Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome

Abstract

BackgroundHurler syndrome (MPS IH), the severe, neurodegenerative form of type one mucopolysaccharidosis, is associated with rapid neurocognitive decline during toddlerhood and multi-system dysfunction. It is now standardly treated with hematopoietic cell transplantation (HCT), which halts accumulating disease pathology and prevents early death. While norm-based data on developmental functioning in untreated children have previously demonstrated neurocognitive decline, advances in methodology for understanding the cognitive functioning of children with neurodegenerative diseases have highlighted that the previous choice of scores to report results was not ideal. Specifically, the lowest possible norm-based score is 50, which obscures the complete range of cognitive functioning at more advanced stages of neurodeterioration. To a set of cognitive data collected on a sample of untreated children, we applied a modern method of score analysis, calculating a developmental quotient based on age equivalent scores, to reveal the full range of cognitive functioning beneath this cutoff of 50, uncovering new information about the rapidity of decline and the profound impairment in these children.ResultsAmong 39 observations for 32 patients with untreated Hurler syndrome, the full array of cognitive functioning below 50 includes many children in the severely to profoundly impaired range. The loss of skills per time unit was 14 points between age 1 and 2. There was a very large range of developmental quotients corresponding to the norm-based cutoff of 50.ConclusionsThis report enables clarification of functioning at levels that extend beneath the floor of 50 in previous work. At the dawn of newborn screening and amidst a proliferation of new therapies for MPS I, these data can provide crucial benchmark information for developing treatments, particularly for areas of the world where transplant may not be available.

Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial

“…MPSI presents with different clinical severity and MPSIH (Hurler syndrome) is the most severe form. If untreated, patients suffer from a severe neurocognitive decline starting at an age of one year and the median DQ declines 14-17 points per year [ 16 ]. As laronidase does not cross the BBB [ 5 ], the only therapeutic option to prevent further neurocognitive decline is HSCT.…”

“…The secondary measures of DQ were also stabilized by valanafusp alpha therapy, including the VABS-II (Table 5 ) and other domains of the BSID-III (Table 6 ). The age equivalent scores (AES) increased over the course of the 52 week study across multiple domains of cognitive testing (Table 4 , 5 and 6 ), which contrasts with the untreated MPSIH patient, where the AES declines after the age of 3 years [ 16 ]. The volume of the total grey matter was stabilized by valanafusp alpha treatment (Table 7 ), and the grey matter volume increased 20-82 cm 3 in younger subjects 2-6 years of age (Table 7 ).…”

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

“…In children with MPS IH, cognitive development slows down beginning around 6-9 months of age, stagnates during the second year of life, and progresses to a decline thereafter, unless the patient receives appropriate treatment at a young age [108]. Even after HCT, children often show below normal cognitive skill levels [79,[109][110][111].…”

Treatment of thoracolumbar kyphosis in patients with mucopolysaccharidosis type I: results of an international consensus procedure

“…Intellectual ability is often expressed as developmental quotient (DQ), defined as the developmental age divided by the chronological age multiplied by 100 [32]. There was full agreement that DQ should be taken into account when considering kyphosis surgery, but that a low DQ is not a contra-indication for surgery if a benefit in quality of life is expected by correcting the kyphosis.…”