Participation française à la SSIEM

Participation françaises

Animation de sessions

ERNDIM Workshop & Meeting. - Chair : Christine Vianey-Saban, France

SSIEM 2023 Symposium Opening  - Chairs: Manuel Schiff, France; Yair Anikster, Israel

SSIEM Nutrition & Dietetics A Session - Chairs: Rani Singh, USA; Bénédicte Samba, France.

What can pediatricians learn from adult IEM. - Fanny Mochel, France.

Update on therapeutic options for adult patients with IMDsLeriglitazone in adult patients with cerebral forms of X-linked adrenoleukodystrophy - Fanny Mochel, France


Communications orales

  • Enasidenib treatment in two individuals with D-2-hydroxyglutaric aciduria carrying a germline IDH2 mutation1

Manuel Schiff1,2,, Birgit Geoerger3,4,, Virginie Penard-Lacronique5, Niklas Darin6, Selim-Maria Saad7, Clarisse Duchon1, Antonin Lamazière8, Aurore Desmons8, Clément Pontoizeau1,2,9, Pablo Berlanga3, Stéphane Ducassou10, Katharine Yen11, Michael Su11, David Schenkein11, Chris Ottolenghi1,2,9, Stéphane De Botton5,12

D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. We report herein the results of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder.


  • Pubertal origin of growth retardation in Inborn Errors of Protein Metabolism: A longitudinal cohort study

Kanetee Busiah1, 2, Celina Roda3, Anne-Sophie Crosnier4, Anais Brassier2, Aude Servais2, Camille Wicker2, 5, Sandrine Dubois2, Murielle Assoun2, Claire Belloche2, Chris Ottolenghi6, Clement Pontoizeau6, Jean-Claude Souberbielle7, Marie-Liesse Piketty7, Laurence Perin4, Yves Le Bouc4, 8, Jean-Baptiste Arnoux2, Irene Netchine4, 8, Apolline Imbard6, Pascale de Lonlay2, 9

Background: Inherited amino-acid metabolism disorders (IAAMDs) require lifelong protein-restricted diet. We aimed to: 1/ describe growth, pubertal, bone mineral density (BMD) or body composition in IAAMDs 2/ investigate associations linking height with amino-acid mixture (AAM) and plasma amino-acids.

Methods: Retrospective longitudinal study of 213 patients with neonatal-onset urea cycle disorders (UCD, n=77), organic aciduria (OA, n=89), maple syrup urine disease (MSUD, n=34), or tyrosinaemia type 1 (n=13). We collected growth parameters, pubertal status, BMD, body composition and protein-intake throughout growth.

Results: Overall final height (n=69) was below target height: -0.9(1.4) vs. -0.1(0.9)SD, p<0.0001. Final height was≤-2SD in 17(25%) patients. Height≤-2SD was more common during puberty than during early-infancy and pre-puberty, in all subgroups of diseases: 32(23.5%) vs. 13(6.9%), p=0.0017; and vs. 18(10.7%), p<0.0001. Pubertal delay was frequent in males: 14/32(43.8%) vs. 10/59(17.0%), p=0.0056. Height(SD) correlated positively with isoleucine concentration: β, 0.008; 95%CI, 0.003 to 0.012; p=0.001. In the pubertal subgroup, height(SD) was lower in patients with vs. without AAM supplementation: ‑1.22(1.40) vs. -0.63(1.46) (p=0.0182). In OA, height was lower during puberty in patients with vs. without AAM: -1.75(1.30) vs. -0.33(1.55)SD, p=0.0004, and median(IQR) isoleucine and valine concentrations(µmol/L) were lower in patients with vs. without AAM supplementation: 40(23) vs. 60(25) (p=0.0179) and 138(92) vs. 191(63) (p=0.0142), respectively. Total body BMD Z-score was≤-2.0 in 26(34%) patients. Lean-mass index was lower than fat-mass index: ‑2.03(1.15) vs. -0.44(0.89), p<0.0001.

Conclusions: In IAAMDs, growth retardation worsened during puberty which was delayed. Height in OA correlated with AAM supplementation and Isoleucine concentration were isoleucine and valine concentrations were lower. We recommend considering puberty when prescribing protein intake.


  • Activating mutation of the Glucokinase gene in Hyperinsulinemic Hypoglycemia : phenotype and genotype in 9 adult patients.

Claire Douillard1, 2, Linda Humbert1, 2, Karine Mention2, Isabelle Fajardy1, 3, Dries Dobbelaere2, Madleen Lemaitre1, Arnaud Jannin1, Marie-Christine Vantyghem1

Background: The glucokinase (GCK) gene is involved in the regulation of insulin secretion. An activating mutation of the GCK gene leads to hyperinsulinemia with hypoglycemia, often of a relatively mild character, which may explain the late diagnosis in some cases. This study aims to describe the phenotype of 9 patients diagnosed in adulthood, originating from 6 unrelated families.

Methods: The study includes the description of the phenotype and results of biological investigations: fasting and postprandial glucose/insulin/c-peptide (n=9), Fast Test (n=5), Oral Glucose Tolerance Test (OGTT) (n=7), and genotype.

Results: 1- Age at diagnosis: median of 30 years (minimum 19 years, maximum 36 years). 2- Age at first symptoms: before the age of 18 in 5/9 cases (at 5 years (n=1), at 12 years (n=1), during adolescence (n=3)). 3- Timing of hypoglycemia: both fasting and postprandial (n=7/9), with more severe hypoglycemia in the postprandial period in 6 of them, exclusively postprandial (n=2/9). 4- Lowest postprandial glucose value: 0.32 g/l. 5- Diazoxide treatment was required in 5 patients, including during pregnancy. 6- Molecular analysis (n=9/9): identification of 4 activating mutations of the GCK gene, including one not previously reported in the literature (c.205T>A (p.Ser69Thr), exon 2).

Conclusion: Hypoglycemia revealing an activating mutation of the GCK gene mainly occurs in the postprandial period but can also occur in the fasting state with few symptoms. The age of onset of hypoglycemia and phenotype severity vary from one mutation to another and within the same family. This condition is the leading cause of genetic hyperinsulinism diagnosed in adulthood and follows an autosomal dominant inheritance pattern.


  • Prospective, multicenter validation of a simple blood

test for the diagnosis of Glut1 deficiency syndrome

Fanny Mochel1, 2, Domitille Gras2, Marie-Pierre Luton1, Manon Nizou3, Donatella Giovannini4, Caroline Delattre1, Melodie Aubart5, Magalie Barth6, Anne de Saint Martin7, Diane Doummar8, Noura Essid9, Alexa Garros10, Caroline Hachon-Le Camus11, Celia Hoebeke12, Sylvie Nguyen the Tich13, Maximilien Perivier14, Serge Rivera15, Anne Rolland16, Agathe Roubertie17, Catherine Sarret18, Caroline Sevin2, 19, Dorothee Ville20, Marc Sitbon4, Jean-Marc Costa21, Roser Pons22, Angeles Garcia-Cazorla23, Sandrine Vuillaumier-Barrot24, Vincent Petit3, Odile Boespflug-Tanguy25, Darryl De Vivo26

GLUT1 deficiency syndrome (Glut1DS) is a treatable neurometabolic disease that causes a wide range of neurological symptoms in children and adults. However, its diagnosis relies on an invasive test, i.e., a lumbar puncture (LP) to measure glycorrhachia, and, sometimes complex, molecular analyses of the SLC2A1 gene. This procedure limits the number of patients able to receive the standard of care. We wished to validate the diagnostic performance of METAglut1™, a simple blood test that quantifies GLUT1 at the erythrocyte surface.

We performed a multicenter validation study in France, involving 33 centers. We studied two patient cohorts: a prospective cohort, consisting of patients with a clinical suspicion of Glut1DS explored through the reference strategy, i.e., LP and analyses of the SLC2A1 gene; a retrospective cohort that included patients previously diagnosed with Glut1DS. All patients were blind-tested with METAglut1™.

We analyzed 428 patients in the prospective cohort, including 15 patients newly diagnosed with Glut1DS, and 67 patients in the retrospective cohort. METAglut1™ was 80% sensitive and >99% specific for the diagnosis of Glut1DS. Concordance analyses showed a substantial agreement between METAglut1™ and glycorrhachia. In the prospective cohort, the positive predictive value of METAglut1™ was slightly higher than that of glycorrhachia. METAglut1™ succeeded to identify patients with Glut1DS with SCL2A1 mosaicism and variants of unknown significance.

METAglut1™ is an easily performed, robust and non-invasive diagnostic test for the diagnosis of Glut1DS, which allows a wide screening of children and adults, including those with atypical forms of this treatable condition.

Classification of Evidence
This study provides class I evidence that a positive METAglut1™ test accurately distinguishes patients with suspected GLUT1 deficiency syndrome from other neurological syndromes as compared to invasive and genetic testing.


  • Standardized protocols to optimize the emergency management of patients with inherited metabolic diseases in France.

Camille Wicker1, 2, Juliette Bouchereau3, 1, 4, Karine Mention1, 4, 5, Marianne Jaroussie3, Aline Cano1, 4, 6, Jeremy Do Cao1, 4, 7, Magali Gorce1, 8, Alexa Garros1, 9, Alice Kuster10, Celia Hoebeke6, Clotilde Marbach3, 1, 4, Claire-Marine Dufeu-Berat3, 1, 4, Claire Mayer3, 1, 4, Anais Brassier3, 1, 4, Laurent Gouya11, Cecile Schrimpf12, Jean-Baptiste Arnoux3, 1, 4, Manuel Schiff3, 1, 4, 13, Cecile Acquaviva-Bourdain14, Jean-Franois Benoist15, Azza Khemiri1, 4, Sandy Courapied3, 1, 4, 17, Pierre Broue1, 8, Mehdi Oualha1, 16, Claire Douillard1, 4, 5

Background: Among over one thousand different inherited metabolic disorders (IMDs), many of them are at risk of metabolic decompensation: patients may need emergency hospital care to prevent life-threatening situations but the healthcare professionals (HCPs) initiating emergency treatment may be unfamiliar with these disorders. Here we describe how a multidisciplinary working group from the French G2M rare disease network has developed short and standardized emergency protocols to provide HCPs with highly practical guidance for the immediate management of children or adults with IMDs at risk of acute decompensation and for practical information in case of hospitalisation.

Methods: The project was initiated by the implementation of a multidisciplinary group of experts in IMDs. The group has been meeting by videoconference once a month since January 2020. The content of each emergency protocol was mostly based on expert opinions and healthcare experience gained within the G2M rare disease clinical network. A bibliographic search was performed if needed, and emergency guidelines from the British Inherited Metabolic Diseases Group (BIMDG) were consulted when appropriate. Before validation, protocols were reviewed by all French reference and competence centres of IMD, by colleagues from other specialties when necessary, by physicians from emergency and intensive care units, and by patient associations.

Results: In total, 35 emergency protocols containing key information have been created for one disease or a group of related diseases, or for one symptom, and given to concerned patients or physicians, respectively. All the emergency protocols are also freely available in French and in English on G2M website. They are also presented to emergency physicians and personnel via webinars and conferences. These protocols are in A4 double-sided paper format, with a constant outline: emergency clinical and biological workup, treatment to be started urgently, orientation according to the severity of the signs, monitoring under treatment, pathophysiology, circumstances in which there is a risk of decompensation, assistance with practical administration of treatments, drug contraindication, surgery advices, centre’s contact information.

Conclusion: These standardized protocols are expected to improve the quality of emergency care of patients, help HCPs emergency decision-making and to saves them time and stress. Moreover, they should limit the waking up of on-call physicians from centres of expertise during the night, thus reducing the risk of errors in infusion calculations and physician burnout. The protocols are planned to be reviewed annually to allow for further improvements according to HCP and patient feedback, and for possible changes in management due to evolving practices.


  • Single AAV gene therapy with mini-GDE for glycogen storage disease type IlI

Antoine Gardin1, 2, Jeremy Rouillon1, 2, Montalvo-Romeral Valle1, 2, Rossiaud Lucille1, 2, 3, Patrice Vidal1, 2, Romain Launay4, Mallaury Vie1, 2, Youssef Krimi Benchekroun1, 2, Berangere Bertin1, 2, Guillaume Dubreuil1, 2, Justine Nozi1, 2, Louisa Jauze1, 2, Romain Fragnoud1, 2, Nathalie Daniele1, Laetitia Van Wittenberghe1, Jeremy Esque4, Isabelle Andre4, Xavier Nissan3, Lucile Hoch3, Giuseppe Ronzitti1, 2

Background. Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart, due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists, and gene therapy appears as a promising approach. The 4.6 kb GDE cDNA size represents the major technical challenge toward the development of a clinically relevant gene therapy strategy based on recombinant adeno-associated virus (rAAV)-derived vector. Clinical translation of the proposed alternative approaches using a bacterial GDE ortholog or dual vectors are limited by immune responses and the high vector doses required.

Methods. Using molecular modelling and the existing information on missense variants described in the AGL gene, we developed a truncated GDE transgene retaining activity suitable for a single rAAV vector strategy. This approach was then evaluated in two rodent models of GSDIII as well as in a cellular model of the human muscle disease.

Results. Among the truncated GDE generated, the N-terminal-truncated mutant ∆Nter2-GDE had a similar efficacy in vivo compared to the full-size GDE enzyme. An rAAV vector bearing the truncated GDE transgene allowed complete glycogen clearance in heart and muscle of Agl-/- mice three months after intravenous injection, as well as normalization of histology features and restoration of muscle strength. Similarly, glycogen accumulation and muscle histology were corrected in a recently generated Agl-/- rat model. Finally, transduction with rAAV vectors encoding ∆Nter2-GDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of GSDIII derived from induced pluripotent stem cells.

Conclusion. Our results demonstrate the ability of a single rAAV approach using a functional truncated GDE transgene to correct the muscle and heart phenotype in multiple models of GSDIII, supporting its clinical translation to GSDIII patients.


  • Correlation between cardiopulmonary exercise tests and biochemical parameters in patients affected by fatty acid oxidation disorders

Apolline Imbard1, 2, Antoine Legendre3, Hortense De Calbiac4, Pascal Laforet5, Marjolene Straube4, Manuel Schiff6, 7, Anais Brassier6, Clement Pontoizeau1, 7, Chris Ottolenghi1, 7, Edouard Le Guillou1, Elise Lebigot8, Stephanie Gobin9, Cecile Acquaviva10, Jean-Francois Benoist1, 2, Caroline Tuchmann-Durand11, Pascale de Lonlay4, 6

Background: Patients with fatty acid oxidation disorders (FAOD) present various symptoms ranging from hepatic and cardiac symptoms in infancy to later muscle manifestations. The symptoms result from an impairment in the ATP metabolism and in the toxicity of accumulated mitochondrial FAO intermediates, especially during catabolic situations. The major issue is the absence of specific and sensible clinical or biological tools available to evaluate metabolic equilibrium. Cardiopulmonary exercise tests (CPETs) can provide an indirect reflection on mitochondrial function by calculating the slope of the relationship between cardiac output and oxygen utilization (VO2) during exercise (dQ/dVO2 slope). Our study aimed to evaluate CPETs as a marker of the FAOD severity.

Methods: We retrospectively collected clinical, biological and treatment data during the follow-up of patients with FAOD older than 6 years-, including a score of severity of the disease, plasma acylcarnitines and CPETs. A high dQ/dVO2 slope (> 5) is observed when the oxidative phosphorylation of exercising skeletal muscles is impaired.

Results: 27 patients with FAOD followed between 2015 and 2022 were included with a deficiency in LCHAD (n=10), CPT2 (n=6), VLCAD (n=7), AG2 (n=4). CPT2D patients with a severe severity score showed significantly highest C18:1-, C16-, C18-acylcarnitines and dQ/dVO2. In these patients, dQ/dVO2 was significantly positively correlated with plasma C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/DVO2 was positively associated with the severity score (P=<0.008) whereas a tendency was observed for triheptanoine as a negative predictor(P=<0.074). No associations were found between severity score, acylcarnitines, treatments and CPETs in the other FAOD.

Conclusion: CPETs might be a useful tool in FAOD to monitor the disease, especially in CPT2D where it could reflect the toxicity of long-chain acylcarnitine/acyl CoA accumulation on mitochondrial functions.


  • Acute neurological symptoms in patients with PMM2-CDG: a link with perturbed hemostasis?

Camille Wicker1, 2, Charles Joris Roux3, 4, Yvan De Feraudy5, Louise Goujon2, Marie Hully6, Anais Brassier2, Claire Marine Berat2, Arnaud Wiedemann7, Lena Damaj8, Marie Therese Abi Warde1, 5, Dries Dobbelaere9, Agathe Roubertie10, Aline Cano11, Alina Arion12, Tiffanie Pascreau13, Anna Kaminska14, Sabrina Da Costa15, Marie Falampin15, Arnaud Bruneel16, Sandrine Vuillaumier16, Nathalie Boddaert3, 4, Delphine Borgel13, Manoelle Kossorotoff6, Annie Harroche17, Pascale De Lonlay2, 3, 18

Objectives. Patients with PMM2-CDG display peripheral or cerebral acute events (stroke like episodes (SLE), thrombosis, hemorrhages, seizures, migraines), associated with abnormal coagulation factors (factor XI, antithrombin, proteins C and S). Practical guidelines are lacking.

Methods. In a multicentric retrospective study, we described the clinical, radiological, coagulation and electroencephalography data from PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, hemorrhage, SLE, or “Stroke Mimic” (SM).

Results. Thirteen patients had a total of 30 acute episodes: 27 cerebral events (7 SLE, 5 venous thrombosis, 4 hemorrhages (3 associated with thrombosis), 15 SM) at a mean age of 7.7 years, and 3 peripheral thrombosis with or without bleeding. A trigger was frequent (infection, head trauma). During these episodes, coagulation factor levels were low, whereas they could be normal under baseline conditions. No correlation was found between coagulation factor levels and the type of acute events.

Discussion. The risk of acute events in PMM2-CDG is not negligible, related to abnormalities of hemostasis. We wrote an emergency protocol with a specialized team of hemostasis physicians ( In cerebral events, Brain MRI with PWI (Perfusion Weight Imaging) and diffusion sequences, EEG and coagulation factors lead to treatment, e.g. anticoagulants, antithrombin, fresh frozen plasma infusion depending of the diagnosis. Preventing treatment of bleeding and thrombosis is required in case of surgery, prolonged immobilization, or ovarian substitution treatment.

Conclusion: acute events occurring in PMM2-CDG are associated with abnormal coagulation factors and require an emergency protocol to provide practical guidance for the prevention and for the immediate management of patients.


  • Abnormal autophagy is a critical mechanism in TANGO2-related rhabdomyolysis

Hortense De Calbiac1, Sebastian Montealegre1, Marjolene Straube1, Loic Chentout1, Apolline Imbard2, Edouard Le Guillou2, Laure Caccavelli1, Arnaud Hubas2, Edor Kabashi3, Pascale de Lonlay1, 2

Background : Patients with pathogenic variants in the TANGO2 gene suffer from severe and recurrent rhabdomyolysis (RM) episodes precipitated by fasting. Since starvation promotes autophagy induction, we wondered whether TANGO2-related muscle symptoms result from autophagy insufficiency to meet cellular demands in stress conditions. 
Methods: Autophagy functioning was analyzed in vitro, in primary skeletal muscle cells from TANGO2 patients in basal and fasting conditions. We developed a tango2 morphant zebrafish model to assess the effect of tango2 knockdown (KD) on locomotor function and autophagy efficiency in vivo. We took advantage of both cellular and animal models to test the effect of the autophagy activator calpeptin on autophagy functioning and RM features.
Results: We report that TANGO2 mutations are associated with decreased LC3-II levels upon starvation in primary muscle cells, but not in fibroblasts. In zebrafish larvae, tango2 knockdown induces locomotor defects characterized by reduced evoked movements which are exacerbated by exposure to atorvastatin, a compound known to cause RM. Importantly, RM features of tango2 KD are also associated with autophagy defects in zebrafish. Calpeptin treatment, a known activator of autophagy, is sufficient to rescue the locomotor function and improves autophagy in zebrafish. LC3-II levels of primary muscle cells of TANGO2 patients are also ameliorated by calpeptin treatment, thus giving rise to new therapeutic perspectives in the prevention of life-threatening RM episodes in TANGO2 pathology.
Conclusion: Overall, we demonstrate that TANGO2 plays an important role in autophagy, the efficiency of which is critical to prevent RM.



  • The French Gaucher disease registry: clinical features, complications, and treatment trends of 688 patients.

Nadia Belmatoug1, Jerome Stirnemann2, Thierry Billette De Villemeur3, Karima Yousfi1, Samira Zebiche1, Dalil Hamroun4, Anais Brassier5, Laure Swiader6, Florence Dalbies7, Berengere Cador8, Anne-Sophie Guemann9, Francis Gaches10, Vanessa Leguy-Seguin11, Agathe Masseau12, Yves-Marie Pers13, Samia Pichard5, Marie Szymanowski14, Leonardo Astudillo15, Christine Serratrice16, Marc G Berger17, Fabrice Camou18, Yann Nadjar19


Gaucher disease (GD) is a rare autosomal-recessive lysosomal disorder caused by β-glucocerebrosidase deficiency. The prognosis of GD has considerably improved since the availability of enzyme replacement therapy (ERT) and oral substrate reduction therapy (SRT). In this study, we aimed to describe the characteristics, complications, and treatment evolution over three decades of patients with GD in France.


The French GD registry includes all known GD patients living in France. We divided the patients into three groups: (1) the entire cohort to describe the main baseline characteristics, (2) patients with at least one recorded treatment to describe the evolution of ERT and SRT prescriptions since their availability, and (3) patients with updated follow-up to describe the prevalence of GD complications and associated diseases.


As of March 2023, the FGDR included 688 GD patients (49% male, 81% type 1, 11% type 2, and 8% type 3). The median (IQR) ages at first symptoms and GD diagnosis were 12 (4-32) and 19 (3-63) years, respectively. The main baseline clinical manifestations were splenomegaly (94%), hepatomegaly (75%), fatigue (18%), and chronic bone pain (16%). Of the 688 patients, 115 (17%) had undergone splenectomy (54% before and 56% after GD diagnosis). The number of splenectomies decreased considerably over time, with only 8 performed after 2002 and none since 2011. Among the currently treated patients (n=311), 57% received Imiglucerase, 18% Velaglucerase, and 25% Eliglustat. Of the patients treated with ERT, 39% received treatment at home. Of the 212 patients with complete follow-up data, followed for a median (IQR) of 25 (14-37) years, 19 (9%) developed malignancies (13 solid cancers, 2 multiple myeloma, 2 lymphomas, and 2 myeloproliferative disorders). Parkinson`s disease developed in 10 (5%) patients at a median of 54 [46-62] years.


The registry enabled us to describe the epidemiology of GD in France, as well as the treatment evolution and the prevalence of GD complications and associated diseases.



  • Design of a phase 3 study of AAV-mediated gene transfer of ornithine transcarbamylase (OTC) in patients with late- onset OTC deficiency.

Jean-Baptiste Arnoux1, Laura L Konczal2, Maria Luz Couce3, Mireia del Toro4, Margreet Wagenmakers5, Andreas Schulze6, Joshua Baker7, T Andrew Burrow8, Norberto Guelbert9, Soledad Kleppe10, Gerald S Lipshutz11, Nicola Longo12, Shiro Matsumoto13, Janet A Thomas14, J Lawrence Merritt, II15

1 Necker-Enfants Malades University Hospital, APHP, Paris, France2 University Hospitals of Cleveland Medical Center, Cleveland, USA3 University of Santiago de Compostela, Santiago de Compostela, Spain
4 Hospital Universitari Vall d’Hebron, Barcelona, Spain
5 University Medical Center Rotterdam, Department of Internal Medicine, Center for lysosomal and metabolic diseases, Erasmus Medical Center, Rotterdam, Netherlands
6 University of Toronto and Hospital for Sick Children, Toronto, Canada
7 Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, USA
8 University of Arkansas for Medical Sciences, Pediatrics, College of Medicine, Little Rock, USA
9 Metabolic Diseases Service, Clínica Universitaria Reina Fabiola, Cordoba, Argentina
10 Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
11 University of California at Los Angeles (UCLA), Los Angeles, USA
12 University of Utah, Salt Lake City, USA13 Kumamoto University Hospital, Kumamoto, Japan14 University of Colorado School of Medicine and the Children’s Hospital Colorado, Aurora, USA
15 Ultragenyx Pharmaceutical Inc, Novato, USA

Objectives: OTC deficiency (OTCD) is an X-linked disorder that leads to acute hyperammonemia, which can result in brain damage and death. DTX301 is an investigational AAV8 vector containing the human wild-type OTC gene. Based on encouraging results from a phase 1/2 study of DTX301, a phase 3 study (NCT05345171) is underway to determine efficacy and confirm safety of DTX301 in patients ≥12 years old with late-onset OTCD.

Methods: This phase 3 randomized, double-blind, placebo-controlled trial will be conducted at ~30 sites worldwide and include ~50 patients ≥12 years old with a confirmed diagnosis of late-onset OTCD. Patients must be on a stable dose of nitrogen-scavenging agents and/or a stable protein-restricted diet for ≥4 weeks prior to screening and have no pre-existing antibodies to the AAV8 capsid.

Patients are randomized 1:1 to receive DTX301 or placebo at first. The DTX301 group will receive one DTX301 injection (IV) and prophylactic steroids on a 58-day taper regimen. The placebo group will receive one IV injection of normal saline and an oral placebo matched to the steroids. At Week 64 (W64), patients will crossover treatment and be followed for up to 260 weeks after receiving DTX301.

Primary endpoints at W64: 1) 24-hour plasma ammonia area under the curve; 2) percentage of patients achieving complete response (discontinuation of all nitrogen-scavenger therapy with no dietary protein restrictions and stabilized or improved plasma ammonia levels).

An unblinded central independent committee (CIC) of independent OTCD experts and a data monitoring committee (DMC) including an independent statistician and independent physicians will provide oversight and monitor patient safety.

Results: The study is ongoing. Multiple patients have been dosed.

Conclusion: This ongoing phase 3 study aims to determine efficacy and confirm safety of DTX301 in patients ≥12 years old with late-onset OTCD by monitoring clinical outcomes, hyperammonemic crises, and biochemical analytes.


  • Low Back Pain Revealing an Inborn Metabolic Disease: A Case Report.

Sarah Nicolas1, Adrien Bigot1, Delphine Chu Miow Lin2, Helene Blasco3, Roseline Froissart4, Nicole Ferreira-Maldent1, Alexandra Audemard-Verger1, Francois Maillot1

Background. Acute low back pain is mostly related to osteoarticular spinal diseases and occasionally to muscular diseases. We present a case of low back pain revealing a metabolic myopathy.

Case report. A 17-year-old man with a history of sensorineural hearing loss and Helicobacter pylori gastritis was admitted for acute disabling low back pain. Clinical examination showed stiffness and an edematous aspect of the lumbar paravertebral muscles. Walking was impossible because of the intensity of lumbar pain. Biochemical tests showed plasma CRP 202 mg/L and CKs 66,000 IU/L. The spinal MRI showed features of necrotising myofasciitis involving the erector spinae muscles of the lumbar iliocostalis, longissimus of the thorax, transverse spinous and square muscles of the lumbar spine, bilaterally extended opposite L1-S3. The muscle biopsy showed signs of complete muscle necrosis. The autoimmune workup, including dot-myositis, was negative. After analgesic treatment with morphine and rest, the pain regressed and the CKs decreased to 1948 IU/L. The subsequent evolution was clinically favorable and the MRI showed clear signs of muscle improvement. CKs remained high over time between 1116 and 1752 IU/L. Investigation showed that the patient had had exercise intolerance from childhood, with a clear limitation of sports activities. The grip test revealed an absence of elevation of lactacidaemia: 0.70 mmol/L before exercise and maximum at 1.18 mmol/L post-exercise, indicating McArdle’s disease. This diagnosis was confirmed by molecular analysis of the PYGM gene showing a compound heterozygosity c.1963GA/c.2178-1GA (2 pathogenic variants).

Discussion/conclusion. McArdle’s disease is a muscular glycogen storage disease (GSD 5) usually revealed by muscular intolerance to effort, including a "second wind" phenomenon that our patient did not clearly describe. Muscle involvement usually predominates in the lower limbs. The involvement of the paravertebral muscles of GSD 5 is not well known because it is rarely in the foreground of the clinical picture of GSD5, as in our case. Nevertheless, deficits in the paraspinal muscles have been described and recent MRI studies have shown that axial muscle damage is underestimated. Clinical involvement of the paraspinal muscles is rare in GSD 5. A revelation of the disease by acute rhabdomyolysis of the paraspinal muscles has not been described to date.


  • Baseline clinical characteristics and disease burden of patients with aromatic L-amino acid decarboxylase deficiency (AADCd) enrolled in the AADCAware registry.

Bruria Ben Zeev1, Agathe Roubertie2, Phillip L Pearl3, Fatih Ezgu4, Paul Lupo5, Emelline Liu5, Shelley Johnson5, J Rafael Sierra5, Roberto Giugliani6, Roberta Battini7, 8, Lucinda Carr9

Background: Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare, often life-limiting genetic neurotransmitter disorder. AADCAware is a patient registry designed to describe the natural history of AADCd in patients receiving standard of care and assess the long-term safety and effectiveness of eladocagene exuparvovec on motor function. Baseline demographics and disease characteristics of untreated patients up to March 2023, are described.

Methods: AADCAware is an international, multicenter, longitudinal, real-world, observational registry of patients with AADCd. Participants are followed up annually for ≥5 years. Motor development status was assessed using the Peabody Developmental Motor Scale-2 (PDMS-2).

Results: At enrolment, the study population (N=45) had a median (min, max) age of 3 (1, 41) years and were predominately White (29 [65.9%]). Median (min, max) ages at onset of first symptoms was 3 (0, 12) months. The most commonly reported central nervous system (CNS) signs and symptoms at enrolment were delayed motor and speech development (both 84.4%), delayed cognitive development (82.2%), hypotonia (77.8%), poor head control (68.9%), oculogyric episodes (57.8%), and hypokinesia/bradykinesia (48.9%). Common autonomic signs/symptoms included excessive sweating (46.7%), excessive drooling (40.0%), nasal congestion (31.1%), ptosis (28.9%), and temperature instability (24.4%). Patients also reported feeding/swallowing (46.7%), gastrointestinal (42.2%) and cardiovascular problems (13.3%). Of 31 patients with data, 24 (77.4%) had not developed full head control or were unable to sit unassisted and 25 (80.7%) were unable to stand or walk with support. Eleven patients (24.4%) discontinued the registry; 32 patients (71.1%) remain in the study; 2 patients (4.4%) died.

Conclusion: These results show that patients with AADC deficiency present with a wide spectrum of CNS and autonomic signs and symptoms. AADCAware will help to gain a better understanding of AADCd.


  • Neonatal AAV8 gene therapy successfully treats severe MSUD in Bckdhb-/- mice.

Manuel Schiff1, 2, Clement Pontoizeau3, 1, 2, Clovis Gaborit2, Nolan Tual2, Marcelo Simon-Sola2, Irina Rotaru2, Marion Benoist2, Pasqualina Colella4, Antonin Lamaziere5, Anais Brassier1, Jean-Baptiste Arnoux1, Agnes Rotig2, Chris Ottolenghi3, 1, 2, Pascale De Lonlay1, 6, Federico Mingozzi4, Marina Cavazzana2, 7

Background: Maple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder due to the dysfunction of the Branched-chain keto acid dehydrogenase (BCKD) enzyme which leads to accumulation of branched chain amino acids causing neonatal death if untreated. MSUD represents an unmet need as its current management is based on a life-long low-protein diet which, however, does not prevent the risk of acute decompensations and long-term neuropsychiatric impairments. We and others have tested AAV gene therapy in mice for two of the three genes involved in MSUD, BCKDHA and DBT. We developed herein a similar approach for the third MSUD gene, BCKDHB.1

Methods: We performed the first characterization of a Bckdhb-/- mouse model. We developed human BCKDHB AAV8 vectors under the control of an ubiquitous EF1α promoter. Animals were treated at birth with intravenous injection at 1014 vg/kg.

Results: The Bckdhb-/- mouse exhibited a lethal neonatal phenotype faithfully mimicking human MSUD. After neonatal injection, BCKDHB gene achieved long-term (> 6 months) rescue of the severe MSUD phenotype of Bckdhb-/- mice.

Discussion: These data further validate the efficacy of gene therapy for MSUD, here in Bckdhb-/- mice, demonstrating its potential for clinical translation.


  • A retrospective and prospective multicenter observational study of bone MRI changes in patients with type 1 Gaucher disease treated with velaglucerase alfa: the EIROS study.

Monia Bengherbia1, Marc G Berger2, Benedicte Hivert3, Florian Rigaudier4, Luc Bracoud5, Ole Vaeterlein6, Karima Yousfi1, Michele Maric7, Marie Malcles7, Nadia Belmatoug1

Background: Gaucher disease type 1 (GD1) is characterized by hepatosplenomegaly, thrombocytopenia, and bone manifestations, which cause major disability and require regular MRI monitoring to assess disease progression and treatment responses. The EIROS study (NCT03333447) was conducted to assess the real-world impact of velaglucerase alfa (VELA) on bone disease in GD1, using MRI data collected in french clinical practice.

Methods: MRIs collected retrospectively from VELA initiation and prospectively until the end of follow-up (12 months) were centrally analyzed by a blinded expert radiologist to evaluate the evolution of bone infiltration using the Bone Marrow Burden score (BMB) and a qualitative method (stable, improved, or worsened; scored for the spine and femur). Bone manifestations, hepatosplenomegaly, and hematologic parameters were analyzed from medical records.

Results: MRI data were available for 20 patients (pts): 6 pts were treatment-naive and 14 pts had switched to VELA from another GD1 treatment. Calculation of BMB scores was only possible for 8 pts for the spine, and 1 pt for the femur, due to inadequate MRI protocols. Qualitative assessments revealed improvements in spine and femur parameters in 80% and 60% of treatment-naive pts; n=5, respectively and stability in 100% and 84.6% of treatment-switched pts; n=13, respectively; no worsening of bone parameters was observed. Liver and spleen volumes and hematologic parameters remained stable in treatment-switched pts and improved in treatment-naive pts.

Conclusions: This study provided real-world evidence showing the long-term effectiveness of VELA for the treatment of GD, including for bone manifestations. The data suggest that if the assessment of MRI and BMB score by a radiologist with experience of GD bone manifestations is not possible, a simplified qualitative assessment provides sufficient evidence in daily clinical practice for the monitoring of bone disease progression and treatment response.


  • Qualitative study in adult and caregiver MPSI, I and VI patients: Understanding their challenges, needs and expectations.

Nathalie Guffon1, Delphine GENEVAZ2, Didier LACOMBE3, Eliane LE PEILLET FEUILLET4, Pascale BAUSSON5, Esther NOEL6, Francois MAILLOT7, Nadia BELMATOUG8, Roland JAUSSAUD9

Background: To improve adult MPS I, II and VI patient management and their caregiver’s support, it is important to understand their care pathways’ perception and identify their respective challenges, needs and expectations.

Method: A qualitative study was conducted, using in-depth interviews alternating spontaneous and more assisted collection phases allowing patients and/or caregivers to express themselves freely.

Results: 36 interviews were conducted. Based on disability, patients (median age 29 years [17–50]) were classified as Group A: 8 patients with severe cognitive impairment, Group B: 10 patients with low/absent cognitive impairment and high motor disability and Group C: 7 patients with low/absent cognitive impairment and low motor impairment). The information satisfaction received about the disease depended on the referral time to expert center and the diagnosis announcement quality. Less satisfied (42%) felt alone due to a lack of support and information. Regarding the impact on daily lives, Group A caregivers assessed very severe disability (8.8/10) and severely affected autonomy (8.5/10). Group B and C reported disability as severe (7.8/10) and moderate (5.5/10) and autonomy moderately decreased (6.4/10) and good (1.4/10), respectively. Pain management was one of the major unmet needs for patients and caregivers. Group A Caregivers wanted more support in finding disability-friendly hospitality facilities and Group B specialty schools, and better disease understanding by outreach care teams for more attentive listening. Group C patients emphasized need for greater flexibility in infusion schedules, including home infusions and more active psychological support.

Conclusion: Management at reference centers is particularly appreciated and preferable. However, more attention should be paid to psychosocial status, pain management, monitoring complications, setting up home infusion, identifying a referrer, and access to specialists with disease knowledge.


  • Long-term efficacy of velmanase alfa treatment in patients with alpha mannosidosis: updated integrated analysis of data from phase I/II, Ill, and follow-up clinical trials.

Benedicte Heron1, Allan M. Lund2, Line Borgwardt2, 3, Henriet Nienhuis4, Amer Joseph4, Feng Zhao4, Nathalie Guffon5

Background: rhLAMAN-10 (NCT02478840) was an integrated analysis of long-term efficacy in patients with alpha-mannosidosis who participated in the velmanase alfa (VA) clinical development program. Previously published data from rhLAMAN-10 (N=33) have now been updated with an additional 7 years of observation.

Methods: This updated analysis incorporated data from patients previously enrolled in VA clinical trials who continued treatment (1 mg/kg, once‑weekly) in long-term extension studies (rhLAMAN-07/rhLAMAN-09 [NCT01908712/NCT01908725]) or in a compassionate use program. Efficacy endpoints were changes in serum oligosaccharides (OLS) and IgG, endurance assessed with 3‑minute stair climb test (3MSCT) and 6‑minute walk test (6MWT), and pulmonary function (forced vital capacity [FVC], % predicted).

Results: Data from 33 patients (19 pediatric and 14 adult [≥18 years], mean age 17.1 [6–35] years) were included in the combined analysis. Mean (standard deviation) serum OLS decreased from baseline to last observation (LO [range] at 5.4 [1.0–11.8] years), with absolute and percentage changes of ‒4.16 (3.33) μmol/L and ‒55.5 (34.9) %, respectively. Mean serum IgG increased by 3.25 (2.08) g/L and 48.5 (27.9) %, p

Discussion/Conclusion: The effect of VA on efficacy outcomes was maintained over a long‑term period, with serum OLS and IgG similarly improved in adult and pediatric patients. Endurance and pulmonary function (corrected for age) improvements were more apparent in patients aged.


  • Measurement of lysosphingolipids in dried blood spots by LC-MSMS: a useful tool for the diagnosis of sphingolipidoses.

Julie Rochat1, Roseline Froissart1, Nathalie Guffon2, Alain Fouilhoux2, Bastien Ferreira1, Emilien Ville1, Severine Ruet1, Cecile Acquaviva-Bourdain1, Magali PETTAZZONI1

1 Biochemistry and Molecular Biology Department, Hospices Civils de Lyon, Bron, France
2 Reference Center for Inherited Metabolic Disorders, Femme Mère Enfant Hospital, Hospices Civils de Lyon, Bron, France

Background: In our laboratory, the diagnosis of Fabry disease (FD) in male patients, Gaucher disease (GD), Krabbe disease (KD) and acid sphingomyelinase deficiency (ASMD) is currently based on enzyme activity measurement in dried blood spots (DBS) (NeoLSD kit, Perkin Elmer). Lysosphingolipids (LysoSL) measurement can be helpful to establish the diagnosis, prior to molecular analysis, especially if the activity is decreased but not clearly deficient. The aim of the study was to set up a LC-MSMS method for the LysoSL measurement in DBS.

Case study / method: LysoSL from 220 unaffected controls, 34 male and 28 female FD, 23 GD, 4 KD and 19 ASMD patients were extracted from one single DBS punch, in a methanol/acetonitrile/water (80/15/5) mix containing internal standards (50 nM), at 45°C for 3 hours. LysoGb3, LysoHexCer, LysoSM and LysoSM509/PPCS were quantified by the LC-MS/MS method routinely used in plasma (Pettazzoni et al, 2017), but using a calibration curve in DBS. The method was validated according to the norm NF EN ISO 15189 and pre-analytical stability tests were carried out. A comparison with paired plasma when available was performed.

Results: For all LysoSL, intra-day and inter-day accuracies were under 15% and 30% respectively. Pathological thresholds were determined to optimize specificity and sensibility for each biomarker. A correlation between DBS and plasma was good for LysoGb3 and LysoHexCer, but poor for LysoSM and LysoSM509/PPCS. DBS lysoSL are stable 8 days, 2 weeks and more than 6 weeks, at room temperature, refrigerated, or frozen at -20°C respectively.

Discussion / Conclusion: LysoSL quantification in DBS was validated, and is useful for the diagnosis of sphingolipidoses, together with enzyme activity measurement and molecular analysis. The ability to perform these three different analyzes from a single DBS avoids additional sampling for the patient, and represents a significant time saving in the diagnostic process.


  • Cardiovascular Risk and Cardiac Disease in Adult Patients with Phenylketonuria: A Review.

Yann Dos Santos1, Francois Labarthe2, Francois Maillot3

Background. Some recent publications have suggested that adult patients with phenylketonuria (PKU) may have an increased cardiovascular (CV) risk. A specific cardiovascular phenotype is also questioned in these patients. The present study reviewed published data about cardiovascular issues in adults with PKU.

Methods. A literature search was performed on Pubmed using MeSH terms including (phenylketonuria AND cardiovascular risk) OR (phenylketonuria AND cardiovascular disease) OR (phenylketonuria AND vascular disease) OR (phenylketonuria AND atherosclerosis) OR (phenylketonuria AND heart disease) OR (Phenylketonuria AND obesity). Only articles in English were selected without any time range.

Results. The Pubmed search identified 253 articles and the most relevant papers suggested that adults with PKU cumulate CV risk factors compared to non-PKU controls. Indeed, the prevalence of dyslipidaemia, overweight/obesity, chronic ischaemic heart disease and diabetes is significantly higher in PKU patients compared to controls. CV features showed that adults with PKU, compared to controls, have thinner left ventricular walls, more dilated left ventricular cavity as well as lower ejection fraction and significant arterial stiffness correlated to phenylalanine levels.

Discussion/Conclusions. This literature review suggests that adult PKU patients have an increased risk of CV disease compared to non-PKU controls, as CV risk factors are more represented in these patients. Other factors associated with an increased CV risk have been studied but further investigations are needed as there are conflicting data about potential systemic low-grade inflammation in these patients. Data about increased homocysteine (Hcy) are also conflicting in children with PKU. Some other potential factors (oxidative stress, kynurenines pathway) may also be involved in CV risk and have to be studied specifically. A specific CV phenotype of PKU is also an emerging problem but requires confirmation. The potential negative effects of hyperphenylalaninemia on the CV system also require investigation. To date, only one study has suggested that phenylalanine could be involved in cardiac ageing.


  • Management of Inherited Metabolic Diseases in France.

Sandy Courapied1, Azza Khemiri1, Laurent Francois1, Aude Pion1, Jean-Meidi Alili1, Diogobe Ndao1, Celine Bensimon1, Nadia Belmatoug1, Pascale De Lonlay1

Background: Rare diseases affect more than 3 million people in France, constituting a major public health issue. The Ministry of Health is driving a proactive policy based on the mobilization of health/research professionals and patient associations in the field of rare diseases.

Methods: Since 2004, there have been three national plans dedicated to rare diseases. These national plans have led to a highly structured organization. In order to reduce wandering and diagnostic impasse, 109 multi-site centers of reference for the management of rare diseases (CRMR) have been labeled for the 2017-2022 period by the ministries in charge of health, research and innovation. They are composed of centers of competence (or resources and skills) and centers of reference, which provide care and organize the health pathways of people affected or suffering from rare diseases. These centers are coordinated by 23 rare diseases health networks, whose missions have been greatly expanded thanks to the third national plan for rare diseases.

Results: The G2M inherited metabolic diseases network is composed of nearly 18 rare diseases reference centers (CRMR) and 46 competence centers for a global follow-up (health, social and medico-social, research) of people with inherited metabolic diseases (IMD) spread throughout the country. In order to help health professionals from CRMR, CCMR and patient associations, the G2M team is composed of a medical coordinator, a project manager, 6 mission’s leaders from various professions and 6 clinical research assistants. The medical coordinator and the project manager are in charge of the animation and coordination of the network, help to achieve the objectives described by the PNMR, and act as a link between the network and the French ministry of health. With all health professionals from, two PhD are in charge of newborn screening project, data banks, projects on emergencies, multidisciplinary consultation meetings, national protocols for diagnosis and care including PNDS and diagnosis keys, communication and information; a pharmacist for the medicine, research and Europe missions and ensures the link with the national health insurance fund; a nurse for therapeutic education programs (TEP) related to lysosomal diseases; a dietician for TEP related to diet related-diseases and creation of tools for patients; a PhD student in psychology who is conducting a research on the psychological impact of the announcement of an inherited metabolic disease in the context of newborn screening and a mission leader dedicated to training and order processing.

Since 2019, we count 40 000 patients with IMD registered in the national database called BNDMR (, 20 published national protocols for IMD diagnosis and care (, 35 standardized protocols to optimize the emergency management of patients with IMD (, 5 TEP, and key tools for the newborn screening of 9 IMD were created ( The network helps to fight against diagnostic errancy by training and informing general practitioners and medical students. All G2M’s information and documents are available on a new website:

Conclusion: France has been a strong supporter of the fight against rare diseases for nearly 20 years and the role of Rare diseases networks is becoming more and more important.

A 4th rare disease plan (PNMR 4) is under construction by the ministry of health and will be published in 2024. It will guide the actions for the next 5 years.


  • Imprinted cell memory in glycogen storage disorder 1a patients fibroblasts.

Uri Sprecher1, Jeevitha D'Souza1, Kumudesh Mishra2, 3, Alexane Cannella4, Gilles Mithieux4, Fabienne Rajas4, Sigal Avraham5, Yair Anikster6, 7, Or Kakhlon2, 3, Miguel Weil1

1 The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty for Life Sciences, Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel
2 Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3 Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
4 Universite Claude Bernard Lyon 1, Universite de Lyon, INSERM UMR-S1213, Lyon, France
5 Department of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Department of Biomedical Engineering, School of Chemistry, Tel Aviv University, Tel Aviv, Israel
6 Edmond and Lily Safra Children's Hospital, Sheba Medical Center Tel-Hashomer, Ramat Efal, Israel
7 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Glycogen storage disorder type 1a (GSD1a) is caused by loss-of-function mutations in the catalytic subunit of glucose-6-phosphatase enzyme (G6PC1) in the liver, kidney and intestine exclusively. Here we show the surprising results that while not expressing G6PC1, primary skin fibroblasts isolated from GSD1a patients’ skin biopsies preserve a distinctive disease phenotype irrespective of the different culture conditions under which they grow. This discovery was initially made by phenotypic image-based high content analysis (HCA). Deeper analysis into this disease phenotype, revealed impaired lysosomal and mitochondrial functions in GSD1a cells, which were driven by a transcriptional dysregulation of the NAD+/NADH-Sirt1-TFEB regulatory axis. This dysregulation impacts the normal balance between mitochondrial biogenesis and mitophagy in the patients’ cells. The distinctive GSD1a fibroblasts phenotype involves elevated H3 K27 histone acetylation and global DNA hypomethylation suggesting that in some way the disease imprinted a distinctive cell phenotype in these cells. Remarkably, GHF201, an established glycogen reducing molecule, which ameliorated GSD1a pathology in a liver-targeted inducible L.G6pc-/- knockout mouse model, also reversed impaired cellular functions in GSD1a patients’ fibroblasts. Altogether, this experimental evidence strongly suggests that these cells express a strong and reversible disease phenotype without expressing the causal G6PC1 gene.


  • A prospective, longitudinal study of neurological disease trajectory in children with late-infantile and juvenile-onset GM1 or GM2 gangliosidoses (PRONTO): Interim results.

Roberto Giugliani1, Benedicte Heron2, Aurelie Bourchany3, Daniel Valle4, Rita Barone5, Brigitte Chabrol6, Andreas Hahn7, Paul Harmatz8, Spiros Batzios9, Susanne Schneider10, Marc Patterson11, Maurizio Scarpa12, Laura Lopez de Frutos13, Renata Quintela13, Ruben Giorgino13, Cecile Luzy-Paquet13

Background: GM1 and GM2 gangliosidoses are inherited lysosomal storage disorders caused by enzymatic deficiencies that lead to pathological ganglioside accumulation and progressive neurological dysfunction. Currently, no specific treatment is available and little is known about the clinical course, thus making the design of interventional trials challenging. Thence, the identification of suitable outcome measures for mapping disease progression is highly warranted.

Methods: The study was designed as a multicenter prospective neurological disease trajectory study, to monitor late infantile/juvenile GM1-GM2 patients. For all patients, demographic and medical information is collected. The assessments comprise Scale for Assessment and Rating of Ataxia (SARA), Time Up and Go (TUG), Inventory of Non-Ataxic Signs (INAS), swallowing test, and an e-diary (for seizures, chocking, and infections). Caregivers are asked to complete the Burden Scale for Family Caregivers and Vineland Adaptative Behavioral Scales.

Results: After 11 months, 19 patients have been enrolled, and 10 of them have been followed for at least 6 months. GM1-GM2 and female-male ratios were 0.9:1. Mean age at diagnosis was 6.0y (±3.9), and age at inclusion was 10.9y (±5.0). Most patients displayed severe motor impairment already at baseline (SARAscore: 30.4±9.3), reflecting their inability to perform TUG. All patients are cognitively impaired (36.8% severe) and only 3patients had normal swallow capability (15.8%). Most patients remained stable after 6 months of follow-up. Increased physical, emotional, and economic burden was reported by the caregivers (55.6%) at the baseline assessment.

Conclusions: These results support the utility of SARA and INAS to evaluate disease severity, but also emphasize the difficulty in measuring progression in a short time period and raise questions regarding the scales’ sensitivity and the clinical meaningfulness of small changes. For the first time, this study quantified caregivers’ burden to assess their quality of life.


  • Vestronidase Alfa for the treatment of

mucopolysaccharidosis VII (MPS VII): Updated results from a novel, longitudinal, multicenter disease monitoring program (DMP).

Roberto Giugliani1, Antonio Gonzalez-Meneses2, Cristina Grant3, Maurizio Scarpa4, Angela Sun5, Raymond Wang6, Barbara Burton7, Ans Van der Ploeg8, Esmeralda Martins9, Consuelo Durand10, Brigitte Chabrol11, Joel Hetzer12, Debora Marsden12, J Lawrence Merritt, II12

Background: MPS VII is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by beta-glucuronidase (GUS) enzyme deficiency. Vestronidase alfa (recombinant human GUS) enzyme replacement therapy is approved in multiple regions across the world for the treatment of MPS VII.

Methods: The DMP is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N≈50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice.

Results: As of data cutoff (17Nov2022), 35 patients were enrolled in the MPS VII DMP: 7 untreated, 23 treated prior to DMP enrollment, and 5 initially treated during DMP. Patients have been followed for up to 48 months. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range 0.0-12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range 1.5-50.2 years). Among patients treated prior to DMP enrollment, dermatan sulfate was reduced >80% since pre-treatment baseline levels, and reductions were maintained at Month 24, the last timepoint with >1 patient. Initial data suggest that recumbent length/standing height and weight z-scores were largely stable, some patients demonstrated modest improvements over time on the 6-minute walk test, cough peak flow generally improved, and the amount of caregiver assistance required decreased relative to pre-treatment baseline levels.

All adverse events were consistent with the known vestronidase alfa safety profile. One patient died (an accidental death considered unrelated to vestronidase alfa).

Conclusion: The benefit-risk profile of vestronidase alfa continues to be unchanged and favorable for use in pediatric and adult patients with MPS VII. Reductions in dermatan sulfate demonstrate effectiveness to at least Month 24 and clinical parameters are stable. Enrollment is ongoing, and patients continue to be assessed.


  • 104-week efficacy and safety of cipaglucosidase alfa+miglustat in patients with late-onset Pompe disease previously treated with alglucosidase alfa

Tahseen Mozaffar1, Drago Bratkovic2, Barry J. Byrne3, Kristl G. Claeys4, Jordi Diaz-Manera5, Priya Kishnani6, Pascal Laforet7, Mark Roberts8, Antonio Toscano9, Jeff Castelli10, Mitchell Goldman10, Hai Jiang10, Sheela Sitaraman Das10, Yasmine Wasfi10, Benedikt Schoser11, On behalf of the ATB200-07 Study Group10

The Phase III double-blind PROPEL study (NCT03729362) compared the investigational two‑component enzyme replacement therapy (ERT) cipaglucosidase alfa+miglustat (cipa+mig) with alglucosidase alfa+placebo (alg+pbo) in adults with late-onset Pompe disease (LOPD). An ongoing open-label extension (OLE) (ATB200-07; NCT04138277) evaluates the long-term efficacy and safety of cipa+mig. This prespecified subgroup analyses evaluated patients who had received alg treatment prior to PROPEL (ERT-experienced).

Outcomes include 6‑minute walk distance (6MWD), forced vital capacity (FVC), manual muscle test (MMT), PROMIS physical function and fatigue scores, creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, and safety. Data are reported as change from the PROPEL baseline to OLE week 52 (104 weeks after the PROPEL baseline).

Of 119 patients in the OLE, 91 were ERT-experienced prior to PROPEL (median duration 7.4 years); 62 continued cipa+mig (cipa+mig group) and 29 switched from alg+pbo in PROPEL to cipa+mig in the OLE (switch group). Mean (standard deviation [SD]) change in % predicted 6MWD was +3.1(8.1) for the cipa+mig group and −0.5(7.8) for the switch group. Mean (SD) change in % predicted FVC was −0.6(7.5) for the cipa+mig group and −3.8(6.2) for the switch group. MMT lower extremity scores improved slightly by +1.6(4.6) for the cipa+mig and by +1.5(2.9) for the switch group. For PROMIS physical function and fatigue scores, mean (SD) change was +1.9(9.1) and −2.1(5.6), respectively, for the cipa+mig and −2.0(10.2) and +1.1(6.9), respectively, for the switch group. Biomarker levels (CK and Hex4) improved with cipa+mig treatment in both groups. No new safety signals were identified.

These data show that switching treatment from alg to cipa+mig was associated with a durable effect up to 104 weeks and was well tolerated, supporting long-term benefits of cipa+mig treatment for patients with LOPD. Supported by Amicus Therapeutics, Inc.


  • Effect size analysis of cipaglucosidase alfa + miglustat versus alglucosidase alfa in ERT-experienced adults with late-onset Pompe disease in PROPEL.

Tahseen Mozaffar1, Drago Bratkovic2, Barry J. Byrne3, Kristl G. Claeys4, Jordi Diaz-Manera5, Mazen M. Dimachkie6, Hani Kushlaf7, Priya Kishnani8, Pascal Laforet9, Mark Roberts10, Antonio Toscano11, Jeff Castelli12, Syed Raza13, Fred Holdbrook12, Sheela Sitaraman Das12, Yasmine Wasfi12, Benedikt Schoser14, On behalf of the PROPEL Study Group12


The randomized, double-blind PROPEL study (ATB200-03; NCT03729362) compared the efficacy and safety of the investigational 2-component enzyme replacement therapy (ERT) cipaglucosidase alfa+miglustat (cipa+mig) with alglucosidase alfa+placebo (alg) in adults with late-onset Pompe disease (LOPD); 77% of patients had received ERT with alg before study entry (median ERT duration 7.4 years).


We analyzed within-group effect sizes of cipa+mig and alg for outcomes including motor function, lung function and muscle strength tests; patient-reported outcomes/quality of life; and biomarkers in ERT-experienced patients. Standardized within-group effect sizes (Cohen’s d for correlated measurements from baseline to week 52) were calculated by dividing mean change from baseline by standard deviations of the difference scores.


ERT-experienced patients remaining on alg (n=30) generally showed worsening (d<−0.2) or stability (−0.2≤d≥+0.2) across most outcomes, while those switching to cipa+mig (n=65) mostly showed improvement (d>0.2) or stability. Patients remaining on alg demonstrated statistically significant within-group worsening for sitting and supine forced vital capacity; slow vital capacity; maximal expiratory pressure; and creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, and no significant improvements for any outcomes. Patients switching to cipa+mig did not demonstrate any significant within-group worsening and showed significant improvements for 6-minute walk distance (absolute and % predicted); upper, lower and overall manual muscle test; PROMIS fatigue; physician and subject global impression of change (5 of 8 subdomains); CK and Hex4 levels.


This analysis shows that ERT-experienced patients with LOPD who switched from alg to cipa+mig treatment achieved improvements in a number of outcomes, highlighting the potential of cipa+mig to become an important treatment option for these patients.


  • Differential diagnosis of inherited metabolic disorders according to organ system involvement: a lesson from the knowledgebase

Nenad Blau1, Corrado Angelini2, David Bakhos3, Helene Blasco3, Camiel J.F. Boon4, Alberto Burlina2, Alessandra Cambi5, Lonneke de Boer5, Paola de Haas5, John J. Galvin III6, Alejandro Garanto5, Rubn Bonilla Guerrero7, Georg F. Hoffmann8, Gabriella A. Horvath9, Karen M. Kloke10, Diego Martinelli11, Denise Salazar12, Clara D.M. van Karnebeek4, Lilly M. Verhagen5, Carlos R. Ferreira13

Background: Given the rapid pace of advances in molecular diagnostics and a growing number of new diseases, we reason it is timely to provide a comprehensive list of inherited metabolic disorders (IMDs) involving different organs and systems.

Methods: We used information from IEMbase (, the IMD knowledgebase, which tabulates 1875 expert-curated disorders with 2623 clinical symptoms and 1436 laboratory findings and includes a diagnostic AI-mini-expert system. Each of the clinical symptoms is assigned to the involved organ or system.

Results: We calculated the frequency of specific symptoms for 11 categories within disorders in the IEMbase. Movement (209 IMDs): ataxia 73%, dystonia 47%, chorea/athetosis 24%, hypokinetic-rigid syndrome 17%, tremor 15% and myoclonus 14%. Liver (142): hepatocellular disease 30%; hepatomegaly 21%; fibrosis or cirrhosis 18%, steatosis 3%, cholestasis 11%. Psychiatric (101); OCD 24%, anxiety 28% and behavioral disturbances, psychosis, and autism 38%, aggression 39% and hyperactivity 35%. Cardiovascular (246): DCM/left ventricular systolic dysfunction 42% and HCM/left ventricular hypertrophy 37%. Cerebral palsy (151): spasticity 43%, extrapyramidal signs 30% and ataxia 27%. Cutaneous (252): hair shaft involvement 25% and abnormal pigmentation 23%. Ocular phenotypes (583): retinal involvement 39%, optic nerve involvement 27% and lens involvement 24%. Ear (219): inner ear or retrocochlear problems 51%, and non-specific hearing loss 34%. Metabolic myopathies (358): weakness 83%, hypotonia 21%, exercise intolerance 8%, and rhabdomyolysis 6%. GI (339): feeding difficulties 37%, intestinal problems 30%, vomiting 22%, and stomach and pancreas involvement 8%. Immunological (171): immunodeficiency and infections 84%, innate immune defects 26%, and autoimmunity 19%.

Conclusions: We provide a comprehensive summary of specific clinical signs and symptoms, along with corresponding laboratory biomarkers, associated with IMDs.


  • Mini-COMET study: Safety and efficacy data after avalglucosidase alfa dosing for ₴145 weeks in patients with infantile-onset Pompe disease (IOPD) who had demonstrated

clinical decline or sub-optimal response whilst receiving alglucosidase alfa.

Priya Kishnani1, David Kronn2, James Davison3, Anais Brassier4, Alexander Broomfield3, Si Houn Hahn5, Satoko Kumada6, Francois Labarthe7, Hirotaka Ohki8, Kristina An Haack9, Susan Sparks10, Swathi Tammireddy10, Atef Zaher11, Tianyue Zhou10, Yin-Hsiu Chien, on behalf of the Mini-COMET Investigators12

Background: Mini-COMET (NCT03019406; phase 2, open-label, ascending-dose, 3-cohort study) enrolled IOPD patients

Methods: In the 25-wk primary analysis period (PAP), 22 patients received avalglucosidase alfa (AVA) 20 or 40mg/kg/qow (n=6 vs n=10) or their pre-enrollment ALG stable dose (range: 20mg/kg/qow to 40mg/kg/qw, n=6). All patients entered an extended treatment period (ETP) to receive AVA.

Results: At data cut-off (Sep 30, 2022), 22 patients had been on-study for ≥145 wks, receiving AVA 40mg/kg/qow (n=20) or AVA 20mg/kg/qow (n=2, per-protocol). PAP data are published. Median AVA compliance=100%. PAP/ETP safety profiles were similar, with increased incidence of treatment-related treatment-emergent adverse event (TEAEs) and infusion-associated reactions during the ETP vs PAP, as expected due to increased exposure; no patient discontinued or died. Treatment-related serious/severe TEAEs occurred in 1 (5%) patient (hypotension, hypoxia). The higher AVA dose (40mg/kg/qow) was well-tolerated with no increased safety risk after switch from PAP to long-term treatment with AVA. Immune response in switched patients was modest, with IgG anti-drug antibody (ADA) peak titers and persistence to AVA no greater than expected with ALG long-term exposure. 2 patients developed neutralizing AVA ADA for uptake inhibition. At enrollment, most patients had motor decline while on ALG. At Wk145, effect on motor outcome measures was durable during long-term treatment as continuous net increase or stabilization in GMFM-88 and QMFT scores was seen. All patients retained a left ventricular mass Z-score

Discussion/Conclusion: AVA ≤40mg/kg/qow was well-tolerated, with no safety risk seen in patients switched from ALG to AVA. The long-term data further support AVA’s durable impact in IOPD. Funding: Sanofi


  • Leukocyte Chondroitin Sulfate (CS) and Dermatan Sulfate (DS) as Biomarkers of Intracellular Glycosaminoglycans (GAG) Accumulation in Patients with Mucopolysaccharidosis Type VI.

Young Bae Sohn1, Ray Wang2, Jane Ashworth3, Pierre Broqua4, Mireille Tallandier4, Jean-Louis Abitbol4, Erin Jozwiak5, Laura Pollard6, Timothy Wood7, Paul Harmatz5

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that lead to cell injury. Total urinary glycosaminoglycans (GAG) is used as a useful biomarker in MPS diseases to monitor disease activity and treatment efficacy. This study evaluated GAG levels in leukocytes (leukoGAG) and skin GAG as biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and injury in the specific tisseus. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoGAG levels, especially leukoCS and leukoDS, were significantly higher in MPS VI patients vs. control subjects with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2 leukoCS and leukoDS were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.