A novel homozygous mutation in the mannose phosphate isomerase gene causing congenital disorder of glycation and hyperinsulinemic hypoglycemia in an infant

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders. They are caused by enzymatic defects in the synthesis and processing of asparagine (N)‐linked glycans or oligosaccharides on glycoproteins. These disorders are recognized by an abnormal isoelectric focusing profile of plasma transferrin 1. Most known cases belong to type I, which, has 12 defined subgroups (CDG‐Ia to CDG‐IL). CDG type 1b results from genetic mutations in the mannose phosphate isomerase gene on chromosome 15q24 that encodes mannose phosphate isomerase (MPI). The MPI gene contains eight exons and spans 5 kb 2. Pelletier et al. (1986) first described the clinical features of CDG Ib. These features include secretory diarrhea with protein‐losing enteropathy, enterocolitis cystica superficialis, intestinal lymphangiectasia, hypoglycemia, coagulopathy, and congenital hepatic fibrosis 3. CDG Ib is clinically distinct from most other CDGs in two main features. Firstly, it lacks the central nervous system involvement and secondly, it can be effectively treated with oral mannose supplementation. Niehues et al. reported an 11‐month‐old boy who presented with diarrhea and vomiting. Laboratory studies showed severe hypoproteinemia, anemia, decreased antithrombin III, and protein‐losing enteropathy. Oral administration of mannose was found to be an effective therapy for CDG Ib as it corrected the clinical phenotype as well as the hypoglycosylation of serum glycoproteins 4. The authors identified a heterozygous mutation in the MPI gene resulting in an arg219‐to‐gln (R219Q) substitution inherited from the father. Subsequently, Schollen identified a a 1‐bp insertion in exon 3 of the MPI gene (116insC; 154550.0004) on the maternal allele in the same patient confirming compound heterozygosity and autosomal recessive inheritance 2. Subsequently, Schollen et al. identified seven other mutations in the MPI gene. Compound heterozygosity in the MPI gene was identified in another patient with a 304C‐T transition resulting in a ser102‐to‐leu (S102L) substitution, and a 413T‐C transition resulting in a met138‐to‐thr (M138T) substitution 5. Hyperinsulinemic hypoglycemia has been described in several cases mostly in CDG Ib. In 1999, De Lonlay et al. reported a 3‐month‐old girl presenting with hypoglycemia. She had severe vomiting and diarrhea, congenital hepatic fibrosis, and coagulation factor deficiencies. Mannose therapy led to dramatic clinical improvement and normalization of several biochemical abnormalities 6. In the same year, another 2.5‐year‐old girl was reported with CDG Ib. She presented with severe persistent hypoglycemia and subsequently developed protein‐losing enteropathy, liver disease, and coagulopathy 7. We report a 4 years old who presented with hyperinsulinemic hypoglycemia and was diagnosed with CDG Ib due to a novel mutation in the MPI gene.