ALG9-CDG: New clinical case and review of the literature

Abstract

Congenital disorders of glycosylation (CDG) are a group of metabolic diseases resulting from defects in glycan synthesis or processing. The number of subgroups and their phenotypic spectrums continue to expand with most related to deficiencies of N-glycosylation. ALG9-CDG (previously CDG-IL) is the result of a mutation in ALG9. This gene encodes the enzyme alpha-1,2-mannosyltransferase. To date, a total of 10 patients from 6 different families have been reported with one of four ALG9 mutations. Seven of these patients had a similar phenotype with failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; the other three patients died in utero from a lethal skeletal dysplasia. This report describes an additional patient with ALG9-CDG who has a milder phenotype. This patient is a term female born to Caucasian, Canadian, non-consanguineous parents of Scottish decent. Prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Post-natally, dysmorphic features included shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata. She developed failure to thrive and seizures. The metabolic work-up included analysis of a transferrin isoelectric focusing, which showed a type 1 pattern. This was confirmed by glycan profiling, which identified ahomozygous mutation in ALG9, c.860A > G (p.Tyr287Cys) (NM_1234567890). This had been previously published as a pathogenic mutation in two Canadian patients. Our goal is to contribute to the growing body of knowledge for this disorder by describing the phenotypic spectrum and providing further insight on prognosis.

ALG-9 Congenital Disorder of Glycosylation: A Patient with Novel Variants and No Dysmorphism

“…However, initial normal MRI brain with progressive development of atrophy has been reported in this entity. 4 This observation may explain the normal neuroimaging in the described child. Transferrin isoelectric focusing (IEF) and glycan profiling have been described to be of help in establishing the diagnosis of CDG.…”

“…2,3 One of these is ALG9-CDG [Online Mendelian Inheritance in Man (OMIM) no: 608776]. 4 Eleven patients have been reported with this CDG. 4 All reported children have demonstrated multiorgan involvement including skeletal dysplasia frontal bossing of skull, hypertelorism, flat nasal bridge, low-set ears, inverted and widely-separated nipples, and abnormal fat pads.…”

“…4 All reported children have demonstrated multiorgan involvement including skeletal dysplasia frontal bossing of skull, hypertelorism, flat nasal bridge, low-set ears, inverted and widely-separated nipples, and abnormal fat pads. 4 LG-9 CDG is associated with a spectrum of skeletal dysplasia, renal malformations such as polycystic and dysplastic kidneys, congenital heart defects (such as atrioventricular septal defects), seizures, developmental delay, and hypotonia. 4 Unusual for this CDG is the absence of dysmorphism and multisystem involvement in the present patient.…”

“…4 LG-9 CDG is associated with a spectrum of skeletal dysplasia, renal malformations such as polycystic and dysplastic kidneys, congenital heart defects (such as atrioventricular septal defects), seizures, developmental delay, and hypotonia. 4 Unusual for this CDG is the absence of dysmorphism and multisystem involvement in the present patient. Delayed myelination and cerebellar atrophy are frequently reported in ALG-9 CDG.…”

“…Transferrin isoelectric focusing (IEF) and glycan profiling have been described to be of help in establishing the diagnosis of CDG. 4 As to diagnosis, serum transferrin IEF was not performed because of resource constraints. The diagnosis came from clinical exome sequencing that is becoming increasingly routine and revealed two novel variants.…”