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Paediatric Laboratory Medicine

Congenital Muscular Dystrophies Panel: Sequencing

Clinical Significance

Congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessively inherited diseases, which include Walker-Warburg syndrome (WWS), Muscle-Eye-Brain Disease (MEB), Fukuyama Congenital Muscular Dystrophy (FCMD)and Congenital Muscular Dystrophy Type 1C (MDC1C).They usually present at birth or within the first 6 months of life. Initial signs include hypotonia, muscle weakness and the variable appearance of contractures characterized by dystrophic changes on skeletal-muscle biopsy. The heterogeneous nature of CMD is reflected by differing degrees of motor developmental delay, physical disability, muscle pathology, elevation of serum creatine kinase (CK) and a variable presence of mental retardation and structural brain defects. WWS, MEB, FCMD and MDC1C are caused by mutations affecting glycosylation enzymes - proteins that add sugars to other proteins. In these diseases, defects in the sugar-adding mechanism disrupt the properties of a-dystroglycan, a protein critical for normal muscle function. Disruption of á-dystroglycan by various mechanisms causes the phenotypes associated with WWS, MEB, FCMD and MDC1C. Congenital muscular dystrophies are among the most frequent autosomal recessively inherited neuromuscular disorders.

Walker-Warburg Syndrome (WWS): WWS is the most severe form of the congenital muscular dystrophies, and often presents in the prenatal period. The life expectancy of individuals with WWS is less than three years. WWS is genetically heterogeneous, mutations in the POMT1, POMT2, POMGnT1 and FKRP genes have been found in about 25% of WWS patients.

Muscle-Eye-Brain (MEB) disease: MEB disease progress is pathologically and clinically slower than the other types of CMDs. Neonatal hypotonia, developmental delay and ocular abnormalities are characteristic of MEB disease. Approximately 80% of MEB patients were found to have mutations in the POMGnT1 gene and 10% in the FKRP gene. Although MEB has been reported in individuals of various ethnic backgrounds, it is more common in Finland. Several mutations have been described in non-Finish patients whereas a single mutation accounts for 99% of the mutant chromosomes in the Finnish population.

Fukuyama Congenital Muscular Dystrophy (FCMD): FCMD presents during the neonatal period with hypotonia, weakness and poor suck reflex. Although FCMD has been reported in individuals of various ethnic backgrounds, it is most common in Japan. The majority of cases (~95%) are due to mutations in FCMD, with mutations in the FKRP gene accounting for about 5%.

Congenital Muscular Dystrophy Type 1C (MDC1C): MDC1C is a severe form of congenital muscular dystrophy with onset at birth, significant facial weakness and hypertrophy of the leg muscles. The majority of cases (~90%) have mutations the FKRP gene.

WWS, MEB, FCMD and CMD1C are autosomal recessive disorders. An individual is said to be affected if s/he receives two copies of a defective gene, one from each parent. Any person with one copy of the defective gene is a carrier. Carriers are not affected themselves by the condition and will never develop the disease. However, if their partner is also a carrier, there is a one in four chance (25%) that their child will be born with the condition. There is a three in four chance (75%) that their child will not have the condition.

Test Name

Congenital Muscular Dystrophies Panel: Sequencing

Alternate Name/ Synonym

  • Fukuyama congenital muscular dystrophy
  • Walker-Warburg syndrome
  • Muscle-Eye-Brain disease
  • Muscular dystrophy-dystroglycanopathy

Gene Name

  • FCMD
  • FKRP
  • POMGnT1
  • POMT1
  • POMT2

Alternate Gene Name

FKTN (FCMD)

Test Code

CMD

Division

Molecular Genetics

Method

Sequencing

External Proficiency Testing

CAP

Turn Around Time

2 weeks (Prenatal samples), 2-3 weeks (Pregnancy/Urgent samples), 4-6 weeks (Routine)

Protein

Fukutin, Fukutin-related protein, Protein-O-mannose beta-1,2-N-acetylglucosaminyltransferase, Protein-O-mannosyltransferase 1, Protein-O-mannosyltransferase 2

Disease/Condition

Congenital Muscular Dystrophies

Specimen Type

Blood; gDNA. 

For details about specimen requirements, please refer to: Specimen Type & Requirements (PDF).

Minimum Specimen Requirements

5-10 mL EDTA or ACD 0.5 mL EDTA (neonate); minimum 10 ug in 100 uL low TE (pH8.0)

Storage/Transportation

Room Temperature

Special Requirements

Special Instructions for Genome Diagnostics Samples

If sample shipment >48 hours, ship on ice.

Approval is not required

CPT Codes

81404, 81405, 81406

Shipping and Contact Information

The Hospital for Sick Children
Rapid Response Laboratory
170 Elizabeth Street, Room 3642
Toronto, ON
M5G 2G3
Canada
Phone: 416-813-7200
Phone: 1-855-381-3212

Interpretation

Interpretation is provided in report

Information Sheet: Congenital Muscular Dystrophies