Neurol Clin N Am 21 (2003) 795816

Muscular dystrophy overview: genetics and diagnosis

Katherine D. Mathews, MD
Department of Pediatrics, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52240, USA

Advances in molecular genetics have had a dramatic impact on the study of muscular dystrophies, which are by denition inherited disorders. Duchenne muscular dystrophy (DMD) was the rst disease gene cloned using modern methods [1]. The impact of molecular genetics on clinical medicine has been largely in diagnostic capability. It is no longer necessary to perform electromyographic studies on a child with muscular dystrophy, and many times a muscle biopsy can be avoided through less invasive diagnostic tests. This review focuses on genetics and molecular diagnosis in muscular dystrophies, with emphasis on those that aect children. Although better understanding of pathophysiology has not yet led to direct treatment, treatment of patients who have muscular dystrophy has evolved in the past 10 years. Patients are living longer and management of complications of disease is improved. Treatment of DMD and Becker muscular dystrophy (BMD) is discussed, because those are the disorders about which the most is known regarding intervention. Many of the general principles apply to other forms of muscular dystrophy.

Overview of physiology and muscular dystrophy Most of the congenital muscular dystrophies (CMDs), some of the limb girdle muscular dystrophies (LGMDs) and DMD and BMD are caused by disruptions of the dystrophin-glycoprotein complex (DGC). This transmembrane complex probably has several functions, including structural support and signaling across the membrane. Components of the complex found associated with the cytoplasmic face of the cell membrane include dystrophin,

E-mail address: katherine-mathews@uiowa.edu (K.D. Mathews). 0733-8619/03/$ - see front matter 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0733-8619(03)00065-3

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syntrophin, neuronal nitric oxide synthase (nNOS), and dystrobrevin. The sarcoglycans (a, b, d, and c) and b-dystroglycan span the membrane, and adystroglycan connects to the extracellular matrix, including merosin [2]. A simplied diagram of the elements of the DGC directly involved in muscular dystrophy is shown in Fig. 1. Most of these disorders have markedly elevated creatine kinase (CK) values during the period of maximal muscle breakdown. They are characterized by a mismatch between muscle membrane breakdown and repair. Facioscapulohumeral muscular dystrophy (FSHD), Emery Dreifuss muscular dystrophy (EDMD), oculopharyngeal dystrophy, and myotonic dystrophy are molecularly complex disorders that disrupt gene expression or chromosomal organization. This process is best understood for the myotonic dystrophies. It remains unclear why muscle is particularly aected in these disorders, although they all involve other systems to some degree. These disorders generally have normal or slightly elevated CK corresponding to a slow degeneration of muscle. The histopathology in this group of disorders is less abnormal than in the CMD/DMD/LGMD group.

Congenital muscular dystrophies CMDs refers to a group of diseases characterized by signicant muscular weakness in early infancy (usually obvious at birth) accompanied by very high CK in the neonatal period. A normal CK immediately after delivery can be as high as 700 but falls to a normal range by 6 to 10 weeks [3]. Children with CMD have CK elevation in the thousands, reecting widespread muscle necrosis in the perinatal period. Later in life these patients

Fig. 1. Simplied diagram of the DGC. Transmembrane elements include b-dystroglycan and the sarcoglycans (a, b, d, and c). Dystrophin localizes to the cytoplasmic face of the muscle cell membrane. The glycosylated proteins a- and b-dystroglycan connect dystrophin to a component of the extracellular matrix, merosin (also called laminin 2), composed of a, b, and c chains of laminin. Abnormality (mutation or abnormal glycosylation) of each of the elements pictured except b-dystroglycan is known to result in muscular dystrophy.

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often have normal or low CK because of a lack of residual muscle and limited mobility. Patients who have CMD have slow or minimal progression of weakness in general. There are two broad categories of CMD: those with major brain malformation and those without brain malformation (Table 1). The CMDs of known genetic basis all have an abnormality of the connection between the extracellular matrix and the DGC. All the CMDs described in this article have autosomal recessive inheritance. Merosin-absent CMD Children with this condition have nonprogressive profound muscle weakness. Most do not walk independently. They generally do not worsen over time and do not have early death. Cardiomyopathy has been reported but is not a prominent clinical feature [4]. MRI of the brain shows striking white matter hyperintensity on T2 images. These changes are not always present in infancy but are clear when myelination is mature. There is no structural abnormality of brain and aected children typically have normal academic performance. Neuropsychologic testing shows minor perceptomotor decits in a small group of children with merosin deciency [5], and somatosensory and visual evoked potentials are abnormal [6]. There is a slightly increased incidence of seizures and mental retardation in children lacking merosin [7]. Merosin, or the a2 chain of laminin, is a component of the extracelllular matrix that connects to a-dystroglycan. The a2 chain of laminin also is found in components of the dermis, so diagnosis can be made by immunostaining a full thickness skin biopsy (Fig. 2) or muscle biopsy. DNA-based diagnosis is not clinically available, because the gene is large and there are no mutational hot spots. Partial merosin deciency Some patients have a partial deciency of merosin by immunostaining. These patients have either a mild mutation of merosin or a secondary deciency of merosin. Two genes that are known to lead to secondary deciencies of merosin are fukutin and fukutin-related protein (FKRP). CMD with fukutin-related protein (FKRP) FKRP mutations lead to a variety of phenotypes. The original description was of a CMD with partial merosin deciency and no brain malformation. Children with this phenotype have normal intelligence. Most aected children are unable to walk independently. The second phenotype described with FKRP mutations was that of LGMD2Ia typical LGMD with onset of weakness in adolescence or young adulthood. Most recently, two patients were described with CMD, cerebellar cysts, mild mental retardation, and homozygous FKRP mutations [8]. Thus, this gene needs to

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Table 1 Congenital muscular dystrophy Muscle only Brain MRI White matter abnormal Elevated early CK Other clinical features Allelic disorders

Disease name Normal

Abnormal protein

Gene location IQ

Merosin-absent CMD

Merosin; a2 chain 6q2 of laminin

CMD Normal Normal Normal

Rigid spine disease (RSMD1) Ullrich myopathy Collagen VI

Fukutin-related protein Selenoprotein N

19q13.3

Normal

Normal

LGMD 21 Bethlem myopathy

1p35-36

21q22.3 Normal (COL6A1 A2) & 2q37 (COL6A3) Complex CMD Brain MRI CK

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Partial decencies lead to milder disease; secondary deciency possible; heart may be aected Elevated Spine rigidity, early restrictive lung disease Normal Spine rigidity, early restrictive lung disease Mildly Very early contractures elevated including arthrogryposis, distal hyperlaxity, at feet

Disease name

Primary genetic defect

Gene location IQ

Other clinical features Eye may be unaected, myopia, cataracts, optic nerve atrophy Almost exclusively in Japanese population

Allelic disorders

Fukuyama CMD

Fukutin

9q31-33

Mild to Cobblestone cortex Elevated moderate malformation, cerebellar MR and brainstem hypoplasia

Muscle-eye-brain disease

POMGnT1

1p32

Myopia, noncongenital cataracts, ganglion cell and optic nerve atrophy. Common in Finland Retinal abnormality, myopia, noncongenital cataracts, ganglion cell and optic nerve atrophy, Peters anomaly

Walker Warburg syndrome

POMT1, others

9q34

Severe MR Cobblestone cortex, Elevated pachygyria/agyria, cerebellar and brainstem hypoplasia, mild hydrocephalus Elevated Severe MR Cobblestone lissencephaly, severe hydrocephalus, abnormal white matter, polymicrogyria, cerebellar and brainstem hypoplasia, midline fusion, abnormal corpus callosum K.D. Mathews / Neurol Clin N Am 21 (2003) 795816 799

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Fig. 2. Merosin immunostaining of full thickness skin biopsies from a healthy control (A) and a patient who has merosin-negative CMD (B). The arrows indicate the basement membrane at the dermal-epidermal junction.

be considered with almost any form of unexplained dystrophy. The exact function of FKRP is not known, but as the name implies, it is in a family with fukutin and both have sequence homology with glycosyltransferases [9]. FKRP is a relatively small gene and sequence analysis is straightforward. It is likely that this will be commercially available soon and FKRP may join dystrophin as a gene analyzed early in the evaluation of a weak patient who has elevated CK. Congenital muscular dystrophy with rigid spine disease CMD with rigid spine disease (RSMD1) is a rare form of CMD distinguished by truncal involvement that exceeds limb weakness. These patients develop weakness and hypotonia in either infancy or early childhood. Most are ambulatory and facial weakness is common. They share the distinctive feature of early spine rigidity (manifested by inability to ex the neck, for example) with early scoliosis. They also have respiratory insuciency that can precede signicant limb weakness. CK is normal or minimally elevated, but muscle is dystrophic on biopsy. CT or MRI of the thighs shows early involvement of the adductors, sartorius, and biceps femoris [10,11]. RSMD1 localizes to 1p35-36, with mutations in selenoprotein N (SEPN1) [12]. It is not yet known why SEPN1 mutations lead to muscular dystrophy, but Moghadaszadeh et al suggest it might be required to maintain a normal oxidative state in muscle [13]. Ullrich myopathy Ullrich myopathy is characterized by very early proximal contractures combined with excessive distal mobility. Weakness and contractures are stable or slowly progressive. Ullrich myopathy is caused by mutations in one of the polypeptide chains that assemble to form collagen VI and aected individuals have reduced or absent immunostaining for collagen VI in muscle [1416]. Collagen VI interacts extensively with the extracelluar matrix. The dystrophic mechanism has not yet been claried, but recent work suggests

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that the muscular dystrophy results from disrupted cell adhesion [17]. Ullrich myopathy is allelic with Bethlem myopathy, a later onset myopathy. Congenital muscular dystrophy with brain malformation CMDs with brain malformation traditionally have been dicult to distinguish on clinical grounds [18]. The recent identication of three distinct genes has provided a laboratory test to test the accuracy of the clinical distinctions. The unifying feature of this group of CMDs is a disorder of neuronal migration referred to as cobblestone cortex [9]. Cobblestone cortex results in lissencephaly in the most severe form. All the CMDs with brain malformation identied thus far result in abnormal glycosylation of a-DG (see Fig. 1). This disrupts the interaction between the membrane and the extracellular matrix in brain and muscle [9]. Fukuyama congenital muscular dystrophy Fukuyama is the most mild of the CMDs with brain malformation. It is common in the Japanese population (estimated carrier frequency of 1 in 90 [19,20]). Most aected children never learn to walk. Mental retardation is universal, with IQs between 30 and 50. Seizures occur in approximately half of patients. Brain MRI shows disordered neuronal migration with pachygyria and polymicrogyria. Variable ndings include abnormal white matter intensity on T2-weighted images, hypoplasia of the pons, and cerebellar cysts [21]. Eye abnormalities are variable and children typically maintain some ability to see. The genetic basis of FCMD was identied in 1998. The mutated gene encodes a protein called fukutin. The common mutation is a single retrotransposon insertion in the 39 untranslated region believed to aect the stability of the transcript, resulting in a marked reduction in the amount of fukutin detected within the cell [22]. Virtually all patients are at least heterozygous for this founder mutation. Point mutations also are seen, but these are rare, hence the rarity or absence of this disease outside of the Japanese population. Deciency of fukutin results in decreased glycosylation of a-dystroglycan [9,23]. Muscle-eye-brain disease Muscle-eye-brain (MEB) disease is a recessive disorder most common in the Finnish population, although it is seen in patients around the world [9]. It is generally intermediate in severity between FCMD and Walker Warburg syndrome (see following discussion). Characteristics dening MEB disease include congenital hypotonia and weakness, survival past age 3 and often into adulthood, mild to moderate hydrocephalus, cobblestone cortex, and mild to moderate cerebellar or vermis hypoplasia. CK is elevated from 10 to 20 times normal in infancy and falls with age, and muscle biopsy shows typical dystrophic features. Ocular abnormalities are moderate in severity, including severe myopia, microphthalmia, colobomata, and optic nerve

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hypoplasia [24,25]. The abnormal gene in MEB is a ubiquitously expressed glycosyltransferase, POMGnT1. Mutation of this gene results in a loss of function of the enzyme [26]. Walker Warburg syndrome Walker Warburg syndrome is the most severe of the CMDs aecting brain formation. It is characterized by severe hydrocephalus often associated with other brain malformations including occipital encephalocele, eye abnormalities similar to those described in patients who have MEB, and muscular dystrophy. These patients typically do not live beyond 3 years. The dysfunctional protein in some of these patients is POMT1, an O-mannosyltransferase. Mutations in POMT1 were found in 6 of 30 unrelated patients, suggesting that this is a genetically heterogeneous disorder [27]. Duchenne and Becker muscular dystrophies The dystrophinopathies (DMD and BMD) are the prototypical LGMDs. Diagnostic evaluation starts with the readily available standard DNA testing that uses multiplex polymerase chain reaction to screen for a large-scale deletions or duplications in the dystrophin gene. This test is abnormal in approximately 70% of patients who have DMD or BMD. If this screen is negative, the next step is generally muscle biopsy and immunostaining or Western blot analysis for the dystrophin protein. A recent adjunct to the biopsy is genetic analysis for point mutations [28]. Several approaches to point mutation screening have been developed and are available on a research or commercial basis. This information is most useful for genetic counseling at present, but it may have an impact on treatment in the future, because some small mutations may be more amenable to either drug treatment or genetic therapeutics. Females who carry a dystrophin mutation have typical muscular dystrophy if there is an abnormality of X inactivation or a chromosomal anomaly, such as XO. These situations are rare. In the usual situation, females are clinically normal through childhood. In older adulthood, testing is likely to demonstrate abnormal cardiac function, but this also is not usually clinically symptomatic. Management of Duchenne and Becker muscular dystrophy patients Management of DMD continues to be largely supportive. Physical therapy, including night splints (ankle foot orthoses [AFOs]) and daily stretching can eliminate the need for surgical release of contractures [29]. Regular use of an incentive spirometer at home may prolong pulmonary function [30,31]. Pulmonary function testing (negative inspiratory force and forced vital capacity) should be followed as disease progresses. Nighttime BiPap is readily available and generally well tolerated [32]. Scoliosis develops after patients have been wheelchair bound for 1 to 2 years. Scoliosis surgery

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improves sitting posture and late in disease improves pulmonary function and comfort. Clinical cardiomyopathy develops late in disease and is best monitored by echocardiography. There are no specic recommendations for dystrophic cardiomyopathy, and standard treatment with an angiotensinconverting enzyme inhibitor, with or without a b-blocker, and a diuretic is recommended [33,34]. Key elements of management are psychologic support and treatment and genetic counseling. Steroids (typically prednisone or deazacort) prolong independent function and delay need for a wheelchair [35]. There are no rm guidelines regarding when to initiate steroids, how long to use them, or how they are best dosed to minimize side eects. Steroids generally are oered in early childhood, around age 5, although some advocate earlier use to maximize benet [36]. The prednisone dosage that showed benet in the original trials was 0.75 mg/kg/d administered as a single dose [37]. Many other protocols have been used in an attempt to maximize benet while minimizing side eects. Dubuwitz et al have used prednisolone, 0.75 mg/kg/d, administered for 10 consecutive days each month, with no steroids the remainder of the month. Case reports have demonstrated that this is safe and there may be less diculty with growth suppression and weight gain on this regimen. It is not known if it is as eective as daily dosing [38]. A recently reported alternative dosing schedule for prednisone is 5 mg/kg/d on 2 consecutive days each week. This regimen resulted in benet similar to that seen in historical controls treated with daily prednisone [39]. Deazacort is a synthetic corticosteroid that is not FDA approved, but is used widely in Europe and Canada. Several studies have demonstrated that deazacort is at least as eective as prednisone in prolonging independent function in DMD and there is less weight gain with deazacort [40,41]. Dosing is approximately 1.0 mg/kg/d. Research on use of steroids in DMD recently was reviewed [42]. Genetic counseling in Duchenne muscular dystrophy Counseling for DMD is complex and should be done by someone familiar with this disorder. As discussed previously, there is no medical reason to determine carrier status of young girls in childhood and genetic testing of siblings of patients who have DMD or BMD should be delayed until they are old enough to participate in the decision-making process. When an aected boy has a deletion or duplication identied by standard DNA screening, it is appropriate to oer testing to his mother, particularly if there are other female relatives of childbearing age who are at risk for being carriers. If a boys mother has a deletion, the implications for her female relatives should be reviewed and genetic counseling made available to them. When the aected boys mother does not carry his mutation in her blood, gonadal mosaicism is seen in up to 15% of cases. This means that her sisters could not have inherited the mutation, but her daughters may have.

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Counseling should be provided and genetic testing oered when they are of childbearing age. When standard DNA testing does not show a deletion or duplication in an aected boy, additional studies for point mutations should be considered to facilitate genetic counseling. If no mutation is known or if tissue for DNA analysis is not available, then linkage analysis can be oered to modify risk of carrier status. In this situation, knowledge of a childhood CK level in the at-risk girl is helpful. Elevated CK in an at-risk female is presumptive evidence that she is a carrier. Muscle biopsy on an asymptomatic female with a normal CK is normal, even if she is a carrier. Muscle biopsy is not a helpful test in determining carrier status. Limb girdle muscular dystrophies LGMD refers to an extremely heterogeneous group of diseases characterized by proximal muscle weakness. After dystrophin mutations have been excluded, LGMD can be either dominant (designated LGMD1) or recessive (LGMD2). The dominant disorders tend to be milder than the recessive conditions. The relative frequencies of these diseases are dependent on ethnicity and geography. A careful family history is an important part of the clinical history in this population. LGMD can have onset in childhood, mimicking DMD. More often, weakness develops in adolescence or young adulthood. Cardiomyopathy is seen in a subset of these disorders and patients who have LGMD should be screened regularly for cardiac disease. Many of the genes involved in LGMD have dierent phenotypic presentation with dierent mutations. The known allelic disorders are identied in Table 2. As noted previously, DMD and BMD patients have limb girdle weakness identical to that of LGMD so it is not surprising that dystrophin mutations are identied in approximately 15% of patients with a clinical diagnosis of LGMD [43]. Therefore, DNA analysis for dystrophin mutations is an appropriate early step in the laboratory evaluation of a patient who has LGMD. In general, muscle biopsy is required to clarify the specic diagnosis when dystrophin DNA testing is negative. Immunostaining is diagnostic in most of the known forms of LGMD (see Table 2). Autosomal dominant limb girdle muscular dystrophies LGMD1A are uncommon disorders; only two LGMD1A pedigrees have been reported to date [44,45]. LGMD1A results from mutations in myotilin, a protein necessary for normal assembly and maintenance of the sarcomere [46]. These patients have dysarthria and proximal limb weakness. LGMD1B is caused by mutations in lamin A/C, a protein that is processed to form lamin A and lamin C. Mutations in lamin A lead to several distinct phenotypes, including autosomal dominant Emery Dreifuss muscu-

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lar dystrophy (AD-EDMD) and familial partial lipodystrophy (FPLD) in addition to LGMD. This is discussed more fully later. LGMD1C results from mutations in the caveolin-3 gene. The phonotypic expression of caveolin-3 mutations is diverse. In addition to AD-LGMD, caveolin-3 mutations lead to isolated hyper-CK-emia [47], rippling muscle disease [48,49], and distal myopathy. Dierent phenotypes can be seen within a single pedigree [50]. Autosomal recessive limb girdle muscular dystrophies LGMD2A; calpain 3 The LGMD2 phenotype consists of limb girdle atrophy and weakness beginning in the glutei and thigh adductors [51]. Muscle hypertrophy is rare. Age at onset of weakness is between 2 years old and middle adulthood [52]. CK ranges from hundreds to more than 9000. The disease shows variable rates of progression. Several populations have a particularly high incidence of calpain mutations, in some cases as a result of a founder eect. Mutations are seen in Reunion Island where it was rst reported [53], some Indiana Amish, and in populations from the Basque region of Spain. Aside from these founder mutations, there are no mutational hot spots in the calpain 3 gene, making genetic diagnosis complicated. Western blotting has been used with some success, but occasionally a patient is missed with this screen. Calpain 3 is an intracellular calcium activated protease. Why mutations in calpain lead to muscular dystrophy is not yet understood, although recent work suggests that calpain might have a role in apoptosis [54], muscle maturation [55], or signaling [56]. LGMD2B; dysferlin Dysferlin is a membrane-associated protein that is not part of the DGC [57,58]. Its function is unknown, but it interacts with caveolin [59] (see discussion of LGMD1C) and may be involved in membrane repair [60]. Two neuromuscular phenotypes are seen in patients who have dysferlin mutations, LGMD2B and Miyoshi myopathy (MM), a distal myopathy. One mutation can produce either phenotype, suggesting some important modifying or interacting factors [61,62]. One characteristic feature of MM and LGMD is dramatic elevation of the serum CK, typically more than 20 times normal. A blood-based diagnostic test for dysferlin deciency recently was described [63]. Ho et al demonstrated that dysferlin is expressed in peripheral blood monocytes and that monocytes and skeletal muscle show similar levels of expression by Western blot. LGMD2CF; a, b, d, and c sarcoglycans The sarcoglycans compose a membrane-spanning component of the DGC (see Fig. 1). A mutation in a, b, d, or c sarcoglycan leads to a limb

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Table 2 Limb girdle muscular dystrophy Commercial testing ++ Isolated cardiomyopathy Cardiac involvement? Allelic disorders

Disease symbol Genetics Genetic location Protein

DMD/BMD

XLR

Xp21

Dystrophin

LGMD1A LGMD1B

AD AD

5q31 1q11-21

Myotilin Lamin A/C

DNA: deletion/duplication screening; point mutation screening Protein on muscle: immunostaining or blotting None DNA based mutation screening +++

LGMD1C

AD

3p25

Caveolin-3

Immunostaining of muscle

+/

AD-EDMD Dunnigan-type familial partial lipodystrophy Dilated cardiomyopathy and cardiac conduction system defect Rippling muscle syndrome Hyper-CK-emia Distal myopathy

LGMD2A

AR

15q15-21

Calpain 3

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LGMD2B

AR

2p13

Dysferlin

Myoshi myopathy; distal myopathy

LGMD2C

AR

13q12

c-Sarcoglycan

LGMD2D

AR

17q12-21

a-Sarcoglycan

Western blot to screen, but DNA conrmation required (testing not readily available) Immunostaining of muscle or immunoblot of blood possible. DNA conrmation recommended Immunostaining of muscle. DNA conrmation recommended Immunostaining of muscle. DNA conrmation recommended

+/

LGMD2E

AR

4q12

b-Sarcoglycan

+++

LGMD2F

AR

5q33-34

d-Sarcoglycan

Immunostaining of muscle. DNA conrmation recommended Immunostaining of muscle. DNA conrmation recommended +++ ++ Congenital muscular dystrophy 1C ? Tibial muscular dystrophy

LGMD2G LGMD2H LGMD2I

AR AR AR

17q11-12 9q31-34 19q13.4

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LGMD2J

AR

2q31

Telethonin TRIM32 None Fukuyama-related Immunostaining of muscle protein suggestive Titin None

807

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girdle phenotype. When one element of the sarcoglycan complex is mutated, all four sarcoglycans are severely reduced by immunostaining, so DNA analysis is required to make a specic diagnosis. Cardiomyopathy is a feature found in all the sarcoglycanopathies except LGMD2D. This is most likely because e sarcoglycan replaces a in vascular smooth muscle and also may substitute in vascular smooth muscle and possibly in cardiac muscle [64,65]. Mutations in e sarcoglycan cause myoclonus-dystonia syndrome [66], which has no neuromuscular phenotype. LGMD2G; telethonin Few patients who have LGMD2G are described. Those reported have onset of progressive weakness at ages 9 to 15. Anterior tibialis weakness was recognized early in the course in some patients. CK generally is mildly elevated (\5 times normal); however, early in the disease it may be more than 10 times normal [67]. Telethonin is a muscle-specic protein that localizes to the Z-disc of skeletal muscle, like myotilin. Mutations are postulated to lead to abnormal sarcomere structure. LGMD2H;TRIM32 LGMD2H has been reported only in the Manitoba Hutterite population. A founder mutation was found in the TRIM32 gene, a proposed E3ubiquitin ligase [68]. LGMD2I;FKRP LGMD2I is allelic with one form of congenital muscular dystrophy, and FKRP was discussed in that section. LGMD2J; titin Patients who have two mutant copies of titin develop childhood onset LGMD. This observation was made in families with an AD disorder, tibial muscular dystrophy (TMD), a slowly progressive adult onset distal myopathy [69]. Patients who have the LGMD phenotype have secondary absence of calpain 3 by Western blot analysis, whereas those with the milder dominant disease had variable reductions in calpain 3 [70]. TMD is found most frequently in the Finnish population but has been reported more widely. The abnormal protein, titin, is an extremely large muscle protein with multiple functions [71]. With the expectation that some recessive LGMD patients who have titan mutations will be identied outside of inbred TMD families, the severe phenotype has been designated LGMD2I. Facioscapulohumeral muscular dystrophy FSHD is an AD disorder distinguished by early weakness of the face, shoulder girdle, and proximal arms. Weak eye closure may manifest by

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sleeping with the eyes slightly open even before other symptoms are present. There is a wide range of clinical severity. The most severely aected children have widespread weakness and an increased incidence of hearing loss. They also have a retinal vasculopathy that rarely is symptomatic [72]. Very rarely, mental retardation and seizures are reported in the most severely aected children [73]; however, the majority of patients who have FSHD have normal intelligence. FSHD is caused by a deletion within a series of 3.3-kb repeats on the long arm of chromosome 4 [74,75]. Recent work demonstrates that each of these repeats contains a binding site for a repressor of gene transcription. It is believed that when the number of repeats falls below a critical number (approximately 10), there is expression of genes or pseudogenes on chromosome 4 that are normally silent. The aberrantly expressed protein(s) are injurious to muscle and other tissues [76]. Diagnostic DNA testing is commercially available. The testing looks for the deletion on 4q. Unfortunately, this region of chromosome 4 is highly homologous with other regions of the human genome, in particular 10q, making the DNA testing dicult to interpret in some cases. There are two standard components to the test. First is the size of the region containing the FSHD mutation. If there is no deletion, the fragment of chromosome 4 that is studied is [40 kb. Second, testing addresses the probability that a short (abnormal) allele is on chromosome 4 (as opposed to chromosome 10, in which case there is no associated phenotype). In the simplest case, there are four alleles, two of the type typically seen on chromosome 10 and two of the chromosome 4 type. If one of the 4-type alleles is less than 35 kb, FSHD is highly probable. If there are three or four of the 4-type alleles, however, it is not possible from the standard testing to know if the short allele is on chromosome 4 or chromosome 10. Additional testing can be helpful, particularly in resolving questions about hybrid chromosomes (repeat fragments composed of 4-type and 10-type alleles) [77], but clinical correlation and judgment are critical in the interpretation of the results. There are very rare families that are phenotypically identical to FSHD but do not map to chromosome 4 and do not have the typical mutation [78]. Therefore, before oering DNA testing for genetic counseling, at least one aected family member should have a documented typical mutation. Emery Dreifuss syndrome (X-linked and autosomal dominant) There are two genetic forms of EDMDX-linked (XL) and autosomal dominant (AD). The XL form is more common. They are clinically indistinguishable in an isolated aected male. Together they are considered disorders of the nuclear membrane. The Emery Dreifuss phenotype consists of childhood-onset weakness starting in the shoulder girdle and lower legs, accompanied by early contractures, particularly of the elbows, Achilles tendons, and neck. Contractures are

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out of proportion to weakness. Cardiomyopathy with prominent arrhythmia is an important associated feature and heart block may cause death [79]. Isolated atrial paralysis strongly suggests the diagnosis of EDMD. CK usually is 2 to 15 times normal, but it can be normal. Female carriers of the XL-EDMD generally do not have any skeletal muscle weakness, but they can develop heart block [80]. XL-EDMD is caused by mutations in emerin, an integral nuclear membrane protein, and AD-EDMD is caused by mutations in the lamin A/C gene. The integral nuclear membrane proteins interact closely with nuclear lamins, which are intermediate lament proteins found on the inner (nucleic) side of the nuclear membrane. Emerin specically binds lamin A, one of the lamin A/ C gene products [81]. The lamins, in turn, interact with chromatin and nuclear proteins. (A recessive form of EDMD also has been reported with lamin A/C mutation [82].) Lamin A/C encodes the proteins lamin A and an alternative splice product, lamin C. The specic functions of the nuclear membrane complexes remain unclear, but they are involved in organization and localization of nuclear materials and nuclear membrane formation during mitosis. The spectrum of disease caused by lamin A/C mutations has grown steadily since the identication of the AD-EDMD gene in 1999. Allelic disorders include isolated dilated cardiomyopathy, CMD1A (which may be just a severe form of AD-EDMD), and FPLD. Markedly reduced subcutaneous fat and insulin resistance with elevated triglycerides and low high-density lipoprotein levels characterizes FPLD. These patients are at increased risk of atherosclerotic vascular disease and diabetes. Because there are overlapping phenotypes, patients who have AD-EDMD should be monitored for these complications. Myotonic dystrophies The myotonic dystrophies are diseases that are perhaps better classied as myotonic disorders and are discussed here briey. Myotonic dystrophy type 1 (DM1) and type 2 (DM2 or proximal myotonic myopathy [PROMM]) are multisystem disorders, and at the level of an individual patient the two disorders are clinically indistinguishable. (As described here, family features may suggest one form over the other.) Features of myotonic dystrophy include myotonia, cardiac conduction defects, premature cataracts, increased incidence of diabetes, and slowly progressive muscular weakness. The most severely aected DM1 patients also have cognitive impairment, a nding that is absent in patients who have DM2. DM2 generally is a milder disease and a severe neonatal form has not been reported [83,84]. Anticipation, or worsening of disease severity in subsequent generations, is prominent in DM1 families and generally absent in DM2. CK is at most mildly elevated. The muscle weakness is only slowly progressive. Smooth muscle involvement and central hypersomnolence are troublesome features of the disease seen more often in DM1 than DM2.

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DM1 is caused by an unstable CTG repeat in the 39 untranslated region of the DMPK gene. This repeat also aects the promoter of the SIX5 gene. Disruption of the protein products of these genes, however, is insucient to produce the myriad features of the disease. The pathophysiology of this disorder became clearer with the discovery of the mutation leading to DM2, an unstable CCTG expansion in the rst intron of a zinc nger protein (ZFF9) [85]. The RNA product of the abnormally expanded repeats in DM1 and DM2 is sequestered in the nucleus where it interferes with the processing of a variety of RNAs. This explains the AD inheritance (as only one mutant allele leads to disease; gain of function mutation) and swhy these diseases aect so many dierent tissues and functions.

Oculopharyngeal muscular dystrophy Oculopharyngeal muscular dystrophy is an AD trinucleotide repeat disorder that presents in mid-adulthood. Typical presenting symptoms are progressive ptosis and dysphagia. The repeat expansion aects function of the PAB gene that is involved in control of gene transcription. As with other adult onset disorders without treatment, presymptomatic testing of at-risk children is not recommended.

Summary A specic genetic diagnosis can be reached for most children with muscular dystrophy. Advanced diagnostics, including genetic testing and analysis of nonmuscle tissues, such as skin and blood, often allow the diagnosis to be reached using minimally invasive procedures. These diagnostic advances accompany improved understanding of pathophysiology and pave the way for specic and curative treatments.

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