Abstract
Introduction: PMM2-CDG is the most common autosomal recessive N-glycosylation disorder with more than 900 patients described worldwide. It is caused by a deficiency of the phosphomannomutase 2 enzyme (PMM2) which catalyzes the second step of the mannose pathway, namely the conversion of mannose-6-phosphate to mannose-1-phosphate.
The clinical presentation is characterised by encephalopathy, neuropathy, typical dysmorphism, cerebellar atrophy and coagulopathy. We present the results of clinical, biochemical and molecular analyses in patients diagnosed in the Czech Republic.
Results: Since 2002, a total of 22 Czech patients from 18 families with PMM2 deficiency have been diagnosed. The age range of the patients spans from 9 months to 29 years with a median of 14 years, except two patients who died during infancy.
Muscle hypotonia, intellectual disability of varying severity, strabismus, ataxia, bone deformities, and coagulopathy were observed in all patients. Cerebellar atrophy was documented in 94% of the investigated patients.
The characteristic dysmorphism (inverted nipples and atypical fat pads) were present in 82% of the patients. Nine patients suffered from seizures, and three patients showed transient neurological deterioration after stroke-like episodes.
In all the patients, increased amount of hypoglycosylated transferrin was found by isoelectric focusing. The diagnosis of the PMM2-CDG was confirmed at enzymatic and/or at molecular levels.
Molecular analyses revealed that all patients are compound heterozygotes for a total of 10 different mutations in PMM2, and that 71% of our patients' alleles have one of the two most frequent genetic variants (c.422G>A, c.338C>T). Conclusion: The estimated incidence of PMM2-CDG is 1:20,000, suggesting that this disorder is underdiagnosed in the Czech Republic.
PMM2-CDG must be considered in differential diagnosis of patients with cerebellar atrophy even if they do not manifest characteristic dysmorphism. We plan to include our patients in a longitudinal international multicenter observational study and potentially the upcoming clinical trial with LipoM1P (lipomised mannose-1-phosphate).