Spinal Muscular Atrophy

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Congenital Muscular Dystrophy Overview Erynn Gordon , MS, CGC Research Center for Genetic Medicine Children's National Medical Center Washington [email protected] Eric P Hoffman , PhD Research Center for Genetic Medicine Children's National Medical Center Washington [email protected] Elena Pegoraro , MD, PhD Department of Neurological and Psychiatric Sciences University of Padova Padova [email protected] Initial Posting: January 22, 2001. Last Revision: December 22, 2006. Summary Disease characteristics. The term congenital muscular dystrophy (CMD) refers to a group of inherited disorders in which muscle weakness is present at birth. Affected infants typically appear "floppy" with low muscle tone and contractures. Muscle weakness tends to be stable over time, but the complications of the dystrophy become more severe with time. Diagnosis/testing. The diagnosis of congenital muscular dystrophy relies on: muscle biopsy that typically shows a dystrophic or myopathic pattern with or without fatty infiltration; serum creatine kinase (CK) concentration that is usually elevated; immunostaining of muscle that is abnormal in specific subtypes; and brain MRI that may show brain structural abnormalities indicative of syndromic congenital muscular dystrophy or abnormal white matter signal. Approximately 50% of CMD is caused by complete merosin deficiency; diagnosis is made by detection of complete merosin deficiency on immunostaining of muscle biopsy and abnormal white matter signal on MRI after four months of age. Molecular genetic testing allows for genetic confirmation of some forms of CMD. Management. Management of the congenital muscular dystrophies is tailored to each individual and each specific subtype. Management includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical assistive devices to help ambulation and mobility, monitoring and surgical intervention for orthopedic complications, and monitoring of respiratory function. Some individuals benefit from assisted cough, noninvasive ventilation, or mechanical ventilation via tracheostomy. Social and emotional support reduces the sense of social isolation common in CMD. Genetic counseling. The congenital muscular dystrophies are inherited in an autosomal recessive manner with the exception of Ullrich congenital muscular dystrophy, for which two instances of autosomal dominant inheritance have been reported. In autosomal recessive forms, Funded by the NIH · Developed at GeneTests ( www.genetests.org), University of Washington, Seattle GeneReviews GeneReviews GeneReviews GeneReviews

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Spinal Muscular Atrophy

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Congenital Muscular Dystrophy OverviewErynn Gordon , MS, CGCResearch Center for Genetic MedicineChildren's National Medical [email protected]

Eric P Hoffman , PhDResearch Center for Genetic MedicineChildren's National Medical [email protected]

Elena Pegoraro , MD, PhDDepartment of Neurological and Psychiatric SciencesUniversity of [email protected]

Initial Posting: January 22, 2001.Last Revision: December 22, 2006.

SummaryDisease characteristics. The term congenital muscular dystrophy (CMD) refers to a group ofinherited disorders in which muscle weakness is present at birth. Affected infants typicallyappear "floppy" with low muscle tone and contractures. Muscle weakness tends to be stableover time, but the complications of the dystrophy become more severe with time.

Diagnosis/testing. The diagnosis of congenital muscular dystrophy relies on: muscle biopsythat typically shows a dystrophic or myopathic pattern with or without fatty infiltration; serumcreatine kinase (CK) concentration that is usually elevated; immunostaining of muscle that isabnormal in specific subtypes; and brain MRI that may show brain structural abnormalitiesindicative of syndromic congenital muscular dystrophy or abnormal white matter signal.Approximately 50% of CMD is caused by complete merosin deficiency; diagnosis is made bydetection of complete merosin deficiency on immunostaining of muscle biopsy and abnormalwhite matter signal on MRI after four months of age. Molecular genetic testing allows forgenetic confirmation of some forms of CMD.

Management. Management of the congenital muscular dystrophies is tailored to eachindividual and each specific subtype. Management includes weight control to avoid obesity,physical therapy and stretching exercises to promote mobility and prevent contractures, use ofmechanical assistive devices to help ambulation and mobility, monitoring and surgicalintervention for orthopedic complications, and monitoring of respiratory function. Someindividuals benefit from assisted cough, noninvasive ventilation, or mechanical ventilation viatracheostomy. Social and emotional support reduces the sense of social isolation common inCMD.

Genetic counseling. The congenital muscular dystrophies are inherited in an autosomalrecessive manner with the exception of Ullrich congenital muscular dystrophy, for which twoinstances of autosomal dominant inheritance have been reported. In autosomal recessive forms,

Funded by the NIH · Developed at GeneTests (www.genetests.org), University of Washington, Seattle

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each sib of a proband has a 25% chance of being affected, a 50% chance of being anasymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Each unaffectedsib of an affected individual has a 2/3 chance of being a carrier. Heterozygotes areasymptomatic. Carrier testing is clinically available for some forms of CMD. Prenatal testingis clinically available for complete merosin deficiency, muscle-eye-brain disease, Fukuyamacongenital muscular dystrophy, Walker-Warburg syndrome congenital muscular dystrophytype 1C, congenital muscular dystrophy type 1D, and congenital muscular dystrophy with earlyspine rigidity. Prenatal testing for other types of congenital muscular dystrophy may beavailable through laboratories offering custom prenatal testing.

DefinitionClinical Manifestations

The term congenital muscular dystrophy (CMD) refers to a group of genetic disorders in whichweakness and an abnormal muscle biopsy are present at birth. Individuals with CMD typicallyappear "floppy" with low muscle tone, contractures, and muscle weakness. Muscle weaknesstends to be stable over time, but the complications of the dystrophy become more severe withtime.

Establishing the DiagnosisThe assessment used to establish that an individual has congenital muscular dystrophy includesthe following:

• Serum creatine kinase (CK) concentration, which is usually elevated• Muscle biopsy, which typically shows a dystrophic or myopathic pattern with or

without fatty infiltration• Immunostaining of muscle, which is abnormal in specific subtypes• Brain MRI, which may show brain structural abnormalities indicative of syndromic

congenital muscular dystrophy or abnormal white matter signal, which can help todistinguish nonsyndromic CMD subtypes

• Genetic testing. Improvements in the identification of causative genes and moleculargenetic testing now allow for genetic confirmation of some forms of CMD.

Differential DiagnosisCongenital muscular dystrophies are differentiated from the following conditions:

• Congenital myopathies (including X-linked myotubular myopathy and nemalinemyopathy) typically have normal or near-normal serum CK concentration andevidence of developmental rather than dystrophic muscle abnormalities on musclebiopsy.

• Bethlem myopathy is part of the spectrum of collagen type VI-related disorderscaused by mutations in the genes COL6A1, COL6A2, and COL6A3. Bethlemmyopathy is characterized by the combination of proximal muscle weakness andvariable contractures, affecting most frequently the long finger flexors, elbows, andankles. Clinical and histologic overlap of Bethlem myopathy with the limb-girdlemuscular dystrophies is considerable. The onset of Bethlem myopathy ranges fromprenatal to mid-adulthood. Prenatal onset is characterized by decreased fetalmovement; neonatal onset by hypotonia or torticollis; early-childhood onset bydelayed motor milestones, muscle weakness, and contractures; and adult onset(between the 4th and 6th decades) by proximal weakness and achilles tendon or long

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finger flexor contractures. Disease progression is slow but continuous; thus, morethan two-thirds of affected individuals over age 50 years rely on supportive meansfor outdoor mobility. Respiratory muscle and diaphragmatic involvement is rare andseems to be related to severe weakness that occurs in later life. Inheritance isautosomal dominant.

• Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feedingdifficulties in early infancy, followed in later infancy by excessive eating and gradualdevelopment of morbid obesity unless externally controlled. Individuals with PWShave some degree of cognitive impairment and a distinctive behavioral phenotype.Hypogonadism is present in both males and females. The methylation-specific patternof the PWS/AS region of chromosome 15q11 establishes the diagnosis in more than99% of individuals.

• Spinal muscular atrophy (SMA) is characterized by progressive degeneration andloss of the anterior horn cells in the spinal cord, and sometimes in the brain stemnuclei, resulting in muscle weakness and atrophy. The onset of weakness ranges frombefore birth to adolescence or young adulthood. The weakness is progressive. Prenatalonset of SMA has been described as congenital axonal neuropathy and arthrogryposismultiplex congenita-SMA; onset before six months of age is designated SMA1. Morethan 98% of individuals with SMA associated with disease-causing mutations of theSMN gene have identifiable SMN gene mutations.

• Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletalmuscle and smooth muscle, as well as the eye, heart, endocrine system, and centralnervous system; it spans the continuum from mild to severe. Congenital DM1 is thesevere early-onset form, characterized by hypotonia and severe generalized weaknessat birth, often with respiratory insufficiency and early death; mental retardation iscommon. Diagnosis rests upon detection of an expansion of the GTC trinucleotiderepeat in the DMPK gene.

PrevalenceThe incidence of all forms of congenital muscular dystrophies has been estimated at 1/21,500with a prevalence of 1/125,000 [Mostacciuolo et al 1996]. It is important to note that the onlyincidence and prevalence figures come from northeastern Italy and may not be representativeof all areas of the world. Using the estimate that approximately 60% of all congenital musculardystrophy is defined as classic CMD (without mental retardation, but including individualswith both merosin-positive and merosin-negative CMD), the incidence of classic CMD can beestimated to be 1/38,000 [Mostacciuolo et al 1996].

CausesHeritable Causes

With one limited exception, all forms of congenital muscular dystrophy identified to date —including syndromic (Fukuyama CMD, muscle-eye-brain disease, Walker-Warburgsyndrome, CMD1C) and nonsyndromic CMD (both merosin positive and negative) — areinherited in an autosomal recessive manner. (The exception is Ullrich CMD, which is normallyautosomal recessive but for which two instances of autosomal dominant inheritance have beenreported.) Molecular genetic testing or biochemical staining can further delineate many formsof CMD. More than ten genes known to cause CMD have been identified to date [Muntoni &Voit 2004].

Syndromic CMD: Molecular Genetics —Within the larger class of congenital musculardystrophies, the syndromic congenital muscular dystrophies are unique in two ways: (1)

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phenotypically, they involve multiple organ systems and result in severe brain malformationsand developmental delay; and (2) from a biochemical and molecular standpoint, they are causedby genetic defects that disrupt post-translational modification of alpha dystroglycan and othercurrently unknown proteins [Grewal & Hewitt 2003]. Alpha dystroglycan is an integralcomponent of the dystrophin-glycoprotein complex, which is involved in stabilizing the musclecell during contraction and relaxation [Cohn 2005]. Disruption of alpha dystroglycan can occurbecause of errors in glycosylation (Fukuyama CMD) and O-mannosylation (Walker-Warburgsyndrome and muscle-eye-brain disease). While glycosylation of proteins is common, the mostcommon form of glycosylation is N-linked glycosylation; however, in the congenital musculardystrophies, the error appears to be in the process of O-linked glycosylation [Martin-Rendon& Blake 2003]. Dystroglycan is also expressed in the developing central nervous system, retina,and cochlea, where it plays an integral role in neuronal migration, organization of synapses,and assembly of the basement membrane [Cohn 2005].

Table 1. Syndromic Congenital Muscular Dystrophy (CMD): Molecular Genetics

Disease Name Gene Symbol Chromosomal Locus Protein Name Molecular Genetic TestAvailability

Fukuyama CMD (FCMD) FCMD 9q31 FukutinClinical

Muscle-eye-brain disease (MEB) POMGNT1 1p34-p33 Protein O-mannoside beta-1,2-N-

acetylglucosaminyltransferase 1Clinical

Walker-Warburg syndrome (WWS)

POMT1 9q34.1 Protein O-mannosyl-transferase 1 Clinical

POMT2 1 14q24.3 Protein O-mannosyl-transferase 2

Congenital muscular dystrophytype 1D (MDC1D) LARGE 22q12.3-q13.1 Glycosyltransferase-

like protein LARGEClinical

1. Van Reeuwijk et al 2005

Fukuyama CMD (FCMD). FCMD is seen primarily in Japan with only rare cases reportedin other countries. A 3-kb retrotransposal insertion in the 3' non-coding region of the geneFCMD accounts for 87% of cases of Fukuyama CMD, suggesting a single ancestral founderfor this disease [Kobayashi et al 1998]. The protein fukutin acts as a glycosyltransferase;mutations in FCMD result in a complete loss of the glycosylated alpha dystroglycan protein.Abnormalities in laminin alpha 2 are also observed in affected individuals [Hayashi et al2001].

Muscle-eye-brain (MEB) disease. Although not all individuals with the clinical diagnosis ofMEB disease have been shown to have mutations in POMGNT1, MEB disease is distinct fromFukuyama CMD and Walker-Warburg syndrome, the other syndromic CMDs. Mutationscloser to the 5' region of the gene appear to be associated with more severe symptoms thanmutations closer to the 3' region [Taniguichi et al 2003]. Mutations in the POMGNT1 genehave been found to correlate with a reduction in POMGnT1 activity in skeletal muscle [Manyaet al 2003]. MEB disease has been seen around the world; however, the largest number of casesis in Finland, where some affected individuals were born to consanguineous couples. A foundermutation in the Finnish population is suspected [Cormand et al 2001].

Walker-Warburg syndrome (WWS). Mutations in the POMT1 gene were found in 20% ofindividuals (n=30) with a clinical diagnosis of WWS [Beltran-Valero et al 2002]. Van Reeuwijket al (2005) identified mutations in POMT2 in three families with WWS. Additional genescoding for glycosyltransferases, yet to be identified, are thought to be the major cause of thisdisorder [Jiminez-Mallebrera et al 2003].

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Congenital muscular dystrophy type 1D (MDC1D). The LARGE gene is a newly recognizedgene with a clear role in the glycosylation of alpha dystroglycan [Kanagawa et al 2004]. Todate, one individual with a compound heterozygous mutation in the LARGE gene has beenidentified [Longman et al 2003].

Syndromic CMD: Clinical FeaturesTable 2. Syndromic CMD: Clinical Features

Disease Name

Presentation Other Findings

Age

Hypotonia Weakness Contractures Onset Walk Death

FukuyamaCMD Generalized Generalized

Hip, knee,ankles, and

elbowspossible

• "Cobblestone complex"1 Neonatal NeverLate

teens-early

twenties

Muscle-eye- brain

diseaseGeneralized Generalized Elbows

• "Cobblestone complex"1

• Eye malformations2

without congenitalcataracts

• Hydrocephalus• White matter changes

present in infancy andearly childhood

Neonatal

Rarely, somewalk by age4 but lose

ambulationby age 20

Walker- Warburgsyndrome

Generalized Generalized Elbows

• "Cobblestone complex"1

• Eye malformations2

• Flat pons• Dandy-Walker

malformation• Cerebellar hypoplasia• Hydrocephalus• White matter changes

Neonatal Never Earlyinfancy

Congenitalmusculardystrophytype 1D (1 case)3

Unknown Unknown Unknown

• Global developmentaldelay

• Moderate musclehypertrophy

• Mild facial weakness• Proximal weakness >

distal weakness• Extensive white matter

changes on MRI

Withinfirst year

of life

Independentambulationat 4.5 yrs

followed bydeteriorationin later years

Unknown

1. Cobblestone complex includes enlarged lateral ventricles, flat brainstem, and cerebellar hypoplasia 2. Eye malformations include any distribution of the following: glaucoma and myopia resulting from coarse trabecular meshwork in the anteriorchamber, progressive retinal atrophy, and juvenile cataracts. Congenital ocular malformations include: cataracts, microphthalmia, buphthalmus,persistent hyperplastic primary vitreous, and Peter anomaly [Cormand et al 2001]. 3. Longman et al 2003

Fukuyama congenital muscular dystrophy (FCMD). FCMD is one of the most commonautosomal recessive disorders and the second most common form of muscular dystrophy inJapan. Main symptoms include hypotonia with a poor suck and a weak cry. Affected individualsmay develop contractures of the hip, knee, ankles, and elbows with onset of contractures priorto age one year. Individuals with FCMD often attain independent sitting but never achieveindependent ambulation. Mental retardation is often severe with IQ ranging from 30 to 50.Other characteristics of FCMD include seizures that occur in virtually all children andophthalmologic complications including myopia, cataracts, pale optic disc, and retinaldetachment. Hypertrophy of the quadriceps, calves, and tongue is common. Nearly all affected

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individuals develop dilated cardiomyopathy and respiratory failure by the second decade.Death often occurs by age 20 years [Toda et al 2000].

Muscle-eye-brain (MEB) disease. Neonatal hypotonia, developmental delay, and ocularabnormalities are the hallmarks of MEB disease. Findings in MEB disease range from severewith no motor control (e.g., inability to sit independently, no head control, very poor visualcontrol) to mild (ability to walk independently for several years and little visual impairment).Speech is possible for those with more mild to moderate disease; however, vocabulary is limitedto only a few words. MRI changes are consistent with clinical disease severity, with severelyaffected individuals showing pachygyria/polymicrogyria/agyria and a cobblestone complexwhile those with mild symptoms show only flattening of the brain stem and cerebellar cysts.Specific eye anomalies include glaucoma, progressive myopia, progressive retinal atrophy,and juvenile cataracts [Cormand et al 2001]. MEB disease progress is pathologically andclinically slower than that of other forms of syndromic CMD [Auranen et al 2000].

Walker-Warburg syndrome (WWS). The clinical features of WWS are similar to those ofMEB disease. Congenital cataracts, microphthalmia, buphthalmus, and Peter's anomaly are thedistinguishing ophthalmologic features of WWS; occipital encephalocele, fusion of thehemispheres, and absence of the corpus callosum are the distinguishing brain malformationsof WWS. Because of the severe brain malformations, feeding is difficult, often requiringgastrostomy feeding. WWS generally has a more severe course than the other syndromiccongenital muscular dystrophies with death in infancy [Cormand et al 2001].

Nonsyndromic CMD: Molecular GeneticsTable 3. Nonsyndromic Congenital Muscular Dystrophy (CMD): Molecular Genetics

% of Individualswith CMD Disease Name Gene Symbol Chromosomal Locus Protein Name Molecular Genetic Test

Availability

~50%CMD with completemerosin deficiency

(MDC1A)LAMA2 6q22-q23 Laminin, alpha-2

chainClinical

1

Rare CMD with partialmerosin deficiency LAMA2 2 6q22-q23 Laminin, alpha-2

chain Research only

UnknownCongenital

muscular dystrophytype 1C (MDC1C)

FKRP 19q13.3 Fukutin-relatedprotein

Clinical

~3% CMD with ITGA7mutations ITGA7 12q13 Integrin alpha-7 Research only

Unknown CMD with earlyspine rigidity (RSS) SEPN1 1p36-p35 Selenoprotein N

Clinical

Unknown Ullrich CMDCOL6A1/2 21q22.3 Alpha 1 and alpha 2

collagen VI Clinical

COL6A3 2q37 Alpha 3 collagen VI

1. Linkage analysis only2. Mutations in LAMA2 account for approximately 22% of cases of CMD with partial merosin deficiency. The cause of the remaining cases isunknown [Tezak et al 2003]

Merosin-deficient congenital muscular dystrophy (laminin alpha2 deficiency; LAMA2deficiency; occidental congenital muscular dystrophy; infantile polymyositis). Merosin-deficient congenital muscular dystrophy shows a relatively high incidence worldwide[Dubowitz 1996].

The LAMA2 gene has 64 exons and mutations are distributed throughout the very large codingsequence of 9.5 kb. No common mutations are observed in LAMA2. Of the six domains in the

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LAMA2 gene, mutations identified in domains I, II, and G predict a more severe phenotype[Muntoni & Voit 2004]. A high incidence of a 2-bp deletion in one study has not been confirmedin subsequent studies.Because several other forms of CMD show a secondary deficiency oflaminin alpha 2, antibody staining for multiple portions of the protein helps distinguish primarydeficiency from secondary deficiency and identifies those with partial merosin deficiency[Cohn et al 1998].

CMD with partial merosin deficiency. Partial merosin deficiency has been defined in anumber of affected individuals by biochemical studies, but in very few by mutation studies[Allamand et al 1997 Pegoraro et al 2000]. Although a few individuals with partial merosindeficiency (2/9) have been found to have mutations in the LAMA2 gene, the majority ofindividuals with partial merosin deficiency on immunostaining do not have mutations of themerosin (LAMA2) gene [Tezak et al 2003].

Congenital muscular dystrophy type 1C (MDC1C). MDC1C is a severe form of CMD withpartial merosin deficiency and a partial deficiency of alpha dystroglycan [Brockington, Blakeet al 2001]. This form of CMD has been mapped to chromosome 19q13.3 with homozygousmutations identified in the FKRP gene. Mutations in this 12-kb gene, which is composed ofthree non-coding exons and one large coding exon, is also the cause of LGMD2I (see Limb-Girdle Muscular Dystrophy Overview), which, despite a variable phenotype, is milder inpresentation than MDC1C [Brockington, Yuva et al 2001]. While one common mutation hasbeen identified in FKRP, this mutation has only been observed in persons with LGMD2I andhas not been seen in MDC1C. Brown et al (2004) correlated both the mutation type andexpression of alpha dystroglycan with the disease phenotype. Specifically, persons withMDC1C consistently show a severe deficiency of alpha dystroglycan and are either compoundheterozygotes for one missense mutation and one nonsense mutation or have two missensemutations. Conversely, individuals with LGMD2I have the common mutation (C826A) andeither a missense or nonsense mutation, and only mild to moderately decreased alphadystroglycan. Individuals with mild LFMD2I are homozygous for the common mutation andshow only a mild deficiency of alpha dystroglycan [Brown et al 2004, Mercuri et al 2003].

CMD with integrin alpha 7 deficiency. This disorder is thought to be extremely rare. Threeindividuals have been reported as showing biochemical deficiency of integrin alpha 7 andmutations of the corresponding gene, ITAG7 [Hayashi et al 1998].

CMD with early rigidity of the spine (RSS). Ten families, all with clinical features of CMDwith early rigidity of the spine, have been identified with mutations in the SEPN1 gene. Thefamilies were of Moroccan (1), Algerian (1), Iranian (2), French (1), Italian (1), and Turkish(4) ancestry. Missense, nonsense, and frameshift mutations were identified across five differentexons, with five of ten families (Iranian and Turkish ancestry) having the same 817G↓Amutation in exon 6. Linkage data from a non-consanguineous American family with a similarphenotype [Flanigan et al 2000] was suggestive but not conclusive.

A second locus (1q42) has been reported in one Arab family and one German family[Brockington et al 2000]. These families show partial, secondary reduction of merosin onimmunostaining of muscle biopsy.

Ullrich congenital muscular dystrophy (UCMD). UCMD is part of the spectrum of collagentype VI-related disorders caused by mutations in the genes COL6A1, COL6A2, and COL6A3.While the majority of UCMD is inherited in an autosomal recessive fashion, two instances ofautosomal dominant inheritance resulting from de novo mutations have been observed [Pan etal 2003]. In UCMD, collagen VI immunolabeling is absent or markedly reduced from theendomysium and basal lamina but may be normal around capillaries. Immunostaining for COL

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VI on muscle biopsy can be a useful diagnostic tool, although clinical correlations must beinterpreted with caution. Complete deficiency of COL VI has been correlated with severeclinical symptoms, while less significant deficiencies of the protein can cause either mild orsevere symptoms [Muntoni & Voit 2004].

Nonsyndromic CMD: Clinical FeaturesTable 4. Nonsyndromic Congenital Muscular Dystrophy (CMD): Clinical Features

Disease Name

PresentationOther Findings

Age

Hypotonia Weakness Contractures Onset Walk Death

CMD withcompletemerosin

deficiencySevere

• Proximal• Distal• Bulbar

Multiple scoliosis

• MRI: abnormalwhite mattersignal after 4months of age

• IQ usually normal• Seizures• Occasional poor

feeding• Respiratory

difficulties

Birth NeverSome in

1stdecade

CMD withpartial

merosindeficiency/MDC1B

Mild to moderate Proximal

• Elbows• Ankles• Rigid

spine

• MRI: abnormalwhite matter

• Signal + structuralbrainabnormalities

1 to 12years

2-3years Variable

Congenitalmusculardystrophytype 1C

(MDC1C)

Severe

• Proximal• Distal• Arms >

legs• Facial

• Elbows• Knees• Fingers

• MRI normal• IQ normal• Highly evelated

CKs• Occasional

cardiomyopathy• Respiratory

failure• Hypertrophy of

calves andquadriceps

• Myopathic EMG• Atrophy of

deltoid andpectoralismuscles

• Macroglossia• Impaired left

ventricularfunction

Birthto 6

monthsNever 2nd

decade

CMD withITGA7

mutations Proximal Torticollis

• Congenital hipdislocation

• ± MR (1individual)

2-3yrs

CMD withearly spine

rigidity(RSS)

• Proximal• Distal• Facial

• Rigidspine

• Elbows• Hips• Ankles

• Nocturnalhypoventilation

• Progressiverespiratory failure

Birth -1 yr

2 1/2yrs -never

Teens -20s

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UllrichCMD

Generalized in theneonatal period

Generalized withdistal > proximal

• Hips• Knees• Fingers• Elbows

• Distalhyperextensibility

• Normal IQ• CK 2-3x normal• Micrognathia• Rigidity of spine/

scoliosis• Rounded face• Atrophy calf >

thigh• Nocturnal

hypoventilation

Birth -1 year

1 year-

never

2nddecade -

adulthood

MRI = magnetic resonance imaging CK = creatin kinase IQ = intelligence quotient MR = mental retardation

Merosin-deficient congenital muscular dystrophy. Neonates with complete merosindeficiency typically present as floppy infants and may or may not require ventilatory assistance[Fardeau et al 1996]. Some infants do not survive the neonatal period; however, most stabilizeand do not require mechanical ventilation. Bulbar musculature is not as severely affected aslimb musculature; however, feeding difficulties result in recurrent aspiration and poor nutritionin some children. Respiratory insufficiency is common, with nocturnal hypoventilation oftennecessitating noninvasive night-time ventilation [Philpot et al 1999]. The best motor milestoneachieved is standing with support; typically affected individuals are not able to ambulate orstand unsupported [Muntoni & Voit 2004]. Contractures and scoliosis are common.

Affected individuals generally show normal cognitive development; however, a subset withmore extensive brain abnormalities can show low performance IQ [Mercuri et al 1999].Approximately 30% of individuals have epilepsy [Herrmann et al 1996f]. The relatively normalcognitive function is notable given that all affected individuals have characteristic white matterchanges seen on MRI, including hypomyelination and hypodensity of white matter, featuresnot unique to CMD. The MRI features may not be present at birth; however, all children developthis enigmatic MRI picture by six months of age. MRI findings may occasionally show brainstructural abnormalities including occipital agyria and pontocerebellar hypoplasia [Caro et al1999]. The cerebellum, cerebrum, corpus collosum, and brain stem are normal. The neuronalmigration defects characteristic of Walker-Warburg syndrome and muscle-eye-brain diseaseare not observed. The distinctive MRI abnormalities of merosin-deficient congenital musculardystrophy have been attributed to abnormal water distribution in the white matter, secondaryto blood/brain barrier dysfunction caused by merosin deficiency in the vasculature [Taratutoet al 1999].

In addition to the well-characterized muscular involvement in merosin-negative CMD and thecharacteristic MRI findings, some individuals have been noted to have additional MRI findingsconsistent with leukoencephalopathy in the periventricular and subcortical white matter. Thisfinding, along with decreased nerve conduction velocity studies, suggests that merosin-deficient CMD may have a demyelinating neuropathy component [Gilhuis et al 2002].

CMD with partial merosin deficiency. The clinical spectrum of partial merosin deficiencyranges from presentation at birth with marked hypotonia and contractures and severely delayedmotor milestones, to a limb-girdle muscular dystrophy-like presentation in the teens, to anadult-onset proximal limb-girdle weakness with high serum CK concentration. In one studyof nine individuals with partial merosin deficiency on immunostaining, 22% had disease-

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causative mutations in the LAMA2 gene. All individuals with LAMA2 mutations have had whitematter abnormalities on MRI [Allamand et al 1997, Pegoraro et al 2000, Tezak et al 2003].

Congenital muscular dystrophy type 1C (MDC1C) can be distinguished from othernonsyndromic forms of CMD by the presence of calf pseudohypertrophy, dilatedcardiomyopathy involving the left ventricle, and absence of white matter changes on MRI. Thepresence of mental retardation in two individuals with MDC1C suggests the existence of asyndromic form of this condition [Kirschner & Bonnemann 2004].

CMD with ITGA7 mutations, also known as integrin alpha 7 deficiency, is a mild form ofCMD that has been reported in three persons to date [Pegoraro et al 2002].

Ullrich congenital muscular dystrophy is characterized by congenital weakness andhypotonia, proximal joint contractures (particularly finger flexion contractures), and strikinghyperlaxity of distal joints. Other features are congenital hip dislocation, prominent calcanei,and transient kyphosis at birth. Some affected children acquire the ability to walkindependently; however, progression of the disease often results in later loss of ambulation.Early and severe respiratory involvement may require ventilatory support in the first or seconddecade of life [Brockington et al 2004, Pan et al 2003]

Unknown CausesTable 5. Gene Unknown Congenital Muscular Dystrophy (CMD): Clinical Features

Disease Name/Locus

PresentationOther Findings

Age

Hypotonia Weakness Contractures Onset Walk Death

Merosin- positive CMD Mild to moderate Proximal Multiple MRI: usually normal Birth 2 years

Firstdecade -

adulthood

CMD withcerebellarhypoplasia

Mild Proximal

• Jointstiffness

• Scoliosis• Pes

cavus

• MRI: cerebellaratrophy andhypoplasia

• Ataxia• Dysmetric

movements• Nystagmus• Dysarthric

speech• Moderate MR

Birth Never Notreported

CMD andmuscle

hypertrophy 1

• Diaphragm• Proximal >

distal• Neck

• Ankles• Spine

• Generalizedmuscularhyperatrophy

• Normal IQ

1 1/2 yrs -2 1/2 yrs

Notreported

CMD withmitochondrial

structuralabnormalities 2

Proximal

• Dilatedcardiomyopathy

• MR Late Not

reported

CMD witharthrogryposisand absent limb

muscles (1case) 3

Distal

• Elbows• Wrists• Fingers• Hips• Knees• Ankles

• Atrophy of armand leg muscles

• Absent musclein arms and legson MRI

• Preservation ofaxial muscles

• Ataxic gait

Birth Never Notreported

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Salih CMD(two related

cases) 4Present at birth Proximal

• Cardiomyopathy• Delayed

atrioventricularconduction onEEG

• Left anteriorfascicular block

• Left atrialenlargementwithout atrialdysarrhythmia

Birth 1-2 years Notreported

CMD withpseudo-

hypertrophy,macroglossia,and respiratoryinsufficiency (4

cases) 5

Present at birth Proximal Elbows and lowerextremities

• Increased CK• Calf pseudo-

hypertrophy• Respiratory

insufficiency• Macroglossia• Amyotrophy of

hands and feet• Round face• Normal IQ• Mild cardiac

involvement

Birth

Variable;2/4

individualsnever

walked

Notreported

CMD withadductedthumbs (2

relatedindividuals) 6

Prominent andpersistent

Generalizedwith distal >

proximal

Congenitalcontracture of

thumbs and toes

• Ptosis• External

ophthalmo-

plegia• MR• Cerebellar

hypoplasia

Birth 2-3 years Notreported

MRI = magnetic resonance imaging IQ = intelligence quotient MR = mental retardation1. Villanova et al 2000 2. Nishino et al 1998 3. Philpot et al 2001 4. Subahi 2001 5. Quijano et al 2002 6. Voit et al 2002

Evaluation StrategyEstablishing the specific subtype of congenital muscular dystrophy in a given individualusually involves medical history, physical examination, neurologic examination, familyhistory, neuroimaging, evaluation of serum CK concentration, and muscle biopsy for histologicexamination and immunostaining.

Family history, and molecular testing when available. Documentation of relevant findingsin family members with congenital weakness or neonatal death can be accomplished throughreview of medical records.

All of the congenital muscular dystrophies described to date show an autosomal recessiveinheritance pattern, and in the non-consanguineous, small nuclear families typical of the USA

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and Europe, this usually involves the occurrence of a single affected individual in a family. Ahistory of neonatal deaths of sibs of the proband, however, warrants further investigation ofmedical records and available tissue samples. A number of individuals with merosin deficiencyhad sibs who died in the neonatal period, presumably of the same disorder [Pegoraro et al1998].

Physical examination. Individuals with ocular abnormalities are likely to have FukuyamaCMD, muscle-eye-brain disease, or Walker-Warburg syndrome.

Neuroimaging. MRI, often the first step in the diagnostic process, can be used to identifythose with normal MRI and to distinguish those with brain malformations/abnormal neuronalmigration (syndromic CMD) from those with benign white matter changes (merosin deficiencyand partial merosin deficiency) [Kirschner & Bonnemann 2004].

Serum CK concentration and muscle biopsy findings (Table 6)

Table 6. Serum CK Concentration and Muscle Biopsy Findings

Disease Name/GeneSerum CK

Concentration(normal 35-160 µ/L)

Muscle Biopsy

HistologyImmunostaining

Findings Biochemical Test Availability

CMD with completemerosin deficiency/LAMA2 mutations

Elevated to markedlyelevated

• Neonatal:inflammatorychanges

• End stage:dystrophicchanges

Merosin: complete deficiency

Clinical

CMD with partialmerosin deficiency

Elevated to markedlyelevated

• Childhood:variable fibersize

• Increasedendomysialconnectivetissue

Merosin: partial deficiency

Merosin-positive CMD

Normal to moderatelyhigh

Myopathic changes (mildnecrosis, regeneration, and

fatty replacement)• Merosin: normal Not available

MDC1C/ FKRPmutations

Markedly elevated(1,000-10,000 U/I) Dystrophic changes

• Merosin: partialdeficiency

• Glycosylatedalphadystroglycan:severely reduced

Research only

CMD with ITGA7mutations (Japanese)

(one report)Mildly elevated

• Mild fiber sizevariation

• Mild-type 1fiber typepredominance(65%)

• No necrosis,regeneration,or fattyreplacement

• Merosin: normal• Integrin alpha 7:

absent

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CMD with earlyspine rigidity (RSS)/

SEPN1 mutationsNormal

• Variable fibersize

• Occasionalnecrotic fibers

• Minimallyincreasedendomysialconnectivetissue

Merosin: normal

Not available

CMD withrespiratory failure

and musclehypertrophy (one

report)

Very high (1700-7600U/I)

• Dystrophicchanges

• Merosin: reduced• Integrins alpha 7

and beta 1D:reduced heparinsulfate

• Proteoglycans:normal

Ullrich CMD Mildly elevated (~2-3xnormal)

• Fiber sizevariation

• Necroticfibers

• Mildendomysialfibrosis

• Merosin: normal• COL6: severely

reduced orcompletelydeficient

CMD witharthrogryposis and

absent limb musclesNormal

• Dystrophicchanges

• Fiber sizevariation

• Fattyinfiltration

Merosin: normal on skinbiopsy

Salih CMD Mildly elevated• Dystrophic

changes

• Dystrophin:normal

• Merosin: normal• Sarcoglycan:

normal

CMD with pseudo-hypertrophy,

macroglossia, andrespiratory

insufficiency

Markedly elevated

• Fiber sizevariation

• Central nuclei• Predominance

of type 1fibers

• Necrotic andregeneratingfibers

• Dystrophin:normal

• Alphasarcoglycan:normal

• Secondarydeficiency ofmerosin

• Up-regulation oflaminin 5

• Reduceddystroglycanlevels

CMD with adductedthumbs (two related

cases)Normal - mildly

elevated

• Fiber sizevariation

• Central nuclei• Endomysial

fibrosis• Lipomatosis

• Merosin: normal• Collagen VI:

normal• Emerin: normal• Lamin A/C:

normal

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Walker-Warburg syndrome Elevated: 2-15 x normal Myopathic

• Merosin: normalor reduced

• Glycosylatedalphadystroglycan:deficient

• Betadystroglycan:normal

Research onlyCMD with cerebellarhypoplasia Markedly elevated

Dystrophic changes withfiber size variation and

marked fibrosisMerosin: normal

CMD withmitochondrial

structuralabnormalities (one

report)

Mildly elevated

• Fiber sizevariation

• Necrosis andregeneration

• EM: enlargedmitochondriawith abnormalstructure

• Merosin: normal• SDH and COX:

increased stainingat periphery oftype 2 fiber;decreasedstaining in centerof fibers

Fukuyama CMD Elevated: 2-15x normal

• Fiber sizevariation

• Increasedconnectivetissue

• Central nuclei

• Fukutin: deficient• Glycosylated

alphadystroglycan:deficient

• Betadystroglycan:normal

Not availableMuscle-eye-brain disease Elevated: 2-15x normal

• Increasednumber ofregeneratingfibers seen byage one year

• Musclebiopsy showsdystrophicchanges, withexcessinfiltration offat andconnectivetissue by ageone year

• Partial reductionof merosin

• Partial reductionof glycosylatedalphadystroglycan

• Increase inlaminin beta 2

MDC1D (one report) Elevated: 2-20x normal Unknown

• Reduction ofantibodies againstglycosylatedbinding sites onalpha

• Normal stainingof betadystroglycan andlaminin alpha 2

CMD with complete merosin deficiency. Serum CK concentration is usually markedlyelevated from birth. Muscle histopathology changes as a function of age. Muscle biopsies inthe neonatal period may show significant inflammation, which is often interpreted as infantilepolymyositis [Pegoraro et al 1996]. The inflammation resolves into a more typically"dystrophic" picture, although regeneration is less active than that seen in other musculardystrophies such as the dystrophinopathies. The poor regenerative potential of the muscleappears to be the consequence of a dysfunctional basal lamina scaffold in which myofiberregeneration must take place. With advancing age, the histopathology appears more similar to

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a static "myopathy" with extensive fatty infiltration and little or no evidence of activedegeneration or regeneration [Pegoraro et al 1998].

As the protein testing for complete merosin deficiency seems quite sensitive and specific,protein testing of muscle tissue obtained by biopsy is typically performed for diagnosis. Proteintesting can be performed on cells obtained by chorionic villus sampling (CVS) for prenataldiagnosis [Vainzof et al 2005].

CMD with partial merosin deficiency. The finding of "partial merosin deficiency" shouldnot be considered diagnostic of any particular etiology. The sensitivity or specificity of thefinding of partial merosin deficiency on muscle biopsy protein studies is not known. Thus, theetiologic significance of the finding of partial merosin deficiency on muscle biopsy must beinterpreted with caution. Partial merosin deficiency can also be seen in individuals with limb-girdle muscular dystrophy.

Congenital muscular dystrophy type 1C (MCD1C). Complete deficiency of fukutin-relatedprotein on muscle biopsy and/or testing for mutations in the FKRP gene performed on a clinicalbasis confirm a diagnosis of MCD1C. This form of CMD shows a partial deficiency of merosinand alpha sarcoglycan and markedly elevated serum CK concentration. The unique clinicalpicture, including macroglossia, should help identify the most appropriate candidates formolecular genetic testing.

CMD with integrin alpha 7. Biochemical testing for integrin alpha 7 appears not to be specificfor individuals with mutations in the gene (ITGA7) [Hayashi et al 1998].

Fukuyama congenital muscular dystrophy (FCMD). Although highly glycosylated alphadystroglycan appears to be deficient in skeletal muscle, cardiac muscle, and brain [Hayashi etal 2001]. Michele et al (2002) established that alpha dystroglycan is present at the musclemembrane in individuals with Fukuyama CMD. However the ability of alpha dystroglycan tobind to laminin, neurexin, and agrin is compromised by hypoglycosylation. Despite recentdiscoveries, biochemical testing for this disorder is not currently available.

Molecular genetic testing. Diagnostic DNA testing for most forms of congenital musculardystrophy is currently not available on a clinical basis.

Genetic CounselingGenetic counseling is the process of providing individuals and families with information onthe nature, inheritance, and implications of genetic disorders to help them make informedmedical and personal decisions. The following section deals with genetic risk assessment andthe use of family history and genetic testing to clarify genetic status for family members. Thissection is not meant to address all personal, cultural, or ethical issues that individuals mayface or to substitute for consultation with a genetics professional. To find a genetics or prenataldiagnosis clinic, see the GeneTests Clinic Directory.

Mode of InheritanceThe congenital muscular dystrophies are inherited in an autosomal recessive manner with theexception of Ullrich congenital muscular dystrophy, which can be inherited in an autosomaldominant or autosomal recessive manner [Pan et al 2003].

Risk to Family Members — Autosomal Recessive CMDParents of a proband

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• The parents of an affected child are obligate heterozygotes and, therefore, carry asingle copy of a disease-causing mutation.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband• At conception, each sib of an individual with autosomal recessive CMD has a 25%

chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25%chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband• Many individuals with congenital muscular dystrophy do not reproduce.• If individuals with autosomal recessive congenital muscular dystrophy reproduce, all

of the offspring are obligate carriers.• Because the general population carrier frequency is low, the risk to offspring of an

individual with autosomal recessive CMD of being affected is greater than the riskfor the general population but less than 1%.

Other family members of a proband. Each sib of an obligate carrier for autosomal recessiveCMD is at a 50% risk of being a carrier.

Carrier DetectionCarrier detection using molecular genetic techniques is available on a clinical basis only forFukuyama muscular dystrophy, muscle-eye-brain disease, Walker-Warburg syndrome,congenital muscular dystrophy type 1C, congenital muscular dystrophy type 1D, congenitalmuscular dystrophy with early spine rigidity and congenital muscular dystrophy with meroisndeficiency once the mutations have been identified in the proband.

Risk to Family Members — Autosomal Dominant Ullrich CMD• Neither of the two individuals diagnosed with autosomal dominant Ullrich congenital

muscular dystrophy to date has had an affected parent.• Both documented cases of autosomal dominant Ullrich congenital muscular

dystrophy are the result of de novo mutations in the egg or the sperm cell that createdthe affected child [Pan et al 2003].

Sibs of a proband• The risk to the sibs of the proband depends upon the genetic status of the proband's

parents.• If the parents are clinically unaffected, the risk to the sibs of a proband appears to be

low.• If the disease-causing mutation found in the proband cannot be detected in the DNA

of either parent, the risk to sibs is low, but greater than that of the general populationbecause the possibility of germline mosaicism exists.

Offspring of a proband. Each child of an individual with dominantly inherited Ullrich CMDhas a 50% chance of inheriting the mutation.

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Related Genetic Counseling IssuesFamily planning. The optimal time for determination of genetic risk, clarification of carrierstatus, and discussion of the availability of prenatal testing is before pregnancy.

Muscle biopsy banking. Future research and diagnostic studies may be performed on muscletissue that has been flash-frozen. Banking tissue or storing leftover samples from a diagnosticbiopsy may be worthwhile for future studies.

DNA banking. DNA banking is the storage of DNA (typically extracted from white bloodcells) for possible future use. Because it is likely that testing methodology and ourunderstanding of genes, mutations, and diseases will improve in the future, considerationshould be given to banking DNA of affected individuals. DNA banking is particularly relevantin situations in which molecular genetic testing is available on a research basis only or thesensitivity of currently available testing is less than 100%. See DNA Banking for a list oflaboratories offering this service.

Prenatal TestingComplete merosin deficiency. Prenatal testing for pregnancies at 25% risk for completemerosin deficiency is possible provided that complete merosin deficiency has been documentedin the muscle of the proband. The diagnostic testing must be done on a sample of direct andflash-frozen chorionic villi (obtained at about 10-12 weeks' gestation) by immunostaining. In70 prenatal cases, concordance between immunostaining of chorionic villi and linkage analysiswas 100%, suggesting that immunostaining on CVS is both accurate and sensitive [Vainzof etal 2005].

Prenatal testing for complete merosin deficiency using molecular testing for mutations thathave been previously identified in the proband is available by CVS or amniocentesis. Linkageanalysis is available but generally not indicated; it may, however, be considered if sequencinghas not been completed on the proband and/or if CVS is not available for biochemical studies.Linkage must be established in the family before prenatal testing can be performed.

Fukuyama muscular dystrophy, muscle-eye-brain disease, Walker-Warburg syndrome,congenital muscular dystrophy type 1C (MDC1C), and congenital muscular dystrophytype 1D (MDC1D), and congenital muscular dystrophy with early spine rigidity. Prenataldiagnosis for pregnancies at increased risk for Fukuyama muscular dystrophy, muscle-eye-brain disease, Walker-Warburg syndrome, MDC1C, MDC1D, and congenital musculardystrophy with early spine rigidity is possible by analysis of DNA extracted from fetal cellsobtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionicvillus sampling (CVS) at about 10-12 weeks' gestation. Both disease-causing alleles of anaffected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day ofthe last normal menstrual period or by ultrasound measurements.

Other types of congenital muscular dystrophy. No laboratories offering molecular genetictesting for prenatal diagnosis of other types of congenital muscular dystrophy are listed inGeneTests Laboratory Directory. However, prenatal testing may be available for families inwhich the disease-causing mutations have been identified in an affected family member in aresearch or clinical laboratory. For laboratories offering custom prenatal testing, see

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Preimplanation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offeringPGD, see .

ManagementNo definitive treatments exist for the congenital muscular dystrophies. Management is similarto that for the limb-girdle muscular dystrophies (LGMD) and should be tailored to eachindividual and each specific subtype. A general approach to appropriate management canprolong survival and improve quality of life for individuals with CMD. This general approachis based on the typical progression and complications of individuals with LGMD as describedby Bushby (1999).

• Weight control to avoid obesity• Physical therapy and stretching exercises to promote mobility and prevent

contractures• Use of mechanical assistive devices, such as canes, walkers, orthotics, and

wheelchairs as needed to help ambulation and mobility• Monitoring and surgical intervention as needed for orthopedic complications such as

foot deformity and scoliosis• Monitoring of respiratory function and use of respiratory aids when indicated;

specifically, some individuals may benefit from assisted cough, noninvasiveventilation, or mechanical ventilation via tracheostomy [Wallgren-Pettersson et al2004]

• Social and emotional support and stimulation to maximize a sense of socialinvolvement and productivity and to reduce the sense of social isolation common inthese disorders [Eggers & Zatz 1998]

ResourcesGeneReviews provides information about selected national organizations and resources forthe benefit of the reader. GeneReviews is not responsible for information provided by otherorganizations. Information that appears in the Resources section of a GeneReview is currentas of initial posting or most recent update of the GeneReview. Search GeneTests for this

disorder and select for the most up-to-date Resources information.—ED.

European Neuromuscular Centre (ENMC)Lt. Gen. van Heutszlaan 6 3743 JN Baarn The Netherlands Phone: +31 35 5480481 Fax: +31 35 5480499 Email: [email protected] www.enmc.org

Muscular Dystrophy Association (MDA)3300 East Sunrise Drive Tucson, AZ 85718-3208 Phone: 800-FIGHT-MD (800-344-4863); 520-529-2000 Fax: 520-529-5300

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Email: [email protected] www.mdausa.org

Muscular Dystrophy Campaign7-11 Prescott Place London SW4 6BS, United Kingdom Phone: (+44) 0 020 7720 8055 Fax: (+44) 0 020 7498 0670 Email: [email protected] www.muscular-dystrophy.org

ReferencesMedical Genetic Searches: A specialized PubMed search designed for clinicians that is locatedon the PubMed Clinical Queries page.

Published Statements and Policies Regarding Genetic TestingNo specific guidelines regarding genetic testing for this disorder have been developed.

Literature CitedAllamand V, Sunada Y, Salih MA, Straub V, Ozo CO, Al-Turaiki MH, Akbar M, Kolo T, Colognato H,

Zhang X, Sorokin LM, Yurchenco PD, Tryggvason K, Campbell KP. Mild congenital musculardystrophy in two patients with an internally deleted laminin alpha2-chain. Hum Mol Genet.1997;6:747–52. [PubMed: 9158149]

Auranen M, Rapola J, Pihko H, Haltia M, Leivo I, Soinila S, Virtanen I, Kalimo H, Anderson LV,Santavuori P, Somer H. Muscle membrane-skeleton protein changes and histopathologicalcharacterization of muscle-eye-brain disease. Neuromuscul Disord. 2000;10:16–23. [PubMed:10677859]

Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B,Kayserili H, Merlini L, Chitayat D, Dobyns WB, Cormand B, Lehesjoki AE, Cruces J, Voit T, WalshCA, van Bokhoven H, Brunner HG. Mutations in the O-mannosyltransferase gene POMT1 give riseto the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet.2002;71:1033–43. [PubMed: 12369018]

Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, Ponting CP, Estournet B,Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F. Mutations in the fukutin-relatedprotein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001;69:1198–209.[PubMed: 11592034]

Brockington M, Brown SC, Lampe A, Yuva Y, Feng L, Jimenez-Mallebrera C, Sewry CA, Flanigan KM,Bushby K, Muntoni F. Prenatal diagnosis of Ullrich congenital muscular dystrophy using haplotypeanalysis and collagen VI immunocytochemistry. Prenat Diagn. 2004;24:440–4. [PubMed:15229843]

Brockington M, Sewry CA, Herrmann R, Naom I, Dearlove A, Rhodes M, Topaloglu H, Dubowitz V,Voit T, Muntoni F. Assignment of a form of congenital muscular dystrophy with secondary merosindeficiency to chromosome 1q42. Am J Hum Genet. 2000;66:428–35. [PubMed: 10677302]

Brockington M, Yuva Y, Prandini P, Brown SC, Torelli S, Benson MA, Herrmann R, Anderson LV,Bashir R, Burgunder JM, Fallet S, Romero N, Fardeau M, Straub V, Storey G, Pollitt C, Richard I,Sewry CA, Bushby K, Voit T, Blake DJ, Muntoni F. Mutations in the fukutin-related protein gene(FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital musculardystrophy MDC1C. Hum Mol Genet. 2001;10:2851–9. [PubMed: 11741828]

Brown SC, Torelli S, Brockington M, Yuva Y, Jimenez C, Feng L, Anderson L, Ugo I, Kroger S, BushbyK, Voit T, Sewry C, Muntoni F. Abnormalities in alpha-dystroglycan expression in MDC1C andLGMD2I muscular dystrophies. Am J Pathol. 2004;164:727–37. [PubMed: 14742276]

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Bushby KM. Making sense of the limb-girdle muscular dystrophies. Brain 122 (Pt. 1999;8):1403–20.[PubMed: 10430828]

Caro PA, Scavina M, Hoffman E, Pegoraro E, Marks HG. MR imaging findings in children with merosin-deficient congenital muscular dystrophy. AJNR Am J Neuroradiol. 1999;20:324–6. [PubMed:10094364]

Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. Neuromuscul Disord.2005;15:207–17. [PubMed: 15725582]

Cohn RD, Herrmann R, Sorokin L, Wewer UM, Voit T. Laminin alpha2 chain-deficient congenitalmuscular dystrophy: variable epitope expression in severe and mild cases. Neurology. 1998;51:94–100. [PubMed: 9674785]

Cormand B, Pihko H, Bayes M, Valanne L, Santavuori P, Talim B, Gershoni-Baruch R, Ahmad A, vanBokhoven H, Brunner HG, Voit T, Topaloglu H, Dobyns WB, Lehesjoki AE. Clinical and geneticdistinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology.2001;56:1059–69. [PubMed: 11320179]

Dubowitz V. 41st ENMC International Workshop on Congenital Muscular Dystrophy 8-10 March 1996,Naarden, The Netherlands. Neuromuscul Disord. 1996;6:295–306. [PubMed: 8887959]

Eggers S, Zatz M. Social adjustment in adult males affected with progressive muscular dystrophy. AmJ Med Genet. 1998;81:4–12. [PubMed: 9514580]

Fardeau M, Tome FM, Helbling-Leclerc A, Evangelista T, Ottolini A, Chevallay M, Barois A, EstournetB, Harpey JP, Faure S, Guicheney P, Hillaire D. Congenital muscular dystrophy with merosindeficiency: clinical, histopathological, immunocytochemical and genetic analysis. Rev Neurol(Paris). 1996;152:11–9. [PubMed: 8729391]

Flanigan KM, Kerr L, Bromberg MB, Leonard C, Tsuruda J, Zhang P, Gonzalez-Gomez I, Cohn R,Campbell KP, Leppert M. Congenital muscular dystrophy with rigid spine syndrome: a clinical,pathological, radiological, and genetic study. Ann Neurol. 2000;47:152–61. [PubMed: 10665485]

Gilhuis HJ, ten Donkelaar HJ, Tanke RB, Vingerhoets DM, Zwarts MJ, Verrips A, Gabreels FJ.Nonmuscular involvement in merosin-negative congenital muscular dystrophy. Pediatr Neurol.2002;26:30–6. [PubMed: 11814732]

Grewal PK, Hewitt JE. Glycosylation defects: a new mechanism for muscular dystrophy? Hum MolGenet 12 Spec No. 2003;2:R259–64. [PubMed: 12925572]

Hayashi YK, Chou FL, Engvall E, Ogawa M, Matsuda C, Hirabayashi S, Yokochi K, Ziober BL, KramerRH, Kaufman SJ, Ozawa E, Goto Y, Nonaka I, Tsukahara T, Wang JZ, Hoffman EP, Arahata K.Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet. 1998;19:94–7.[PubMed: 9590299]

Hayashi YK, Ogawa M, Tagawa K, Noguchi S, Ishihara T, Nonaka I, Arahata K. Selective deficiencyof alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology. 2001;57:115–21. [PubMed: 11445638]

Herrmann R, Straub V, Meyer K, Kahn T, Wagner M, Voit T. Congenital muscular dystrophy withlaminin alpha 2 chain deficiency: identification of a new intermediate phenotype and correlation ofclinical findings to muscle immunohistochemistry. Eur J Pediatr. 1996;155:968–76. [PubMed:8911899]

Jimenez-Mallebrera C, Torelli S, Brown SC, Feng L, Brockington M, Sewry CA, Beltran-Valero DeBernabe D, Muntoni F. Profound skeletal muscle depletion of alpha-dystroglycan in Walker-Warburgsyndrome. Eur J Paediatr Neurol. 2003;7:129–37. [PubMed: 12788039]

Kanagawa M, Saito F, Kunz S, Yoshida-Moriguchi T, Barresi R, Kobayashi YM, Muschler J, DumanskiJP, Michele DE, Oldstone MB, Campbell KP. Molecular recognition by LARGE is essential forexpression of functional dystroglycan. Cell. 2004;117:953–64. [PubMed: 15210115]

Kirschner J, Bonnemann CG. The congenital and limb-girdle muscular dystrophies: sharpening the focus,blurring the boundaries. Arch Neurol. 2004;61:189–99. [PubMed: 14967765]

Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, YoshiokaM, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, NakamuraY, Tokunaga K, Toda T. An ancient retrotransposal insertion causes Fukuyama-type congenitalmuscular dystrophy. Nature. 1998;394:388–92. [PubMed: 9690476]

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Longman C, Brockington M, Torelli S, Jimenez-Mallebrera C, Kennedy C, Khalil N, Feng L, Saran RK,Voit T, Merlini L, Sewry CA, Brown SC, Muntoni F. Mutations in the human LARGE gene causeMDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormalglycosylation of alpha-dystroglycan. Hum Mol Genet. 2003;12:2853–61. [PubMed: 12966029]

Manya H, Sakai K, Kobayashi K, Taniguchi K, Kawakita M, Toda T, Endo T. Loss-of-function of an N-acetylglucosaminyltransferase, POMGnT1, in muscle-eye-brain disease. Biochem Biophys ResCommun. 2003;306:93–7. [PubMed: 12788071]

Martin-Rendon E, Blake DJ. Protein glycosylation in disease: new insights into the congenital musculardystrophies. Trends Pharmacol Sci. 2003;24:178–83. [PubMed: 12707004]

Mercuri E, Brockington M, Straub V, Quijano-Roy S, Yuva Y, Herrmann R, Brown SC, Torelli S,Dubowitz V, Blake DJ, Romero NB, Estournet B, Sewry CA, Guicheney P, Voit T, Muntoni F.Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol.2003;53:537–42. [PubMed: 12666124]

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Chapter NotesAuthor History

Erynn Gordon, MS, CGC (2003-present) Eric P Hoffman, PhD (2001-present) Elena Pegoraro, MD, PhD (2001-present) Cheryl Scacheri, MS; GeneDx, Inc (2001-2003)

Revision History• 22 December 2006 (cd) Revision: clinical testing, carrier testing, and prenatal testing

available for CMD with early spine rigidity; clinical testing and carrier testingavailable for CMD with merosin deficiency

• 13 January 2006 (me) Comprehensive update posted to live Web site

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• 25 March 2005 (cd) Revision: Clinical testing available for MDC1D• 26 July 2004 (eh) Revision: Bethlem and Ullrich CMD• 2 January 2004 (cd) Revision: test availability• 22 September 2003 (cd) Revision: test availability, prenatal testing• 19 June 2003 (ca) Comprehensive update posted to live Web site• 22 January 2001 (me) Overview posted to live Web site• 20 April 2000 (eh) Original submission

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