Genetic and metabolic analysis of the first adult with congenital disorderof glycosylation type Ib: Long-term outcome and effects of mannose supplementation

We report the diagnosis and follow-up of two sibs reported in 1980 with rec urrent venous thromboses and protein-losing enteropathy; one sib with biops y-proven hepatic fibrosis died at age 5. The combination of symptoms was su ggestive of the recently characterized congenital disorder of glycosylation type Ib (CDG-Ib), which is caused by a deficiency of the enzyme phosphoman nose isomerase (PMI). An abnormal serum transferrin isoelectric focusing (I EF) pattern and a reduced PMI activity confirmed the diagnosis of CDG-Ib. F urthermore, mutational analysis of the MPI gene revealed two missense mutat ions, 419 T --> C (I140T) and 636 G -->A (R219Q), a single base substitutio n in intron 5, 670 + 9G --> A, as well as a polymorphism 1131A --> C (V377V ) in both sibs. The surviving 33-year-old sib has had no further symptoms f ollowing childhood. Short-term low-dose oral mannose supplementation improv ed her transferrin IEF pattern and normalized her antithrombin III activity , further substantiating the beneficial effect of mannose in CDG-Ib. When h er mannose blood level was measured, she showed a lower steady-state level but a faster mannose clearance rate. These results suggest that the clinica l manifestations of PMI deficiency, although serious in childhood, can impr ove with age, even without mannose therapy, and allow for a normal adult li fe. However, the long-term prognosis may vary from patient to patient. (C) 2001 Academic Press.