A Mild Form of COG5 Defect Showing Early-Childhood-Onset Friedreich's-Ataxia-Like Phenotypes with Isolated Cerebellar...

Area of Science:

• Genetics
• Neurology
• Pediatrics

Background:

• Progressive cerebellar ataxias are rare in children under 6 years old.
• Autosomal recessive cerebellar ataxias present with diverse phenotypes.
• Conserved oligomeric Golgi complex (COG) subunit 5 (COG5) gene defects are associated with severe neurological disorders.

Observation:

• Three siblings presented with Friedreich's-ataxia-like phenotypes before age 2, including progressive cerebellar atrophy, intellectual disability, and scoliosis.
• This family's phenotype was milder than typical COG5 defects, lacking seizures, movement disorders, ophthalmologic, cardiac, or cutaneous issues.
• Whole-exome sequencing identified a heterozygous frameshift mutation (c.1209delG) in the COG5 gene in affected siblings.

Findings:

• The identified COG5 mutation (p.Met403IlefsX3) resulted in reduced full-length COG5 protein and aberrant smaller proteins in skin tissues.
• This suggests a loss-of-function mechanism for the identified COG5 mutation.
• The study reports a novel, milder phenotype associated with COG5 deficiency, distinct from previously described severe forms.

Implications:

• This finding expands the phenotypic spectrum of COG5-related disorders.
• It highlights the importance of genetic testing for COG5 mutations in pediatric cerebellar ataxias, even with atypical presentations.
• Understanding milder COG5 defects can improve diagnosis and management strategies for affected children.