A prevalent pathogenic GAMT mutation (c.59G>C) in Portugal.

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder affecting creatine biosynthesis.
• Clinical manifestations include intellectual disability, extrapyramidal symptoms, autistic-like behavior, epilepsy, cerebral creatine deficiency, and elevated guanidinoacetate levels.
• Fifteen distinct mutations in the GAMT gene have been identified globally in 29 patients.

Purpose of the Study:

• To investigate the carrier rate of the c.59G>C; p.Trp20Ser mutation in GAMT deficiency across different Portuguese regions.
• To confirm the pathogenicity of the c.59G>C; p.Trp20Ser missense mutation.
• To assess the need for newborn screening in Portugal for this treatable disorder.

Main Methods:

• Screening of 1002 anonymous bloodspots using SNaPshot technology to detect the c.59G>C; p.Trp20Ser mutation.
• Transient transfections were employed to validate the pathogenic nature of the identified mutation.

Main Results:

• Eight carriers of the c.59G>C; p.Trp20Ser mutation were identified among the 1002 screened individuals.
• Four of the detected carriers originated from the Portuguese Archipelagos, suggesting a higher prevalence in these islands.
• The study identified a significant carrier rate for this specific mutation in Portugal.

Conclusions:

• The c.59G>C; p.Trp20Ser mutation is prevalent in Portugal, likely due to a founder effect and high carrier frequency.
• The findings support the need for targeted newborn screening programs in Portugal, particularly in the Archipelagos, for GAMT deficiency.
• Early detection through newborn screening can facilitate timely intervention and management of this treatable genetic disorder.