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

Abstract

The lysosomal enzyme alpha-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. Methods Of 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. Results No 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. Discussion The 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.

Cognitive outcomes and age of detection of severe mucopolysaccharidosis type 1

“…Of the 29 MPSI-A patients, only those evaluated as children (<25 years of age, n = 25) are reported in the present study. Comparison groups based on phenotype and age at visit, further categorized as 2 to <6 years and ≥6 years to 25 years, based on use of different cognitive tests. c As reported by Al-Sannaa et al 23 . Excludes one younger sibling who started ERT at age 8.6 years.…”

“… c As reported by Al-Sannaa et al 23 . Excludes one younger sibling who started ERT at age 8.6 years.…”

“…8,23 Cognitive outcomes for MPS IA merit further attention by researchers. In particular, researchers might investigate the impact of verbal versus nonverbal abilities and attention skills on cognitive measures and whether earlier initiation of ERT for children with MPS IA associated with the L238Q missense mutation leads to less cognitive impairment.…”

“…One study 23 identified a subset of individuals with MPS IA who were at risk for both psychiatric problems and cognitive impairment, specifically those carrying an L238Q missense mutation. In a sample of 14 patients with MPS IA who were ages 15–25 years, the mean IQ score for six L238Q carriers was 74 (below average) compared with 95 (average) for non-L238Q carriers ( P = 0.016).…”

Mucopolysaccharidosis (MPS) Physical Symptom Score: Development, Reliability, and Validity

“…These physical signs and symptoms together with increased urinary excretion of GAG (glycosaminoglycan), and absent or deficient alpha-L-iduronidase enzyme activity are observed in all forms of MPS I (Terlato and Cox 2003;Scott et al 1995;Beesley et al 2001), but no method exists to accurately summarize phenotypic disease burden in retrospective or prospective research studies. Genotype-phenotype correlations have been established to a limited degree in Hurler syndrome and even more limited in the attenuated forms (Pastores et al 2007;Terlato and Cox 2003;Scott et al 1995;Beesley et al 2001;Bertola et al 2011;Ahmed et al 2014a). Standard of care treatments such as hematopoietic cell transplant (HCT) (Peters et al 1996;Peters et al 1998;Souillet et al 2003;Staba et al 2004) in Hurler syndrome and enzyme replacement therapy (ERT) (Kakkis et al 2001;Wraith et al 2004) for the attenuated syndromes ameliorate some but not all symptoms.…”