Congenital disorders of glycosylation IIa cause growth retardation, mental retardation, and facial dysmorphism.

EDITOR—Congenital disorders of glycosylation (CDG) are a heterogeneous group of autosomal recessive multisystemic conditions causing severe central nervous system and multivisceral disorders resulting from impairment of the glycosylation pathway. Two disease causing mechanisms have been identified so far. CDG I is caused by a defect in the assembly of the dolicholpyrophosphate oligosaccharide precursor of N-glycans and its transfer to the peptide chain, while CDG II results from a defect in the processing of N-glycans. CDG I and II have distinct patterns of abnormal glycosylation depending on the reduction of the glycan chain number or its structure. CDG I, the most frequent form, is the result of diVerent enzyme deficiencies: phosphomannomutase (CDG Ia), phosphomannose isomerase (CDG Ib), and glucosyltransferase (CDG Ic). CDG IIa is characterised by a defect in N-acetylglucosaminyltransferase II and only two cases have been reported previously. Here, we report a new case of CDG IIa sharing a number of clinical features with the two previously reported cases and emphasising the clinical differences from CDG I. A boy was born at term to unrelated, healthy parents after a normal pregnancy and delivery, birth weight 3050 g, length 48 cm, and OFC 35 cm. At 3 months of age, hypotonia, feeding diYculties, and diarrhoea were noted. A milk protein intolerance was suspected and he was put on a milk free formula until the age of 4 years. He was first referred to our genetic unit at 8 years of age because of mental retardation and facial dysmorphism. On examination, he had severe mental retardation with no speech and an unstable gait. Dysmorphic features included fine hair, large ears, a beaked nose with hypoplastic nasal alae, a long philtrum, thin vermilion border of the upper lip, everted lower lip, large teeth, and gum hypertrophy (fig 1). Long standing feeding diYculties and diarrhoea had resulted in severe growth retardation (height 109.9 cm (−3 SD), weight 20 kg (−2.5 SD), OFC 50.5 cm (−2 SD)). Chromosome analysis was normal and no diagnosis was made at that time. At 11 years of age, dysmorphic features, severe mental retardation, diarrhoea, and growth retardation were still present (height 120.8 cm (−4 SD), weight 23 kg (−2.5 SD), OFC 50.5 cm (−2 SD)). Kyphosis, widely spaced (but not inverted) nipples, and pectus excavatum were also noted. Echocardiography, MRI, and fundoscopy were normal but an electroretinogram was altered with a severe reduction of both cone and rod responses. Routine laboratory investigations were performed and showed normal serum creatinine, cholesterol, and alkaline phosphatase concentrations but raised ASAT (195 U/l, normal <20 U/l). Coagulation studies were performed before a tooth extraction and showed decreased blood coagulation factors (factor IX 60%, normal 65-160; factor XI 30%, normal 60-160; factor XII 73%, normal 50-160; protein C 30%, normal 70-130; protein S 60%, normal 70-130), abnormal prothrombin time (19 seconds, normal 25 seconds), and activated partial prothromboplastin time (46 seconds, normal 32 ± 8 seconds). The combination of mental retardation, failure to thrive, abnormal electroretinogram, and coagulation abnormalities were highly suggestive of CDG. Western blot analysis of various serum glycoproteins (transferrin, á1-antitrypsin, haptoglobin) were performed as previously described 13 and showed an abnormal pattern with one single lower band (fig 2A). Similarly, isoelectric focusing of serum transferrin showed a markedly abnormal pattern corresponding to an increase of the disialotransferrin and a nearly complete absence of hexa-, penta-, and tetrasialotransferrins in the patient (fig 2B). These patterns were identical to those previously reported in CDG IIa. Activity of N-acetylglucosaminyltransferase II (MGAT2) was determined at 37°C on cultured skin fibroblasts, according to Tan et al, and was profoundly deficient (1.9 ± 0.4 μmol/g protein/h, control 38.9 ± 2.4 μmol/g protein/h). Finally, direct sequencing of the coding region for the catalytic domain of the MGAT2 gene identified two distinct point mutations: a missense mutation changing an adenine into a guanine at nt 952 (N318D) and a nonsense mutation at nucleotide 1017 (C339X) leading to a premature stop codon. The father was found to be heterozygous for the N318D mutation and the mother for the C339X mutation. We report the third observation of CDG IIa in a child with chronic feeding diYculties of early onset, severe mental retardation, and dysmorphic facial features. The two patients reported previously had severe psychomotor retardation with no speech, stereotypic hand washing behaviour, and epilepsy (the last two features were not observed in our case) (table 1). Growth retardation was also consistently observed in all three cases, but major feeding diYculties with chronic diarrhoea were only observed in our case. Dysmorphic features were mentioned in all cases and appeared distinctive with a beaked nose, long philtrum, thin vermilion border of the upper lip, large ears, gum hypertrophy, and thoracic deformity. Ventricular