DEGS1 variant causes neurological disorder.

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Sphingolipidoses are inherited metabolic disorders resulting from defects in lipid synthesis or breakdown.
• Complex neurological disorders can arise from genetic mutations affecting lipid metabolism pathways.

Purpose of the Study:

• To identify the genetic cause of a rare autosomal recessive neurological disorder characterized by intellectual disability and spastic quadriplegia.
• To investigate the molecular basis of a novel sphingolipidosis affecting a consanguineous family.

Main Methods:

• Homozygosity mapping and whole exome sequencing were employed to identify disease-associated variants.
• Lipidomics analysis was performed on patient blood samples to assess metabolic alterations.
• Sanger sequencing was used to validate the identified genetic variant.

Main Results:

• A homozygous missense variant in the DEGS1 gene, encoding C4-dihydroceramide desaturase, was identified as the cause of the disorder.
• Affected individuals exhibited elevated levels of dihydroceramides and related lipids, with reduced levels of ceramides and sphingolipids.
• Clinical presentation included intellectual disability, spastic quadriplegia, and neurological deterioration starting in infancy.

Conclusions:

• The study describes a new form of sphingolipidosis resulting from DEGS1 variants.
• Defective C4-dihydroceramide desaturase activity leads to a severe regressive neurological disease.
• This finding expands the spectrum of known sphingolipidosis and highlights the role of DEGS1 in neurological health.