Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Carbohydrate-deficient glycoprotein syndrome (CDGS) is a group of rare inherited metabolic disorders.
• CDGS type 1 is characterized by specific clinical symptoms and abnormal serum transferrin electrophoresis.
• The syndrome often presents in infancy with significant morbidity and mortality.

Purpose of the Study:

• To investigate the genetic basis and clinical spectrum of CDGS type 1 in UK patients.
• To identify mutations in the phosphomannomutase (PMM2) gene associated with CDGS type 1.
• To explore genotype-phenotype correlations in affected individuals.

Main Methods:

• Diagnosis based on clinical presentation and serum transferrin electrophoresis.
• Enzyme assays for phosphomannomutase (PMM) and phosphomannose isomerase.
• Genetic analysis of the PMM2 gene, including mutation screening and sequencing.

Main Results:

• 18 UK patients (14 families) diagnosed with CDGS type 1.
• Eleven of 16 infants died before age 2.
• Eleven patients (10 families) with typical transferrin profile had PMM deficiency (CDGS type 1a), all compound heterozygotes for PMM2 mutations. Seven families had the R141H mutation.
• No correlation between residual enzyme activity and disease severity.
• Three patients, including one with a normal transferrin profile, did not have PMM or phosphomannose isomerase deficiency (CDGS 1b).
• No genotype-phenotype correlation observed, though siblings showed similar phenotypes.

Conclusions:

• PMM2 gene mutations are a primary cause of CDGS type 1a.
• The common R141H mutation is prevalent in the UK CDGS type 1a population.
• While siblings share similar phenotypes, genotype does not predict disease severity in CDGS type 1.
• CDGS type 1b represents a distinct subtype not linked to PMM or phosphomannose isomerase deficiency.