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Mucopolysaccharidosis type II (MPS II) is an X-linked inherited disease caused by pathogenic variants in the IDS gene, leading to deficiency of the lysosomal enzyme iduronate-2-sulfatase and consequent widespread storage of glycosaminoglycans, leading to several clinical consequences, with progressive manifestations which most times includes cognitive decline. MPS II has wide allelic and clinical heterogeneity and a complex genotype-phenotype correlation. We evaluated data from 501 Brazilian patients diagnosed with MPS II from 1982 to 2020. We genotyped 280 of these patients (55.9%), which were assigned to 206 different families. Point mutations were present in 70% of our patients, being missense variants the most frequent. We correlated the IDS pathogenic variants identified with the phenotype (neuronophatic or non-neuronopathic). Except for two half-brothers, there was no discordance in the genotype-phenotype correlation among family members, nor among MPS II patients from different families with the same single base-pair substitution variant. Mothers were carriers in 82.0% of the cases. This comprehensive study of the molecular profile of the MPS II cases in Brazil sheds light on the genotype-phenotype correlation and helps the better understanding of the disease and the prediction of its clinical course, enabling the provision of a more refined genetic counseling to the affected families.

Background Morquio B disease (MBD) is a distinct GLB1‐related dysostosis multiplex presenting a mild phenocopy of GALNS‐related Morquio A disease. Previously reported cases from European countries carry the W273L variant on at least one GLB1 allele and exhibit a pure skeletal phenotype (pure MBD). Only a minority of MBD cases have been described with additional neuronopathic findings (MBD plus). Objectives and Methods With the aim to further describe patterns of MBD‐related dysostosis multiplex, we analyzed clinical, biochemical, and genetic features in 17 cases with GLB1‐related dysostosis multiplex living and diagnosed in Brazil. Results About 14 of the 17 individuals had three or more skeletal findings characteristic of Morquio syndrome. Two had no additional neuronopathic features (pure MBD) and 12 exhibited additional neuronopathic features (MBD plus). Three of the 17 cases had mild dysostosis without distinct features of MBD. Seven of the 12 MBD plus patients had signs of spinal cord compression (SCC), as a result of progressive spinal vertebral dysostosis. There was an age‐dependent increase in the number of skeletal findings and in the severity of growth impairment. GLB1 mutation analysis was completed in 10 of the 14 MBD patients. T500A occurred in compound heterozygosity in 8 of the 19 alleles. Conclusion Our study extends the phenotypic spectrum of GLB1‐related conditions by describing a cohort of patients with MBD and GM1‐gangliosidosis (MBD plus). Targeting the progressive nature of the skeletal manifestations in the development of new therapies for GLB1‐related conditions is warranted.

The COVID‐19 pandemic has led to a reorganization of health systems to prioritize the fight against the virus. The adoption of social distancing interfered with the flow of existing policies, and may thus negatively affect the most vulnerable groups, such as the rare disease community. Aimming at characterizing the perception of the impact of COVID‐19 on the health care of the Brazilian rare disease community, an online questionnaire addressed to patients with rare diseases and their caregivers was disseminated in the Brazilian territory between June 1st to July 5th, 2020. The questions dealt with the sanitary measures adopted; access to medical services; and mental suffering during the pandemic. The survey was answered by 1,466 participants (

Aim Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, leading to progressive deterioration of neurological functions commonly occurring in children aged 2-4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes. Methods Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in Sao Paulo, Brazil, in October 2018. Results Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified. Conclusion Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy.

Objectives: To characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. Method: Observational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age = 36 months, 25–75 IQR = 10–108; males = 810) submitted to the TfIEF test during the period were reviewed. Results: Fifty-one individuals (3%) had an altered TfIEF pattern (5 ± 2.8 cases/year; median age = 24 months, 25–75 IQR = 11–57 months; males = 27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia = 4; hereditary fructose intolerance = 4; peroxisomal diseases = 2; PMM2-CDG = 2; MPDU1-CDG = 1; SLC35A2-CDG = 1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. Conclusions: The data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation. Resumo Objetivos: Caracterizar os casos com suspeita de CDG investigados em laboratório do sul do Brasil pelo exame de IEFTF de 2008 a 2017. Metodologia: Estudo observacional, transversal, retrospectivo. Foram revisadas as fichas laboratoriais de 1.546 indivíduos (mediana de idade = 36 meses, IQ 25-75 = 10-108; sexo masculino = 810) que fizeram o exame de IEFTF no período. Resultados: Cinquenta e um indivíduos (3%) apresentaram padrão alterado na IEFTF (5 ± 2,8 casos/ano; mediana de idade = 24 meses, IQ 25-75 = 11-57 meses; sexo masculino = 27, 53%). Para 14 deles, estavam disponíveis dados sobre a conclusão do diagnóstico (galactosemia clássica = 4; intolerância hereditária à frutose = 4; doenças peroxissomais = 2; PMM2-CDG = 2; MPDU1-CDG = 1; SLC35A2-CDG = 1). Comparando os casos com padrão normal e alterado na IEFTF, houve maior prevalência de casos alterados na faixa etária de 11 meses a 3 anos. Verificou-se um aumento na probabilidade de alteração na IEFTF principalmente na presença de mamilos invertidos ou de hepatopatia. Conclusões: Os nossos dados sugerem que a investigação de um caso com suspeita de CDG é complexa, é agravada pela existência de outros EIM associados a padrão alterado na IEFTF e pela falta de acesso a exames confirmatórios. A presença principalmente de mamilos invertidos e de hepatopatia em indivíduos na faixa etária de 11 meses a 3 anos deve sugerir a necessidade de investigação por IEFTF.

Mucopolysaccharidosis type IIIB is a rare autosomal recessive disorder characterized by deficiency of the enzyme N-acetyl-alpha-d-glucosaminidase (NAGLU), caused by biallelic pathogenic variants in the NAGLU gene, which leads to storage of heparan sulfate and a series of clinical consequences which hallmark is neurodegeneration. In this study clinical, epidemiological, and biochemical data were obtained from MPS IIIB patients diagnosed from 2004-2019 by the MPS Brazil Network ("Rede MPS Brasil"), which was created with the goal to provide an easily accessible and comprehensive investigation of all MPS types. One hundred and ten MPS IIIB patients were diagnosed during this period. Mean age at diagnosis was 10.9 years. Patients were from all over Brazil, with a few from abroad, with a possible cluster of MPS IIIB identified in Ecuador. All patients had increased urinary levels of glycosaminoglycans and low NAGLU activity in blood. Main clinical symptoms reported at diagnosis were coarse facies and neurocognitive regression. The most common variant was p.Leu496Pro (30% of alleles). MPS IIIB seems to be relatively frequent in Brazil, but patients are diagnosed later than in other countries, and reasons for that probably include the limited awareness about the disease by health professionals and the difficulties to access diagnostic tests, factors that the MPS Brazil Network is trying to mitigate.

The association between bone mineral density (BMD) and hepatic glycogen storage diseases (GSDs) is still unclear. To evaluate the BMD of patients with GSD I, IIIa and IXα, a cross-sectional study was performed, including 23 patients (GSD Ia = 13, Ib = 5, IIIa = 2 and IXα = 3, median age = 11.9 years, IQ = 10.9–20.1) who underwent a dual-energy X-ray absorptiometry (DXA). Osteocalcin (OC, n = 18), procollagen type 1 N-terminal propeptide (P1NP, n = 19), collagen type 1 C-terminal telopeptide (CTX, n = 18) and 25-OH Vitamin D (n = 23) were also measured. The participants completed a 3-day food diary (n = 20). Low BMD was defined as a Z-score ≤ −2.0. All participants were receiving uncooked cornstarch (median dosage = 6.3 g/kg/day) at inclusion, and 11 (47.8%) presented good metabolic control. Three (13%) patients (GSD Ia = 1, with poor metabolic control, IIIa = 2, both with high CPK levels) had a BMD ≤ −2.0. CTX, OC and P1NP correlated negatively with body weight and age. 25-OH Vitamin D concentration was decreased in seven (30.4%) patients. Our data suggest that patients with hepatic GSDs may have low BMD, especially in the presence of muscular involvement and poor metabolic control. Systematic nutritional monitoring of these patients is essential.

Background Glycogen storage disease type 1a (GSD Ia) is characterized by severe fasting hypoglycemia. The clinical management includes the administration of uncooked cornstarch (UCCS). Although such a diet approach is effective in achieving euglycemia, its impact on the quality of life of patients should be considered. In vitro analyses suggest a longer release of glucose when using sweet manioc starch (SMS). Methods We compared the efficacy and safety of the administration of SMS and UCCS during a short-fasting challenge in patients with GSD Ia in a randomized, triple-blind, phase I/II, cross-over study. GSD Ia patients aged ≥ 16 years and treated with UCCS were enrolled. Participants were hospitalized for two consecutive nights, receiving UCCS or SMS in each night. After the administration of the starches, glucose, lactate and insulin levels were measured in 1-h interval throughout the hospitalization period. The procedures were interrupted after 10 h of fasting or in a hypoglycemic episode ( Results Eleven individuals (mean age: 21.6 ± 4.3 years; all presenting body mass index > 25 kg/m2) participated in the study. The average fasting period was 8.2 ± 2.0 h for SMS and 7.7 ± 2.3 h for UCCS (p = 0.04). SMS maintained euglycemia for a greater period over UCCS. Increased lactate concentrations were detected even in absence of hypoglycemia, not being influenced by the different starches investigated (p = 0.17). No significant difference was found in total cholesterol, HDL, triglycerides and uric acid levels in both arms. None of the patients showed severe adverse events. Conclusions SMS appears to be non-inferior to UCCS in the maintenance of euglycemia, thus emerging as a promising alternative to the treatment of GSD Ia.

GM1 gangliosidosis is a lysosomal storage disorder caused by β‐galactosidase deficiency. To date, prospective studies for GM1 gangliosidosis are not available, and only a few have focused on the adult form. This retrospective cross‐sectional study focused on clinical findings in Brazilian patients with the adult form of GM1 gangliosidosis collected over 2 years. Ten subjects were included in the study. Eight were males and two females, with median age at diagnosis of 11.5 years (IQR, 4‐34 years). Short stature and weight below normal were seen in five out of the six patients with data available. Radiological findings revealed that the most frequent skeletal abnormalities were beaked vertebrae, followed by hip dysplasia, and platyspondyly. Neurological examination revealed that dystonia and swallowing problems were the most frequently reported. None of the patients presented hyperkinesia, truncal hypertonia, Parkinsonism, or spinal cord compression. Clinical evaluation revealed impairment in activities of cognitive/intellectual development and behavioral/psychiatric disorders in all nine subjects with data available. Language/speech impairment (dysarthria) was found in 8/9 patients, fine motor and gross motor impairments were reported in 7/9 and 5/9 patients, respectively. Impairment of cognition and daily life activities were seen in 7/9 individuals. Our findings failed to clearly identify typical early or late alterations presented in GM1 gangliosidosis patients, which confirms that it is a very heterogeneous condition with wide phenotypic variability. This should be taken into account in the evaluation of future therapies for this challenging condition.

Background Mucopolysaccharidoses (MPS) is a group of hereditary multisystemic lysosomal disorders. Most neuroimaging studies in MPS have focused on the supratentorial compartment and craniocervical junction abnormalities, and data regarding posterior fossa findings are scarce in the literature. Thus, our purpose is to describe posterior fossa findings on magnetic resonance imaging (MRI) of MPS patients. Methods We reviewed routine MRI scans of MPS patients being followed up at our institution (types I, II, III, IV, and VI), focusing on posterior fossa structures. Results Forty‐seven MPS patients were included. MRI‐visible perivascular spaces were commonly found in the midbrain and adjacent to the dentate nuclei (85% and 55% of patients, respectively). White‐matter lesion was not identified in most cases. Its most frequent localizations were in the pons and cerebellum (34% and 30% of patients, respectively). Enlargement of cerebrospinal fluid (CSF) spaces in the posterior fossa was present in 55% of individuals and was more frequent in neuronopathic patients (73% vs 40%; P = .02). Cerebellar volume was classified as normal, apparent macrocerebellum, atrophic, and hypoplastic in 38%, 38%, 21%, and 3% of patients, respectively. A depression of the posterior fossa floor in the midline sagittal plane was found in 22 patients (47%), which was statistical significantly associated with enlargement of CSF spaces (P = .02) and with apparent macrocerebellum (P = .03). Conclusion The present study compiled the main posterior fossa findings in MPS patients. Classically described in the supratentorial compartment, MRI‐visible perivascular spaces, white matter lesions, and enlarged perivascular spaces were also found in the posterior fossa. However, atrophy, which commonly affects cerebral hemispheres, was not the most frequent cerebellar morphology found in our study. Moreover, potential findings for future research were described.

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.

Classic homocystinuria (HCU), or cystathionine beta-synthase (CBS) deficiency, is a rare inborn error of methionine metabolism. Main clinical features may include skeletal and vascular manifestations, developmental delay, intellectual disability and eye disorders.This is an observational and retrospective study aiming at describing eye abnormalities presented by a cohort of late-diagnosed HCU patients. Data regarding ophthalmological evaluation included visual acuity, refraction, biomicroscopy, Perkins tonometry, fundus examination, retinography, biometry, ocular ultrasound, optical coherence tomography, anterior segment photography and topography.Ten patients with HCU (20 eyes) were included. The most frequent findings wereEye abnormalities are very frequent in late-diagnosed HCU patients. The presence of

Precision medicine (PM) is an emerging approach for disease treatment and prevention that accounts for the individual variability in the genes, environment, and lifestyle of each person. Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately 70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primary lysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzyme activators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and the phenotype of the affected individual depends on the type of substrate and where it accumulates, which may be impacted by the type of genetic change and residual enzymatic activity. LDs are individually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapies are already available for several LDs, and many more are in development. Early identification may enable disease course prediction and a specific intervention, which is very important for clinical outcome. Driven by advances in omics technology, PM aims to provide the most appropriate management for each patient based on the disease susceptibility or treatment response predictions for specific subgroups. In this review, we focused on the emerging diagnostic technologies that may help to optimize the management of each LD patient and the therapeutic options available, as well as in clinical developments that enable customized approaches to be selected for each subject, according to the principles of PM.

Mucopolysaccharidoses (MPS) are inborn errors of metabolism caused by deficient lysosomal enzymes, leading to organomegaly, hip osteonecrosis, coarse facial features, bone deformities, joint stiffness, cardiac and pulmonary symptoms (MPS VI) or hypermobility (MPS IVA). Some patients may present with non-classical forms of the disease in which osteoarticular abnormalities are the initial symptoms of non-classical forms. As orthopedists and surgeons are the specialists most frequently consulted before the diagnosis, it is critical that MPS may be considered as a differential diagnosis for patients with bone dysplasia. Experts in Latin America reviewed medical records focusing on disease onset, first symptoms and the follow-up clinical and surgical outcomes of non-classical MPS VI and IVA patients. All patients displayed orthopedic issues, which worsened over time, followed by cardiac and ophthalmological abnormalities. Our findings enlighten the necessity of including non-classical MPS as possible diagnosis for patients who report osteoarticular abnormalities in absence of inflammation.

Introduction Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders.Methods: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD.Results: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/ 774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol.Conclusions: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.

Mucopolysaccharidoses (MPS) are disorders characterized by impaired glycosaminoglycan (GAG) catabolism as a consequence of a deficiency or the absence of lysosomal enzymes directly involved in their degradation. Multiple organ systems are involved in MPS, including the cardiovascular system. Recently, aortic root dilatation (ARD) has been described in these patients. Thus, we reviewed aortic root diameter measurements in 69 MPS patients from a single center from 2000 to 2016. Aortic root diameter z scores were calculated based on data published by Colan et al. according to the body surface area (BSA) determined using the Haycock formula. The overall incidence of ARD in MPS patients was 39.1%. Higher mean z scores were present in patients with MPS IVA and VI when compared to MPS I and II. Aortic root z scores were higher in older MPS IVA patients, which may suggest a progressive ARD change in this MPS type. No significant differences were found before and after enzyme replacement therapy (ERT) in 11 patients with available data (2 with MPS I; 4 with MPS II; 2 with MPS IVA, and 3 with MPS VI). This work provides further evidence that ARD is common in different types of MPS, being especially evident in MPS IVA, but with a significant occurrence also in MPS VI.

Recent studies have shown that patients with phenylketonuria (PKU), even with the early diagnosis and continuous treatment, may have symptoms of attention-deficit hyperactivity disorder (ADHD) and that the prevalence of ADHD in this population would be higher than in the general population. This study aims to determine the prevalence of ADHD in a sample of PKU patients from Southern Brazil. Patients were prospectively assessed by clinical interviews, neurological examination, and application of the MTA-SNAP-IV scales for patients aged 5–17 years and the Adult Self-Report Scale for patients over 17 years. Thirty-one patients (mean age = 17.4; early diagnosis = 27) were followed. Patients with ADHD and younger than 17 years had a median Phe in the last 6 months of life higher than those without the diagnosis of ADHD (ADHD patients = 617.1 µmol/L, no-ADHD patients 393.2 µmol/L, and p = 0.03). There was a predominantly hyperactive/impulsivity clinical presentation of ADHD (n = 4/5 patients), which differs from that reported elsewhere in the literature. Future studies are essential to better define the clinical presentation of ADHD in these patients and further elucidate its pathophysiology.

Although hyperinsulinism is the predominant inherited cause of hypoglycemia in the newborn period, inborn errors of metabolism are the primary etiologies after 1 month of age. Disorders of carbohydrate metabolism often present with hypoglycemia when fasting occurs. The presentation, diagnosis, and management of the hepatic glycogen storage diseases and disorders of gluconeogenesis are reviewed.

Lysosomal storage diseases (LSDs) are genetic disorders, clinically heterogeneous, mainly caused by defects in genes encoding lysosomal enzymes that degrade macromolecules. Several LSDs already have specific therapies that may improve clinical outcomes, especially if introduced early in life. With this aim, screening methods have been established and newborn screening (NBS) for some LSDs has been developed. Such programs should include additional procedures for the confirmation (or not) of the cases that had an abnormal result in the initial screening. We present here the methods and results of the additional investigation performed in four babies with positive initial screening results in a program of NBS for LSDs performed by a private laboratory in over 10,000 newborns in Brazil. The suspicion in these cases was of Mucopolysaccharidosis I - MPS I (in two babies), Pompe disease and Gaucher disease (one baby each). One case of pseudodeficiency for MPS I, 1 carrier for MPS I, 1 case of pseudodeficiency for Pompe disease and 1 carrier for Gaucher disease were identified. This report illustrates the challenges that may be encountered by NBS programs for LSDs, and the need of a comprehensive protocol for the rapid and precise investigation of the babies who have an abnormal screening result.

Background Very little is known about the incidence and prevalence of hydrocephalus in patients with mucopolysaccharidoses (MPS). The biggest challenge is to distinguish communicating hydrocephalus from ventricular dilatation secondary to brain atrophy, because both conditions share common clinical and neuroradiological features. The main purpose of this study is to assess the relationship between ventriculomegaly, brain and cerebrospinal fluid (CSF) volumes, aqueductal and cervical CSF flows, and CSF opening pressure in MPS patients, and to provide potential biomarkers for abnormal CSF circulation. Methods Forty-three MPS patients (12 MPS I, 15 MPS II, 5 MPS III, 9 MPS IV A and 2 MPS VI) performed clinical and developmental tests, and T1, T2, FLAIR and phase-contrast magnetic resonance imaging (MRI) followed by a lumbar puncture with the CSF opening pressure assessment. For the analysis of MRI variables, we measured the brain and CSF volumes, white matter (WM) lesion load, Evans’ index, third ventricle width, callosal angle, dilated perivascular spaces (PVS), craniocervical junction stenosis, aqueductal and cervical CSF stroke volumes, and CSF glycosaminoglycans concentration. Results All the scores used to assess the supratentorial ventricles enlargement and the ventricular CSF volume presented a moderate correlation with the aqueductal CSF stroke volume (ACSV). The CSF opening pressure did not correlate either with the three measures of ventriculomegaly, or the ventricular CSF volume, or with the ACSV. Dilated PVS showed a significant association with the ventriculomegaly, ventricular CSF volume and elevated ACSV. Conclusions In MPS patients ventriculomegaly is associated with a severe phenotype, increased cognitive decline, WM lesion severity and enlarged PVS. The authors have shown that there are associations between CSF flow measurements and measurements related to CSF volumetrics. There was also an association of volumetric measurements with the degree of dilated PVS.

The precise incidence of hydrocephalus in patients with mucopolysaccharidoses (MPS) is hard to determine, because the condition lacks a formal, consensus-based definition. The diagnosis of hydrocephalus depends on symptom profile, presence of neuroimaging features, and the outcome of diagnostic tests. Although numerous techniques are used to identify MPS patients who are most likely to have hydrocephalus and respond to treatment, no definitive method exists to prove diagnosis. The authors propose an algorithm to aid in the diagnosis and management of hydrocephalus in MPS patients. The theory of venous hypertension associated with the morphological changes in the skull base and craniocervical junction indicate the need for future neuroimaging studies including cerebrospinal fluid (CSF) and venous flow measurements to monitor hydrocephalus progression and select therapeutic interventions in MPS patients. Preoperative planning should also be based on the increased risk of intraoperative and postoperative hemorrhagic complications.

Pathogenic variants in GNB5 cause an autosomal recessive neurodevelopmental disorder with neonatal sinus bradycardia. Seizures or epilepsy occurred in 10 of 22 previously reported cases, including 6 children from one family. We delineate the epileptology of GNB5 encephalopathy. Our nine patients, including five new patients, were from seven families. Epileptic spasms were the most frequent seizure type, occurring in eight of nine patients, and began at a median age of 3 months (2 months to 3 years). Focal seizures preceded spasms in three children, with onset at 7 days, 11 days, and 4 months. One child presented with convulsive status epilepticus at 6 months. Three children had burst suppression on electroencephalography (EEG), three had hypsarrhythmia, and one evolved from burst suppression to hypsarrhythmia. Background slowing was present in all after age 3 years. Magnetic resonance imaging (MRI) showed cerebral atrophy in one child and cerebellar atrophy in another. All nine had abnormal development prior to seizure onset and ultimately had profound impairment without regression. Hypotonia was present in all, with contractures developing in two older patients. All individuals had biallelic pathogenic variants in GNB5, predicted by in silico tools to result in protein truncation and loss-of-function. GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment. Wiley Periodicals, Inc. © 2019 International League Against Epilepsy

Background Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency, resulting in accumulation of glycosaminoglycans (GAG). Ophthalmological manifestations are common in MPS I patients and often lead to visual impairment. Accumulation of GAG in corneal or retinal tissues reduces vision causing corneal opacity and neurosensory complications. One available treatment for MPS I patients is enzyme replacement therapy (ERT), but the results of such treatment on eye disease are still debatable. Therefore, we aimed to determine the progression of ocular manifestations as well as the effectiveness of intravenous ERT in MPS I. Methods Corneal and retinal analyses were perform in eyes from 2- to 8-month normal and MPS I mice. Some MPS I mice received ERT (1.2 mg/kg of laronidase) every 2 weeks from 6 to 8 months and histological findings were compared with controls. Additionally, cornea from two MPS I patients under ERT were evaluated. Results Mouse corneal tissues had GAG accumulation early in life. In the retina, we found a progressive loss of photoreceptor cells, starting at 6 months. ERT did not improve or stabilize the histological abnormalities. MPS I patients, despite being on ERT for over a decade, presented GAG accumulation in the cornea, corneal thickening, visual loss and needed corneal transplantation. Conclusion We provide data on the time course of ocular alteration in MPS I mice. Our results also suggest that ERT is not effective in treating the progressive ocular manifestations in MPS I mice and fails to prevent corneal abnormalities in patients.

Mucopolysaccharidosis type VI (MPS VI) is a clinically heterogeneous lysosomal disease, which can be divided into 2 main categories on the basis of age of onset and severity of symptoms. The diagnosis of the attenuated form is often delayed given subtle facial features rather than the typical coarse facial features of the classic form. Here, we discuss the difficulties in establishing the diagnosis of MPS VI on the basis of the report of 4 individuals. The most common signs and symptoms in our series were bone abnormalities and hip pain as initial manifestations and cardiac changes detected after follow-up studies. On the basis of our cohort and others worldwide, awareness of attenuated forms of MPS VI should be increased particularly among general practitioners, pediatricians, rheumatologists, orthopedists, ophthalmologists, and cardiologists. Moreover, these health care providers should be aware of the technical aspects involved in the molecular and biochemical diagnosis process so that they are aware how diagnostic errors may occur.

Mucopolysaccharidosis (MPS) is an inherited metabolic disease and a member of the group of lysosomal storage disorders. Its hallmark is a deficiency of lysosomal enzymes involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). The products of GAG degradation accumulate within lysosomes and in the extracellular space, thereby interfering with the degradation of other macromolecules. This process leads to chronic degeneration of cells, which in turn affects multiple organs and systems. There are seven distinct types of MPS (I, II, III, IV, VI, VII, and IX), which are divided into subtypes according to the deficient enzyme and the severity of the clinical picture. Although clinical manifestations vary considerably among the different types of MPS, the central nervous system (CNS) is characteristically affected, and magnetic resonance (MR) imaging is the method of choice to evaluate brain and spinal cord abnormalities. Enlarged perivascular spaces, white matter lesions, hydrocephalus, brain atrophy, cervical spinal canal stenosis with or without spinal cord compression and myelopathy, and bone abnormalities in the skull and spine (dysostosis multiplex) are typical imaging findings described in the literature and reviewed in this article. The differential diagnosis of MPS is limited because the constellation of imaging findings is highly suggestive. Thus, radiologists should be aware of its typical neuroimaging findings so they can recognize cases not yet diagnosed, exclude other metabolic diseases, monitor CNS findings over time, and assess treatment response. (©)RSNA, 2016.

Hepatic glycogen storage diseases (GSDs) are inborn errors of metabolism whose dietary treatment involves uncooked cornstarch administration and restriction of simple carbohydrate intake. The prevalence of feeding difficulties (FDs) and orofacial myofunctional disorders (OMDs) in these patients is unknown. Objective: To ascertain the prevalence of FDs and OMDs in GSD. Methods: This was a cross-sectional, prospective study of 36 patients (19 males; median age, 12.0 years; range, 8.0–18.7 years) with confirmed diagnoses of GSD (type Ia = 22; Ib = 8; III = 2; IXa = 3; IXc = 1). All patients were being treated by medical geneticists and dietitians. Evaluation included a questionnaire for evaluation of feeding behavior, the orofacial myofunctional evaluation (AMIOFE), olfactory and taste performance (Sniffin’ Sticks and Taste Strips tests), and facial anthropometry. Results: Nine (25%) patients had decreased olfactory perception, and four (11%) had decreased taste perception for all flavours. Eight patients (22.2%) had decreased perception for sour taste. Twenty-six patients (72.2%) had FD, and 18 (50%) had OMD. OMD was significantly associated with FD, tube feeding, selective intake, preference for fluid and semisolid foods, and mealtime stress (p < 0.05). Thirteen patients (36.1%) exhibited mouth or oronasal breathing, which was significantly associated with selective intake (p = 0.011) and not eating together with the rest of the family (p = 0.041). Lower swallowing and chewing scores were associated with FD and with specific issues related to eating behavior (p < 0.05). Conclusion: There is a high prevalence of FDs and OMDs in patients with GSD. Eating behavior, decreased taste and smell perception, and orofacial myofunctional issues are associated with GSD.

A 10-year-old female patient was brought to the outpatient clinic with a history of neurodevelopmental delay, gait and limb incoordination, and oculomotor apraxia. According to her parents, the girl had always showed delayed acquisition of motor milestones when compared to other children, which became more evident when she was 8 months old and was not able to sit. She was able to sit by age of 2, and walked independently, but unsteady, when she was 3.5 years old. She presented with cognitive impairment. Reviewing her history, it became clear that she was hypotonic at birth and subsequently developed gait ataxia in early childhood. She was born to nonconsanguineous parents and there were no other similar cases in her family. On physical examination, she held her head preferentially in a lateralized position to her right side. She showed gait ataxia in tandem walking, abnormal stance with a positive Romberg’s sign, dysmetria, dysdiadochokinesia, diffuse hyperreflexia, bilateral Babinski sign, and oculomotor apraxia. The Wechsler Intelligence Scale for Children-III (WISC-III) demonstrated an IQ of 67 (intellectual disability). There were no other abnormalities on physical examination. Electroencephalogram showed focal paroxysmal discharges of moderate intensity in the posterior parietal-temporal region. Brain magnetic resonance imaging (MRI) demonstrated agenesis of the cerebellar vermis with a slit in the medial line sparing the two cerebellar hemispheres (Figure 1), lengthening and thickening of the cerebellar peduncles, associated with reduction of the anteroposterior diameter of the mesencephalon, the so-called “molar tooth sign” (MTS) (Figure 2). Morphological alterations in the posterior fossa showed a 4th ventricle with a typical “bat wing” appearance (Figure 3). These findings were highly suggestive of Joubert syndrome (JS).

Purpose: Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood–brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age. Methods: Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. Results: Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. Conclusion: As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.

The mucopolysaccharidosis (MPS) constitutes a heterogeneous group of rare genetic disorders caused by enzymatic deficiencies that lead to the accumulation of glycosaminoglycans. Several types of MPS are described, historically numbered from I to IX. Clinical observations strongly suggest the presence of chronic pain in patients with all types of MPS. There are few data in the literature on the evaluation and management of pain in these patients, a fact that can compromise the quality of life even more. Professionals with extensive experience in the care for patients with MPS held a meeting in April 2017 to discuss and propose recommendations for the evaluation and management of pain in patients with MPS in Latin America. This article summarizes the content of the discussions and presents the recommendations produced at the meeting. Patients with MPS present joint, bone, and muscle pain, as well as entrapment syndromes (spinal, optic nerve, carpal tunnel). The panel suggests the use of the following instruments for pain assessment: Face, Legs, Activity, Cry and Consolability Scale for children of up to four years of age and patients unable to communicate their pain; Child Health Assessment Questionnaire Scale; Facial Pain Scale and Numerical Pain Scale for patients of five to18 years of age; Brief Pain Inventory and Short Form Health Survey 36 scales for patients aged 18 years or older. Based on the scores verified in these scales, the panel proposes pharmacological interventions for pain relief in this population of patients.

Enzyme replacement therapy for mucopolysaccharidosis II (MPS II) with Idursulfase (ElapraseR) has proven effective in reducing urinary glycosaminoglycan (uGAG) levels, liver and spleen volumes and in increasing walking distance. During phase II/III studies, 0.5mg/kg every other week (EOW) showed effectiveness in combined outcomes (6-minute walk test - 6MWT, pulmonary function and uGAG reduction), although some were not significantly effective when individually analyzed. A weekly 1.5mg/kg dose was tested in 4 patients for 48weeks and proven safe (Muenzer et al, 2007). Double dose EOW infusions was considered an acceptable treatment option in MPS I in a dose study (Giugliani et al, 2009) and proven safe and effective in 20 patients (Horovitz et al., 2016). Such data might suggest that double dose Idursulfase every other week infusions for MPS II might also be effective. A dose of 1mg/kg EOW substituted the recommended weekly dose in seven MPS II patients in three different centers in Brazil. Patients had to be under enzyme replacement therapy with Idursulfase for at least one year without adverse events. Before switching to EOW thorough clinical examination, 4 week uGAG collection, and additional evaluations (echocardiogram, endurance tests, pulmonary function studies, abdominal ultrasound and quality of life questionnaires) were performed whenever possible. Upon completion of 48 weeks under EOW intravenous infusions of 1mg/kg of ERT evaluations were repeated. Six patients completed 48 weeks on EOW one patient died from acute complications of cardiac surgery after 4 months under the protocol. No infusion-associated adverse events were observed. uGAG evaluated regularly showed stable excretion, similar to when receiving the weekly dose. Patients were well and families very satisfied with the new dosing regimen repeated evaluations after one year on EOW therapy showed no difference when compared to the previous dose. Most patients chose to continue with the EOW regimen after the protocol.

Objective: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. Methods: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. Results: Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57–7). Median age at onset of symptoms was 10 days (IQR 5–30), whereas median age at diagnosis was 60 days (IQR 29–240, p = 0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n = 12) and without (n = 71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. Conclusion: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country. Resumo: Objetivo: Caracterizar uma amostra de pacientes brasileiros com a doença da urina de xarope de bordo (DXB) diagnosticados entre 1992 e 2011. Métodos: Neste estudo retrospectivo, os pacientes foram identificados por meio de um laboratório de referência nacional para o diagnóstico de DXB e por meio do contato com outros serviços de genética médica no Brasil. Os dados foram coletados por meio de uma revisão de prontuários. Resultados: 83 pacientes de 75 famílias foram incluídos no estudo (idade média: 3 anos; intervalo interquartil (IQR): 0,57-7). A idade média no surgimento dos sintomas era de 10 dias (IQR: 5-30), ao passo que a idade média no diagnóstico era de 60 dias (IQR: 29-240; p = 0,001). Somente três (3,6%) pacientes foram diagnosticados antes do surgimento de manifestações clínicas. Uma comparação entre pacientes com (n = 12) e sem (n = 71) um diagnóstico precoce mostra que o diagnóstico precoce está associado à presença de histórico familiar positivo e à redução na prevalência de manifestações clínicas no momento do diagnóstico, porém sem melhor resultado. Em geral, 98,8% dos pacientes têm algum atraso no desenvolvimento psicomotor ou neurológico. Conclusão: No Brasil, os pacientes com DXB normalmente recebem um diagnóstico tardio e exibem um envolvimento neurológico e baixa sobrevivência, mesmo com um diagnóstico precoce. Sugerimos que políticas públicas específicas para o diagnóstico e tratamento da DXB sejam desenvolvidas e implementadas no país. Keywords: Maple syrup urine disease, MSUD, Inborn errors of metabolism, Diagnosis, Palavras-chave: Doença da urina de xarope de bordo, DXB, Erros inatos do metabolismo, Diagnóstico

In this article, the genotype-MR phenotype correlation of the most common or clinically important inherited metabolic diseases (IMD) in the pediatric population is reviewed. A nonsystematic search of the PubMed/Medline database of relevant studies about "genotype-phenotype correlation" in IMD was performed. Some MR phenotypes related to specific gene mutations were found, such as bilateral hypertrophy of inferior olives in patients harboring POLG and SURF1 mutations, and central lesions in the cervical spinal cord in patients with nonketotic hyperglycinemia harboring GLRX5 gene mutation.

Introduction: Hunter syndrome (Mucopolysaccharidosis II, MPS II) is a lysosomal storage disease inherited as an X-linked trait. The disease is progressive, affects multiple systems and is clinically heterogeneous. Patients with the so-called ‘attenuated’ form have somatic manifestations affecting bone, joints, respiratory, cardiac, auditory and other systems. Patients with the ‘severe form’ have, in addition to the somatic manifestations, neurocognitive decline. Areas covered: Diagnosis is reached with biochemical tests (urinary glycosaminoglycans [GAGs] and enzyme assay), usually complemented with genetic analysis. Mutation identification could play a role in phenotype prediction and could help to identify carriers, which is very important in an X-linked disease. Specific treatment with enzyme replacement therapy (ERT) became available few years ago and improved significantly the natural course of the disease. However, treatment with intravenous ERT has limitations, and the possibility of alternative the...

Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects branched-chain amino acid (BCAA) catabolism and is associated with acute and chronic brain dysfunction. Recent studies have shown that inflammation may be involved in the neuropathology of MSUD. However, these studies have mainly focused on single or small subsets of proteins or molecules. Here we performed a case-control study, including 12 treated-MSUD patients, in order to investigate the plasmatic biomarkers of inflammation, to help to establish a possible relationship between these biomarkers and the disease. Our results showed that MSUD patients in treatment with restricted protein diets have high levels of pro-inflammatory cytokines [IFN-γ, TNF-α, IL-1β and IL-6] and cell adhesion molecules [sICAM-1 and sVCAM-1] compared to the control group. However, no significant alterations were found in the levels of IL-2, IL-4, IL-5, IL-7, IL-8, and IL-10 between healthy controls and MSUD patients. Moreover, we found a positive correlation between number of metabolic crisis and IL-1β levels and sICAM-1 in MSUD patients. In conclusion, our findings in plasma of patients with MSUD suggest that inflammation may play an important role in the pathogenesis of MSUD, although this process is not directly associated with BCAA blood levels. Overall, data reported here are consistent with the working hypothesis that inflammation may be involved in the pathophysiological mechanism underlying the brain damage observed in MSUD patients.

Hepatic glycogen storage diseases (GSDs) are genetic diseases associated with fasting hypoglycemia. Periodic intake of uncooked cornstarch is one of the treatment strategies available for those disorders. For reasons that are still not clear, patients with hepatic GSDs may be overweight. Aims: To assess nutritional status and body composition in patients with hepatic GSDs receiving uncooked cornstarch. Methods: The sample included 25 patients with hepatic GSD (type Ia = 14; Ib = 6; III = 3; IX? = 1; IX? = 1), with a median age of 11.0 years (interquartile range [IQR] = 9.0-17.5), matched by age and gender with 25 healthy controls (median age = 12.0 years, IQR = 10.0-17.5). Clinical, biochemical, and treatment-related variables were obtained from medical records. Nutritional status and body composition were prospectively evaluated by bioelectrical impedance. Results: Patients and controls did not differ with regard to age and gender. Height was significantly reduced in patients (median = 1.43 m, IQR = 1.25-1.54) in comparison to controls (median = 1.54 m, IQR = 1.42-1.61; P = .04). Body mass index for age z-score and fat mass percentage were higher in patients (median = 1.84, IQR = 0.55-3.06; and 27.5%, IQR = 22.6-32.0, respectively) than in controls (median = 0.86, IQR = ?0.55 to 1.82; P = .04 and 21.1%, IQR = 13.0-28.3; P = .01, respectively). When patients were stratified by type, those with GSD Ia had significantly higher adiposity (median fat mass = 28.7%, IQR = 25.3-32.9) than those with GSD III and GSD IX?/? (median fat mass = 20.9%, IQR = 14.9-22.6; P = .02). Conclusions: Our findings suggest that patients with hepatic GSD on treatment with cornstarch, especially those with GSD Ia, exhibit abnormalities in nutritional status and body composition, such as short stature and a trend toward overweight and obesity.

Objectives: To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism. Methods: This was a cross-sectional outpatient study based on a convenience sampling strategy. Data on diagnosis, management, anthropometric parameters, and follow-up were assessed. Results: Twenty-one patients were included (median age 10 years, range 1–25 years), all using uncooked cornstarch therapy. Median age at diagnosis was 7 months (range, 1–132 months), and 19 patients underwent liver biopsy for diagnostic confirmation. Overweight, short stature, hepatomegaly, and liver nodules were present in 16 of 21, four of 21, nine of 14, and three of 14 patients, respectively. A correlation was found between height-for-age and BMI-for-age Z-scores (r = 0.561; p = 0.008). Conclusions: Diagnosis of glycogen storage disease type I is delayed in Brazil. Most patients undergo liver biopsy for diagnostic confirmation, even though the combination of a characteristic clinical presentation and molecular methods can provide a definitive diagnosis in a less invasive manner. Obesity is a side effect of cornstarch therapy, and appears to be associated with growth in these patients. Resumo: Objetivos: Caracterizar o perfil clínico, laboratorial e antropométrico de uma amostra de pacientes brasileiros com doença de depósito de glicogênio tipo I tratados em um ambulatório de referência para erros inatos do metabolismo. Métodos: Este foi um estudo ambulatorial transversal com base em uma estratégia de amostragem de conveniência. Foram avaliados os dados com relação ao diagnóstico, tratamento, parâmetros antropométricos e acompanhamento. Resultados: Foram incluídos 21 pacientes (idade média de 10 anos, faixa 1-25 anos de idade), e todos se encontravam em terapia de amido de milho cru. A idade média na época do diagnóstico foi de sete meses (faixa, 1-32 meses), e 19 pacientes foram submetidos a biópsia hepática para confirmação do diagnóstico. Sobrepeso, baixa estatura, hepatomegalia e nódulos hepáticos foram fatores presentes em 16 de 21, quatro de 21, nove de 14 e três de 14 pacientes, respectivamente. Foi encontrada uma correlação entre os escores z para peso para idade e IMC para idade (r = 0,561; p = 0,008). Conclusões: O diagnóstico da doença de depósito de glicogênio tipo I tem sido tardio no Brasil. A maioria dos pacientes foi submetida a confirmação do diagnóstico, apesar de o quadro clínico característico e os métodos moleculares poderem fornecer um diagnóstico definitivo de forma menos invasiva. Obesidade é um efeito colateral da terapia com amido de milho e parece estar associada a crescimento nesses pacientes. Keywords: Inborn errors of metabolism, Glycogen storage disease type I, Clinical aspects, Diagnoses, Nutritional status, Palavras-chave: Erros inatos do metabolismo, Doença de depósito de glicogênio tipo I, Aspectos clínicos, Diagnósticos, Estado nutricional

Introduction No published clinical trial data are available to inform the use of enzyme replacement therapy (ERT) in patients with the severe (neuropathic) phenotype of mucopolysaccharidosis II (MPS II). Current guidelines recommend ERT administered intravenously be used on a trial basis in this population. Aims/methods A retrospective chart review was conducted at five international centers for this case series of 22 patients with neuropathic MPS II who received intravenous idursulfase 0.5 mg/kg weekly for at least 2 consecutive years. We collected data about urinary glycosaminoglycan levels, adverse events, and the following somatic signs/symptoms: skeletal disease, joint range of motion, liver/spleen size, respiratory infections, cardiac disease, diarrhea, skin/hair texture, and hospitalizations. Results The age at diagnosis was 2 months to 5 years, and the age at idursulfase initiation was between 18 months and 21 years. One of 22 patients experienced improvements in seven somatic signs/symptoms; 17/22 experienced improvements in five to six somatic signs/symptoms; and 4/22 experienced improvements in four somatic signs/symptoms. None experienced fewer than four improvements. No new safety concerns arose. Infusion-related reactions were experienced by 4/22 patients but were successfully managed using accepted strategies. Conclusions Long-term treatment with idursulfase was associated with improvements in somatic manifestations in this case series of patients with neuropathic MPS II. The family and medical team should maintain open lines of communication to make treatment decisions that take into consideration the benefits and limitations of ERT in this population. Electronic supplementary material The online version of this article (doi:10.1007/s10545-014-9686-7) contains supplementary material, which is available to authorized users.

Introduction The gut microbiome has been related to several features present in Glycogen Storage Diseases (GSD) patients including obesity, inflammatory bowel disease (IBD) and liver disease. Objectives The primary objective of this study was to investigate associations between GSD and the gut microbiota. Methods Twenty-four GSD patients on treatment with uncooked cornstarch (UCCS), and 16 healthy controls had their faecal microbiota evaluated through 16S rRNA gene sequencing. Patients and controls were ≥3 years of age and not on antibiotics. Faecal pH, calprotectin, mean daily nutrient intake and current medications were recorded and correlated with gut microbiome. Results Patients’ group presented higher intake of UCCS, higher prevalence of IBD (n = 04/24) and obesity/overweight (n = 18/24) compared to controls (n = 0 and 06/16, respectively). Both groups differed regarding diet (in patients, the calories’ source was mainly the UCSS, and the intake of fat, calcium, sodium, and vitamins was lower than in controls), use of angiotensin-converting enzyme inhibitors (patients = 11, controls = 0; p-value = 0.001) multivitamins (patients = 22, controls = 01; p-value = 0.001), and mean faecal pH (patients = 6.23; controls = 7.41; p = 0.001). The GSD microbiome was characterized by low diversity and distinct microbial structure. The operational taxonomic unit (OTU) abundance was significantly influenced by faecal pH (r = 0.77; p = 6.8e-09), total carbohydrate (r = -0.6; p = 4.8e-05) and sugar (r = 0.057; p = 0.00013) intakes. Conclusions GSD patients presented intestinal dysbiosis, showing low faecal microbial diversity in comparison with healthy controls. Those findings might be due to the disease per se, and/or to the different diets, use of UCSS and of medicines, and obesity rate found in patients. Although the main driver of these differences is unknown, this study might help to understand how the nutritional management affects GSD patients.

Pompe disease is a rare autosomal recessive lysosomal storage disease caused by defi ciency of acid α-glucosidase (GAA). This defi ciency results in glycogen accumulation in the lysosomes, leading to lysosomal swelling, cellular damage, and organ dysfunction. In early onset patients (the classic infantile form), this glycogen accumulation leads to death, usually before the age of 1 year. Some patients with early onset do not develop cardiomyopathy and their progression is slower (atypical infantile form). We reported a case with an atypical infantile form.

Contains fulltext : 167862.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in

Sanofi Genzyme Sanofi Genzyme, Cambridge, MA, USA Background: Enzyme replacement therapy (ERT) with laronidase (recombinant human alpha-L-iduronidase, Aldurazyme (R)) is indicated for non-neurological signs and symptoms of mucopolysaccharidosis type I (MPS I). The approved laronidase dose regimen is weekly infusions of 0.58mg/kg, however, patients and caregivers may have difficulty complying with the weekly regimen. We examined clinical outcomes, tolerability, compliance, and satisfaction in a series of patients who switched to every other week infusions. Methods: This multinational, retrospective, chart review case series analyzed data from 20 patients who had undergone ERT with laronidase 0.58mg/kg weekly for more than one year, and who then switched to 1.2mg/kg every other week. Results: The majority of patients had attenuated MPS I phenotypes (9 with Hurler-Scheie and 8 with Scheie syndromes) and 3 patients had severe MPS I (Hurler syndrome). Most patients presented with organomegaly (17/ 20), umbilical and/or inguinal hernia (16/20), cardiac abnormalities (17/20), musculoskeletal abnormalities (19/20), and neurological and/or developmental deficits (15/20). Following laronidase treatment, signs stabilized or improved. No deterioration or reversal of clinical outcome was noted in any patient who switched from the weekly dose of 0.58mg.kg to 1.2mg/kg every other week. There were no safety issues during the duration of every other week dosing. Patient compliance and satisfaction with the dosing regimen were greater with every other week dosing than weekly dosing. Conclusions: An alternative dose regimen of 1.2mg/kg laronidase every other week was well tolerated and clinically similar to the standard dose for patients who were stabilized with weekly 0.58 mg/kg for one year or more. When an individualized approach to laronidase therapy is necessary, every other week dosing may be an alternative for patients with difficulty receiving weekly infusions. Fiocruz MS, Inst Nacl Saude Mulher Crianca & Adolescente Fern, BR-21045900 Rio De Janeiro, Brazil Univ Fed Bahia, Dept Pediat, Serv Genet Med, Salvador, BA, Brazil Hosp Clin Alegre, Med Genet Serv, Porto Alegre, RS, Brazil Comenius Univ, Childrens Hosp, Dept Pediat 2, Bratislava, Slovakia Westmead Hosp, Dept Med Genet, Sydney, NSW, Australia Univ Sydney, Sydney, NSW 2006, Australia Univ Fed Sao Paulo, Dept Pediat, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Pediat, Sao Paulo, Brazil Web of Science

Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD). Objective To describe survival and neurological outcomes after HSCT for these disorders. Methods Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor. RESUMO O transplante de células tronco hematopoiéticas (TCTH) é o único tratamento disponível para o envolvimento neurológico de doenças como a leucodistrofia metacromática (MLD), a mucopolissacaridose tipo I-Hurler (MPS-IH) e a adrenoleucodistrofia (CALD). Objetivos Descrever a sobrevida e os desfechos neurológicos após o TCTH nessas doenças. Métodos Sete pacientes CALD, 2 MLD e 2 MPS-IH realizaram TCTH entre 2007 e 2014. Avaliações neurológicas, ressonância nuclear magnética e estudos bioquímicos e moleculares foram feitos no baseline e repetidos quando apropriado. Resultados Desfechos favoráveis foram obtidos em 4/5 TCTH de doadores relacionados e em 3/6 não relacionados. Dois pacientes faleceram de complicações do procedimento. Nove transplantados sobreviveram após uma mediana de 3,7 anos: estabilização neurológica foi obtida em 5/6 CALD, ½ MLD e em um caso MPS-IH. As lesões encefálicas de um caso MPS-IH reduziram-se quatro anos após o TCTH. Conclusão Bons desfechos foram obtidos quando o TCTH foi feito antes da vida adulta, cedo no curso clínico e/ou a partir de um doador relacionado.