Congenital Disorder Of Glycosylation, Type Il

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Il (CDG Il; CDG1L) is caused by homozygous mutation in the ALG9 gene (606941) on chromosome 11q23.

Description

Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type I. For a general description and a discussion of the classification of CDGs, see CDG1A (212065).

Clinical Features

Frank et al. (2004) described a patient with a novel type of CDG I. Clinical features included severe microcephaly, central hypotonia, seizures, hepatomegaly, developmental delay, and bronchial asthma. The lipid-linked oligosaccharide (LLO) profile showed dual accumulation of DolPP-GlcNAc(2)Man(6) and DolPP-GlcNAc(2)Man(8), suggesting a possible defect at the level of ALG9 alpha-1,2-mannosyltransferase, which in S. cerevisiae catalyzes the addition of the seventh and ninth mannose residues on growing LLOs.

Weinstein et al. (2005) reported a female infant with psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples. Lipodystrophy and dysmorphic facial features were absent. Transferrin isoelectric focusing revealed an abnormal, type I pattern with elevated disialo- and asialotransferrin isoforms.

AlSubhi et al. (2016) reported a large consanguineous Saudi Arabian family in which 4 children had CDG1L. The proband was a 6-year-old girl who presented at birth with hip dislocation, dysmorphic features, and minor tricuspid regurgitation. The mother had noted decreased fetal movements during pregnancy. The proband developed seizures at age 4 months, and EEG showed slow background activity with bursts of spikes and sharp waves, consistent with an epileptic encephalopathy. However, the patient became seizure-free with a normal EEG at age 5. At age 6, she had global developmental disability, poor overall growth, hypotonia, and hyperreflexia. She could sit, make sounds, and recognize her family. Dysmorphic features included microcephaly, frontal bossing, depressed nasal bridge, low-set ears, large mouth, hypertelorism, inverted widely spaced nipples, abnormal distribution of fat on the buttocks, cutis marmorata, cutis aplasia congenita, and broad thumbs. She also had mild hepatomegaly. Skeletal survey showed delayed bone age and mild skeletal dysplasia with mesomelic brachymelia, thickened skull bones, mild kyphosis, and brachycephaly. Brain MRI showed cerebral and cerebellar atrophy with delayed myelination. Serum transferrin analysis showed a CDG type I pattern. The patient had 3 similarly affected cousins, the youngest of whom was 25 days old. This infant presented with nonimmune hydrops fetalis and had facial dysmorphism, atrial septal defect, and mild skeletal dysplasia.

Inheritance

The transmission pattern of CDG1L in the family reported by AlSubhi et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient with type I CDG, Frank et al. (2004) detected a homozygous mutation in the ALG9 gene (E523K; 606941.0001). Analysis of the mutant human cDNA in a yeast complementation assay demonstrated a detrimental effect of the mutation on ALG9 function and confirmed functional homology between human and yeast ALG9.

In a female infant with type I CDG, Weinstein et al. (2005) identified homozygosity for a missense mutation in the ALG9 gene (Y286C; 606941.0002); the deleterious effect of the mutation was verified by yeast complementation assays and functional analysis demonstrating severely reduced enzyme activity.

In 4 affected members of a large consanguineous Saudi Arabian family with CDG1L, AlSubhi et al. (2016) identified a homozygous missense mutation in the ALG9 gene (E530K; 606941.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but patient cells showed hypoglycosylation of serum transferrin, consistent with CDG type I.