ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients

Abstract

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2, was seen in all twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Congenital nephrotic syndrome in an infant with ALG1‐congenital disorder of glycosylation

“…The infant (patient # 18, reference [10]) was a full term male, born at a community hospital. Due to recurrent apnea, feeding difficulties, and Enterobacter cloacae sepsis, he was transferred to neonatal intensive care unit at one month of age.…”

“…ALG1 -CDG has also been associated with recurrent infantile seizures, cerebellar hypoplasia, hypotonia, and failure to thrive. There are 58 described cases of ALG1 -CDG in the existing literature with twelve of those cases also reporting the presence of renal failure and congenital nephrotic syndrome [2, 8, 9, 10]. We report details of one case of congenital nephrotic syndrome associated with ALG1 -CDG, formerly known as CDG type 1k, and discuss the use of peritoneal dialysis in management of this rare patient population.…”

“…In the perinatal period, this disorder can present as a component of a multi-system, generalized syndrome. In particular, congenital nephrotic syndrome has been reported to occur concurrently with failure to thrive, microcephaly, deteriorating neurological status, and sepsis in the setting of congenital disorders of glycosylation due to mutations in the ALG1 gene [1–6, 10]. …”

“…The genetic sequencing information presented in this paper has been described in reference 10. Institutional Review Board at our institution deemed that informed consent was not required for the purposes of this case report. …”

“…In particular, congenital NS has been reported to occur concurrently with failure to thrive, microcephaly, deteriorating neurological status, and sepsis in the setting of congenital disorders of glycosylation (CDG) due to mutations in gene ALG1. [1][2][3][4][5][6][7] Congenital disorders of glycosylation are rare multisystem diseases due to impaired synthesis, transfer, and processing of sugar chains resulting in hypoglycosylation of ubiquitously expressed proteins throughout the body. 8 The CDG associated with ALG1 mutations (ALG1-CDG; OMIM 608 540) is described as an inherited error of metabolism resulting in deficiency of b-1,4 mannosyltransferase (OMIM 605 907).…”