Clinical and biochemical features associated with BCS1L mutation.

Area of Science:

• Genetics
• Neurology
• Biochemistry

Background:

• Lactic acidosis can result from mitochondrial respiratory chain complex III deficiency.
• Mutations in the BCS1L gene are known causes of several genetic syndromes.
• Clinical presentation of BCS1L-related disorders is typically severe and presents in neonates.

Purpose of the Study:

• To describe a novel phenotype in Saudi patients with lactic acidosis.
• To identify the genetic cause of the observed phenotype.
• To investigate the clinical heterogeneity associated with BCS1L gene mutations.

Main Methods:

• Genetic studies including linkage, homozygosity mapping, and targeted sequencing.
• Clinical evaluation of nine patients from four consanguineous families.
• Neuroradiological imaging, muscle histopathology, and respiratory chain studies.

Main Results:

• Identified a causative identical mutation (p.Gly129Arg) in the BCS1L gene in all affected patients.
• Observed a novel behavioral and psychiatric phenotype, including hypomania and psychosis, in affected individuals.
• Confirmed respiratory chain dysfunction and subtle white matter abnormalities on neuroradiology.

Conclusions:

• The BCS1L p.Gly129Arg mutation can cause a variable neuro-psychiatric phenotype, including late-onset psychiatric symptoms and visual dysfunction.
• Clinical heterogeneity of BCS1L mutations is significant, even within the same family.
• BCS1L gene defects should be considered in the differential diagnosis of lactic acidosis with multi-organ involvement.