The evolution of pulmonary function in childhood onset Mucopolysaccharidosis type I.

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.

Ten years of enzyme replacement therapy in paediatric onset mucopolysaccharidosis II in England.

The outcome of 110 patients with paediatric onset mucopolysaccharidosis II (MPS II) since the commercial introduction of enzyme replacement therapy (ERT) in England in 2007 is reported. Median length of follow up was 10 years 3 months (range = 1 y 2 m to 18 years 6 month). 78 patients were treated with ERT, 18 had no ERT or disease modifying treatment 7 had haematopoietic stem cell transplant, 4 experimental intrathecal therapy and 3 were lost to follow up. There is clear evidence of improved survival (median age of death of ERT treated (n = 16) = 15.13 years (range = 9.53 to 20.58 y), and untreated (n = 17) = 11.43 y (0.5 to 19.13 y) p = .0005). Early introduction of ERT improved respiratory outcome at 16 years, the median FVC (% predicted) of those in whom ERT initiated <8 years = 69% (range = 34-86%) and 48% (25-108) (p = .045) in those started >8 years. However, ERT appears to have minimal impact on hearing, carpal tunnel syndrome or progression of cardiac valvular disease. Cardiac valvular disease occurred in 18/46 (40%), with progression occurring most frequently in the aortic valve 13/46 (28%). The lack of requirement for neurosurgical intervention in the first 8 years of life suggests that targeted imaging based on clinical symptomology would be safe in this age group after baseline assessments. There is also emerging evidence that the neurological phenotype is more nuanced than the previously recognized dichotomy of severe and attenuated phenotypes in patients presenting in early childhood.

Outcomes from 18 years of cervical spine surgery in MPS IVA: a single centre's experience.

PURPOSE: This study examines the long-term outcomes of paediatric Morquio (MPS IVA) patients undergoing cervical spine surgery and evaluates the factors that impacting this. METHODS: A retrospective review was performed on all MPS IVA patients undergoing cervical spine surgery, since the introduction of standardised neuroradiological screening. The impact of preoperative neurological status, growth, genotype and radiological status on outcome is assessed, whilst long-term surgical, radiological and neurological outcomes are documented. RESULTS: Twenty-six of the eighty-two MPS IVA patients (31%) reviewed underwent cervical spine surgery at a median age of 6.1 years (range, 1.45 to 15.24). Preoperatively, cord signal change was seen in 11 patients with 5 being myelopathic; however, 6 clinically manifesting patients had no overt cord signal change. Postoperatively, none of the 14 preoperatively clinically asymptomatic patients followed long term progressed neurologically during a median follow-up of 77.5 months (range = 18-161). Of the ten preoperatively clinically symptomatic patients who were followed up for the same duration, seven continued to deteriorate, two initially improved and one remained stable. Radiological follow-up performed for a median duration of 7 years (range = 0.5-16) has shown a degree of stenosis at the level immediately caudal to the termination of the graft in 76% of patients, though only one has become clinically symptomatic and required revision. CONCLUSIONS: Once clinically elicitable neurological signs become evident in patients with MPS IVA, they tend to progress despite surgical intervention. Referring clinicians should also not be falsely reassured by the lack of T2 spinal cord signal change but should consider surgical intervention in the face of new clinical symptomology or radiological signs of progressive canal stenosis or instability.

Rapidly Progressive White Matter Involvement in Early Childhood: The Expanding Phenotype of Infantile Onset Pompe?

Glycogen accumulation in the central nervous system of patients with classical infantile onset Pompe disease (IOPD) has been a consistent finding on the few post-mortems performed. While delays in myelination and a possible reduction in processing speed have previously been noted, it has only been recently that the potential for clinically significant progressive white matter disease has been noted. The limited reports thus far published infer that in some IOPD patients, this manifests as intellectual decline in the second decade of life. We present a CRIM negative patient, immunomodulated with rituximab and methotrexate at birth, who despite an initial good clinical response to ERT, at the age of just under 4 years, presented with evolving spasticity in the lower limbs. The investigation of which revealed progressive central nervous system involvement. Given both the earlier onset of the symptoms and consanguineous familial pedigree, extensive biochemical and genetic investigation was undertaken to ensure no alternative pathology was elucidated. In light of these findings, we review the radiology and post-mortems of previous cases and discuss the potential mechanisms that may underlie this presentation.