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International audience; We present the phenotypes of seven previously unreported patients with Marbach-Schaaf neurodevelopmental syndrome, all carrying the same recurrent heterozygous missense variant c.1003C>T (p.Arg335Trp) in PRKAR1B. Clinical features of this cohort include global developmental delay and reduced sensitivity to pain, as well as behavioral anomalies. Only one of the seven patients reported here was formally diagnosed with autism spectrum disorder (ASD), while ASD-like features were described in others, overall indicating a lower prevalence of ASD in Marbach-Schaaf neurodevelopmental syndrome than previously assumed. The clinical spectrum of the current cohort is similar to that reported in the initial publication, delineating a complex developmental disorder with behavioral and neurologic features. PRKAR1B encodes the regulatory subunit R1beta of the protein kinase A complex (PKA), and is expressed in the adult and embryonal central nervous system in humans. PKA is crucial to a plethora of cellular signaling pathways, and its composition of different regulatory and catalytic subunits is cell-type specific. We discuss potential molecular disease mechanisms underlying the patients' phenotypes with respect to the different known functions of PKA in neurons, and the phenotypes of existing R1beta-deficient animal models.

Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.

Background Transition from childhood to adulthood (TCA) is usually difficult in rare, progressive and multisystemic diseases. New treatments and modalities of care for many lysosomal diseases (LD) can increase life expectancy, and a successful TCA can help patient who reach adulthood to avoid disruption to health care. In France, some TCA initiatives have been taken by referral centers but in view of the problems encountered by Vaincre les Maladies Lysosomales (VML), the LD patient association, they seem to be insufficient. The aim of this study is to determine the current state of the TCA process and to identify actions to improve it through interviews with patient families and physicians in LD referral centers. The study is based upon an observational, non-interventional, cross-sectional, national survey which used two anonymous questionnaires. These questionnaires, developed by a scientific committee including representatives from VML and medical specialists in LD, were sent to patients who were receiving care in pediatric departments at age 15 years or older. Questionnaires were also sent to their referral pediatricians. Results Fifty-four patients were included. Forty-two questionnaires were completed by patients and their corresponding physicians and 12 were completed by physicians only. The majority of the patients (80%) were informed that transfer to adult healthcare would occur, but 52% were informed after their eighteenth birthday. Forty-eight percent indicated that they were informed that a TCA coordinator would be appointed; for 39% the time frame for the transfer was communicated, and 31% were informed of the composition of the adult medical team. Among the actions that patients rated as “important/very important”, and considered to be a priority in their comments, the most frequently cited were the provision of explanatory documents on the TCA (94%), the transmission of the medical file from the pediatric sector to the adult sector (94%) and a joint consultation with both pediatrician and adult unit physician (91%). Physicians were in agreement concerning the primary importance of the last two actions. Conclusion This study provides a basis for the deployment, on the national level, of transition programs which include specific actions that patients view as priorities.

PurposeIn this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,CC2D2A.MethodsWe selected 53 patients with pathogenic variants onCC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature.ResultsDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype–phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.ConclusionThis study contradicts previous literature stating an association betweenCC2D2A-related JS and ventriculomegaly. Our study implies thatCC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

To describe the clinical features and course of liver involvement in a cohort of patients with Niemann-Pick type C disease (NP-C), a severe lysosomal storage disorder.Patients with genetically confirmed NP-C (NPC1, n = 31; NPC2, n = 3) and liver involvement before age 6 months were retrospectively included. Clinical, laboratory test, and imaging data were collected until the last follow-up or death; available liver biopsy specimens were studied using anti-CD68 immunostaining.At initial evaluation (median age, 17 days of life), all patients had hepatomegaly, 33 had splenomegaly, and 30 had neonatal cholestasis. Portal hypertension and liver failure developed in 9 and 4 patients, respectively. Liver biopsy studies, performed in 16 patients, revealed significant fibrosis in all 16 and CD68Liver involvement in NP-C consisted of transient neonatal cholestasis with hepatosplenomegaly, was associated with liver fibrosis, and was responsible for death in 9% of patients. The combination of liver anti-CD68 immunostaining, serum alpha-fetoprotein measurement, and studies of plasma biomarkers should facilitate early identification of NP-C.

IntroductionThis study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB).MethodsClinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.ResultsThe clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.ConclusionThis study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.

Objective Asparagine‐linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. Methods We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. Results The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one‐half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one‐third of all cases paroxysms of fast activity with electrodecrement. ALG13‐related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one‐third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. Significance X‐linked ALG13‐related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.

In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,We selected 53 patients with pathogenic variants onDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.This study contradicts previous literature stating an association between

Miglustat has been indicated for the treatment of Niemann‐Pick disease type C (NP‐C) since 2009. The aim of this observational study was to assess the effect of miglustat on long‐term survival of patients with NP‐C. Data for 789 patients from five large national cohorts and from the NPC Registry were collected and combined. Miglustat‐treated and untreated patients overall and within sub‐groups according to age‐at‐neurological‐onset, that is, early infantile‐onset (

The guanine exchange factor subunit eEF1Bα encoded by the EEF1B2 gene belongs to the eukaryotic elongation translational machinery. Pathogen variants in genes of the translational machinery have been associated with several neurodevelopmental disorders. However, only one family of three siblings with intellectual disability (ID) has been reported so far with a homozygous variant in EEF1B2. Here, we report a second family with a novel homozygous loss of function (LoF) variant p.(Ser128*), carried by two siblings with moderate ID and seizures. Our findings confirm the role of EEF1B2 variants in the pathogenesis of autosomal-recessive ID, expand the variant spectrum and precisely describe the clinical consequences of the LoF of EEF1B2.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P=.046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P=.006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n=2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Background MPS IIIA is a rare, degenerative pediatric genetic disease characterized by symptoms impacting cognition, mobility and behavior; the mean age of death is around 15 years of age. Currently, there are no approved therapies for MPS IIIA. Methods A two-year, multi-center, prospective, descriptive cohort study was conducted to document the natural history course of MPS IIIA. In the context of this study, semi-structured interviews were performed with parents of children at study entry and one year later. Interview transcripts were analyzed using thematic analysis methods to identity concepts of interest to children and parents, identify what factors impacted parents’ burden the most, and develop qualitatively-derived disease severity stages. Children were sorted into these stages according to the symptoms their parents described at the entry interview. This sorting was compared quantitatively to the sorting of children at baseline according to the child’s calendar age and their BSID development quotient (DQ). Results 22 parents in France, Germany, the Netherlands and the UK were interviewed. Children ranged in age from 28 to 105 months (mean 61.4 months). The conceptual models for children’s symptoms and impacts and parents’ impacts provided a detailed and comprehensive picture of what it is like for children of various ages and their parents to live with MPS IIIA. Four factors were identified as mediating the burden perceived by parents: state support, family support, time since diagnosis, and parent coping strategy. Four disease stages were developed, accounting for both the presence and the severity of MPS IIIA symptoms. The comparison of children’s sorting into these stages with the BSID DQ and the child’s calendar age showed strong statistical associations. Conclusions The findings of this qualitative research embedded in a natural history study add to the current understanding of MPS IIIA as a complex disease that impacts every aspect of the lives of children and their families. This study demonstrates the unique potential of mixed methods research in rare diseases to address some of the current limitations of more traditional quantitative approaches by providing an individualized, detailed understanding of the patient experience.

Objective To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy‐causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype‐phenotype‐physiological correlations. Methods Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole‐exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the Kv3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two‐electrode voltage clamping were used. Results Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole‐cell current, but no dominant‐negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole‐cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance. Interpretation These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.

International audience; Hereditary spastic paraplegias (HSP) are heterogeneous disorders, with more than 70 causative genes. Variants in SPAST are the most frequent genetic etiology and are responsible for spastic paraplegia type 4 (SPG4). Age at onset can vary, even between patients from the same family, and incomplete penetrance is described. Somatic mosaicism is extremely rare with only three patients reported in the literature. We report here SPAST mosaic variants in four unrelated patients. We confirm that mosaicism in SPAST is a very rare event with only four identified cases on more than 300 patients with a SPAST variant previously described by our clinical diagnostic laboratory.

Background and ObjectivesTo determine common clinical and biological traits in 2 individuals with variants in ISCU and FDX2, displaying severe and recurrent rhabdomyolyses and lactic acidosis.MethodsWe performed a clinical characterization of 2 distinct individuals with biallelic ISCU or FDX2 variants from 2 separate families and a biological characterization with muscle and cells from those patients.ResultsThe individual with FDX2 variants was clinically more affected than the individual with ISCU variants. Affected FDX2 individual fibroblasts and myoblasts showed reduced oxygen consumption rates and mitochondrial complex I and PDHc activities, associated with high levels of blood FGF21. ISCU individual fibroblasts showed no oxidative phosphorylation deficiency and moderate increase of blood FGF21 levels relative to controls. The severity of the FDX2 individual was not due to dysfunctional autophagy. Iron was excessively accumulated in ISCU-deficient skeletal muscle, which was accompanied by a downregulation of IRP1 and mitoferrin2 genes and an upregulation of frataxin (FXN) gene expression. This excessive iron accumulation was absent from FDX2 affected muscle and could not be correlated with variable gene expression in muscle cells.DiscussionWe conclude that FDX2 and ISCU variants result in a similar muscle phenotype, that differ in severity and skeletal muscle iron accumulation. ISCU and FDX2 are not involved in mitochondrial iron influx contrary to frataxin.

An amendment to this paper has been published and can be accessed via the original article.

BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (ppp=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937). ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.

5-Amino-4-imidazolecarboxamide-ribosiduria (AICA)-ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH (ATIC), which catalyzes the last two steps of de novo purine synthesis. It is characterized biochemically by the accumulation of AICA-riboside in urine. AICA-ribosiduria had been reported in only one individual, 15 years ago. In this article, we report three novel cases of AICA-ribosiduria from two independent families, with two novel pathogenic variants in ATIC. We also provide a clinical update on the first patient. Based on the phenotypic features shared by these four patients, we define AICA-ribosiduria as the syndromic association of severe-to-profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante-postnatal growth impairment, and severe scoliosis. Dysmorphic features were observed in all four cases, especially neonatal/infancy coarse facies with upturned nose. Early-onset epilepsy is frequent and can be pharmacoresistant. Less frequently observed features are aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis. Alteration of the transformylase activity of ATIC might result in a more severe impairment than the alteration of the cyclohydrolase activity. Data from literature points toward a cytotoxic mechanism of the accumulated AICA-riboside.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutieres syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate. Yanick J. Crow acknowledges The University of Maryland Brain and Tissue Bank of the NIH NeuroBioBank. Yanick J. Crow acknowledges the European Research Council (786142-E-T1IFNs), a state subsidy managed by the National Research Agency (France) under the "Investments for the Future" program bearing the reference ANR-10-IAHU-01 and the MSDAvenir fund (DEVO-DECODE Project). Tracy A. Briggs acknowledges the National Institute for Health Research (NIHR; NIHR Transitional Research Fellowship, TRF-2016-09-002; with the views expressed were those of the author and not necessarily those of the NHS, the NIHR or the Department of Health). Adeline L. Vanderver is supported by the Kamens endowed chair for Translational Neurotherapeutics and the Myelin Disorders Bioregistry Project. Adeline L. Vanderver and Laura A. Adang acknowledge the CURE Pennsylvania Frontiers in Leukodystrophy grant and U01HD082806. Laura A. Adang also acknowledges the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. Lien Van Eyck received funding from Research Foundation Flanders (FWO).

Background Niemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (Clinical Trials.gov ID: NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥ 3 weeks. Intraclass correlation coefficients (ICCs) were calculated. Results Of the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (± SD) increase in 5-domain NPCCSS scores of 1.4 (± 2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (± SD) progression of 2.7 (± 4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p p p = 0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p = 0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient = 0.265, p = 0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC = 0.995) and intra-rater reliability (ICC = 0.937). Conclusions Progression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals. Trial registration CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030; EudraCT 2014–005,194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE. OR-REL-NPC-01: Unregistered.

Background Carpal tunnel syndrome (CTS) is a common complication of the mucopolysaccharidoses. In severe or attenuated mucopolysaccharidoses patients, clinical symptoms of CTS usually appear at a late stage of median nerve compression. Relying on CTS symptoms is often too late and there is a risk of axonal damage and further irreversible sequelae. Electroneurography is a powerful technique to detect the initial preclinical signs of median nerve compression. In a retrospective series of 13 children with mucopolysaccharidoses (10 Hunter, one Hurler-Scheie and 2 Hurler children), we describe the electroneurography progression of CTS (43 hand evaluations) and the severity of median nerve damage. Results The average age at mucopolysaccharidoses diagnosis was 33.6 months (11–66 months). Clinical signs of CTS appeared on average 44.6 months (0–73 months) after diagnosis of mucopolysaccharidoses. Electroneurography anomalies suggestive of CTS appeared as early as the age of 3.5 years and probably preceded clinical signs of CTS. Median nerve compression was bilateral and distal, initially on the sensory pathway then becoming motor-sensory. Beyond a threshold of 14 m/sec median distal motor nerve conduction velocity (MNCVd) and index of terminal latency (MNCVd/MNCVp) of 0.27, there was true distal conduction slowdown. Conclusions To prevent irreversible sequelae of median nerve compression, we suggest annual electroneurography testing for mucopolysaccharidoses patients starting as early as 3 years of age, including both motor and sensory nerve pathways, on median and, in reference to the ulnar nerves, bilaterally at the wrist and the elbow. Timely surgical intervention can greatly improve the overall function and quality of life of these patients.

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. Electronic supplementary material The online version of this article (10.1007/s10545-018-0185-0) contains supplementary material, which is available to authorized users.

Introduction Les mucopolysaccharidoses (MPS) sont des maladies de surcharge lysosomale : il s’agit de maladies genetiques rares (1/25 000 a 30 000 naissances). Ces maladies ont une evolution chronique, progressive et multisystemique avec des symptomes pouvant debuter des la petite enfance, voire avant la naissance. L’esperance de vie des patients atteints est raccourcie [1] . La cohorte RaDiCo-MPS porte sur les differents types de MPS : MPS-I, MPS-II, MPS-III, MPS-IV, MPS-VI, MPS-VII, MPS-IX et DMS. Elle est soutenue par la plateforme RaDiCo qui est un programme national du plan d’investissement d’avenir, developpe a l’INSERM U933, finance par l’ANR et dedie a la construction et a l’analyse de cohortes longitudinales de patients atteints de maladies rares. Depuis 2015, en partenariat avec les centres de competences, de References et les filieres de sante maladies rares, RaDiCo construit, enrichit et analyse des collections de donnees en vie reelle [2] . L’objectif de RaDiCo-MPS est de constituer une base de donnees prospectives et retrospectives s’inscrivant dans la recherche de l’amelioration de la prise en charge et de l’organisation des soins. Le developpement de traitements specifiques pour certains types de MPS a permis d’ameliorer les perspectives d’evolution des patients [3] . En partenariat avec la cohorte, un projet de recherche specifique portant sur l’effet de l’enzymotherapie chez les patients atteints de MPS-II est en cours. Methode La population d’etude concerne tout patient (adulte ou enfant) avec un diagnostic confirme de MPS ou de maladie d’Austin (DMS) ayant un consentement eclaire signe. Les donnees sont collectees de maniere anonymisee sur la plateforme Inserm RaDiCo, RGPD compatible, via REDcap, application web securisee avec une interface intuitive et un controle qualite du circuit des donnees [4] . La periode de recrutement est prevue pour durer 2 ans et le suivi 5 ans. Les Resultats presentes proviennent d’une extraction de la base de donnees du 27 janvier 2021. Resultats Au total, 254 patients MPS ont ete recrutes depuis decembre 2017 par 14 centres francais dont 55 % des patients par 3 centres (Trousseau-AP–HP, Necker-AP–HP et La Timone-AP–HM). Les trois-quarts des patients etaient de type MPS-I, MPS-II ou MPS-III et aucun patient MPS-IX n’avait ete inclus ( Fig. 1 et Fig. 2 ). A l’inclusion, 76 % des patients etaient vivants et 24 % concernaient des dossiers retrospectifs de patients decedes. Parmi les 69 patients atteints de MPS-II, un seul patient etait de sexe feminin (1 %) ( Tableau 1 ). L’ensemble des moyennes et des medianes de l’âge au diagnostic etait inferieur a 10 ans, indiquant que, globalement, il s’agit plus souvent de maladies debutant dans l’enfance ( Fig. 3 ). Pour les patients retrospectifs, l’âge moyen de deces etait compris entre 8,8 ± 5,8 ans (MPS-I) et 24,2 ± 3,8 ans (DMS) ( Fig. 4 ). La moitie des patients (52 %, n = 132) avait recu au moins une fois pendant l’etude un traitement specifique de correction de deficits enzymatiques (58 % MPS-I, 77 % MPS-II, 7 % MPS-III, 83 % MPS-IV et 27 % MPS-VI) ( Tableau 2 ). Conclusion Le suivi des patients n’etant pas acheve, les Resultats presentes sont preliminaires. RaDiCo-MPS est une opportunite unique d’acquerir une meilleure connaissance des differents types de MPS, de leur histoire naturelle aux effets des traitements specifiques ou non, ainsi que de la qualite de vie.

International audience; Lipoic acid (LA) is the cofactor of the E2 subunit of mitochondrial ketoacid dehydrogenases and plays a major role in oxidative decarboxylation. De novo LA biosynthesis is dependent on LIAS activity together with LIPT1 and LIPT2. LIAS is an iron-sulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III. All of them harbor at least one [Fe-S] cluster and their activity is dependent on the mitochondrial [Fe-S] cluster (ISC) assembly machinery. Disorders in the ISC machinery affect numerous Fe-S proteins and lead to a heterogeneous group of diseases with a wide variety of clinical symptoms and combined enzymatic defects. Here, we present the biochemical profiles of several key mitochondrial [Fe-S]-containing proteins in fibroblasts from 13 patients carrying mutations in genes encoding proteins involved in either the lipoic acid (LIPT1 and LIPT2) or mitochondrial ISC biogenesis (FDX1L, ISCA2, IBA57, NFU1, BOLA3) pathway. Ten of them are new patients described for the first time. We confirm that the fibroblast is a good cellular model to study these deficiencies, except for patients presenting mutations in FDX1L and a muscular clinical phenotype. We find that oxidative phosphorylation can be affected by LA defects in LIPT1 and LIPT2 patients due to excessive oxidative stress or to another mechanism connecting LA and respiratory chain activity. We confirm that NFU1, BOLA3, ISCA2 and IBA57 operate in the maturation of [4Fe-4S] clusters and not in [2Fe-2S] protein maturation. Our work suggests a functional difference between IBA57 and other proteins involved in maturation of [Fe-S] proteins. IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3. Finally, our study establishes different biochemical profiles for patients according to their mutated protein.

Resume Le syndrome de Joubert est une malformation rare d’origine genetique qui touche le cervelet et le tronc cerebral. Afin d’etudier ses retentissements sur le developpement cognitif, nous avons evalue le developpement psychomoteur de six enfants, âges en moyenne de 23 mois, et l’efficience intellectuelle de 17 enfants et adolescents, âges en moyenne de 8 ans, atteints de ce syndrome. Nos resultats ont montre une heterogeneite intra- et inter-individuelle des profils developpementaux et cognitifs. En ce qui concerne le developpement psychomoteur, seul un enfant presentait un retard global. Sur les six enfants, cinq presentaient un retard postural, trois un retard de coordination visuomotrice et trois un retard au niveau du langage et de la socialisation. Au niveau cognitif, huit sujets presentaient une deficience intellectuelle. Parmi les autres sujets, les troubles cognitifs etaient frequents et caracterises par une predominance de troubles neurovisuels, praxiques, langagiers et attentionnels. La frequence des troubles et la diversite des profils mettent en evidence l’importance d’un suivi neuropsychologique systematique pour les enfants souffrant d’un syndrome de Joubert.

Introduction Les atteintes musculaires isolees des maladies mitochondriales sont souvent liees a des modifications de l’ADN mitochondrial. Voici une observation de myopathie mitochondriale (MM) due a une mutation du gene nucleaire FXDL1. Observation Nous rapportons l’observation d’une patiente âgee de 21 ans, ayant un developpement psychomoteur normal et des antecedents d’embolie pulmonaire et de cholecystite aigue. A partir de l’âge de 6 ans, elle a presente des episodes de rhabdomyolyse (CPK jusqu’a 100 000 UI/L) associes a une acidose lactique majeure (lactacidemie entre 3,76 et 18,4 mmol/L). La frequence de ces episodes etait de deux a trois par an, avec de severes complications (insuffisances renales aigues et arret cardio-respiratoire). La frequence de ces episodes a progressivement diminue, sans recidive depuis l’âge de 18 ans. Il s’y associait une discrete faiblesse musculaire proximale des membres superieurs, et une intolerance a l’effort. Le profil des acylcarnitines etait normal, mais la chromatographie des acides organiques urinaires retrouvait une augmentation des acides 3 methyle glutaconique et 3 methyle glutarique (3-MG). Une premiere biopsie musculaire (BM) realisee a 6 ans etait normale, mais une seconde biopsie (18 ans), retrouvait un deficit severe des activites SDH et COX avec une surcharge lipidique. L’analyse en exome de l’ADN nucleaire a detecte une mutation pathogene homozygote du gene FDX1L (c.1A > T (M/L)). Discussion Le gene FXDL1 code pour la ferredoxine mitochondriale 2 (Fxd2), permettant l’assemblage des complexes Fer-Souffre ([Fe-S]). Un seul autre cas a ete rapporte avec une mutation de ce gene, avec un tableau clinique similaire, une augmentation d’acide 3-MG urinaire et un deficit severe en SDH sur la BM. D’autres tableaux similaires sont decrits chez les patients avec mutations du gene ISCU, participant aussi a l’assemblage des complexes [Fe-S]. Conclusion Les MM dues aux mutations du gene FDXL1 montrent des caracteristiques cliniques, biologiques et pathologiques originales : dominance d’episodes de rhabdomyolyse, d’acidose lactique et un deficit en activite SDH sur la BM.

Background Knowledge of the health status and care management of elderly individuals with polyhandicap* is lacking; however, a better understanding of the natural course of ageing in persons with severe and complex disability would help optimize preventive and curative care management strategies. Objectives To describe persons with severe and complex disability aged 18–68 years by providing i) a description of their health status and ii) a description of their medications, medical devices and rehabilitation procedures. Methods This was an 18-month cross-sectional study including people aged 18–68 years with a combination of severe motor deficiency and profound intellectual impairment. They were recruited from 4 specialized rehabilitation centres, 9 residential facilities, and a neurological department. The following data were collected: aetiology of severe and complex disability, health status, medical devices, and rehabilitation procedures. Results A total of 474 persons with severe and complex disability were included (N = 219 [18–34 years], N = 151 [35–49 years], N = 104 [50–68] years). The aetiology of severe and complex disability was unknown for 13%–17% of persons with severe and complex disability across the 3 age classes. Behavioural disorders and pain were more frequent in the oldest age classes. Elderly persons with severe and complex disability had more severe but less unstable severe and complex disability. Their neurodevelopmental was close to that of a 4-month-old child without progression across age. Gastrostomy was the most frequent device needed by the persons with severe and complex disability. Conclusions The longevity of persons with severe and complex disability is improving; some of these persons, among whom are the least unstable and with less comorbidity, can survive for more than 50 years due to the improvement of preventive actions and supportive care.

To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).