A 4-month-old boy is brought to the pediatric neurology clinic with progressive hypotonia, weak cry, and difficulty feeding. His parents are unaffected and non-consanguineous. Examination reveals absent deep tendon reflexes, tongue fasciculations, and a "frog-leg" posture. The pedigree pattern shown in the diagram at **A** is consistent with autosomal recessive inheritance. Genetic testing confirms homozygous deletion of the SMN1 gene on chromosome 5q13 with only 1 copy of SMN2. Which of the following best describes the pathophysiologic basis of this condition and the expected clinical course?

Question

Accepted Answer

A. Loss of SMN protein leads to impaired SnRNP biogenesis and motor-neuron degeneration; SMA Type 1 with historically poor prognosis (death by age 2 without treatment) due to low SMN2 copy number. ## Why Option 1 is correct

The clinical presentation (hypotonia, weak cry, absent reflexes, tongue fasciculations, frog-leg posture in a 4-month-old) combined with the autosomal recessive pedigree pattern at **A** and homozygous SMN1 deletion with only 1 SMN2 copy is pathognomonic for **SMA Type 1 (Werdnig-Hoffmann disease)**. The anchor fact is that SMA is caused by homozygous loss of SMN1 gene function, leading to deficiency of the SMN protein, which is essential for SnRNP (small nuclear ribonucleoprotein) biogenesis and motor-neuron survival. The SMN2 copy number is the principal modifier of disease severity; patients with 1–2 copies typically present with Type 1 (onset <6 months, never sit unsupported, historically fatal by age 2 from respiratory failure). The autosomal recessive inheritance pattern shown at **A** (affected siblings, unaffected carrier parents, horizontal transmission, 25% recurrence risk) is the hallmark of SMN1 mutations. This pedigree pattern and genetic finding directly establish the diagnosis and prognosis.

## Why each distractor is wrong

- **Option 2**: Describes Duchenne muscular dystrophy (dystrophin gene mutation), which is **X-linked recessive**, not autosomal recessive. Males are predominantly affected; females are carriers. The pedigree at **A** shows autosomal recessive inheritance (affected siblings of both sexes, unaffected parents), not X-linked. Preserved reflexes and calf hypertrophy are features of DMD, not SMA.

- **Option 3**: Describes mitochondrial encephalomyopathy with **maternal transmission** (pedigree **D** in the diagram). The inheritance pattern at **A** is autosomal recessive, not maternal. Mitochondrial disorders present with multi-system involvement (lactic acidosis, developmental regression) not typical of SMA Type 1.

- **Option 4**: Describes Huntington disease, an **autosomal dominant** disorder with **vertical transmission** (pedigree **B** in the diagram). Huntington presents with chorea and cognitive decline, not the motor-neuron degeneration, hypotonia, and absent reflexes seen in SMA. The pedigree at **A** is recessive, not dominant.

**High-Yield:** SMA Type 1 = homozygous SMN1 loss + 1–2 SMN2 copies + onset <6 months + never sit + historically fatal by age 2 (now treatable with nusinersen, onasemnogene abeparvovec, or risdiplam).

[cite: AAN/MDA SMA Standard of Care; ENDEAR/NURTURE/SPR1NT trials]

Answer

B. Defective mitochondrial oxidative phosphorylation inherited maternally; multi-system involvement with lactic acidosis and developmental regression

Answer

C. Mutation in the dystrophin gene causes X-linked inheritance with selective involvement of males; progressive weakness with preserved reflexes and calf hypertrophy

Answer

D. Dominant negative effect of mutant huntingtin protein with vertical transmission; progressive chorea and cognitive decline in childhood

Explanation

Why Option 1 is correct

Why each distractor is wrong

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