Congenital Muscular Dystrophy

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Congenital muscular dystrophy (CMD) refers to a group of genetic disorders in which weakness and an abnormal muscle biopsy are present at birth.

GENETICS/BASIC DEFECTS

1. Inheritance

a. Genetic heterogeneity

b. Autosomal recessive in general 2. Classification

a. Merosin—negative (laminin α2 deficient) CMD (complete or partial)

i. Chromosome locus: 6q22–q23

ii. Caused by mutations of the laminin α2-chain (LAMA2) gene

iii. “Classical CMD”: deficient in merosin, the α2 chain of laminin-2, a major constituent of the basal lamina of skeletal muscle fibers linking the extracellular matrix to the dystrophin-associated proteins and integrins

iv. A milder phenotype caused by partial deficiency of merosin

b. Merosin-positive CMD consisting of a genetically more heterogeneous group

i. Rigid spine syndrome

a) Caused by mutations in the selenoprotein N- 1 (SEPN1) gene which is mapped to chro- mosome 1p35–p36

b) Early onset of hypotonia c) Rigidity of the spine d) Scoliosis

ii. Ullrich syndrome: congenital muscular dystrophy with proximal joint contractures and distal joint laxity

iii. Pure CMD: either with normal or deficient levels of laminin-α2 (merosin)

iv. Other merosin-positive CMD

a) Merosin-positive CMD with mental retardation

b) Merosin-positive CMD with cerebellar hypoplasia

c. Merosin-positive CMD with mental retardation and neuronal migration disorders

i. Fukuyama CMD

a) Chromosome locus: 9q31–q33 b) FCMD gene encodes fukutin

c) Fukutin gene defect represents a novel mutation with a retrotransposal insertion of tandemly repeated sequences on chromosome 9q31-q33

ii. Muscle-eye-brain disease

a) Caused by mutation in the protein O-manno- side N-acetylglucosaminyltransferase-1

(POMGnT1) gene which is mapped to chro- mosome 1p32-p34

b) Sharing features with Fukuyama CMD c) Milder phenotype with survival ranging

from early childhood to the seventh decade

iii. Walker-Warburg syndrome

a) Caused by mutation in the protein O-manno- syltransferase-1 (POMT1) gene

b) Similar to muscle-eye-brain disease

c) Comparatively more severe leading to death in the first few months of life

iv. Other CMD with neuronal migration defects

CLINICAL FEATURES

1. Typical features a. Floppy infant b. Low muscle tone c. Contractures d. Muscle weakness

i. Tends to be stable over time

ii. Complications of dystrophy becoming more sever with time

2. Merosin-negative CMD

a. Demonstrating clinical homogeneity i. Severe hypotonia

ii. Multiple contractures

iii. Delayed developmental milestones iv. Normal mentation

v. Variable degrees of central hypomyelination seen on neuroimaging

b. Patients with complete merosin deficiency i. Typically presenting as floppy infants ii. May or may not require ventilatory assistance iii. Most patients stabilize and able to continue

developing without mechanical ventilation iv. Feeding difficulty leading to recurrent aspiration

and poor nutrition in some patients

v. The best motor milestone achieved: standing with support

vi. Unable to ambulate vii. Cognitive development

a) Generally normal

b) Mental retardation in patients with brain anomalies

viii. Epilepsy

c. Patients with partial merosin deficiency i. Wide clinical spectrum

a) Marked hypotonia at birth, contractures, and severely delayed motor milestones

b) Limb-girdle muscular dystrophy-like pres- entation in the teen

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c) An adult-onset proximal limb-girdle weakness with elevated CK concentration ii. White matter abnormalities by MRI in all patients

with documented merosin gene mutations 3. Merosin-positive CMD

a. Rigid spine disease i. Onset in infancy ii. Axial muscle weakness iii. Early rigidity of the spine

iv. Prominent nasal voice

v. Nocturnal respiratory insufficiency vi. Early respiratory failure

b. Ullrich disease

i. Proximal contractures ii. Distal joint laxity

iii. Delayed motor milestones a) Ability to walk in some cases

b) Wheelchair dependent in majority of cases iv. Normal intelligence

c. Pure CMD

i. Normal intelligence ii. Normal brain imaging d. Other merosin-positive CMD

4. Merosin-positive CMD with mental retardation and neuronal migration defects

a. Fukuyama CMD

i. An autosomal recessive disorder ii. Prevalent in Japan

iii. Early onset (before nine months) iv. Muscle weakness

v. Accompanied by joint contractures vi. Hypotonia/hypokinesia

vii. Severe mental retardation viii. Epilepsy

ix. Eye anomalies a) Myopia

b) Congenital nystagmus c) Cortical blindness d) Optic atrophy

e) Choreoretinal degeneration

x. Brain anomalies (cobblestone lissencephaly;

type 2 lissencephaly) a) Micropolygyria b) Pachygyria

c) White matter lucency

d) Minor cerebellar alterations (cortical dys- plasia

b. Muscle-eye-brain disease

i. An autosomal recessive disorder

ii. Mimics Walker-Warburg syndrome but overall changes tend to be much milder

iii. Present as a floppy infant with suspected blindness

iv. Severe mental retardation

v. Extensive neuronal migration disorder a) Pachygyria and polymicrogyria b) Brain stem hypoplasia

c) Cerebellar dysgenesis d) Hydrocephalus

vi. Muscle involvement: typical features of muscular dystrophy with ongoing de- and regeneration vii. Normal expression of laminin α2

c. Walker-Warburg syndrome

i. An autosomal recessive disorder ii. Type II lissencephaly

a) Micropolygyric ‘cobblestone’ cortex b) Extensive white matter abnormalities c) Hydrocephaly with enlarged ventricles d) Brainstem hypoplasia

e) Hypoplasia of the cerebellum, particularly the cerebellar vermis

iii. Ocular dysgenesis a) Megacornea b) Buphthalmos c) Corneal clouding d) Cataracts

e) Abnormal vitreous f) Retinal hypopigmentation g) Hypoplasia of the optic nerve h) Clinically blind

iv. Muscular dystrophy

a) Variable in severity: ranges from myopathy with increased variation of fiber size to severe, end-stage muscular dystrophy b) Well preserved expression of laminin α2 v. Complete lack of psychomotor development

(severe mental retardation) for those who survive for some years

DIAGNOSTIC INVESTIGATIONS

1. Elevated serum creatine kinase (CPK) levels 2. Brain MRI with variety of findings

a. Pachygyria (with normal cognitive function)

b. Cerebellar hypoplasia (with normal cognitive function but delay of speech development)

c. Cerebellar cysts (in connection with pure CMD) d. Abnormal white matter signal (in connection with

pure CMD of merosin-deficient type) e. Large lissencephalic changes

f. Hydrocephalus

3. EMG: the motor units show myopathy with small ampli- tude and duration

4. Muscle biopsy

a. Dystrophic or myopathic pattern

b. Varying degrees of muscle fiber degeneration and replacement of muscle fibers by connective tissue and fat

c. In the severe merosin-deficient form of CMD: very few muscle fibers left

d. Immunohistochemic staining for merosin i. Normal in most of the subgroups of CMD ii. Deficient or totally lacking in CMD with

merosin deficiency

iii. Merosin is deficient in 5% of patients with Fukuyama type CMD

5. Molecular genetic analyses

a. Fukuyama CMD: sequencing of entire coding region or select exons of FCMD gene

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b. Muscle-eye-brain disease: sequencing of entire coding region or select exons or targeted mutation analy- sis of POMGnT1 gene

c. Walker-Warburg syndrome: sequencing of entire coding region or select exons or mutation scanning of POMT1 gene

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib: 25% (autosomal recessive) b. Patient’s offspring:

i. Many individuals not living long enough to reproduce

ii. All offspring are carriers

iii. Recurrence risk to offspring probably less than 1%

2. Prenatal diagnosis

a. Available for pregnancies at 25% risk for complete merosin deficiency by linkage analysis, provided complete merosin deficiency has been documented in the muscle of the proband

b. Prenatal diagnosis by DNA mutation analysis is available for pregnancies at increased risk of Fukuyama MD, muscle-eye-brain disease, or Walker-Warburg MD by analysis of fetal DNA, obtained by amniocen- tesis or CVS, provided both disease-causing alleles of an affected family member have been identified 3. Management

a. No definitive treatment available b. General approaches

i. Weight control to avoid obesity

ii. Physical therapy and stretching exercises a) To promote mobility

b) To prevent contractures

iii. Using mechanical devices to help ambulation and mobility

iv. Surgical interventions for scoliosis and foot deformity

v. Medications for seizure control vi. Respiratory aids as needed vii. Social and emotional support

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Fig. 1. An infant with congenital muscular dystrophy showing hypo- tonic frog-leg posture, the chest deformity due to weakness of the intercostal muscles, and contractures of joints.