Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the α-L-iduronidase gene in Hurler-Scheie syndrome

Alia Ahmed, Chester B. Whitley, Renee Cooksley, Kyle Rudser, Stephanie Cagle, Nadia Ali, Kathleen Delaney, Brianna Yund, Elsa Shapiro

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


The lysosomal enzyme α-L-iduronidase hydrolyzes terminal iduronic acid from heparan sulfate and dermatan sulfate, and is an essential step in GAG degradation. Mutations of its gene, IDUA, yield a spectrum of mucopolysaccharidosis (MPS) type I clinical disorders. The IDUA mutation, c.712T>A (p.L238Q) was previously noted as a mild mutation. In a longitudinal study of MPS brain structure and function (Lysosomal Disease Network), we found this mutation in 6 of 14 Hurler-Scheie syndrome patients in the age range of 15 to 25. years. We hypothesized that L238Q, when paired with a nonsense mutation, is significantly more severe than other missense-nonsense combinations. MethodsOf 6 patients with a L238Q mutation, the L238Q allele was paired with a nonsense mutation in 4 patients, paired with a deletion in 1, and with a splice site mutation in another. This group was compared to 6 Hurler-Scheie patients closely matched in age and mutation type. IQ and other neuropsychological tests were administered as part of the protocol. Medical history was compiled into a Physical Symptom Score (PSS). Assessment of IQ, attention, memory, spatial ability, adaptive function and psychological status were measured. ResultsNo group differences were found in mean age at evaluation (17.8 and 19.0. years), duration of ERT, or PSS. By history, all were reported to be average in IQ (4/6 with documentation) in early childhood. All (100%) of the L238Q group had a psychiatric history and sleep problems compared to none (0%) of the comparison group. Significant differences were found in depression and withdrawal on parent report measures. IQ was lower in the L238Q group (mean IQ 74) than the comparison group (mean IQ 95; p < 0.016). Attention, memory, and visual-spatial ability scores were also significantly lower. Three occurrences of shunted hydrocephalus, and 4 of cervical cord compression were found in the L238Q group; the comparison group had one occurrence of unshunted hydrocephalus and two of cord compression. DiscussionThe missense mutation L238Q, when paired with a nonsense mutation, is associated with significant, late-onset brain disease: psychiatric disorder, cognitive deficit, and general decline starting at a later age than in Hurler syndrome with a mutation-related rate of GAG accumulation and its pathologic sequelae. This particular genotype-phenotype may provide insight into the genesis of psychiatric illnesses more broadly. Consideration of methods for early, brain-targeted treatment in these patients might be considered.

Original languageEnglish (US)
Pages (from-to)123-127
Number of pages5
JournalMolecular Genetics and Metabolism
Issue number2
StatePublished - 2014

Bibliographical note

Funding Information:
We are thankful for the support provided by NIH U54-NS065768 and UL1TR000114 (NINDS, NIDDK, ORDR, and NCATS), National MPS Society , Genzyme–Sanofi and The Ryan Foundation for Orphan Disease Research as well as other investigators who contributed patient material and information.


  • Hurler-Scheie syndrome
  • L238Q
  • Missense mutation
  • Mucopolysaccharidosis Type I
  • Nonsense mutation
  • α-L-iduronidase


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