Alternative titles; symbols
SNOMEDCT: 720978005; ORPHA: 79328; DO: 0080564;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q23.1 | Congenital disorder of glycosylation, type Il | 608776 | Autosomal recessive | 3 | ALG9 | 606941 |
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.
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).
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.
Himmelreich et al. (2022) reported 2 unrelated patients. Patient 1 had severe feeding difficulties, diarrhea, and failure to thrive in the neonatal period. He developed epilepsy and an EEG showed hypsarrhythmia, suggestive of West syndrome. At 6 months of age he had severe developmental delay and hypotonia with sparse movements. At 5 years of age he had severely impaired intellectual development and absent speech, and was unable to sit or crawl. Patient 2 was diagnosed with epilepsy at 6 months of age and an EEG showed hypsarrhythmia. At 10 months of age he had microcephaly, global hypotonia, and limited movements. He also had bilateral sensorineural hearing loss. A brain MRI showed cerebral atrophy. He had feeding difficulties and required a feeding tube. At 3 years of age he had severe global developmental delay, hypotonia, and absent speech.
The transmission pattern of CDG1L in the family reported by AlSubhi et al. (2016) was consistent with autosomal recessive inheritance.
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.
In 2 unrelated patients with CDG1L, Himmelreich et al. (2022) identified the same homozygous missense mutation in the ALG9 gene (L487P; 606941.0005). In patient 1 the mutation was identified by Sanger sequencing of the ALG9 gene and in patient 2 it was identified by sequencing of a panel of genes underlying congenital disorders of glycosylation. ALG9 protein expression was reduced in fibroblasts from patient 1 compared to controls. Treatment of the fibroblasts with cycloheximide, followed by Western blot analysis, demonstrated that the reduced expression in patient cells was due to protein instability.
AlSubhi, S., AlHashem, A., AlAzami, A., Tlili, K., AlShahwan, S., Lefeber, D., Alkuraya, F. S., Tabarki, B. Further delineation of the ALG9-CDG phenotype. JIMD Rep. 27: 107-112, 2016. [PubMed: 26453364] [Full Text: https://doi.org/10.1007/8904_2015_504]
Frank, C. G., Grubenmann, C. E., Eyaid, W., Berger, E. G., Aebi, M., Hennet, T. Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL. Am. J. Hum. Genet. 75: 146-150, 2004. [PubMed: 15148656] [Full Text: https://doi.org/10.1086/422367]
Himmelreich, N., Dimitrov, B., Zielonka, M., Hullen, A., Hoffmann, G. F., Juenger, H., Muller, H., Lorenz, I., Busse, B., Marschall, C., Schluter, G., Thiel, C. Missense variant c.1460 T-C (p.L487P) enhances protein degradation of ER mannosyltransferase ALG9 in two new ALG9-CDG patients presenting with West syndrome and review of the literature. Molec. Genet. Metab. 136: 274-281, 2022. [PubMed: 35839600] [Full Text: https://doi.org/10.1016/j.ymgme.2022.06.005]
Weinstein, M., Schollen, E., Matthijs, G., Neupert, C., Hennet, T., Grubenmann, C. E., Frank, C. G., Aebi, M., Clarke, J. T. R., Griffiths, A., Seargeant, L., Poplawski, N. CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features. Am. J. Med. Genet. 136A: 194-197, 2005. [PubMed: 15945070] [Full Text: https://doi.org/10.1002/ajmg.a.30851]