S. Grunewald et al., High residual activity of PMM2 in patients' fibroblasts: Possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency), AM J HU GEN, 68(2), 2001, pp. 347-354
Citations number
45
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
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.