Severe infantile acute encephalopathy and COG4 mutation: CDG IIJ

Abstract

Objective and Methods: Type II congenital disorders of glycosylation (CDG) are a group of inherited multisystem disorders caused by defects in the processing of the protein-bound glycans either late in the endoplasmic reticulum (ER) or in the Golgi compartment. Mutations in members of the Conserved Oligomeric Golgi (COG) complex cause CDG type II and are being increasingly diagnosed with widespread use of NGS. Mutations in the COG4 gene define the very unusual CDG-IIj subtype. We report the second patient with COG4–associated encephalopathy. Results: A 3 year-old male, the son of consanguineous Moroccan parents, had normal development until age 6 mo when, after febrile illness, presented with acute encephalopathy. Motor regression and developmental delay were noted thereafter. Evaluation at 3 years showed mild dysmorphic features, no visceromegalies, profound retardation, progressive microcephaly and hypotonic tetraparesis. Hyperlactacidemia, hyperammonemia and mild/diffuse white and grey matter loss on brain MRI were noted. A subsequent dental infection at 3 years was complicated by obtundation, dehydration, increased serum transaminases, pancytopenia, coagulopathy and hyperammonemia. Metabolic screening was normal/nonspecific and ophthalmological/cardiological investigations were also normal. Study of sialotransferrin isoforms showed a CDG type II profile. WES identified a homozygous c.973T>A variant in COG4, leading to a p.F325I substitution. Functional studies using the brefeldin A assay in patient's skin fibroblasts revealed an alteration in retrograde Golgi-to-ER transport. Conclusion: This is the second case described in the literature linking COG4 mutations with CDG II, a further metabolic defect presenting as infantile acute neurological deterioration with multiorgan failure.