Primary newborn screening disorders

Duchenne muscular dystrophy (DMD)

background

background

Duchenne muscular dystrophy (DMD) is an X-linked rare disease (affects approximately 1 in 3000-6000 live male births worldwide).  DMD occurs as a result of mutations in the dystrophin gene. It leads to an absence of or defects in the protein dystrophin and is manifested by progressive muscle degradation. 


clinical

clinical

DMD boys as young as 1 year develop neurocognitive delays, scoring lower in motor, speech, and language function on the Bayley III Motor Assessment compared to age-matched controls, but it can take several years before the final diagnosis is made. Progressive muscle weakness in the lower limbs spreads to the arms, neck and other areas. As the condition progresses, muscle tissue experiences wasting and is eventually replaced by fat and fibrotic tissue (fibrosis). Typically the disorder is diagnosed only around 4-5 years of age. Treatment is usually initiated at age 5 years or older, only after muscle fibrosis has started. Duchenne patients are often wheelchair bound between the ages of seven and 13 years old. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. The condition is universally fatal, and without intervention the mean age at death is around 19 years

testing

testing

The currently used primary biomarker test for Duchenne muscular dystrophy looks for the presence of creatine kinase (CK) enzyme activity in serum by fluorescence measurement of enzyme activity in blood, followed by confirmation by muscle biopsy or genetic testing to identify dystrophin mutations, e.g. by multiplex PCR, multiplex ligation –dependent probe amplification, single-condition amplification /internal primer or multiplex amplifiable probe hybridization. Recently, next-generation sequencing (NGS)-based targeted gene analysis has become clinically available for detection of point mutations and other sequence variants (small insertions, deletions, and indels). CK is a protein found in muscle but when the muscles are damaged, owing to disease or injury, it leaks into the bloodstream. The same assay concept has been converted for use with dried blood spot (DBS) samples in the pilots or early screening programs. 

Creatine kinase is an isoenzyme and several different forms exist. CK-MM is the predominant isoform present in skeletal muscle and is elevated in patients with muscular dystrophies. The CK is a nonspecific marker for DMD since other conditions such as muscle trauma during birth cause transient elevated levels of CK-MM in blood. In addition, CK can be elevated in other rarer forms of muscular dystrophy. 


treatment

treatment

Although no cure exists for the progressive muscle weakness of DMD, corticosteroid treatment improves muscle strength and function, and in combination with supportive medical care is associated with delayed loss of ambulation and markedly improved survival.  In addition, novel molecular therapies are under development and therefore interest towards newborn screening is increasing.


inheritance

inheritance

DMD is inherited in an X-linked recessive pattern. Females will typically be carriers for the disease while males will be affected. Typically, a female carrier will be unaware they carry a mutation until they have an affected son. Female carriers of an X-linked recessive condition, such as DMD, can show symptoms depending on their pattern of X-inactivation.

Duchenne muscular dystrophy has an incidence of 1 in 3,600 male infants. Mutations within the dystrophin gene can either be inherited or occur spontaneously during germline transmission.


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