Diabetes mellitus in an adolescent girl with intellectual disability caused by novel single base pair duplication in the PTRH2 gene: Expanding the clinical spectrum of IMNEPD

Brain Dev. 2021 Feb;43(2):314-319. doi: 10.1016/j.braindev.2020.09.009. Epub 2020 Oct 20.


Background: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) is an extremely rare autosomal recessive disorder with variable expressivity, caused by biallelic mutations in the PTRH2 gene. Core features are global developmental delay or isolated speech delay, intellectual disability, sensorineural hearing loss, ataxia, and pancreatic insufficiency (both exocrine and endocrine). Additional features may include postnatal microcephaly, peripheral neuropathy, facial dysmorphism, and cerebellar atrophy. In literature, there are only a few anecdotal case reports and none of the previous cases presented with diabetic ketoacidosis.

Methods: We are reporting a 12-year old adolescent girl with mild intellectual disability who presented with fever, pain abdomen for 2 days, and fast breathing for one day.

Results: Her random blood sugar was 472 mg/dl and arterial blood gas revealed high anion gap metabolic acidosis. Urine examination showed ketonuria. On further evaluation, she was found to have demyelinating sensorimotor polyneuropathy and sensorineural hearing loss. Neuroimaging and other ancillary investigations were normal. Whole exome sequencing revealed a novel homozygous single base pair duplication in exon 1 of the PTRH2 gene (c.127dupA, p.Ser43LysfsTer11), confirming the diagnosis of IMNEPD.

Conclusions: Apart from describing a novel single base pair duplication causing protein truncation in the PTRH2 gene for the first time, our case also expanded the clinical spectrum of IMNEPD, as this is the first case with seemingly pure neurodevelopmental phenotype, who later developed diabetes mellitus, without any exocrine pancreatic abnormality. IMNEPD should be considered in children or adolescents with global developmental delay or intellectual disability when they develop diabetes mellitus.

Keywords: Developmental delay; Diabetes mellitus; IMNEPD; Intellectual disability; Pancreatic deficiency.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Ataxia / genetics
  • Base Pairing / genetics
  • Carboxylic Ester Hydrolases / genetics*
  • Carboxylic Ester Hydrolases / metabolism
  • Developmental Disabilities / genetics
  • Diabetes Mellitus / genetics*
  • Exome / genetics
  • Female
  • Gene Duplication / genetics
  • Hearing Loss, Sensorineural / genetics
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Mutation / genetics
  • Nervous System Malformations / genetics
  • Pancreatic Diseases / genetics
  • Pedigree
  • Phenotype


  • Mitochondrial Proteins
  • Carboxylic Ester Hydrolases
  • PTH2 protein, human