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Concept: Lysosomal storage disease

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BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with alpha-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear. METHODS: Renal, cardiac, and cerebral outcomes were prospectively studied in males and females with Fabry disease treated with ERT. Additionally, the occurrence of major cardiac events, stroke, end-stage renal disease and death was compared to a natural history (NH) cohort meeting treatment criteria. RESULTS: Of 75 patients on ERT (median treatment duration 5.2 years, range 0.05-11.0), prospective follow-up was available for 57 adult patients (30 males) and 6 adolescents. Renal function declined in males (-3.4 ml/min/1.73 m2 per year, SE 0.2; p < 0.001) despite ERT, but followed the normal course in females (-0.8 ml/min/1.73 m2 per year, SE 0.3; p = 0.001). Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; p < 0.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; p = 0.52). ERT did not prevent the occurrence of cerebral white matter lesions. Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age (OR 1.05 (95% CI: 1.0-1.1) per year, p = 0.012). For development of a first or second complication the odds declined with longer treatment duration (OR 0.81 (95% CI: 0.68-0.96) per year of ERT, p = 0.015;OR 0.52 (0.31-0.88), p = 0.014 respectively). CONCLUSIONS: Long term ERT does not prevent disease progression, but the risk of developing a first or second complication declines with increasing treatment duration. ERT in advanced Fabry disease seems of doubtful benefit.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Death, Lysosomal storage disease, Enzyme replacement therapy, Fabry disease

172

BACKGROUND: Families of children living with a rare disease report significant health and social burden, however, few studies have systematically examined family needs by using validated tools to assess the scope and extent of this burden. Our aim was to develop a comprehensive survey to assess health, psychosocial and financial impacts on Australian families caring for a child with a rare disease. METHODS: We developed a self-administered survey for parents/carers incorporating pre-validated tools. The survey included questions about experiences of diagnosis, health services use and needs, needs for peer and financial supports. Forty-seven families attending the state-wide Genetic Metabolic Disorders Service at the Children’s Hospital at Westmead, Sydney were invited to participate. RESULTS: Of 46 families who received the survey, 30 (65%) completed it. Most (93%) found the survey acceptable and relevant (91%). Patients were 1–17 years old, 14 (47%) male, and 12 (40%) non-Caucasian. Eighteen (60%) had a lysosomal storage disease and 12(40%) had a mitochondrial disorder. Eleven (38%) saw 3–5 doctors and four (14%) saw 6–10 doctors before receiving the correct diagnosis; 43% felt diagnosis was delayed. Seven (33%) were dissatisfied with the way diagnosis was given, due to insensitive style of communication, inadequate information and psychological support. Psychosocial impact was moderate to high for 90% of families and the level of impact was not dependent on the level of health functioning of the child. Twenty-six (87%) wanted, but only 13(43%) received, information about peer-support groups. The 30 children accounted for 168 visits to general practitioners and 260 visits to specialist doctors; 21 (70%) children had at least one admission to hospital, including one who had 16 admissions in the previous 12 months. Most families (77%) received financial assistance but 52% believed this was insufficient. Families benefited from a specialised multi-disciplinary clinic but called for patient-held electronic medical records. CONCLUSIONS: Australian families caring for children with genetic metabolic disorders are adversely impacted by delays in diagnosis, lack of easy access to peer support groups and lack of psychological support. Further research is needed to estimate economic impact and to analyse health service delivery models for children with rare diseases in Australia.

Concepts: Health care, Medicine, Health, Epidemiology, Metabolism, Lysosomal storage disease, Physician, Inborn errors of metabolism

170

Mucopolysaccharidosis (MPS) III has 4 enzymatically distinct forms (A, B, C, and D), and MPS IIIC, also known as Sanfilippo C syndrome, is an autosomal recessive lysosomal storage disease caused by a deficiency of heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). Here, we report a case of MPS IIIC that was confirmed by molecular genetic analysis. The patient was a 2-yr-old girl presenting with skeletal deformity, hepatomegaly, and delayed motor development. Urinary excretion of glycosaminoglycan (GAG) was markedly elevated (984.4 mg GAG/g creatinine) compared with the age-specific reference range (<175 mg GAG/g creatinine), and a strong band of heparan sulfate was recognized on performing thin layer chromatography. HGSNAT enzyme activity in leukocytes was 0.7 nmol/17 hr/mg protein, which was significantly lower than the reference range (8.6-32 nmol/17 hr/mg protein). PCR and direct sequencing of the HGSNAT gene showed 2 mutations: c.234+1G>A (IVS2+1G>A) and c.1150C>T (p.Arg384(*)). To the best of our knowledge, this is the first case of MPS IIIC to be confirmed by clinical, biochemical, and molecular genetic findings in Korea.

Concepts: DNA, Molecular biology, Metabolism, Enzyme, Lysosomal storage disease, Chromatography, Mucopolysaccharidosis, Sanfilippo syndrome

167

Morquio A syndrome is a lysosomal storage disease associated with mucopolysaccharidosis. It is caused by a deficiency of the lysosomal enzyme, N-acetylgalactosamine-6-sulfate sulfatase, which leads to accumulation of keratan sulfate and condroitin-6 sulfate in multiple organs. Patients present with multisystemic complications involving the musculoskeletal, respiratory, cardiovascular, and digestive systems. Presently, there is no definitive cure, and current management options are palliative. Enzyme replacement therapy and hematopoietic stem cell therapy have been proven effective in certain lysosomal storage diseases, and current investigations are underway to evaluate the effectiveness of these therapies and others for the treatment of Morquio A syndrome. This review discusses the current and emerging treatment options for Morquio A syndrome, citing examples of the treatment of other mucopolysaccharidoses.

Concepts: Cell, Lysosomal storage disease, Therapy, Mucopolysaccharidosis, Lysosomal storage diseases, Morquio syndrome

165

The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a “model disease” of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea.

Concepts: Respiratory physiology, Lysosomal storage disease, Sleep, White matter, Sleep apnea, Abnormal respiration, Apnea, Respiration

165

To date, a plethora of studies have provided evidence favoring an association between Gaucher disease (GD) and Parkinson’s disease (PD). GD, the most common lysosomal storage disorder, results from the diminished activity of the lysosomal enzyme β-glucocerebrosidase (GCase), caused by mutations in the β-glucocerebrosidase gene (GBA). Alpha-synuclein (ASYN), a presynaptic protein, has been strongly implicated in PD pathogenesis. ASYN may in part be degraded by the lysosomes and may itself aberrantly impact lysosomal function. Therefore, a putative link between deficient GCase and ASYN, involving lysosomal dysfunction, has been proposed to be responsible for the risk for PD conferred by GBA mutations. In this current work, we aimed to investigate the effects of pharmacological inhibition of GCase on ASYN accumulation/aggregation, as well as on lysosomal function, in differentiated SH-SY5Y cells and in primary neuronal cultures. Following profound inhibition of the enzyme activity, we did not find significant alterations in ASYN levels, or any changes in the clearance or formation of its oligomeric species. We further observed no significant impairment of the lysosomal degradation machinery. These findings suggest that additional interaction pathways together with aberrant GCase and ASYN must govern this complex relation between GD and PD.

Concepts: DNA, Protein, Enzyme, Lysosomal storage disease, Parkinson's disease, Lysosome, Gaucher's disease, Glucocerebrosidase

140

Human β-glucuronidase (GUS; EC 3.2.1.31) is a lysosomal enzyme that catalyzes the hydrolysis of β-d-glucuronic acid residues from the non-reducing termini of glycosaminoglycans. Impairment in GUS function leads to the metabolic disorder mucopolysaccharidosis type VII, also known as Sly syndrome. We produced GUS from a CHO cell line grown in suspension in a 15 L perfused bioreactor and developed a three step purification procedure that yields ∼99% pure enzyme with a recovery of more than 40%. The method can be completed in two days and has the potential to be integrated into a continuous manufacturing scheme.

Concepts: Protein, Cell, Metabolism, Enzyme, Lysosomal storage disease, Cell culture, Chinese hamster ovary cell, Inborn errors of metabolism

115

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a “safe harbor” site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6-9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases.

Concepts: DNA, Gene, Genetics, Lysosomal storage disease, Therapy, Fabry disease, Mucopolysaccharidosis, Hunter syndrome

36

A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.

Concepts: Immune system, Macrophage, Apoptosis, Lysosomal storage disease, Tuberculosis, Mycobacterium, Mycobacterium tuberculosis, Mycobacterium marinum

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Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.

Concepts: Medicine, Enzyme, Lysosomal storage disease, Therapy, Enzyme replacement therapy, Fabry disease