong ambulation by

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS 1 to 3 years, thus blurring the clinical hypertrophic cardiomyopathy, and con- h Steroids help patients distinction between BMD and DMD. gestive heart failure are common. Regular with Duchenne Patients with dystrophinopathy have surveillance with ECG, long-term heart mon- muscular dystrophy highly elevated CKs, usually 100 to itoring, and echocardiogram in conjunc- prolong ambulation and 200 times the normal level. EMG usually tion with a cardiologist is recommended. increase longevity. shows an irritable, proximal-predominant Angiotensin-converting enzyme inhibitors h Cardiomyopathy is myopathy. Currently, muscle biopsy is and beta-blockers have been proven to common in patients very seldom indicated but will show be beneficial. Lung functions decline with with Duchenne rounded fibers, significant size variability, disease progression as well. Pulmonary muscular dystrophy. increased endomysial thickness, hyper- functions can be followed with time, and contracted fibers, inflammatory cells, and necessary noninvasive/invasive strategies occasional ring fibers. Immunohisto- may be employed (in conjunction with chemical stains with antibodies generated a pulmonologist) to improve the quality against the various epitopes (DYS3, DYS1, of life. In consultation with orthopedic and DYS2) may show absent staining in surgeons, scoliosis may be surgically certain fibers. fixed if indicated and necessary. Patients Dystrophinopathies are multisystem with DMD demonstrate calf hypertro- disorders with multidisciplinary teams phy (Figure 10-3) in earlier stages and necessary for optimal management. Pa- contractures in later stages (Figure 10-4) tients with dystrophinopathies eventually and may experience severe nighttime have involvement of the cardiac, pulmo- cramps. Cramps may be readily treated nary, musculoskeletal, and cognitive sys- with nighttime stretches and gabapentin. tems. Cardiac involvement progresses Several types of cognitive issues, including with progression of the muscle disease. attention deficit disorder, autism spectrum Sinus tachycardia, arrhythmia, dilated or disorders, obsessive-compulsive disorder,

FIGURE 10-3 Images of a 6-year-old boy with Duchenne muscular dystrophy showing calf hypertrophy evaluated from posterior view (A) and from lateral view, further accentuated by standing on toes (B).

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the quality of life of the patient and the family members (Case 10-3). Becker muscular dystrophy. In general, patients with BMD display a milder phenotype in comparison to patients with DMD, and the weakness onset is also later. Lateonsetofweaknessisassociatedwith a milder phenotype. Despite the milder weakness noted in the skeletal muscles, the cardiac muscles are affected just the same as in patients with DMD. Therefore, treatments for cardiac management should not be delayed. Breathing functions are affected as in patients with DMD, butatalatertimecourse.Somepatients with BMD may require noninvasive ventilation. Although the benefit of corticoste- FIGURE 10-4 Contractures in a patient with Duchenne muscular dystrophy. Ankle and foot roids in patients with BMD is unclear, contractures are common in the later course of Duchenne muscular dystrophy. some clinicians employ prednisone at 0.75 mg/kg/d in patients with BMD as well. Female carriers of dystrophin muta- KEY POINT and depression are commonly seen. tions. Female carriers of the X-linked h Female carriers of Referral to a psychiatrist and treatment of dystrophin mutations may present with dystrophin mutations may these disorders are helpful in improving a DMD-like phenotype. However, it is present with a Duchenne muscular dystrophyYlike phenotype and may have cardiomyopathy as well. Case 10-3 A 5-year-old boy was brought by his mother to his pediatrician because of ‘‘running difficulties.’’ The mother noted that the boy was the product of a normal pregnancy, but was not able to walk until 16 months of age. She also had noticed prominent calves in the boy. She volunteered the history of her brotherwhohadhadsimilarcalvesandhaddiedattheageof12withheart complications. The patient’s vital signs were significant for mild hypertension. Examination revealed normal cranial nerves, proximal weakness of the upper and lower extremities, calf hypertrophy, diminished reflexes (except at the ankles), normal sensation, and normal plantar responses bilaterally. Laboratory evaluation revealed an elevated creatine kinase level at 200 times the upper limit of normal. Based on the clinical presentation and family history, Duchenne muscular dystrophy (DMD) was suspected, and the patient was referred to a local neuromuscular expert for further evaluation. Gowers sign (Supplemental Digital Content 10-1, links.lww.com/CONT/A210) was noted on that examination. DNA analysis of the dystrophin gene revealed a deletion of exons 21 to 24, leading to premature termination of the dystrophin protein, and a diagnosis of DMD was confirmed. The patient was started on prednisone 1 mg/kg/d, and a cardiology referral was made. Comment. This case demonstrates a classic presentation of DMD in a young boy with early-onset motor delay and calf hypertrophy. Whenever high creatine kinase, motor delay, and calf hypertrophy are encountered, dystrophinopathy should be considered.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT more common in affected women at ages mutation either by supplying additional h Gene therapy, 30 or older. In subtle cases, the manifes- wild-type dystrophin or minidystrophin exon-skipping strategies, tation may be related to asymptomatic or under high-expression promoters (gene and suppression of symptomatic hyperCKemia or nocturnal therapy strategies), or “reading” through premature termination cramps. Although these symptoms may premature stop codons introduced by approaches are being be benign, dilated cardiomyopathy and missense mutations (premature termina- developed for treatment left ventricular dilatation are noted in 20% tion elimination), or skipping the exons of Duchenne muscular dystrophy. of the carriers.24 These patients should be containing out-of-frame mutations (exon referred to cardiologists as well for opti- skipping technology). Clinical trials are mal management and treatment. For this underway to assess the efficacy of these reason, from a genetic standpoint, female specific therapeutic agents in patients first-degree relatives of male patients with with DMD/BMD, with several companies DMD/BMD and sisters of mothers of male seeking approval by the US Food and patients with DMD/BMD should be of- Drug Administration (FDA) for specific fered testing for the dystrophin mutation exon skipping agents. At the time of this identified in the affected male relative. writing, the FDA has approved the first Treatment of dystrophinopathies. exon-skipping medication, eteplirsen, for As with the other LGMDs, no definitive use in a select subset of patients with treatment for dystrophinopathies cur- DMD. This medication enables preY rentlyexists.Inadditiontothegeneral messenger RNA to skip exon 51 in the outline for treatments described previously dystrophin reading frame, producing for all of the LGMDs, patients with DMD truncated dystrophin. Approximately (and probably BMD) respond to treatment 20% of boys with DMD have mutations with various regimens of corticosteroids in exon 51 of the dystrophin gene and may (prednisone, deflazacort, or prednisolone) benefit from this treatment. However, with unequivocal benefit in prolonging although the medication has been ap- ambulation, delaying the decline of muscle proved by the FDA, there remains some function, reducing falls, and delaying controversy within the academic commu- pulmonary and (probably) cardiac com- nity over whether the studies to date plications.25 Corticosteroids (mainly demonstrate enough clinical benefit to prednisone in the United States) are justify the approval. The study that was usually started in patients of ages 5 and done contained only 12 patients and used up, but some clinicians choose to start historical controls to assess changes in a corticosteroid treatment at diagnosis, 6-minute walk test, which was the func- even at younger ages. Prednisone treat- tional end point. Follow-up biopsies did ment of 0.75 mg/kg/d has been used show a significant increase in dystrophin, quite widely. Other regimens involve com- but this was not clearly shown to correlate bining this weekly dose to be distributed with functional improvement.26,27 on Saturdays and Sundays. Prophylaxis with calcium, vitamin D, proton pump CONCLUSION inhibitors, and antidepressants may be The LGMDs are a heterogeneous group necessary, concomitant with steroid treat- of disorders that, as the name suggests, ment. A large international FOR-DMD manifest as weakness in the shoulder (Finding the Optimal Steroid Regimen girdle and the pelvic girdle muscles. for Duchenne Muscular Dystrophy) study Dominant, recessive, and X-linked is currently comparing deflazacort and forms of LGMDs have been described. prednisone regimens for managing DMD. The current classification system of In addition, novel treatment method- LGMDs uses the notation type 1 for ologies have relied on correcting the DMD dominant forms and type 2 for recessive

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forms. Physical characterization and di- generationYbased multigene LGMD agnostic imaging may be helpful in panel gene-testing options are available identifying the specific form. Specific to help with diagnosis. Multigene panel distinguishing characteristics (Table 10-4), testing combined with traditional involvement of muscle pattern on phenotype-based approaches have MRI (Table 10-5) and muscle biopsy been instrumental in identifying newer features (Table 10-6) may be helpful in LGMDs. With the advancement of delineating between the subtypes. How- sequencing technologies, the list of ever, definite diagnosis is achieved by LGMDs has grown and is expected to genetic testing. Several commercial next grow. Understanding of gene functions

TABLE 10-4 Distinguishing Features of Limb-Girdle Muscular Dystrophies

Type Feature LGMD1A (myotilinopathy) Upper extremities distal weakness and contractures, dysarthria, palatal hypophonia, footdrop, and areflexia

LGMD1B (laminopathy) Contractures and cardiac conduction defects

LGMD1C (caveolinopathy) Rippling muscles and muscle hypertrophy

LGMD1E (desminopathy) Facial weakness and cardiac conduction defect LGMD1F (transportinopathy) Early respiratory muscle involvement

LGMD1G (HNRPDL Finger and toe flexion limitation proteinopathy)

LGMD2A (calpainopathy) Contractures and atrophy of shoulder and pelvic girdle muscles LGMD2B (dysferlinopathy) Medial gastrocnemius atrophy

LGMD2C, LGMD2D, LGMD2F Tongue hypertrophy (sarcoglycanopathies)

LGMD2H (sarcotubular myopathy, Scapular winging and calf hypertrophy TRIM32 proteinopathy)

LGMD2I (fukutinopathy) Tongue and calf hypertrophy, cardiac and respiratory muscle involvement

LGMD2L (anoctaminopathy) Asymmetric atrophy of muscles, mandibular dysplasia

LGMD2R (desminopathy) Facial weakness, respiratory muscle involvement, high-arched palate

LGMD2S (TRAPPC11 Scapular winging, hyperkinetic movements proteinopathy)

LGMD2V (acid maltase deficiency) Proximal weakness and respiratory insufficiency

LGMD2W (LIMS2 proteinopathy) Calf and tongue hypertrophy and triangular tongue

Dystrophinopathy Calf hypertrophy, distal contractures, preserved ankle reflex despite the weakness LGMD = limb-girdle muscular dystrophy.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 10-5 Pattern of Affected Thigh Muscles in Magnetic Resonance Imaging Evaluation of Patients With Limb-Girdle Muscular Dystrophy

Type Affected Thigh Muscle(s) LGMD1A (myotilinopathy) Adductor magnus, biceps femoris, semimembranosus, vastus medialis, vastus intermedius

LGMD1B (laminopathy) Adductor magnus, biceps femoris, vastus medialis and vastus lateralis

LGMD1C (caveolinopathy) Normal at the level of the thigh

LGMD1D (HSP40 Adductor magnus, biceps femoris, semimembranosus, proteinopathy) adductor longus

LGMD1E (desminopathy) Semitendinosus, sartorius, gracilis LGMD1F Vastus lateralis (transportinopathy)

LGMD2A (calpainopathy) Adductor magnus, semimembranosus LGMD2B (dysferlinopathy) Adductor magnus, vastus lateralis, semimembranosus

LGMD2I (fukutinopathy) Adductor magnus, biceps femoris, semimembranosus

LGMD2L Adductor magnus, biceps femoris, semimembranosus, (anoctaminopathy) semitendinosus, rectus femoris, vastus medialis and vastus lateralis

LGMD2V (acid maltase Adductor magnus, vastus medialis, vastus intermedius, deficiency) biceps femoris

Dystrophinopathy (Duchenne Adductor magnus, vastus medialis and vastus lateralis, muscular dystrophy) rectus femoris

Dystrophinopathy (Becker All anterior and posterior compartment muscles, muscular dystrophy) sparing sartorius, gracilis LGMD = limb-girdle muscular dystrophy.

TABLE 10-6 Muscle Biopsy Features of Limb-Girdle Muscular Dystrophies

Type Feature(s) LGMD1A, LGMD1E, LGMD1F, LGMD1G Rimmed or autophagic vacuoles

LGMD1A, LGMD2R Hyaline inclusions, spheroid bodies LGMD1B Mislocalization of lamin

LGMD1C, LGMD2A, LGMD2B, Inflammation sarcoglycanopathies, LGMD2L, dystrophinopathies

LGMD1E Eosinophilic inclusions, cytoplasmic bodies LGMD1F, LGMD1H Central nuclei Continued on page 1976

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TABLE 10-6 Muscle Biopsy Features of Limb-Girdle Muscular Dystrophies Continued from page 1975

Type Feature(s) LGMD1G Atrophic angular fibers LGMD2A Lobulated fibers

LGMD2A Eosinophilic infiltrates

LGMD2A Amyloid deposition (Congo red positivity)

LGMD2H Small rounded vacuoles in type 2 fibers LGMD2I Type 1 predominance

LGMD2Q, LGMD2T, LGMD2W Increased internal nuclei

LGMD2R, LGMD2V Periodic acid-SchiffYpositive or Ynegative, amorphous subsarcolemmal inclusions

Dystrophinopathies Hypercontracted fibers

Dystrophinopathies Ring fibers LGMD = limb-girdle muscular dystrophy.

and mutation pathology will give insight 2. Ghaoui R, Cooper ST, Lek M, et al. Use of into the disease process and possible whole-exome sequencing for diagnosis of limb-girdle muscular dystrophy: therapy in the future. Given the lack of outcomes and lessons learned. JAMA Neurol definitive treatment, as of now, only strat- 2015;72(12):1424Y1432. doi:10.1001/ egies for management and supportive jamaneurol.2015.2274. treatment have been suggested as guide- 3. Iyadurai SJ, Kassar D. Limb-girdle muscular 25,28 dystrophies. In: Katirji B, Kaminski HJ, lines. However, several clinical trials Ruff RJ, editors. Neuromuscular disorders in utilizing various therapeutic approaches clinical practice. 2nd ed. New York, NY: are currently underway. The day of Springer, 2013:1193Y1212. definitive treatments for these inherited 4. Hauser MA, Conde CB, Kowaljow V, et al. disorders is not far away. Myotilin mutation found in second pedigree with LGMD1A. Am J Hum Genet 2002; 71(6):1428Y1432. doi:10.1086/344532.

VIDEO LEGEND 5. Verhaert D, Richards K, Rafael-Fortney JA, Supplemental Digital Content 10-1 Raman SV. Cardiac involvement in patients Gowers sign. A5-year-oldboywith with muscular dystrophies: magnetic resonance imaging phenotype and genotypic Duchenne muscular dystrophy demon- considerations. Circ Cardiovasc Imaging strating the Gowers sign. Notice how he 2011;4(1):67Y76. doi:10.1161/CIRCIMAGING. “climbs on himself” to stand up. 110.960740. 6. Harms MB, Sommerville RB, Allred P, et al. links.lww.com/CONT/A210 Exome sequencing reveals DNAJB6 B 2016 American Academy of Neurology. mutations in dominantly-inherited myopathy. Ann Neurol 2012;71(3):407Y16. doi:10.1002/ ana.22683.

REFERENCES 7. Messina DN, Speer MC, Pericak-Vance MA, 1. Ankala A, da Silva C, Gualandi F, et al. McNally EM. Linkage of familial dilated A comprehensive genomic approach for cardiomyopathy with conduction defect and neuromuscular diseases gives a high muscular dystrophy to chromosome 6q23. diagnostic yield. Ann Neurol 2015;77(2): Am J Hum Genet 1997;61(4):909Y917. 206Y214. doi:10.1002/ana.24303. doi:10.1086/514896.

1976 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 8. Weihl CC, Iyadurai S, Baloh RH, et al. Autophagic dystrophy: titin is the candidate gene. vacuolar pathology in desminopathies. Neurology 2001;56(7):869Y877. doi:10.1212/ Neuromuscul Disord. 2015;25(3):199Y206. WNL.56.7.869. doi:10.1016/j.nmd.2014.12.002. 20. Dinçer P, Balci B, Yuva Y, et al. A novel form 9. Bisceglia L, Zoccolella S, Torraco A, et al. A new of recessive limb girdle muscular dystrophy locus on 3p23-p25 for an autosomal-dominant with mental retardation and abnormal limb-girdle muscular dystrophy, LGMD1H. expression of alpha-dystroglycan. Neuromuscul Eur J Hum Genet 2010;18(6):636Y641. Disord 2003;13(10):771Y778. doi:10.1016/ doi:10.1038/ejhg.2009.235. S0960-8966(03)00161-5.

10. Gallardo E, Saenz A, Illa I. Limb-girdle 21. Godfrey C, Clement E, Mein R, et al. Refining muscular dystrophy 2A. Handb Clin genotype phenotype correlations in muscular Neurol 2011;101:97Y110. doi:10.1016/ dystrophies with defective glycosylation of B978-0-08-045031-5.00006-2. dystroglycan. Brain 2007;130(pt 10):2725Y2735. 11. Pathak P, Sharma MC, Sarkar C, et al. Limb doi:10.1093/brain/awm212. girdle muscular dystrophy type 2A in India: a 22. Godfrey C, Escolar D, Brockington M, study based on semi-quantitative protein et al. Fukutin gene mutations in analysis, with clinical and histopathological steroid-responsive limb girdle muscular Y correlation. Neurol India 2010;58(4):549 554. dystrophy. Ann Neurol 2006;60(5):603Y610. doi:10.4103/0028-3886.68675. doi:10.1002/ana.21006. 12. Merlini L, Kaplan JC, Navarro C, et al. 23. Preisler N, Lukacs Z, Vinge L, et al. Late-onset Homogeneous phenotype of the gypsy Pompe disease is prevalent in unclassified limb-girdle MD with the gamma-sarcoglycan limb-girdle muscular dystrophies. Mol Genet C283Y mutation. Neurology 2000;54(5): Metab 2013;110(3):287Y289. doi:10.1016/ 1075Y1079. doi:10.1212/WNL.54.5.1075. j.ymgme.2013.08.005. 13. Moreira ES, Vainzof M, Marie SK, et al. The 24. Hoogerwaard EM, van der Wouw PA, seventh form of autosomal recessive limb-girdle Wilde AA, et al. Cardiac involvement in muscular dystrophy is mapped to 17q11-12. Am carriers of Duchenne and Becker J Hum Genet 1997;61(1):151Y159. muscular dystrophy. Neuromuscul Disord 14. Moreira ES, Wiltshire TJ, Faulkner G, et al. 1999;9(5):347Y351. doi:10.1016/ Limb-girdle muscular dystrophy type 2G S0960-8966(99)00018-8. is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat 25. Abbs S, Tuffery-Giraud S, Bakker E, et al. Genet 2000;24(2):163Y166. doi:10.1086/513889. Best practice guidelines on molecular diagnostics in Duchenne/Becker muscular 15. Frosk P, Del Bigio MR, Wrogemann K, dystrophies. Neuromuscul Disord 2010;20(6): Greenberg CR. Hutterite brothers both affected 422Y427. doi:10.1016/j.nmd.2010.04.005. with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. Eur J Hum 26. Mendell JR, Goemans N, Lowes LP, et al; Genet 2005;13(8):978Y982. doi:10.1038/ Eteplirsen Study Group and Telethon Foundation sj.ejhg.5201436. DMD Italian Network. Longitudinal effect of eteplirsen versus historical control on ambulation 16. Yilmaz A, Gdynia HJ, Ponfick M, et al. The in Duchenne muscular dystrophy. Ann Neurol proteoglycan-dystrophin complex in genetic 79(2):257Y271. doi:10.1002/ana.24555. cardiomyopathiesVlessons from three siblings with limb-girdle muscular dystrophy-2I (LGMD-2I). 27. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al; Clin Res Cardiol 2011;100(7):611Y615. doi:10.1007/ Eteplirsen Study Group. Eteplirsen for the s00392-011-0291-6. treatment of Duchenne muscular dystrophy. Ann Neurol 74(5):637Y647. doi:10.1002/ 17. Bushby K, Anderson LV, Pollitt C, et al. ana.23982. Abnormal merosin in adults. A new form of late onset muscular dystrophy not linked 28. Narayanaswami P, Weiss M, Selcen D, et al. to chromosome 6q2. Brain 1998;121(pt 4): Evidence-based guideline summary: diagnosis and 581Y588. doi:10.1093/brain/121.4.581. treatment of limb-girdle and distal dystrophies: report of the guideline development 18. Palmieri A, Manara R, Bello L, et al. Cognitive subcommittee of the American Academy of profile and MRI findings in limb-girdle Neurology and the practice issues review panel of muscular dystrophy 2I. J Neurol 2011;258(7): the American Association of Neuromuscular & 1312Y1320. doi:10.1007/s00415-011-5930-3. Electrodiagnostic Medicine. Neurology 19. Haravuori H, Vihola A, Straub V, et al. Secondary 2014;83(16):1453Y1463. doi:10.1212/ calpain3 deficiency in 2q-linked muscular WNL.0000000000000892.

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