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Observing the advanced disease course in mucopolysaccharidosis, type IIIA; a case series.

ABSTRACT: This follow-up study of a subgroup of the patients seen in a natural history study of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A) addressed the adaptive and medical characteristics of their advanced disease manifestations. Of the original 24 patients, specific data was collected on only 58% primarily due to difficulty in locating families and coordinating time for interviews two to four years after the original study. At the last contact with the patient, age range was 8 to 24years of age. Data were collected from telephone interviews from the Vineland Adaptive Behavior Scales II and medical and treatment history. We report the case data from rapid progressing and slow progressing patients separately. By the end of our data collection, 5 patients had died; 4 rapid progressing patients between 8 and 12years of age and 1 slow progressing patient at age 21. Two patients were in out-of-home placements in the year before they died. We found that the incidence of surgeries and epilepsy was relatively low and that behavior problems largely subsided. Adaptive levels were very low with children functioning at below a two-year age equivalent level in all adaptive functions, but motor skills were slightly more intact. Only one slow progressing patient was functioning above a three-year level. Parent burden had shifted from behavioral control to physical management. Although their quality of life was clearly negatively impacted by physical management and palliative care, parents were more able to cope and adapt to such demands than in the initial stages of the disease.

SUBMITTER: Shapiro E

PROVIDER: S-EPMC7814869 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Observing the advanced disease course in mucopolysaccharidosis, type IIIA; a case series.

Shapiro Elsa E Ahmed Alia A Whitley Chester C Delaney Kathleen K

Molecular genetics and metabolism 20171128 2

This follow-up study of a subgroup of the patients seen in a natural history study of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A) addressed the adaptive and medical characteristics of their advanced disease manifestations. Of the original 24 patients, specific data was collected on only 58% primarily due to difficulty in locating families and coordinating time for interviews two to four years after the original study. At the last contact with the patient, age range was 8 to 24ye ...[more]

PMID: 29198891

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Project description:Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4-9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4-9 months.

Project description:BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data.MethodsWe have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease.ResultsWe collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS.ConclusionsMPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.

Dataset Information

Observing the advanced disease course in mucopolysaccharidosis, type IIIA; a case series.

Publications

Observing the advanced disease course in mucopolysaccharidosis, type IIIA; a case series.

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