Publications by authors named "Nathalie Guffon"

75 Publications

Clinical outcomes in a series of 18 patients with long chain fatty acids oxidation disorders treated with triheptanoin for a median duration of 22 months.

Mol Genet Metab 2021 Apr 10;132(4):227-233. Epub 2021 Feb 10.

CHU de Lyon, Centre de Biologie et de Pathologie Est, Unité Maladies Héréditaires du Métabolisme, Service de Biochimie et Biologie Moléculaire, Bron, France.

Introduction: Triheptanoin provides long-chain fatty acid oxidation disorder (LC-FAOD) patients with an alternative to medium-even-chain triglycerides therapy.

Material-methods: Retrospective analysis of 18 French LC-FAOD patients benefiting from early access to triheptanoin treatment.

Results: Eight female and 10 male patients with LC-FAOD (VLCAD, LCHAD, CACT, CPTII and MTP) were treated with triheptanoin for a median duration of 22 months (range: 9-228 months). At last consultation, triheptanoin accounted for 15-35% of their daily caloric intake. In the year following the introduction of triheptanoin, patients reported a reduction of intermittent snacking and nocturnal meals. Three patients, including 1 adult, became free of severe hypoglycaemic events. Ten of 12 paediatric patients and 4 of 6 adult patients reported reduced fatigue with reductions in the number and severity of episodes of myalgia. Of 6 patients, including 1 adult, that had required the use of a wheelchair in the year prior to triheptanoin, all but one no longer required its use. The number of emergency hospitalizations decreased, and none were recorded for paediatric patients during these 12 months. Cumulative annual days of emergency care in the home were reduced from 286 to 51 days in the year before and after initiation, respectively, and 13 patients required no such interventions. Adverse events were limited to digestive issues that dissipated over time.

Conclusions: Our case-series suggests that long-term treatment of LC-FAOD paediatric and adult patients with triheptanoin is safe and leads to marked improvement of symptoms and an improved quality of life.
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http://dx.doi.org/10.1016/j.ymgme.2021.02.003DOI Listing
April 2021

The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis.

Orphanet J Rare Dis 2020 09 29;15(1):271. Epub 2020 Sep 29.

International Center for Lysosomal Disorders (ICLD), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively.

Results: The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality-of-life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned.

Conclusion: This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.
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http://dx.doi.org/10.1186/s13023-020-01549-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525940PMC
September 2020

Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of velmanase alfa as enzyme therapy for alpha-mannosidosis.

Mol Genet Metab Rep 2020 Jun 8;23:100586. Epub 2020 Apr 8.

Centre for Inherited Metabolic Diseases, Department of Paediatrics and Department of Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Objectives: Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults.

Methods: Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years.

Results: Patients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients <18 years (mean percent increase from baseline to last observation 23%) compared to adults (mean decrease of -0.7%). Subtest analysis of individual BOT-2 items captured some improvement following velmanase alfa treatment in pediatric patients.

Conclusions: There was limited ability to assess the BOT-2 change responses in adults. Pediatric patients showed stability or improvement in scaled scores relative to healthy peers, indicating continued skill acquisition, which may increase independence and contribute to improved patient quality of life.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149402PMC
June 2020

Health Status of French Young Patients with Inborn Errors of Metabolism with Lifelong Restricted Diet.

J Pediatr 2020 05 4;220:184-192.e6. Epub 2020 Mar 4.

Department of Epidemiology and Health Economics, AP-HM/EA 3279 CEReSS (Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie), Aix-Marseille Univ, Marseille, France.

Objective: To describe the health status of young patients affected by inborn errors of metabolism that require adherence to a restricted diet (IEMRDs) and to describe and compare their self- and proxy (parent)-reported quality of life (QoL) with reference values.

Study Design: A cross-sectional study was conducted in 2015-2017 in patients affected by IEMRDs (except phenylketonuria) younger than 18 years. Data collection was based on medical records, clinical examinations, parents' and children's interviews, and self-reported questionnaires. Measurements included clinical and healthcare data, child and family environment data, and self- and proxy (parent)-reported QoL.

Results: Of the 633 eligible participants, 578 were recruited (50.3% boys; mean age: 8.7 years); their anthropometric status did not differ from the general population. Approximately one-half of them had at least 1 complication of the disease. Their self-reported global QoL did not differ from that of the general population. However, relations with friends and leisure activities QoL domains were negatively impacted, whereas relations with medical staff, relations with parents, and self-esteem QoL domains were positively impacted. Their proxy (parent)-reported QoL was negatively impacted.

Conclusions: Young patients affected by IEMRDs present a high rate of clinical complications. Although their proxy (parent)-reported QoL was negatively impacted, their self-reported QoL was variably impacted (both positively and negatively). These results may inform counseling for those who care for affected patients and their families.
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http://dx.doi.org/10.1016/j.jpeds.2020.01.059DOI Listing
May 2020

Growth patterns for untreated individuals with MPS I: Report from the international MPS I registry.

Am J Med Genet A 2019 12 22;179(12):2425-2432. Epub 2019 Oct 22.

Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant, Lyon, France.

Mucopolysaccharidosis Type I (MPS I), caused by deficiency of α-L-iduronidase results in progressive, multisystemic disease with a broad phenotypic spectrum including patients with severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) disease. Disordered growth is common with either phenotype. The study objectives were to construct sex- and age-specific estimated length/height and head circumference growth curves for untreated individuals with severe and attenuated disease and compare them with clinical reference standards. Untreated individuals in the MPS I Registry with at least one observation for length/height and/or head circumference and assigned phenotype as of May 2017 were included. Median growth for 463 untreated individuals with severe disease deviated from reference growth curves by ~6 months of age and fell below the third percentile by 4 years of age. Median head circumference was above reference curves from 3 to 4 months through 3 years of age. Among 207 individuals with untreated attenuated disease, median height fell below the third percentile by 9 years of age with divergence from reference curves by 2 years of age. MPS I-specific growth curves will be useful in evaluation of long-term outcomes of therapeutics interventions and will provide a foundation for understanding the pathogenesis of skeletal disease in MPS I.
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http://dx.doi.org/10.1002/ajmg.a.61378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899772PMC
December 2019

A rare late progression form of Sly syndrome mucopolysaccharidosis.

JIMD Rep 2019 Sep 29;49(1):1-6. Epub 2019 Jul 29.

Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant Hospices Civils de Lyon Bron France.

Mucopolysaccharidoses VII, or Sly syndrome, is linked to mutations in the beta-glucuronidase encoding gene. Sly syndrome is a rare condition and presentation is highly variable, ranging from a prenatal form with severe, lethal fetal hydrops to more benign adolescent or adult forms with simple thoracic kyphosis. Molecular diagnosis of this adult male patient identified two missense mutations in the gene that led to a deficiency in beta-glucuronidase catalytic activity and the resulting accumulation of chondroitin sulfate glycosaminoglycans. During childhood, bilateral inguinal hernia was repaired at 1 year of age and gait abnormalities were noted, leading to a bilateral femoral varization osteotomy due to a bilateral coxa valga with hip subluxation at the age of 7.5. The patient suffered regular upper respiratory infections and required numerous orthopedic surgeries. Despite learning difficulties with visual and hearing deficits, the patient worked full-time and undertook regular leisure activities. At 33 years of age, the patient's health deteriorated; a hip replacement and glaucoma leading to reductions in his visual field limited his capacity to travel independently. The patient was hospitalized at 51. Although he remained self-sufficient for taking meals, he needed help with many daily activities. Following a period marked by major asthenia with a general loss of autonomy, the patient died at 52 years of age. With the advent of new enzyme replacement therapies, this medical history of this rare untreated attenuated patient may provide benchmarks to judge the efficacy of treatment in future patients.
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http://dx.doi.org/10.1002/jmd2.12039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718110PMC
September 2019

Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry.

Clin Genet 2019 10 2;96(4):281-289. Epub 2019 Jul 2.

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.
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http://dx.doi.org/10.1111/cge.13583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852151PMC
October 2019

Betaine anhydrous in homocystinuria: results from the RoCH registry.

Orphanet J Rare Dis 2019 03 14;14(1):66. Epub 2019 Mar 14.

CHRU de Tours, Service de Médecine Interne, Université François Rabelais, Tours, France.

Background: The Registry of Adult and Paediatric Patients Treated with Cystadane® - Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year.

Results: A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine β-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns.

Conclusions: Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients.
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http://dx.doi.org/10.1186/s13023-019-1036-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419445PMC
March 2019

Growth impairment and limited range of joint motion in children should raise suspicion of an attenuated form of mucopolysaccharidosis: expert opinion.

Eur J Pediatr 2019 Apr 11;178(4):593-603. Epub 2019 Feb 11.

Groupe de Pédiatrie Générale - Société Française de Pédiatrie, Boulogne-Billancourt, Department of Pediatrics and Pediatric Emergency, Ambroise-Paré Hospital, Boulogne-Billancourt, France.

Growth impairment together with bone and joint involvement is common to most patients with mucopolysaccharidosis (MPS) disorders. The genetic basis for these metabolic disorders involves various enzyme deficiencies responsible for the catabolism of glycosaminoglycans (GAGs). The incomplete degradation and subsequent accumulation of GAGs result in progressive tissue damage throughout the body. Bone ossification is particularly affected, with the consequent onset of dysostosis multiplex which is the underlying cause of short stature. Joint manifestations, whether joint contractures (MPS I, II, VI, VII) or hyperlaxity (MPS IV), affect fine motor skills and quality of life. Subtle decreases in growth velocity can begin as early as 2-4 years of age. Pediatricians are in the front line to recognize or suspect MPS. However, given the rarity of the disorders and variable ages of symptom onset depending on disease severity, recognition and diagnostic delays remain a challenge, especially for the attenuated forms. Prompt diagnosis and treatment can prevent irreversible disease outcomes.Conclusion: We present a diagnostic algorithm based on growth velocity decline and bone and joint involvement designed to help pediatricians recognize early manifestations of attenuated forms of MPS. We illustrate the paper with examples of abnormal growth curves and subtle radiographic nuances. What is Known: • As mucopolysaccharidoses (MPSs) are rare genetic disorders infrequently seen in clinical practice, there can be a lag between symptom onset and diagnosis, especially of attenuated forms of the disease. • This highlights the need for increased disease awareness to recognize early clinical signs and subsequently initiate early treatment to improve outcomes (normal height potential) and possibly prevent or delay the development of irreversible disease manifestations. What is New: • Growth impairment co-presenting with limited range of joint motion and radiographic anomalies in children should raise suspicions of possible attenuated MPS (AMPS). • Experts present a diagnostic algorithm with detailed focus on the decline in growth velocity, delayed puberty and limitation in joint mobility seen in children with AMPS, to shorten time-to-diagnosis and treatment and potentially improve patient outcome.
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http://dx.doi.org/10.1007/s00431-019-03330-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438949PMC
April 2019

Treatment of thoracolumbar kyphosis in patients with mucopolysaccharidosis type I: results of an international consensus procedure.

Orphanet J Rare Dis 2019 01 18;14(1):17. Epub 2019 Jan 18.

Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Meibergdreef 9, Amsterdam, Netherlands.

Background: In all patients with mucopolysaccharidosis type I (MPS I), skeletal disease (dysostosis multiplex) is a prominent, debilitating, condition related complication that may impact strongly on activities of daily living. Unfortunately, it is not alleviated by treatment with hematopoietic cell transplantation (HCT) or enzyme replacement therapy (ERT). Although early kyphosis is one of the key features of dysostosis multiplex, there is no international consensus on the optimal management. Therefore, an international consensus procedure was organized with the aim to develop the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients.

Methods: A literature review was conducted to identify all available information about kyphosis and related surgery in MPS I patients. Subsequently, a modified Delphi procedure was used to develop consensus statements. The expert panel included 10 spinal orthopedic surgeons, 6 pediatricians and 3 physiotherapists, all experienced in MPS I. The procedure consisted of 2 written rounds, a face-to-face meeting and a final written round. The first 2 rounds contained case histories, general questions and draft statements. During the face-to-face meeting consensus statements were developed. In the final round, the panel had the opportunity to anonymously express their opinion about the proposed statements.

Results: Eighteen case series and case reports were retrieved from literature reporting on different surgical approaches and timing of thoracolumbar kyphosis surgery in MPS I. During the face-to-face meeting 16 statements were discussed and revised. Consensus was reached on all statements.

Conclusion: This international consensus procedure resulted in the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients, focusing on the goals and timing of surgery, as well as the optimal surgical approach, the utility of bracing and required additional assessments (e.g. radiographs). Most importantly, it was concluded that the decision for surgery depends not only on the kyphotic angle, but also on additional factors such as the progression of the deformity and its flexibility, the presence of symptoms, growth potential and comorbidities. The eventual goal of treatment is the maintenance or improvement of quality of life. Further international collaborative research related to long-term outcome of kyphosis surgery in MPS I is essential as prognostic information is lacking.
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http://dx.doi.org/10.1186/s13023-019-0997-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339313PMC
January 2019

International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome.

Acta Paediatr 2018 12 23;107(12):2059-2065. Epub 2018 Oct 23.

Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague, Czech Republic.

Aim: Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening.

Methods: An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East.

Results: It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available.

Conclusion: Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre-symptomatic treatment, but existing hurdles need to be overcome.
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http://dx.doi.org/10.1111/apa.14587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282980PMC
December 2018

Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial.

J Inherit Metab Dis 2018 11 30;41(6):1215-1223. Epub 2018 May 30.

Department of Paediatrics and Adolescent Medicine, Centre for Inherited Metabolic Diseases, Copenhagen, Denmark.

Introduction: This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients.

Methods: Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT).

Results: Mean relative change in S-oligo in the VA arm was -77.6% [95% confidence interval (CI) -81.6 to -72.8] at week 52 and -62.9% (95% CI -85.8 to -40.0) at LO; mean relative change in the placebo arm was -24.1% (95% CI -40.3 to -3.6) at week 52 and -55.7% (95% CI -76.4 to -34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was -1.1% (95% CI -9.0 to 7.6) and - % (95% CI -13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI -5.5 to 13.2) in the VA arm and 9.0% (95% CI -10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age.

Conclusions: These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age.
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http://dx.doi.org/10.1007/s10545-018-0185-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326984PMC
November 2018

Easy-to-use algorithm would provide faster diagnoses for mucopolysaccharidosis type I and enable patients to receive earlier treatment.

Acta Paediatr 2018 08;107(8):1402-1408

Center for Rare Diseases, Clinic for Paediatric and Adolescent Medicine, HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.

Aim: The aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I).

Methods: An international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real-world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested.

Results: An algorithm was developed. In patients under two years of age, kyphosis or gibbus deformity were the key symptoms that raised clinical suspicion of MPS I and in those over two years they were kyphosis or gibbus deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler-Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) - 16 Hurler, nine Hurler-Scheie and seven Scheie patients - would have been referred earlier if the algorithm had been used.

Conclusion: The expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment.
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http://dx.doi.org/10.1111/apa.14417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055821PMC
August 2018

Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis.

J Inherit Metab Dis 2018 11 3;41(6):1225-1233. Epub 2018 May 3.

Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant, Lyon, France.

Introduction: Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM).

Methods: Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT).

Results: Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation.

Conclusions: Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.
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http://dx.doi.org/10.1007/s10545-018-0175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326957PMC
November 2018

Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis.

Mol Genet Metab 2018 06 18;124(2):152-160. Epub 2018 Apr 18.

Centre for Inherited Metabolic Diseases, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.
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http://dx.doi.org/10.1016/j.ymgme.2018.04.003DOI Listing
June 2018

Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison.

Genet Med 2018 11 8;20(11):1423-1429. Epub 2018 Mar 8.

Department of Pediatrics and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

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.
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http://dx.doi.org/10.1038/gim.2018.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129229PMC
November 2018

Carpal tunnel syndrome in mucopolysaccharidosis I: a registry-based cohort study.

Dev Med Child Neurol 2017 12 11;59(12):1269-1275. Epub 2017 Sep 11.

Department of Orthopedics, University of Utah, Salt Lake City, UT, USA.

Aim: To characterize carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I).

Method: Data were included for patients with MPS I who had either nerve conduction examination that included a diagnosis of CTS or who had CTS release surgery. Although this represented a subset of patients with CTS in the MPS I Registry, the criteria were considered the most objective for data analysis.

Results: As of March 2016, 994 patients were categorized with either severe (Hurler syndrome) or attenuated (Hurler-Scheie or Scheie syndromes) MPS I. Among these, 291 had a CTS diagnosis based on abnormal nerve conduction (n=54) or release surgery (n=237). Median ages (minimum, maximum) at first CTS diagnosis were 5 years 2 months (10mo, 16y 2mo) and 9y 11mo (1y 8mo, 44y 1mo) for patients with severe and attenuated MPS I respectively. Most patients had their first CTS diagnosis after MPS I diagnosis (94%) and treatment (hematopoietic stem cell transplant and/or enzyme replacement therapy) (74%). For 11% of patients with attenuated disease, CTS diagnosis preceded MPS I diagnosis by a mean of 7 years 6 months.

Interpretation: CTS is a rare complication in pediatric patients and should alert medical care providers to the potential diagnosis of MPS I. Significant delays exist between diagnosis of CTS and MPS I for patients with attenuated disease.

What This Paper Adds: There are significant delays in diagnosing carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I). Enzyme replacement therapy or hematopoietic stem cell transplant do not prevent the development of CTS. Testing for CTS in patients with MPS I is recommended to prevent irreparable damage. CTS in pediatric patients should alert physicians to potential diagnosis of MPS I.
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http://dx.doi.org/10.1111/dmcn.13545DOI Listing
December 2017

LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: A novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease.

PLoS One 2017 27;12(7):e0181700. Epub 2017 Jul 27.

Service de Biochimie et Biologie Moléculaire Grand Est, Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.

Background: The biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma.

Methodology: We developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i.e. lysoglucosylceramide and/or lysogalactosylceramide) for Gaucher and Krabbe diseases, lysosphingomyelin and its carboxylated analogue lysosphingomyelin-509 for Niemann-Pick type A or B, and C diseases, lysoGM1 ganglioside for GM1gangliosidosis and lysoGM2 ganglioside for GM2 gangliosidosis.

Findings: The diagnostic performances were validated in plasma samples analysing a large series of patients affected with sphingolipidoses and Niemann-Pick type C disease (n = 98), other inborn errors of metabolism (n = 23), and controls (n = 228). The multiplex measurement of lysosphingolipids allowed the screening of Fabry (including female patients and late-onset variants), Gaucher and infantile Krabbe, Niemann-Pick type A/B and C diseases with high sensitivity and specificity. LysoGM1 and LysoGM2 were elevated in most of the patients affected with GM1 and GM2 gangliosidosis respectively. In amniotic fluid supernatant from pregnancies presenting non-immune hydrops fetalis (n = 77, including previously diagnosed Gaucher (n = 5), GM1 gangliosidosis (n = 4) and galactosialidosis (n = 4) fetuses) and from normal pregnancies (n = 15), a specific and dramatic increase of lysohexosylceramide was observed only in the Gaucher amniotic fluid samples.

Interpretation: This multiplex assay which allows the simultaneous measurement of lysosphingolipids in plasma modifies the diagnostic strategy of sphingolipidoses and Niemann-Pick type C. Furthermore, in pregnancies presenting non-immune hydrops fetalis, lysohexosylceramide measurement in amniotic fluid offers a rapid screening of fetal Gaucher disease without waiting for glucocerebrosidase activity measurement in cultured amniocytes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531455PMC
September 2017

Open-Label Single-Sequence Crossover Study Evaluating Pharmacokinetics, Efficacy, and Safety of Once-Daily Dosing of Nitisinone in Patients with Hereditary Tyrosinemia Type 1.

JIMD Rep 2018 23;38:81-88. Epub 2017 Jun 23.

Swedish Orphan Biovitrum (Sobi), 112 76, Stockholm, Sweden.

Background: Although nitisinone is successfully used to treat hereditary tyrosinemia type 1 (HT-1) with the recommended twice-daily dosing, data describing a long half-life motivate less frequent dosing. Therefore, in agreement with the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency, this study was performed to investigate the switch to once-daily dosing.

Methods: This open-label, non-randomized, single-sequence crossover study evaluated the pharmacokinetics, efficacy, and safety of once-daily compared to twice-daily dosing of nitisinone in patients with HT-1 (NCT02323529). Well-controlled patients of <2, 2 to <12, 12 to <18, and ≥18 years of age who were on twice-daily dosing were eligible for participation. Nitisinone and succinylacetone levels were determined from dry blood spots by tandem mass spectrometry. The primary endpoint was C of nitisinone after ≥4 weeks of treatment on each dosing regimen. Secondary objectives were evaluation of efficacy and safety during each dosing regimen.

Results: In total, 19 patients were enrolled and 17 included in the per-protocol analysis set. The mean (SD) nitisinone C decreased by 23%, from 26.4 (10.2) to 21.2 (9.9) μmol/L in dry blood spot samples (not equivalent to plasma concentrations), when patients switched from twice- to once-daily dosing. There was no apparent age- or bodyweight-related trend in the degree of C decrease. No patient had quantifiable succinylacetone levels during the once-daily treatment period, indicating efficacious treatment. All adverse events were mild or moderate and judged unrelated to nitisinone.

Conclusion: The switch to once-daily treatment with nitisinone appeared efficacious and safe in the treatment of patients with HT-1.
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http://dx.doi.org/10.1007/8904_2017_29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874213PMC
June 2017

Ten years of the Hunter Outcome Survey (HOS): insights, achievements, and lessons learned from a global patient registry.

Orphanet J Rare Dis 2017 05 2;12(1):82. Epub 2017 May 2.

Shire Human Genetic Therapies, Inc., 300 Shire Way HA100-310, Lexington, MA, 02421, USA.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare lysosomal storage disease with progressive multisystem manifestations caused by deficient activity of the enzyme iduronate-2-sulfatase. Disease-specific treatment is available in the form of enzyme replacement therapy with intravenous idursulfase (Elaprase®, Shire). Since 2005, the Hunter Outcome Survey (HOS) has collected real-world, long-term data on the safety and effectiveness of this therapy, as well as the natural history of MPS II. Individuals with a confirmed diagnosis of MPS II who are untreated or who are receiving/have received treatment with idursulfase or bone marrow transplant can be enrolled in HOS. A broad range of disease- and treatment-related information is captured in the registry and, over the past decade, data from more than 1000 patients from 124 clinics in 29 countries have been collected. Evidence generated from HOS has helped to improve our understanding of disease progression in both treated and untreated patients and has extended findings from the formal clinical trials of idursulfase. As a long-term, global, observational registry, various challenges relating to data collection, entry, and analysis have been encountered. These have resulted in changes to the HOS database platform, and novel approaches to maximize the value of the information collected will also be needed in the future. The continued evolution of the registry should help to ensure that HOS provides further insights into the burden of the disease and patient care and management in the coming years.
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http://dx.doi.org/10.1186/s13023-017-0635-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414331PMC
May 2017

Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis.

J Inherit Metab Dis 2017 05 2;40(3):415-422. Epub 2017 Mar 2.

Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France.

Background: Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects ketone body and isoleucine catabolism. Neurological impairment may occur secondary to ketoacidotic episodes. However, we observed neuromotor abnormalities without ketoacidotic events in two T2-deficient families. We hypothesized that the neurological signs were related to the genetic defect and may occur independently of ketoacidotic episodes. We therefore conducted a retrospective review on a French T2-deficient patient series searching for neuromotor impairment.

Methods: In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data.

Results: Neurological findings were observed for 6/26 (23%) patients. Among these, two had never experienced ketoacidotic episodes, though they developed extrapyramidal signs with putamen involvement. Two of the other four patients developed neurological abnormalities before the first ketoacidotic crisis, with putamen involvement in one case. The third patient developed extrapyramidal symptoms more than 10 years after the initial decompensation with globus pallidus involvement. The last patient developed extrapyramidal signs immediately after a severe ketoacidotic crisis with putaminal lesions.

Conclusions: Most T2-deficient patients achieved normal neurodevelopment. However, on account of the role of T2 in isoleucine catabolism, these patients are potentially exposed to accumulation of toxic isoleucine-derived metabolites, which may contribute to neurological impairment. Our findings confirm previous observations that neurological symptoms in T2 deficiency may occur unrelated to ketoacidosis. The role of protein restriction as a preventive measure against neurological symptoms could not be established in this study and deserves further evaluation. Long-term follow-up data on children diagnosed by newborn screening may clarify the pathogenesis of this neurometabolic association.
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http://dx.doi.org/10.1007/s10545-017-0021-yDOI Listing
May 2017

Efficacy and safety of i.v. sodium benzoate in urea cycle disorders: a multicentre retrospective study.

Orphanet J Rare Dis 2016 Sep 23;11(1):127. Epub 2016 Sep 23.

Reference Centre for Inherited Metabolic Disorders (MaMEA), Hôpital Necker-Enfants Malades, Institut Imagine, Université Paris Descartes, 149 rue de Sèvres, 75743, Paris, Cedex 15, France.

Background: The efficacy and safety of intra-venous (i.v.) sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders (UCD) is well known. However, published data do not provide a clear picture of the benefits and risks of this drug. We report a retrospective multicentre study on the use of i.v. sodium benzoate in patients treated for UCD between 2000 and 2010 in the 6 French reference centres for metabolic diseases.

Results: Sixty-one patients with UCDs - 22 ornithine transcarbamylase (20 confirmed, 2 suspected), 18 arginino-succinate synthetase, 15 carbamoyl phosphate synthetase, 3 arginosuccinate lyase, 1 arginase deficiency, 1 N-acetylglutamate synthetase, 1 HHH syndrome - required i.v. sodium benzoate over the course of 95 acute episodes (NH3 > 100 μmol/L or high-risk situations, i.e., gastroenteritis, surgery). Forty out of 61 patients experienced only one episode of decompensation (neonatal coma, 68.6 %). The most frequent cause of late decompensation was infection (55.5 %). A loading dose of i.v. sodium benzoate (median 250 mg/kg over 2 h) was administered for 41/95 acute episodes. The median maintenance dose was 246.1 mg/kg/day, administered via peripheral venous infusion in all cases except one via a central line. The total median duration of i.v. sodium benzoate treatment per episode was 2 days (0-13 days). The median durations of hospitalization in intensive care and metabolic units were 4 days (0-17 days) and 10 days (0-70 days), respectively. Eight patients died during the neonatal coma (n = 6) or surgery (n = 2). The median plasma ammonium level before treatment was 245.5 μmol/L (20.0-2274.0 μmol/L); it decreased to 40.0 μmol/L in patients who were alive (13.0-181.0 μmol/L) at the end of treatment with i.v. sodium benzoate. A decrease in ammonium level to ≤ 100 μmol/L was obtained in 92.8 % of episodes (64/69 of the episodes recorded for the 53 surviving patients). Five patients required another treatment for hyperammonemia (sodium phenylacetate + sodium benzoate, haemofiltration). Eighteen side effects were reported related to the i.v. infusion (local diffusion, oedema).

Conclusion: This 10-year retrospective study shows that i.v. sodium benzoate associated with an emergency regimen is an effective and safe treatment for acute episodes of UCD.
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http://dx.doi.org/10.1186/s13023-016-0513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034629PMC
September 2016

Pregnancy in patients with mucopolysaccharidosis: a case series.

Mol Genet Metab Rep 2016 Sep 29;8:111-5. Epub 2016 Aug 29.

Birmingham Women's NHS Foundation Trust, Birmingham, UK.

The mucopolysaccharidoses (MPS disorders) are rare inherited diseases associated with multi-organ accumulation of glycosaminoglycans, leading to musculoskeletal, respiratory, cardiac, neurological, ophthalmological, otolaryngological, and gastrointestinal abnormalities. As a result of improvements in diagnosis, multi-disciplinary care, and therapies such as enzyme replacement therapy and hematopoietic stem cell transplantation, an increasing number of patients with MPS are reaching adulthood and are involved in family planning. Data on fertility and pregnancy outcome in MPS is sparse and comprises primarily isolated case reports. To address this evidence gap, we present a case series on fertility and pregnancy in eight mothers and five fathers with MPS. This case series demonstrates that women with MPS have high-risk pregnancies and deliveries secondary to their underlying disease. However, with appropriate pre-conceptual multi-disciplinary evaluation, optimization and discussion regarding potential risks, combined with regular multi-disciplinary maternal and fetal surveillance in a tertiary center, the outcome of most pregnancies in this case series seems to be favorable with all babies developing normally. Partners of fathers with MPS had uncomplicated pregnancies and deliveries. All children were healthy, with normal growth and development.
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http://dx.doi.org/10.1016/j.ymgmr.2016.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007877PMC
September 2016

Cervical cord compression in mucopolysaccharidosis VI (MPS VI): Findings from the MPS VI Clinical Surveillance Program (CSP).

Mol Genet Metab 2016 08 3;118(4):310-8. Epub 2016 Jun 3.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Objectives: To gain insight into the frequency, age of onset, and management of cervical cord compression in mucopolysaccharidosis VI (MPS VI).

Methods: Cervical spine magnetic resonance imaging (MRI) data and/or cervical decompression surgery data collected between 30 June 2005 and 1 September 2015 were analyzed from subjects enrolled in the MPS VI Clinical Surveillance Program (CSP) (ClinicalTrials.gov: NCT00214773), an ongoing multicenter, observational, retrospective and prospective registry.

Results: Of 213 subjects enrolled in the CSP, 134 (62.9%) had at least one documented cervical spine MRI assessment. An additional four subjects were identified through surgery records alone to yield a study population comprising 138 subjects (mean age at enrollment =15.1years; age range=0.80-65.0years). Cervical cord compression was documented in 101 (75.4%) of the 134 subjects with ≥1 MRI assessment, the majority (95.0%) by the time of the first recorded MRI. In general, subjects with cervical cord compression had significantly lower height Z-scores compared to those without cervical cord compression (p<0.0001); nevertheless, a few subjects of taller stature had documented cervical cord compression at a young age. Most subjects >20years of age (31/33, 93.9%) presented with cervical cord compression. There was an insufficient number of subjects with both pre- and post-enzyme replacement therapy (ERT) MRI data to determine any association between ERT and cervical cord compression. Surgical decompression was performed on 58 subjects (42.0%), with mean age at first surgery of 13.1years. Decompression plus stabilization procedures accounted for 12.1% of surgeries. Eight subjects (13.8%) underwent reoperation. Complications during or following surgery were reported in 3 subjects, with anesthesia-related complications resulting in two deaths.

Conclusions: All individuals with MPS VI are at high risk of developing cervical cord compression at an early age. Routine MRI assessments should be initiated from the time of MPS VI diagnosis. The perioperative management of MPS VI patients can be challenging. This study contributes to the understanding of the natural history of MPS VI.
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http://dx.doi.org/10.1016/j.ymgme.2016.06.001DOI Listing
August 2016

Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study.

Orphanet J Rare Dis 2016 Mar 31;11:32. Epub 2016 Mar 31.

Reference Center for Metabolic Diseases, Pediatric Neurology & Metabolic diseases, Robert Debre University Hospital, Paris, France.

Background: Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation.

Methods: Eligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 μmol/L) in ≥1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at ≤18 hours after the last carglumic acid administration, or on Day 15) for each episode. Secondary outcomes included clinical response and safety.

Results: The efficacy population (received ≥1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (±365.3) μmol/L in neonates (29 episodes) and 171.3 (±75.7) μmol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (±36.5) μmol/L in neonates and 55.2 (±21.8) μmol/L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation.

Conclusion: Carglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients.
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http://dx.doi.org/10.1186/s13023-016-0406-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815113PMC
March 2016

CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.

Am J Hum Genet 2016 Feb 28;98(2):310-21. Epub 2016 Jan 28.

Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address:

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.
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http://dx.doi.org/10.1016/j.ajhg.2015.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746332PMC
February 2016

Long-Term Follow-Up on a Cohort Temporary Utilization Authorization (ATU) Survey of Patients Treated with Pheburane (Sodium Phenylbutyrate) Taste-Masked Granules.

Paediatr Drugs 2016 Apr;18(2):139-44

Hôpital Femme-Mère-Enfant, Centre de Référence des maladies héréditaires du métabolisme, 59 Boulevard Pinel, 69577, Bron Cedex, France.

Objectives: The aim was to describe the status of patients with urea cycle disorders (UCD) at the latest long-term clinical follow-up of treatment with a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane). These patients are a subset of those treated under a cohort temporary utilisation study (ATU) previously reported and now followed for 2 years.

Methods: From a French cohort temporary utilization authorization (ATU) set up to monitor the use of Pheburane on a named-patient basis in UCD patients in advance of its marketing authorization, a subset of patients were followed up in the long term. Data on demographics, dosing characteristics of NaPB, concomitant medications, adverse events and clinical outcomes were collected at a follow-up visit after 1-2 years of treatment with the drug administered under marketing conditions. This paper reports on the subset of patients who were included in further long-term follow-up at the principal recruiting metabolic reference center involved in the original cohort.

Results: No episode of metabolic decompensation was observed over a treatment period ranging from 8 to 30 months with Pheburane, and the range of ammonia and glutamine levels continued to improve and remained within the normal range, thus adding valuable longer-term feedback to the original ATU report. In all, no adverse events were reported with Pheburane treatment. These additional data demonstrate the maintenance of the safety and efficacy of Pheburane over time.

Conclusions: The recently developed taste-masked formulation of NaPB granules (Pheburane) improved the quality of life for UCD patients. The present post-marketing report on the use of the product confirms the original observations of improved compliance, efficacy and safety with this taste-masked formulation of NaPB.
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http://dx.doi.org/10.1007/s40272-015-0159-8DOI Listing
April 2016

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

J Med Genet 2016 Feb 26;53(2):98-110. Epub 2015 Oct 26.

Centre de Référence des Manifestations Odontologiques des Maladies Rares, Pôle de Médecine et Chirurgie Bucco-dentaires, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France Institut de Génétique et de Biologie Moléculaire and Cellulaire-Centre Européen de Recherche en Biologie et en Médecine, CNRS UMR7104, INSERM U964 Université de Strasbourg, Illkirch, France.

Background: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders.

Methods: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption.

Results: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases.

Conclusions: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease.

Trial Registration Numbers: NCT01746121 and NCT02397824.
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http://dx.doi.org/10.1136/jmedgenet-2015-103302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752661PMC
February 2016

Diagnosis, quality of life, and treatment of patients with Hunter syndrome in the French healthcare system: a retrospective observational study.

Orphanet J Rare Dis 2015 Apr 12;10:43. Epub 2015 Apr 12.

Centre de Référence Maladies Métaboliques de l'enfant et de l'adulte, Hôpital Universitaire Necker-Enfants Malades et Institut IMAGINE, Paris, France.

Background: Mucopolysaccharidosis II (MPS II) is associated with a broad spectrum of chronic and progressive, life-limiting symptoms. Idursulfase is approved for MPS II enzyme replacement therapy (ERT) in over 50 countries. This retrospective study evaluated the MPS II burden, organization of clinical care, and effects of idursulfase treatment on the disease in France.

Methods: MPS II patients who had received idursulfase ERT in the French healthcare system were enrolled. In addition to clinician and patient questionnaires, the Clinical Global Impression-Improvement (CGI-I); Patient Global Impression-Improvement (PGI-I); KIDSCREEN-27, and EuroQoL-5D for adult patients scales were used to assess quality of life (QoL) and efficacy.

Results: Fifty-two patients were enrolled from 5 sites in France. The majority of patients (69.2%) presented a severe MPS II phenotype with progressive neurocognitive impairment. Major impacts on QoL were apparent, with at least 1 member of the family having to reorganize working hours (45.5%) or to stop working (22.7%). KIDSCREEN-27 and EuroQoL-5D scale scores were well below those for referent (control) populations. Most families (70.0%) experienced a diagnostic delay of at least 3 years after the initial observation of symptoms. The MPS II diagnosis was often delivered without adequate sensitivity, psychological support, or comprehensive information about the disease. The study population had received a mean of 3.8 ± 1.3 years ERT. Forty-four percent of patients with the attenuated phenotype (without progressive neurocognitive impairment) showed symptom improvement during both the first year (Period 1) and from the end of the first year of treatment to "the present" (Period 2), as measured by CGI-I/PGI-I. 30.3% and 9.1% of severe patients experienced symptom improvement during Periods 1 and 2, respectively, while 63.6% and 51.5% displayed no change. The most common adverse reactions reported were skin rash and other infusion-associated reactions.

Conclusions: MPS II adversely affects multiple domains of QoL for patients and families, requiring multiple healthcare services and social aid programs. The majority of patients with either phenotype experienced either improvement or stability in their symptoms during the first year of ERT, but this was clearly less so for patients with the severe phenotype after the first year of treatment.
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http://dx.doi.org/10.1186/s13023-015-0259-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407793PMC
April 2015

Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency.

Orphanet J Rare Dis 2015 Mar 15;10:31. Epub 2015 Mar 15.

Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, Toulouse, France.

Background: Multiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care.

Methods: The phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient's molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models.

Results: The most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses.

Conclusions: This detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype-phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment development.
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http://dx.doi.org/10.1186/s13023-015-0244-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375846PMC
March 2015