TY - JOUR
T1 - Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations
AU - Morava, Eva
AU - Vodopiutz, Julia
AU - Lefeber, Dirk J.
AU - Janecke, Andreas R.
AU - Schmidt, Wolfgang M.
AU - Lechner, Silvia
AU - Item, Chike B.
AU - Sykut-Cegielska, Jolanta
AU - Adamowicz, Maciej
AU - Wierzba, Jolanta
AU - Zhang, Zong H.
AU - Mihalek, Ivana
AU - Stockler, Sylvia
AU - Bodamer, Olaf A.
AU - Lehle, Ludwig
AU - Wevers, Ron A.
PY - 2012/10
Y1 - 2012/10
N2 - Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood. The dysmorphic features, including abnormal fat distribution and strabismus highly resemble CDG due to phosphomannomutase-2 deficiency (PMM2-CDG), the most common type of CDG. We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events.
AB - Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood. The dysmorphic features, including abnormal fat distribution and strabismus highly resemble CDG due to phosphomannomutase-2 deficiency (PMM2-CDG), the most common type of CDG. We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events.
KW - CDG-Ik
KW - Microcephaly
KW - Seizures
KW - Short chain lipid-linked oligosaccharides
KW - β-1,4 mannosyltransferase
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U2 - 10.1542/peds.2011-2711
DO - 10.1542/peds.2011-2711
M3 - Article
C2 - 22966035
AN - SCOPUS:84867180277
SN - 0031-4005
VL - 130
SP - e1034-e1039
JO - Pediatrics
JF - Pediatrics
IS - 4
ER -