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OBJECTIVE: To describe the clinical, preliminary electroretinographic and optical coherence tomography features of a newly identified form of progressive retinal atrophy (PRA) in German Spitzes, and identify the causal gene mutation. ANIMALS: Thirty-three client-owned German Spitz dogs were included. PROCEDURES: All animals underwent a full ophthalmic examination, including vision testing. In addition, fundus photography, ERG, and OCT were performed. A DNA-marker-based association analysis was performed to screen potential candidate genes and the whole genomes of four animals were sequenced. RESULTS: Initial fundus changes were pale papilla and mild vascular attenuation. Oscillatory nystagmus was noted in 14 of 16 clinically affected puppies. Vision was impaired under both scotopic and photopic conditions. Rod-mediated ERGs were unrecordable in all affected dogs tested, reduced cone-mediated responses were present in one animal at 3 months of age and unrecordable in the other affected animals tested. Multiple small retinal bullae were observed in three clinically affected animals (two with confirmed genetic diagnosis). OCT showed that despite loss of function, retinal structure was initially well-preserved, although a slight retinal thinning developed in older animals with the ventral retina being more severely affected. Pedigree analysis supported an autosomal recessive inheritance. A mutation was identified in GUCY2D, which segregated with the disease (NM_001003207.1:c.1598_1599insT; p.(Ser534GlufsTer20)). Human subjects with GUCY2D mutations typically show an initial disconnect between loss of function and loss of structure, a feature recapitulated in the affected dogs in this study. CONCLUSION: We identified early-onset PRA in the German Spitz associated with a frameshift mutation in GUCY2D.

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Abstract The mucopolysaccharidoses (MPS) are a relatively uncommon group of inherited metabolic disorders, with significant negative implications for life span and aspects of quality of life. Their rarity means that producing evidence to guide best practice has often entailed assimilating findings from multiple studies. Core outcome sets (COS) are being increasingly used across medicine as a potential solution to the problems arising from heterogeneous reporting of outcomes in effectiveness studies. A COS is a recommended minimum set of outcomes that should be measured for a given condition in an effectiveness study, with the ultimate aim of increasing the value of clinical information by enabling meaningful comparison and combination of data from various sources. A systematic review identified 41 outcomes measured in published studies and ongoing and completed clinical trials, with individual outcomes being measured using a variety of measurement instruments/tools. This work represents the important initial steps in the development of COS for head, neck, and respiratory disorders in MPS type II, raising awareness of the extent of heterogeneity in outcome reporting and determining the scope of outcomes and corresponding instruments currently used. The next step will be to use the generated "longlist" of outcomes to develop an electronic Delphi prioritization exercise with the intention of reaching a consensus regarding the most important outcomes to measure in effectiveness studies for head, neck, and respiratory disease in MPS type II.

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Abstract Alpha-mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequelae leading to intellectual disability, ataxia, impaired hearing and speech, recurrent infections, skeletal abnormalities, muscular pain, and weakness. This study aimed to investigate disability, pain, and overall health using the Childhood Health Assessment Questionnaire (CHAQ) and the EuroQol 5 Dimension-5 Level Questionnaire (EQ-5D-5L) in patients with alpha-mannosidosis participating in rhLAMAN-10, a phase III open-label, clinical trial of velmanase alfa, a recombinanthumanlysosomalalpha-mannosidase. Long-termprognosesformost patients withuntreatedalpha-mannosidosisarepoor due to progressive neuromuscular, skeletal, and intellectual deterioration, leading to increased dependence in mobility and activities of daily living and increased caregiver and health-care burden. Long-term CHAQ and EQ-5D-5L data highlight improvement trends in health-related quality of life and a reduction in disability and pain in patients receiving up to 48 months of velmanase alfa treatment.

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Abstract Mucopolysaccharidosis VI (MPS VI) is a progressive lysosomal storage disorder with multiorgan and multisystemic pathology. Currently, galsulfase enzyme replacement therapy (ERT) is the only approved treatment for MPS VI. A crosssectional survey study of 121 patients with MPS VI conducted in 2001 to 2002 and a 10-year follow-up study of the same patients (resurvey study; ClinicalTrials.gov NCT01387854) found that those receiving galsulfase at any time showed physical improvements and a lower mortality rate (16.5%) versus treatment-naive patients (50%). After *15 years, galsulfasetreated patients (n » 104) continue to have a survival advantage over treatment-naive patients (n » 14), as demonstrated by a 24% versus 57% mortality rate. This survival advantage is further supported by data from the commercial use of galsulfase (2005-2016), which show a 5-year mortality rate for galsulfase-treated patients of 12.5%. Together, these findings suggest that galsulfase ERT can increase life expectancies for patients with MPS VI over a period of at least 15 years.

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OBJECTIVE: To describe a form of progressive retinal atrophy (PRA) in Whippets including clinical, electroretinographic, optical coherence tomographic changes and pedigree analysis. ANIMALS STUDIED: Client-owned Whippet dogs (n = 51) living in Brazil. PROCEDURES: All animals were submitted for routine ophthalmic screening for presumed inherited ocular disease, which included the following: visual tests, such as obstacle course tests, in scotopic and photopic conditions, cotton ball test, dazzle reflex, ocular fundus evaluation by indirect ophthalmoscopy followed by fundus photography. Additionally, electroretinography (ERG) and optical coherence tomography (OCT) were performed in 24 and four dogs, respectively. RESULTS: Sixteen dogs were diagnosed with PRA. Vision deficits in dim light were detected in dogs examined at a young age associated with nystagmus. Funduscopic changes included the development of multifocal retinal bullae from 6 months of age. Retinal thinning became apparent later, at which time the bullae were no longer detected. OCT examination of selected young dogs revealed that the retinal bullae were due to separation between photoreceptors and the retinal pigment epithelium, and of dogs with more advanced disease confirmed the development of retinal thinning. Electroretinography in young dogs revealed a negative ERG due to a lack of b-wave in both scotopic and photopic recordings. With progression, the ERG became unrecordable. Pedigree analysis suggested an autosomal recessive mode of inheritance. CONCLUSION: The retinal dystrophy reported here in Whippet dogs has a unique phenotype of an initial lack of ERG b-wave, development of retinal bullae then a progressive generalized retinal degeneration.

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Abstract Patients with mucopolysaccharidosis (MPS), and Morquio A syndrome (MPS IVA) in particular, often report substantial pain burden. MOR-008 was a randomized, double-blind, pilot study assessing the safety and efficacy, including impact on patient-reported pain, of 52 weeks of treatment with elosulfase alfa (at a dose of 2.0 or 4.0 mg/kg/week) in patients with Morquio A syndrome (?7 years old). Assessment of pain at baseline revealed that patients (N = 25) had a mean number of pain locations of 5.7, mean pain intensity score of 4.6 (indicative of medium pain), and a mean number of selected pain descriptors of 7.4 words. Treatment with elosulfase alfa improved subjective pain score (reduced to 3.2), pain locations (reduced by a mean of 1 location), and pain descriptor words (reduced to 4.9 words) over 1 year (52 weeks), suggesting that elosulfase alfa can reduce pain in some patients with Morquio A.

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OBJECTIVE: To evaluate long-term outcomes of laronidase enzyme replacement therapy in patients with attenuated mucopolysaccharidosis type I. STUDY DESIGN: Retrospective analyses of case notes, laboratory results, and data from clinical trials were used to evaluate urinary glycosaminoglycans, forced vital capacity (FVC), 6-minute walk test (6MWT), height-for-age Z score, cardiac valve function, corneal clouding, and visual acuity in 35 patients with attenuated mucopolysaccharidosis type I (Hurler-Scheie and Scheie syndromes) for up to 10 years following the initiation of laronidase therapy. RESULTS: Statistically significant (P < .001) reductions in mean urinary glycosaminoglycan levels relative to baseline were observed 6 months after treatment initiation and were sustained throughout follow-up. Disease remained stable after treatment initiation with no statistically significant changes in mean FVC, 6MWT, or height-for-age Z score. At last assessments, mitral and aortic valve function remained stable in 65% (22/34) of patients; corneal clouding remained stable in 78% (18/23); visual acuity remained stable in 33% (8/24) and improved in 42% (10/24) of patients. Younger patients (<10 years at treatment initiation) maintained disease measures closer to norms for age for FVC, 6MWT, and height and showed fewer deteriorations in mitral and aortic valve disease and corneal clouding compared with patients aged ≥10 years at treatment initiation. CONCLUSION: Laronidase treatment resulted in disease stabilization in the majority of patients with a mean follow-up of 6.1 years. Data suggest that early treatment may result in better outcomes.

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OBJECTIVE: The purpose of this study was to investigate the inheritance and phenotype of retinal dysplasia (RD) in the American pit bull terrier. ANIMALS STUDIED: A breeding colony established from a single female pure-bred American pit bull terrier dog with RD. PROCEDURES: A female pure-bred American pit bull terrier with RD was donated to the Veterinary Hospital of Federal University of Paraná, Curitiba, Brazil. A breeding colony was established and the phenotype and inheritance of the condition investigated. Regular ophthalmic examinations and fundus photography were performed on three generations of offspring from the founder animal. Some animals were additionally studied by optical coherence tomography. Ocular histopathology was performed on some animals from the colony. RESULTS: Fifty-seven offspring were produced in two generations from the affected founder female. Thirty-two were diagnosed with RD and showed a spectrum of severity of lesions including multifocal, and or geographic lesions and some developed retinal detachment. Histologic examination demonstrated retinal folds, rosettes, and areas of retinal detachment. The affected dogs were shorter in stature than the unaffected littermates. Breeding studies suggested the trait has an autosomal dominant mode of inheritance. DNA testing showed that the affected dogs were negative for the known gene mutations for canine dwarfism with RD. CONCLUSION: This is a report of a novel inherited form of RD that affects American pit bull terriers.

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Abstract The mucopolysaccharidoses (MPSs) are a group of inherited, metabolic disorders characterized by progressive multisystem accumulation of partially degraded glycosaminoglycans. This manifests with multilevel airway obstruction, presenting with obstructive sleep apnea (OSA). We systematically reviewed the literature to determine the severity and prevalence of OSA in MPS based on polysomnography analysis. Fifteen studies with 294 participants met the inclusion criteria for review. The pretreatment prevalence of OSA in MPS was 81% with a mean apnea-hypopnea index (AHI) of 10.4. Patients with MPS I are most significantly affected, with 75% suffering with moderate to severe OSA (mean AHI, 16.6). Enzyme replacement therapy (ERT) results in an almost significant reduction in OSA in MPS I (P = .06), while adenotonsillar surgery significantly improves AHI (P = .002). Obstructive sleep apnea least affects MPS III. There is a lack of long-term post-ERT and hematopoietic stem cell transplant data relating to OSA outcomes in this population, with further prospective studies required to determine the ongoing response to treatment.

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The impacts of oocyte parasites on the reproductive success of molluscs are largely unknown. In this study, we evaluated the presence of gonad parasites in 6 species of marine bivalve molluscs native to southern Brazil. Cultured bivalves included the mangrove oyster Crassostrea gasar (sometimes called C. brasiliana), the brown mussel Perna perna, the lion's paw scallop Nodipecten nodosus and the wing pearl oyster Pteria hirundo. Another species of mangrove oyster, C. rhizophorae, and the carib pointed venus clam Anomalocardia brasiliana (syn. A. flexuosa) were collected from the wild. Molluscs were collected in winter 2009 and summer 2010 for histopathological and molecular evaluation. An unknown ovarian parasite (UOP) was observed in histopathological sections of female gonads of C. gasar and C. rhizophorae. The UOP possessed features suggestive of amoebae, including an irregular outer membrane, frothy cytoplasm, a nucleus with a prominent central nucleolus and a closely associated basophilic parasome. PCR analysis was negative for Marteilioides chungmuensis, Perkinsus spp. and Paramoeba perurans. However, real-time PCR successfully amplified DNA from oyster gonads when using universal Paramoeba spp. primers. Also, conventional PCR amplified DNA using primers specific for Perkinsela amoebae-like organisms (syn. Perkinsiella), which are considered as endosymbionts of Parameoba spp., previously thought to be the parasome. Our results suggest that this UOP is a species of amoeba belonging to 1 of the 2 families of the order Dactylopodida, possibly related to Paramoeba spp. This study represents the first report of this type of organism in oysters. We found that C. gasar and C. rhizophorae were the most susceptible molluscs to these UOPs.

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Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4-7-year-old baseline age group and by 16.8 cm in the 8-12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those ≥13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the ≥13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10-0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival.

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The discovery of new compounds active against Toxoplasma gondii is extremely important due to the severe disease caused by this pathogen in immunocompromised hosts and to congenital infection. Type II fatty acid biosynthesis has shown to be a promising target for drug intervention in toxoplasmosis. Here we describe the inhibitory effect of 8 thiolactomycin (TLM) analogues against tachyzoite-infected LLC-MK(2) cells. The TLM analogues demonstrated anti-T. gondii activity, arresting tachyzoite proliferation with IC(50) values in the micromolar level after 24 h and 48 h of treatment. Metabolic labelling of extracellular parasites treated with TLM analogues using [(3)H]acetate demonstrated that these drugs affected acylglycerol synthesis. The rapid reduction of parasite load suggests that these compounds have selective cytotoxic effects against T. gondii. Transmission electron microscopy demonstrated that TLM analogues interfered with membrane-bounded organelles and parasite division and this in turn affected parasite development and survival.

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We describe the use of enzyme replacement therapy in conjunction with hematopoietic stem cell transplantation in 18 consecutive patients with severe mucopolysaccharidosis type I. The survival and engraftment rate was 89% overall and 93% for the 15 patients who received full-intensity conditioning.

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