Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG

J Inherit Metab Dis. 2021 Jul;44(4):987-1000. doi: 10.1002/jimd.12367. Epub 2021 Mar 1.


Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

Keywords: N-glycans; congenital disorders of glycosylation; endocrine; immunodeficiency; neural tube defect.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Child, Preschool
  • Congenital Disorders of Glycosylation / genetics*
  • Congenital Disorders of Glycosylation / pathology
  • Congenital Disorders of Glycosylation / physiopathology
  • Female
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mannosyltransferases / genetics*
  • Phenotype
  • Young Adult


  • ALG3 protein, human
  • Mannosyltransferases