Congenital Muscular Dystrophy refers to a group of neuromuscular disorders manifesting as hypotonia and muscle weakness within the first 2 years of life, often from birth.

Definition and Presentation

• CMD refers to a group of neuromuscular disorders manifesting as hypotonia and muscle weakness within the first 2 years of life, often from birth.
• Muscle biopsies typically show dystrophic abnormalities, and affected children may present with:
  • Congenital joint contractures
  • Central nervous system involvement, affecting the brain and/or eyes
  • Elevated serum creatine kinase (CK), which may be markedly high.

Clinical Course

• CMD weakness is generally slowly progressive, though some children may have a static clinical course.

Advances in Classification

• CMD classification has shifted from structural abnormalities in the CNS to systems reflecting:
  • Genetic mutations
  • Muscle pathology

Diagnostic Tools

1. Neonatal Presentation: Hypotonia and arthrogryposis.
2. MRI Findings: Often abnormal, reflecting specific CMD conditions.
3. Muscle Biopsy:
   • Typical dystrophic changes
   • Immunostaining to detect deficiencies (e.g., alpha-2 laminin or alpha-dystroglycan).
4. Genetic Testing:
   • Identifies specific mutations (though some cases suggest additional genetic heterogeneity).

Inheritance Patterns

• Most CMDs are recessively inherited.
• Exceptions include dominant inheritance forms such as:
  • Collagen VI-related CMDs (e.g., UCMD)
  • LMNA muscular dystrophy

Notable CMD Subtypes

MDC1A (Merosin-Deficient CMD)

• Severe muscle weakness from infancy
• Early joint contractures and scoliosis
• Normal intelligence
• Associated with cerebral and peripheral nerve dysmyelination.
• Caused by mutations in the LAMA2 gene, affecting laminin alpha-2.

Collagen VI-Related CMDs (UCMD and BM)

• UCMD: Severe with early-onset scoliosis, proximal joint contractures, distal hyperlaxity, and "sandpaper-like" skin.
• BMD: Milder phenotype; inheritance typically dominant but variable.
• Mutations in COL6A1, COL6A2, COL6A3.

Rigid Spine CMD (SEPN1 Mutations)

• Spinal rigidity, early respiratory failure despite ambulation.

LMNA CMD

• Severe neck extensor weakness
• Life-threatening cardiac arrhythmias, cardiomyopathy, and respiratory insufficiency.

Alpha-Dystroglycanopathies

Alpha-dystroglycanopathies are a genetically heterogeneous group of muscle disorders caused by hypoglycosylation of alpha-dystroglycan (ADG), as seen on muscle biopsy. These disorders include a wide spectrum of clinical phenotypes, ranging from severe syndromal congenital muscular dystrophies (CMDs) to later-onset limb-girdle muscular dystrophies (LGMDs).

• Key Characteristics

• Common Pathology:

  • Muscle biopsy reveals hypoglycosylated alpha-dystroglycan and classic dystrophic changes.
  • Serum creatine kinase (CK) is markedly elevated.

• Phenotypic Range:

  • Severe CMDs:
    • Walker-Warburg Syndrome (WWS)
    • Muscle-Eye-Brain Disease (MEB)
    • Fukuyama Congenital Muscular Dystrophy (FCMD)
    • These are often associated with developmental abnormalities in the eyes and brain, leading to:
      • Cognitive deficits
      • Epilepsy
      • Visual loss
  • Limb-Girdle Muscular Dystrophies (LGMDs): Milder, later-onset phenotypes.

• Weakness Distribution:

  • More pronounced in upper extremities than lower extremities.

• Cardiac Involvement:

  • Variable but severe in Fukuyama CMD, WWS, and MEB.

Diagnostic Approach

1. Muscle Biopsy:
   • Shows absent or decreased staining for alpha-dystroglycan.
2. Genetic Testing:
   • Requires analysis of multiple genes.
   • Next-generation sequencing (NGS) facilitates comprehensive testing.
3. Associated Genes:
   • There is significant overlap between genes and phenotypes.
   • Individual genes are associated with multiple CMD phenotypes.
   • Defined phenotypes are often linked to various genes.

Clinical Implications

• Severe CMDs are associated with systemic involvement, including neurological, ocular, and cardiac manifestations.
• Accurate diagnosis requires integrating clinical, histological, and genetic data.
• Treatment focuses on symptom management, though future therapies may target underlying glycosylation defects.

Fukuyama Congenital Muscular Dystrophy (FCMD)

• Epidemiology: Predominantly observed in Japan.
• Clinical Features:
  • Severe muscle weakness
  • Cognitive deficits and developmental delay
  • Seizures
  • Cardiomyopathy
• Brain Anomalies:
  • Occipital pachygyria and polymicrogyria
  • Pontine hypoplasia
  • Cerebellar abnormalities
• Genetic Cause:
  • Mutations in the FKTN gene.
  • Rare milder phenotypes are also associated with FKTN mutations.

Walker-Warburg Syndrome (WWS)

• Clinical Features:
  • Severe muscle weakness
  • Brain and eye malformations
  • Hydrocephalus
• Genetic Causes:
  • Mutations in the following genes:
    • POMT1, POMT2, FKTN, FKRP, POMGNT1, LARGE
    • ISPD, GTDC2, DAG1
  • Phenotypes range from severe (WWS) to milder congenital muscular dystrophy and autosomal recessive limb-girdle muscular dystrophies (LGMDs).

Muscle-Eye-Brain Disease (MEB)

• Clinical Features:
  • Similar to WWS but milder.
  • Associated with brain and eye involvement.
• Genetic Causes:
  • Mutations in several alpha-dystroglycanopathy genes, overlapping with those causing WWS.

Management of CMDs

Management principles align with general guidelines for neuromuscular disorders:

1. Physical Therapy:
   • Maintain muscle strength and range of motion.
   • Prevent and manage joint contractures and scoliosis.
2. Monitoring and Interventions:
   • Bulbar Dysfunction: Monitor for swallowing difficulties.
   • Respiratory Function: Anticipate and manage respiratory insufficiency.
   • Cardiac Function: Regular cardiac evaluations for cardiomyopathy.
3. Multidisciplinary Approach:
   • Neurology, cardiology, pulmonology, orthopedics, and rehabilitation services are crucial for comprehensive care.