title: Genetic and metabolic analysis of the first adult with congenital disorder of glycosylation type Ib: long-term outcome and effects of mannose supplementation.
abstract: We report the diagnosis and follow-up of two sibs reported in 1980 with recurrent venous thromboses and protein-losing enteropathy; one sib with biopsy-proven hepatic fibrosis died at age 5. The combination of symptoms was suggestive of the recently characterized congenital disorder of glycosylation type Ib (CDG-Ib), which is caused by a deficiency of the enzyme phosphomannose isomerase (PMI). An abnormal serum transferrin isoelectric focusing (IEF) pattern and a reduced PMI activity confirmed the diagnosis of CDG-Ib. Furthermore, mutational analysis of the MPI gene revealed two missense mutations, 419 T --> C (I140T) and 636 G --> A (R219Q), a single base substitution 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 following childhood. Short-term low-dose oral mannose supplementation improved her transferrin IEF pattern and normalized her antithrombin III activity, further substantiating the beneficial effect of mannose in CDG-Ib. When her mannose blood level was measured, she showed a lower steady-state level but a faster mannose clearance rate. These results suggest that the clinical manifestations of PMI deficiency, although serious in childhood, can improve with age, even without mannose therapy, and allow for a normal adult life. However, the long-term prognosis may vary from patient to patient.
authors.affiliation: The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: V
authors.initials: V
authors.lastname: Westphal
authors.forename: S
authors.initials: S
authors.lastname: Kjaergaard
authors.forename: J A
authors.initials: JA
authors.lastname: Davis
authors.forename: S M
authors.initials: SM
authors.lastname: Peterson
authors.forename: F
authors.initials: F
authors.lastname: Skovby
authors.forename: H H
authors.initials: HH
authors.lastname: Freeze
mesh_terms: D000328:Adult; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008358:Mannose / Q000008:administration & dosage / Q000097:blood; D008359:Mannose-6-Phosphate Isomerase / Q000172:deficiency / Q000235:genetics*; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D013997:Time Factors; D014168:Transferrin / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018076:DNA, Complementary; D014168:Transferrin; D004247:DNA; D008359:Mannose-6-Phosphate Isomerase; D008358:Mannose