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Mucopolysaccharidosis III (MPS III) is a rare inherited metabolic disease primarily affecting the central nervous system, leading to developmental and/or speech regression. Early diagnosis of the disease is important to introduce appropriate management measures and to optimize therapeutic outcomes. The diagnosis of MPS III is often significantly delayed due to the rarity of the disease, the more attenuated somatic presentation compared to other MPS types, and the symptom overlap with other developmental disorders. To shorten the time to diagnosis, a list of eight early signs and symptoms was identified through an expert system approach by a global, multidisciplinary working group of 13 specialists with expertise in various aspects of MPS and developmental disorders and three parents of MPS III patients. Coarse facial features and persistent hirsutism or prominent, thick eyebrows were identified as the most important MPS III early signs. The list of eight early MPS III signs and symptoms is the first step towards the development of a clinical algorithm aiming to identify neonates and infants with MPS III before the onset of neurocognitive damage, ultimately shortening the diagnostic journey of MPS III patients.

Summary Background Diabetes is a cause of at least a third of all deaths in Mexican adults aged 35–74 years, with the excess mortality due mainly to vascular disease, renal disease, infection, and acute diabetic crises. We aimed to analyse the effect of diabetes duration and glycaemic control on death rate ratios (RRs) for these causes and to assess the relevance to cause-specific mortality of undiagnosed diabetes. Methods About 100 000 women and 50 000 men aged 35 years or older from Mexico City were recruited into a blood-based prospective study between April 14, 1998, and Sept 28, 2004, and followed up until Jan 1, 2016, for cause-specific mortality. Participants who, at recruitment, reported any chronic disease other than diabetes and those who had missing data for HbA 1c or diabetes duration were excluded. We used Cox models to estimate the associations of undiagnosed or previously diagnosed diabetes (almost all type 2) with risk of mortality from vascular disease, renal disease, and infection, exploring among those with previously diagnosed diabetes the independent relevance of diabetes duration ( 1c ( 1c with mortality in participants without diabetes at recruitment. Findings 133 662 participants were aged 35–74 years and had complete data and no other chronic disease. 16 940 (13%) had previously diagnosed diabetes, 6541 (5%) had undiagnosed diabetes, and 110 181 (82%) had no diabetes. Among participants with previously diagnosed diabetes, glycaemic control was poor (median HbA 1c 8·9% [IQR 7·0–10·9]), and was worse in those with longer duration of disease at recruitment. Compared with participants without diabetes, the death RRs at ages 35–74 years for the combination of vascular, renal, or infectious causes were 3·0 (95% CI 2·7–3·4) in those with undiagnosed diabetes, 4·5 (4·0–5·0) for the 5042 participants with a diabetes duration of less than 5 years, 6·6 (6·1–7·1) for the 7713 participants with a duration of 5 years to less than 10 years, and 11·7 (10·7–12·7) for the 4185 participants with a duration of at least 10 years. Similarly, the death RRs were 5·2 (4·8–5·7) for those with HbA 1c less than 9%, 6·8 (6·2–7·4) for those with HbA 1c of 9% to less than 11%, and 10·5 (9·7–11·5) for those with HbA 1c of at least 11%. Diabetes was not strongly associated with the combination of deaths from other causes apart from acute glycaemic crises. Among participants without diabetes, higher HbA 1c was not positively related to mortality. Interpretation In Mexico, the rates of death from causes strongly associated with diabetes increased steeply with duration of diabetes and were higher still among people with poor glycaemic control. Delaying the onset of type 2 diabetes, as well as improving its treatment, is essential to reduce premature adult mortality in Mexico. Funding Wellcome Trust, the Mexican Health Ministry, the Mexican National Council of Science and Technology, Cancer Research UK, British Heart Foundation, and the UK Medical Research Council Population Health Research Unit.

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96weeks (reaching 120weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N=173), analyses were also performed for a modified per-protocol (MPP) population (N=124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3)m and 39.9 (10.1)m for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study (N=56) and 15.1 (7.1)m and 31.7 (6.8)m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0)stairs/min for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3)stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was -59.4 (1.8)% and -62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P

As therapies are developed for rare disorders, challenges of early diagnosis become particularly relevant. This article focuses on clinical recognition of mucopolysaccharidoses (MPS), a group of rare genetic diseases related to abnormalities in lysosomal function. As quality of outcomes with current therapies is impacted by timing of intervention, minimizing time to diagnosis is critical. The objective of this study was to characterize how, when, and to whom patients with MPS first present and develop tools to stimulate earlier recognition of MPS. A tripartite approach was used, including a systematic literature review yielding 194 studies, an online physician survey completed by 209 physicians who described

Mucopolysaccharidosis IVA is an autosomal recessive condition caused by mutations in the GALNS gene, which encodes N-acetylgalactosamine-6-sulfatase, also called galactosamine-6-sulfatase (GALNS). A reduction in or absence of effective GALNS leads to faulty catabolism of keratan sulfate and chondroitin-6-sulfate within the lysosome; their accumulation causes cell, tissue, and organ dysfunction. The connective tissue, cartilage, ligaments, and bone of patients with Morquio A syndrome are particularly affected. Patients with Morquio A syndrome are at high risk of neurological complications because of their skeletal abnormalities; many patients are in danger of cervical myelopathy due to odontoid hypoplasia and ligamentous laxity leading to atlantoaxial subluxation. The multisystemic involvement of patients with Morquio A syndrome requires treatment by multidisciplinary teams; not all members of these teams may be aware of the potential for subluxation and quadriparesis. A multinational, multidisciplinary panel of 10 skeletal dysplasia or Morquio A syndrome specialists convened in Miami, FL on December 7 and 8, 2012 to develop consensus recommendations for early identification and effective management of spinal cord compression, for anesthesia and surgical best practices, and for effectual cardiac and respiratory management in patients with Morquio A syndrome. The target audience for these recommendations includes any physician who may encounter a patient with Morquio A syndrome, however doctors who do not have access to the full spectrum of specialists and resources needed to support patients with Morquio A syndrome should attempt to refer patients to a center that does. Physicians who manage Morquio A syndrome or comorbid conditions within specialty centers should review these expert panel recommendations and fully understand the implications of spinal cord instability for their own practices. © 2014.