Impact of genotype on neutropenia in a large cohort of Serbian patients with glycogen storage disease type Ib

Eur J Med Genet. 2020 Mar;63(3):103767. doi: 10.1016/j.ejmg.2019.103767. Epub 2019 Sep 16.

Abstract

Background: Glycogen storage disease type Ib (GSD-Ib) is an inherited metabolic disorder caused by autosomal recessive mutations in SLC37A4 coding for the glucose-6-phosphate transporter. Neutropenia represents major feature of GSD-Ib along with metabolic disturbances. Previous research in GSD-Ib patients did not reveal significant genotype-phenotype correlation. Our objective was to explore the frequency and severity of neutropenia and it's complications in relation to genotype of GSD-Ib patients.

Methods: We estimated cumulative incidence of neutropenia and severe neutropenia, relation of genotype to absolute neutrophil count (ANC), and dynamics of ANC during serious bacterial infections (SBI) in a cohort of Serbian GSD Ib patients. Impact of genotype on GSD Ib-related inflammatory bowel disease (IBD) was also assessed.

Results: Absolute neutrophil count (ANC) < 1500/mm3 was present in all 33 patients, with severe neutropenia (ANC<500/mm3) occurring in 60.6% of patients. The median age at neutropenia onset was 24 months, while severe neutropenia developed at median of 4.5 years. The ANC was elevated during 90.5% episodes of SBI. Genotypes c.81T>A/c.785G>A and c.81T>A/c.1042_1043delCT are associated with earlier onset of neutropenia. Patients carrying c.785G>A mutation express a higher capacity for ANC increase during SBI. Inflammatory bowel disease was diagnosed in 8 patients (24.2% of total) with median age of onset at 7 years. Risk for IBD occurrence was not significantly affected by gender, genotype and severity of neutropenia.

Conclusions: We may conclude that certain mutations in SLC37A4 influence the risk for severe neutropenia occurrence but also affect the capacity to increase ANC during SBI.

Keywords: Genotype; Glycogen storage disease type Ib; Neutropenia; Phenotype.

MeSH terms

  • Adolescent
  • Adult
  • Antiporters / genetics*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Genetic Association Studies
  • Genotype
  • Glycogen Storage Disease Type I / complications
  • Glycogen Storage Disease Type I / genetics*
  • Humans
  • Incidence
  • Inflammatory Bowel Diseases / complications*
  • Inflammatory Bowel Diseases / genetics
  • Male
  • Monosaccharide Transport Proteins / genetics*
  • Mutation
  • Neutropenia / blood
  • Neutropenia / cerebrospinal fluid
  • Neutropenia / genetics*
  • Neutropenia / physiopathology
  • Neutrophils / cytology
  • Phenotype
  • Serbia

Substances

  • Antiporters
  • Monosaccharide Transport Proteins
  • SLC37A4 protein, human

Supplementary concepts

  • Glycogen Storage Disease IB