The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation

J Inherit Metab Dis. 2010 Dec:33 Suppl 3:S5-11. doi: 10.1007/s10545-008-1063-y.

Abstract

The urinary creatine:creatinine (Cr:Crn) ratio was measured in males from 49 families with a family history compatible with X-linked mental retardation (XLMR) in order to estimate the prevalence of SLC6A8 deficiency in Estonia. We identified 11 boys from 9 families with an increased urinary Cr:Crn ratio (18%). In three related boys, a hemizygous missense mutation (c.1271G>A; p.Gly424Asp) was identified. Their mother was heterozygous for the same mutation. Although many missense mutations have been described, the p.Gly424Asp mutation has not been previously reported. The clinical expression varied widely among affected males of this family. Patients 1 and 3 had relatively mild clinical expression (mild mental retardation (MR) and attention deficit disorder), but patient 2 had all typical clinical signs of SLC6A8 defect such as moderate MR, autistic features, expressive dysphasia and epilepsy. Among our patients, we saw significant problems in speech and language development combined with attention and behavioural difficulties. The number of false-positive biochemical results with increased urinary Cr:Crn ratio was higher (18%) in our study than in previous reports (1.8–10%). We therefore suggest that repeated biochemical testing should be performed before DNA sequencing analysis. Our study suggests that 2% (95% confidence limits: 0.05–11.1%) of this Estonian XLMR panel are due to mutations in the SLC6A8, which is similar to the prevalence reported in other populations. We therefore conclude that creatine transporter deficiency is a relatively common genetic disorder in males with sporadic or familiar MR and diagnostic screening of them should always include screening for SLC6A8 deficiency.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers / urine
  • Brain Diseases, Metabolic, Inborn / diagnosis*
  • Brain Diseases, Metabolic, Inborn / epidemiology
  • Brain Diseases, Metabolic, Inborn / genetics
  • Brain Diseases, Metabolic, Inborn / psychology
  • Brain Diseases, Metabolic, Inborn / urine
  • Child
  • Creatine / deficiency*
  • Creatine / genetics
  • Creatine / urine
  • Creatinine / urine
  • DNA Mutational Analysis*
  • Estonia / epidemiology
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing / methods*
  • Heredity
  • Heterozygote
  • Humans
  • Intelligence / genetics
  • Male
  • Mental Retardation, X-Linked / diagnosis*
  • Mental Retardation, X-Linked / epidemiology
  • Mental Retardation, X-Linked / genetics
  • Mental Retardation, X-Linked / psychology
  • Mental Retardation, X-Linked / urine
  • Middle Aged
  • Mutation, Missense*
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Persons with Mental Disabilities
  • Phenotype
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency*
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics
  • Plasma Membrane Neurotransmitter Transport Proteins / urine
  • Predictive Value of Tests
  • Prevalence
  • Severity of Illness Index
  • Young Adult

Substances

  • Biomarkers
  • Nerve Tissue Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • SLC6A8 protein, human
  • Creatinine
  • Creatine

Supplementary concepts

  • Creatine deficiency, X-linked

Associated data

  • OMIM/OMIM300036
  • OMIM/OMIM300352