Progressive brain atrophy and severe neurodevelopmental phenotype in siblings with biallelic COASY variants

Area of Science:

• Genetics
• Neurology
• Metabolic Disorders

Background:

• Biallelic pathogenic variants in the COASY gene are linked to COASY-protein associated neurodegeneration (CoPAN) and pontocerebellar hypoplasia type 12 (PCH 12).
• COASY-related disorders represent a spectrum of neurodevelopmental conditions.

Observation:

• Two siblings presented with severe hypotonia and respiratory insufficiency at birth, along with contractures and absent respiratory drive.
• Comprehensive genetic testing identified homozygous variants in the COASY gene in both siblings.

Findings:

• The siblings exhibited unique, progressive clinical and neuroradiologic findings not previously described in COASY-related disorders.
• Magnetic resonance imaging revealed diffuse parenchymal loss in cerebral hemispheres and atrophy of the basal ganglia and brainstem.
• Newborn screening acylcarnitine profiles mimicked carnitine palmitoyl transferase 1a (CPT1a) deficiency.

Implications:

• These cases expand the phenotypic spectrum of COASY-related disorders.
• The distinct presentation highlights the importance of considering COASY variants in infants with severe hypotonia and respiratory failure.
• The observed acylcarnitine profile similarity to CPT1a deficiency warrants further investigation into metabolic pathways.