X-linked recessive diseases

Bruton agammaglobulinemia, Duchenne and Becker muscular dystrophies, Fabry disease, G6PD deficiency, hemophilia A and B, Hunter syndrome, Lesch-Nyhan syndrome, ocular albinism, ornithine transcarbamylase deficiency, Wiskott-Aldrich syndrome. Females with Turner syndrome (45,XO) are more likely to have an X-linked recessive disorder. X-inactivation (lyonization)—during development, one of the X chromosomes in each XX cell is randomly deactivated and condensed into a Barr body (methylated heterochromatin). If skewed inactivation occurs, XX individuals may express X-linked recessive diseases (eg, G6PD); penetrance and severity of X-linked dominant diseases in XX individuals may also be impacted.

Duchenne Muscular Dystrophy

X-linked recessive disorder typically due to frameshift deletions or nonsense mutations → truncated or absent dystrophin protein → progressive myofiber damage. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle. Waddling gait. Onset before 5 years of age. Dilated cardiomyopathy is common cause of death.

Duchenne Muscular Dystrophy: Genetics

Duchenne = deleted dystrophin. Dystrophin gene (DMD) is the largest protein-coding human gene → ↑ chance of spontaneous mutation. Dystrophin helps to anchor muscle fibers to the extracellular matrix, primarily in skeletal and cardiac muscles. Loss of dystrophin → myonecrosis. ↑ CK and aldolase; genetic testing confirms diagnosis.

Gowers Sign

Gowers sign—patient uses upper extremities to help stand up. Classically seen in Duchenne muscular dystrophy, but also seen in other muscular dystrophies and inflammatory myopathies (eg, polymyositis).

Becker Muscular Dystrophy

X-linked recessive disorder typically due to non-frameshift deletions in dystrophin gene (partially functional instead of truncated). Less severe than Duchenne (Becker is better). Onset in adolescence or early adulthood. Deletions can cause both Duchenne and Becker muscular dystrophies. ⅔ of cases have large deletions spanning one or more exons.

Myotonic Dystrophy

Autosomal dominant. Onset 20-30 years. CTG trinucleotide repeat expansion in the DMPK gene → abnormal expression of myotonin protein kinase → myotonia (eg, difficulty releasing hand from handshake), muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia. Cataracts, Toupee (early balding in males), Gonadal atrophy.

Topics Covered:

• X-linked Recessive Diseases Introduction
• Duchenne Muscular Dystrophy: Clinical Features
• Duchenne Muscular Dystrophy: Genetics & Diagnosis
• Gowers Sign and Muscular Dystrophy
• Becker Muscular Dystrophy
• Myotonic Dystrophy