High dose genistein in Sanfilippo syndrome: A randomised controlled trial

From Wiley via Jisc Publications RouterHistory: received 2021-02-09, rev-recd 2021-05-25, accepted 2021-05-27, pub-electronic 2021-06-13Article version: VoRPublication status: PublishedFunder: UK MPS SocietyFunder: National MPS society; Id: http://dx.doi.org/10.13039/100013927Funder: GEM AppealAbstract: The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double‐blinded, randomised, placebo‐controlled study with open‐label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty‐one participants were randomised and 20 completed the placebo‐controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P = .26), and CSF heparan sulfate increased in both groups during the open‐label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P = .0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III

Diagnosing mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process

Use of the PRIME-MD Patient Health Questionnaire for estimating the prevalence of psychiatric disorders in French primary care: comparison with family practitioner estimates and relationship to psychotropic medication use.

International audienceOBJECTIVES: The objectives of this study were to establish provisional psychiatric diagnoses using the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PHQ) and to describe family practitioner (FP) case recognition, survey-day prescription of anxiolytic and antidepressant medications and overall consumption rates (medication use). METHODS: Between October 2003 and April 2004, 1151 consecutive patients (> or = 18 years old) of 46 FPs practicing in and around the city of Montpellier, France, completed the PHQ. During the consultation, FPs rated the severity of any psychiatric disorder. RESULTS: PHQ prevalence rates (FP case recognition percentages are given in parentheses) were as follows: 10.9% (36%) for probable alcohol abuse/dependence; 11.3% (40%) for somatoform disorder; 9.1% (75%) for major depression; 7.4% (42%) for other depressive disorders; 7.5% (69%) for panic disorder; and 6% (69%) for other anxiety disorders. The prescription rate for all study patients was 11.3%, ranging from 6.2% for those without a PHQ disorder to 30.3% for those with a PHQ diagnosis of anxiety or depression to 48.2% for FP-recognized cases. The estimated survey-day consumption rate for these medications was 19.4%. CONCLUSIONS: High consumption of anxiolytic and antidepressant medications in France is confirmed but not explained either by higher prevalence rates of psychiatric disorders as compared with other locations or by unusually high survey-day prescription rates. A possible explanation would be the organization of the French health care system, which has multiple sources for obtaining medication

Maternal mosaicism for IDUA deletion clarifies recurrence risk in MPS I.

Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in IDUA, encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of IDUA exons 1 and 2, c.(?_-88)_(299+1_300-1)del and a whole-gene deletion of IDUA (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechanism for this disorder

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

BACKGROUND: Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown. DESIGN AND METHODS: We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism. RESULTS: High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26–137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels. CONCLUSIONS: We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy