Mitochondrial respiratory complex I deficiency simulating spinal muscular atrophy

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by motor neuron loss.
• Diagnostic criteria for SMA typically involve genetic testing for deletions in the survival motor neuron (SMN) gene.
• Infantile hypotonia and proximal weakness are hallmark symptoms that can present similarly across various neuromuscular conditions.

Observation:

• Two female patients presented with clinical and electrophysiological findings suggestive of SMA, including hypotonia and motor weakness.
• Neither patient had the characteristic SMN gene deletions associated with SMA.
• Both patients later developed symptoms atypical for SMA, such as epileptic seizures, cardiomyopathy, and spasticity.

Findings:

• Muscle biopsy findings were initially consistent with SMA, but genetic analysis was negative for SMA-defining mutations.
• Analysis of cultured skin fibroblasts revealed decreased mitochondrial respiratory chain complex I enzyme activity in both patients.
• This pattern suggests an isolated complex I deficiency as the underlying cause.

Implications:

• The study suggests that mitochondrial complex I deficiency should be considered in the differential diagnosis of infants presenting with SMA-like symptoms, especially when genetic testing for SMA is negative.
• This highlights the importance of comprehensive metabolic investigations in pediatric neurology to ensure accurate diagnosis and appropriate management.
• Expanding diagnostic approaches beyond genetic screening for known neuromuscular disorders can uncover alternative underlying pathologies like mitochondrial diseases.