Question

A 2-month-old boy is brought to the emer- gency department with respiratory insuffi- ciency and failure to thrive. The pregnancy and perinatal course were uneventful. Gener- alized hypotonia, tongue fasciculations, and flaccid paralysis are noted on physical exami- nation. His hospital stay is complicated by the development of tracheobronchomalacia and respiratory insufficiency that necessitates me- chanical ventilation. Despite these efforts, the patient dies of respiratory complications. Muscle biopsy shows denervation and panfas- cicular atrophy. A genetics consult yields the pedigree shown in the image. Which of the following diseases is most consistent with this patient’s presentation and the pedigree shown in the image?

(A) Becker muscular dystrophy
(B) Duchenne muscular dystrophy 

(C) Kugelberg-Welander disease

 (D) Spinal muscular atrophy, type II

 (E) Werdnig-Hoffmann disease

Answer 1

The correct answer is E. Spinal muscular atrophy (SMA) is one of the most common autosomal-recessive diseases, affecting ap- proximately one in 10,000 live births. It has a carrier frequency of approximately one in 50 and is characterized by symmetric proximal muscle weakness due to the degeneration of the anterior horn cells of the spinal cord. SMA is classically divided into three subtypes based on age of onset and clinical severity. Type I SMA (Werdnig-Hoffmann disease), the most severe, is characterized by the onset of signifi- cant muscle weakness and hypotonia in the first few months of life, and the inability to sit or walk. Manifestations may even occur in utero with reduced fetal movement. Fatal res- piratory failure usually occurs before the age of 2 years. Muscle biopsy demonstrates large numbers of atrophic fibers that involve entire fascicles (panfascicular atrophy). Unlike SMA types II and III, this patient’s disease developed at an early age, so early milestones were not achieved. This is not the case in the less severe forms of SMA.

Answer A is incorrect. BMD involves the same genetic locus that is affected in DMD, but its occurrence is less common. It follows a more indolent course, with onset often occur- ring in late childhood.

Answer B is incorrect. Duchenne muscular dystrophy (DMD) and Becker muscular dystro- phy (BMD) are both characterized by defects in the 427-kDa protein dystrophin, encoded on the Xp21 region. DMD is the most common form of muscular dystrophy, with an incidence of about one in 3500 live births. Onset typi- cally occurs after infancy and before the age of five. The clinical course is characterized by progressive muscle weakness and wasting that lead to wheelchair dependence by 10-12 years of age. Early motor milestones are met in pa- tients with BMD and DMD.

Answer C is incorrect. Type III spinal muscu- lar atrophy, or Kugelberg-Welander disease, is characterized by the onset of proximal muscle weakness after the age of 2 years, the ability to walk independently until the disease pro- gresses, and survival into adulthood.

Answer D is incorrect. Type II spinal mus- cular atrophy is characterized by the onset of proximal muscle weakness before 18 months of age, the ability to sit but not to walk un- aided, and survival beyond 4 years of age.