High residual activity of PMM2 in patients' fibroblasts: Possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency)

Congenital disorders of glycosylation (CDGs) are a rapidly enlarging group of inherited diseases with abnormal N-glycosylation of glycoconjugates. Mos t patients have CDG-Ia, which is due to a phosphomannomutase (PMM) deficien cy. In this article, we report that a significant portion (9 of 54) of pati ents with CDG-Ia had a rather high residual PMM activity in fibroblasts inc luded in the normal range (means of the controls +/- 2 SD) and amounting to 35%-70% of the mean control value. The clinical diagnosis of CDG-Ia was ma de difficult by the fact that most (6 of 9) of these patients belong to a s ubgroup characterized by a phenotype that is milder than classical CDG-Ia. These patients lack some of the symptoms that are suggestive for the diagno sis, such as inverted nipples and abnormal fat deposition, and, as a mean, had higher residual PMM activities in fibroblasts (2.05 +/- 0.61 mU/mg prot ein, n = 9; vs. controls 5.34 +/-1.74 mU/mg protein, n = 22), compared with patients with moderate (1.32 +/- 0.86 mU/mg protein, n = 18) or severe (0. 63 +/- 0.56 mU/mg protein, n = 27, P< .001) cases. yet they all showed mild mental retardation, hypotonia, cerebellar hypoplasia, and strabismus. All of them had an abnormal serum transferrin pattern and a significantly reduc ed PMM activity in leukocytes. Six of the nine patients with mild presentat ions were compound heterozygotes for the C241S mutation, which is known to reduce PMM activity by only <similar to>2-fold. Our results indicate that i ntermediate PMM values in fibroblasts may mask the diagnosis of CDG-Ia, whi ch is better accomplished by measurement of PMM activity in leukocytes and mutation search in the PMM2 gene. They also indicate that there is some deg ree of correlation between the residual activity in fibroblasts and the cli nical phenotype.