Publications by authors named "Roseline Froissart"

53 Publications

A novel PHKA1 mutation associating myopathy and cognitive impairment: Expanding the spectrum of phosphorylase kinase b (PhK) deficiency.

J Neurol Sci 2021 May 18;424:117391. Epub 2021 Mar 18.

APHP-GH Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Myology Institute, Paris, France. Electronic address:

Muscle phosphorylase kinase b deficiency (PhK) is a rare disorder of glycogen metabolism characterized by exercise-induced myalgia and cramps, myoglobinuria and progressive muscle weakness. PhK deficiency is due to mutations in the PHKA1 gene inherited in an X-linked manner and is associated to glycogenosis type VIII (GSD VIII also called GSD IXd). PHKA1 gene codes for the αM subunit of the PhK, a multimeric protein complex responsible for the control of glycogen breakdown in muscle. Until now, few patients have been reported with X-linked recessive muscle PhK deficiency due to PHKA1 mutations. All reported patients presented with exercise intolerance and mild myopathy and one of them had cognitive impairment, leading to speculate about a central nervous system involvement in GSD VIII. Here we report in a sibling a novel mutation in the PHKA1 gene associated with a progressive myopathy, exercise intolerance, muscle hypertrophy and cognitive impairment as an associated feature. This report expands the genetic and clinical spectrum of the extremely rare PHKA1-related PhK deficiency and presents new evidences about its involvement in brain development.
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http://dx.doi.org/10.1016/j.jns.2021.117391DOI Listing
May 2021

Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency.

J Med Genet 2021 Mar 18. Epub 2021 Mar 18.

Department of Pediatric Metabolism, Reference Center of Inherited Metabolic Disorders, Femme Mère Enfant Hospital, Lyon, France.

Introduction: This 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).

Methods: Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.

Results: The 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 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.

Conclusion: This 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.
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http://dx.doi.org/10.1136/jmedgenet-2020-107510DOI Listing
March 2021

A Cross-Sectional Retrospective Study of Non-Splenectomized and Never-Treated Patients with Type 1 Gaucher Disease.

J Clin Med 2020 Jul 22;9(8). Epub 2020 Jul 22.

University Hospital of Clermont Ferrand, Hematology Biology Department, 63000 Clermont-Ferrand, France.

Patients with type 1 Gaucher disease (GD1) present thrombocytopenia, anemia, organomegaly, and bone complications. Most experts consider that the less aggressive forms do not require specific treatment. However, little is known about the disease course of these forms. The objective of this cross-sectional retrospective study was to compare the clinical, radiological, and laboratory characteristics of patients with less severe GD1 at diagnosis and at the last evaluation to identify features that might lead to potential complications. Non-splenectomized and never-treated patients (19 women and 17 men) were identified in the French Gaucher Disease Registry (FGDR). Their median age was 36.6 years (2.4-75.1), and their median follow-up was 7.8 years (0.4-32.4). Moreover, 38.7% were heterozygous for the N370S variant, and 22.6% for the L444P variant. From diagnosis to the last evaluation, GD1 did not worsen in 75% of these patients. Some parameters improved (fatigue and hemoglobin concentration), whereas platelet count and chitotriosidase level remained stable. In one patient (2.7%), Lewy body dementia was diagnosed at 46 years of age. Bone lesion onset was late and usually a single event in most patients. This analysis highlights the genotypic heterogeneity of this subgroup, in which disease could remain stable and even improve spontaneously. It also draws attention to the possible risk of Lewy body disease and late onset of bone complications, even if isolated, to be confirmed in larger series and with longer follow-up.
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http://dx.doi.org/10.3390/jcm9082343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464688PMC
July 2020

Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin.

J Med Chem 2020 08 15;63(15):8231-8249. Epub 2020 Jul 15.

SPPIN - Saints-Pères Paris Institute for the Neurosciences, CNRS, Université de Paris, F-75006 Paris, France.

Sialin, encoded by the gene, is a lysosomal sialic acid transporter defective in Salla disease, a rare inherited leukodystrophy. It also enables metabolic incorporation of exogenous sialic acids, leading to autoantibodies against -glycolylneuraminic acid in humans. Here, we identified a novel class of human sialin ligands by virtual screening and structure-activity relationship studies. The ligand scaffold is characterized by an amino acid backbone with a free carboxylate, an -linked aromatic or heteroaromatic substituent, and a hydrophobic side chain. The most potent compound, (LSP12-3129), inhibited -acetylneuraminic acid (Neu5Ac) transport in a non-competitive manner with IC ≈ 2.5 μM, a value 400-fold lower than the for Neu5Ac. In vitro and molecular docking studies attributed the non-competitive character to selective inhibitor binding to the Neu5Ac site in a cytosol-facing conformation. Moreover, compound rescued the trafficking defect of the pathogenic mutant (R39C) causing Salla disease. This new class of cell-permeant inhibitors provides tools to investigate the physiological roles of sialin and help develop pharmacological chaperones for Salla disease.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02119DOI Listing
August 2020

Urine glucose tetrasaccharide: A good biomarker for glycogenoses type II and III? A study of the French cohort.

Mol Genet Metab Rep 2020 Jun 1;23:100583. Epub 2020 May 1.

Centre de Référence des Maladies Neuromusculaires Nord-Est-Ile de France, Service de Neurologie, CHU Raymond Poincaré, AP-HP, 104 bd Raymond Poincaré, 92380 Garches, France.

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http://dx.doi.org/10.1016/j.ymgmr.2020.100583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200937PMC
June 2020

A rare late progression form of Sly syndrome mucopolysaccharidosis.

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

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

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

Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease.

Neurology 2019 08 23;93(7):e647-e652. Epub 2019 Jul 23.

From the Department of Neurology, Reference Center for Lysosomal Diseases, UF Neuro-Genetics and Metabolism (L.C., R.D., Y.N.), and Department of Neuroradiology (B.L.-Y., N.P., D.L.), Pitié-Salpêtrière Hospital, Paris; Service de Biochimie et Biologie Moléculaire Grand Est (R.F., M.P.), Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron; UMR 5305 CNRS/UCBL (R.F.), Lyon, France; Department of Medicine, Surgery and Neurosciences (A.F., S.S.), Unit of Neurology and Neurometabolic Diseases, Medical School, University of Siena; Neuroradiology Unit (A.C.), Azienda Ospedaliera Universitaria Senese, Siena, Italy; Department of Neurology (M.C.M., J.D.), Coimbra Hospital and University Centre, Portugal; Department of Neurology (S.H.K.), College of Medicine, Hanyang University, Seoul, Korea; Division of Neurology (H.A.), Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan; Department of Neurology (B.A.), La Timone Hospital; Aix-Marseille University (B.A.), CNRS, CRMBM UMR, Marseille; Department of Neurology (X.A.), Montpellier University Hospital, France; Department of Neurology (Y.D.), Xuan Wu Hospital, Capital Medical University, Beijing, China; Department of Neurology (R.H.), Royal Brisbane Hospital, Brisbane, Australia; Laboratory of Neurogenetics of Motion and Department of Neuroradiology (R.L.P.), Montréal Neurological Institute and Hospital, McGill University, Montréal; Department of Radiology (C.L.), Department of Pathology and Laboratory Medicine (C.L.), International Collaboration on Repair Discoveries (ICORD) (C.L.), Department of Physics and Astronomy (C.L.), and Division of Endocrinology, Department of Medicine (S.M.S.), University of British Columbia, Vancouver, Canada; Department of Neurology (K.N.), Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Radiology (R.R.), Uppsala University, Sweden; Department of Neurology and Hertie-Institute for Clinical Brain Research (L.S.), Eberhard-Karls-University; German Center of Neurodegenerative Diseases (DZNE) (L.S.), Tübingen, Germany; Department of Neurology (F.V.), Caen-Normandie University Hospital, Caen; Inserm U1077 (F.V.), EPHE, Caen-Normandie University, Caen, France; and Department of Neurology and Stroke (K.J.), Medical University of Lodz, Poland.

Objective: To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease.

Methods: We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center.

Results: The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1).

Conclusions: We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.
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http://dx.doi.org/10.1212/WNL.0000000000007943DOI Listing
August 2019

Homozygous pArg610del Mutation Unusually Associated With Severe Delay of Growth in 2 Acid Sphingomyelinase Deficiency-affected Sibs.

J Pediatr Hematol Oncol 2020 08;42(6):e499-e502

Biochemistry Laboratory, Habib Bourguiba Hospital and UR12ES17 Sfax Medicine School.

Background: Typically, patients with Acid Sphingomyelinase Deficiency (ASMD) because of p.Arg610del mutation, have mild phenotype with normal linear growth.

Observation: We reported the case of 2 Tunisian brothers who have been referred for splenomegaly, polyadenopathies, pubertal, and growth delay. Molecular testing of SMPD1 gene revealed the presence of a homozygous p.Arg610del mutation. Lysosphingomyelin and its isoform-509 were both increased confirming ASMD for both cases. Growth hormone deficiency was highly suspected but growth hormone response after stimulating tests was acceptable for both patients.

Conclusions: There is no correlation between phenotype-genotype in case of p.Arg610del mutation that could be associated to a severe delay of growth.
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http://dx.doi.org/10.1097/MPH.0000000000001447DOI Listing
August 2020

A National French consensus on gene lists for the diagnosis of myopathies using next-generation sequencing.

Eur J Hum Genet 2019 03 14;27(3):349-352. Epub 2018 Dec 14.

CHRU Montpellier, Laboratoire de Génétique moléculaire, Montpellier, France.

Next-generation sequencing (NGS) gene-panel-based analyses constitute diagnosis strategies which are adapted to the genetic heterogeneity within the field of myopathies, including more than 200 implicated genes to date. Nonetheless, important inter-laboratory diversity of gene panels exists at national and international levels, complicating the exchange of data and the visibility of the diagnostic offers available for referring neurologists. To address this issue, we here describe the initiative of the genetic diagnosis section of the French National Network for Rare Neuromuscular Diseases (Filière Nationale des Maladies Rares Neuromusculaires, FILNEMUS), which led to set up a consensual nationwide diagnostic strategy among the nine French genetic diagnosis laboratories using NGS for myopathies. The strategy is based on the determination of 13 clinical and/or histological entry-diagnosis groups, and consists for each group either in a successive NGS analysis of a "core gene list" followed in case of a negative result by the analysis of an "exhaustive gene list", or in the NGS analysis of a "unique exhaustive gene list".
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http://dx.doi.org/10.1038/s41431-018-0305-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460575PMC
March 2019

A new case of SMA phenotype without epilepsy due to biallelic variants in ASAH1.

Eur J Hum Genet 2019 03 5;27(3):337-339. Epub 2018 Oct 5.

APHP, Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-de-France, Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.

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http://dx.doi.org/10.1038/s41431-018-0250-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460556PMC
March 2019

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study.

J Inherit Metab Dis 2018 11 28;41(6):937-946. Epub 2018 Aug 28.

Centre de Référence des Maladies Neuromusculaires Nord-Est-Ile de France, Service de Neurologie, CHU Raymond Poincaré, AP-HP, 104 bd Raymond Poincaré, 92380, Garches, France.

Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.
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http://dx.doi.org/10.1007/s10545-018-0243-7DOI Listing
November 2018

Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1.

Clin Pharmacokinet 2019 04;58(4):469-482

Hématologie Biologique, CHU Clermont-Ferrand, CHU Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France.

Background And Objectives: Intravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses.

Methods: Glucocerebrosidase intra-monocyte activity was studied by flow cytometry. The pharmacokinetics of imiglucerase was analyzed using a population-pharmacokinetic model from a cohort of 31 patients with Gaucher disease type 1 who either started or were receiving long-term treatment with imiglucerase.

Results: A pharmacokinetic analysis of imiglucerase showed a two-compartment model with a high peak followed by a two-phase exponential decay (fast phase half-life: 0.36 days; slow phase half-life: 9.7 days) leading to a median 1.4-fold increase in glucocerebrosidase intra-monocyte activity from the pre-treatment activity (p = 0.04). In patients receiving long-term treatment, for whom the imiglucerase dose per infusion was chosen on the basis of disease aggressiveness/response, imiglucerase clearance correlated with the administered dose. However, the residual glucocerebrosidase intra-monocyte activity value was dose independent, suggesting that the maintenance of imiglucerase residual activity is patient specific. Endogenous pre-treatment glucocerebrosidase intra-monocyte activity was the most informative single parameter for distinguishing patients without (n = 10) and with a clinical indication (n = 17) for starting enzyme replacement therapy (area under the receiver operating characteristic curve: 0.912; 95% confidence interval 0.8-1; p < 0.001), as confirmed also by a factorial analysis of mixed data.

Conclusion: This study provides novel pharmacokinetic data that support current imiglucerase administration regimens and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher disease type 1 aggressiveness. These findings can potentially improve Gaucher disease type 1 management algorithms and clinical decision making.
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http://dx.doi.org/10.1007/s40262-018-0708-8DOI Listing
April 2019

Deep characterization of the anti-drug antibodies developed in Fabry disease patients, a prospective analysis from the French multicenter cohort FFABRY.

Orphanet J Rare Dis 2018 07 31;13(1):127. Epub 2018 Jul 31.

Sorbonne Université, INSERM, UMR 974, Centre of Research in Myology, Association Institut de Myologie, Pitié-Salpêtrière University Hospital, 75013, Paris, France.

Background: Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes.

Results: Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005).

Conclusion: Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.
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http://dx.doi.org/10.1186/s13023-018-0877-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069887PMC
July 2018

Contribution of tandem mass spectrometry to the diagnosis of lysosomal storage disorders.

J Inherit Metab Dis 2018 05 19;41(3):457-477. Epub 2018 Mar 19.

Unité Maladies Héréditaires du Métabolisme, Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 59 boulevard Pinel, 69677, Bron cedex, France.

Tandem mass spectrometry (MS/MS) is a highly sensitive and specific technique. Thanks to the development of triple quadrupole analyzers, it is becoming more widely used in laboratories working in the field of inborn errors of metabolism. We review here the state of the art of this technique applied to the diagnosis of lysosomal storage disorders (LSDs) and how MS/MS has changed the diagnostic rationale in recent years. This fine technology brings more sensitive, specific, and reliable methods than the previous biochemical ones for the analysis of urinary glycosaminoglycans, oligosaccharides, and sialic acid. In sphingolipidoses, the quantification of urinary sphingolipids (globotriaosylceramide, sulfatides) is possible. The measurement of new plasmatic biomarkers such as oxysterols, bile acids, and lysosphingolipids allows the screening of many sphingolipidoses and related disorders (Niemann-Pick type C), replacing tedious biochemical techniques. Applied to amniotic fluid, a more reliable prenatal diagnosis or screening of LSDs is now available for fetuses presenting with antenatal manifestations. Applied to enzyme measurements, it allows high throughput assays for the screening of large populations, even newborn screening. The advent of this new method can modify the diagnostic rationale behind LSDs.
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http://dx.doi.org/10.1007/s10545-017-0126-3DOI Listing
May 2018

Limited benefits of presymptomatic cord blood transplantation in neurovisceral acid sphingomyelinase deficiency (ASMD) intermediate type.

Eur J Paediatr Neurol 2017 Nov 29;21(6):907-911. Epub 2017 Jul 29.

Reference Centre for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France; UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address:

Acid sphingomyelinase (ASM) deficient Niemann-Pick disease is a lysosomal storage disorder resulting from mutations in the SMPD1 gene. The clinical spectrum distinguishes a severe infantile neurological form (type A), a non-neurological visceral form (type B) and a rare intermediate neurovisceral form. We report the first case of presymptomatic cord blood transplantation in a child with the intermediate type of ASM deficiency due to a homozygous Tyr369Cys mutation, whose affected elder brother had developed neurodevelopmental delay from 19 months of age, and had died from severe visceral complications at the age of 3. In the transplanted propositus, neurological deterioration became evident by 4 years of age; the child was alive at age 8, although severely disabled. Whereas the transplant prevented visceral progression and early death, it could only delay neurocognitive deterioration.
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http://dx.doi.org/10.1016/j.ejpn.2017.07.015DOI Listing
November 2017

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

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

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

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

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

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

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

Development of a new tandem mass spectrometry method for urine and amniotic fluid screening of oligosaccharidoses.

Rapid Commun Mass Spectrom 2017 Jun;31(11):951-963

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

Rationale: The first step in the diagnosis of oligosaccharidoses is to evidence abnormal oligosaccharides excreted in urine, usually performed by the poorly sensitive but efficient thin layer chromatography (TLC) method. Developing a tandem mass spectrometry (MS/MS) technique could be of great interest to replace TLC.

Methods: Abnormal underivatized oligosaccharides have been recently studied using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, allowing the unambiguous identification of oligosaccharidoses. Based on this previous work, we developed an advantageous and efficient liquid chromatography (LC)/MS/MS method using a more common triple quadrupole tandem mass spectrometer for oligosaccharides analysis.

Results: Oligosaccharidoses (n = 97) and control (n = 240) urine samples were analysed. A specific pattern was obtained for each oligosaccharidosis using this method. In urine, it allows not only the identification of all the oligosaccharidoses previously identified by TLC (fucosidosis, alphamannosidosis, aspartylglucosaminuria, GM1 gangliosidosis, sialidosis, galactosialidosis and Schindler disease), but also extends the field of diagnosis to mucolipidosis type II, Sandhoff disease, and β-mannosidosis. The same technique was applied to 16 amniotic fluid supernatants from oligosaccharidosis-affected foetuses (n = 16) compared with 37 unaffected. All the affected foetuses could be clearly identified: sialidosis (n = 3), galactosialidosis (n = 4), aspartylglucosaminuria (n = 1), mucolipidosis type II (n = 4) or GM1 gangliosidosis (n = 4). This technique can be applied to early prenatal diagnosis as well as to the oligosaccharidosis screening in the case of non-immune hydrops fetalis.

Conclusions: The method is quick and easy to run, with an LC analysis time of 13 min per sample. The quantitative validation could not be obtained in the absence of a specific standard and of a labelled internal standard for each compound. Even if this LC/MS/MS method is only qualitative, it is very specific and much more sensitive than TLC. It allows the urinary screening of oligosaccharidoses, even mild or late-onset forms, and the screening of antenatal forms in amniotic fluid. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/rcm.7860DOI Listing
June 2017

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments.

Int J Mol Sci 2017 Feb 17;18(2). Epub 2017 Feb 17.

CHU Estaing et Université Clermont Auvergne, Hematology (Biology) et EA 7453 CHELTER, F-63000 Clermont-Ferrand, France.

Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD-but also carriers of mutation-have been found to be predisposed to developing Parkinson's disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).
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http://dx.doi.org/10.3390/ijms18020441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343975PMC
February 2017

Novel variant in the PYGM gene causing late-onset limb-girdle myopathy, ptosis, and camptocormia.

Muscle Nerve 2018 Jan 21;57(1):157-160. Epub 2017 Mar 21.

Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière, 67098, Strasbourg, France.

Introduction: McArdle disease is a glycogen storage disease caused by mutations in the PYGM gene encoding myophosphorylase. It manifests classically with childhood-onset exercise-induced pain.

Methods: We report the characteristics of 2 unrelated patients with a new homozygous mutation of the PYGM gene.

Results: Two patients, aged 76 and 79 years, presented with severe upper and lower limb atrophy and weakness. Additionally, 1 patient presented with bilateral ptosis, and the other with camptocormia. In both patients, symptoms had developed progressively in the 2 preceding years, and there was no history of exercise intolerance. Both patients demonstrated myogenic abnormalities on electromyography, multiple glycogen-containing vacuoles and undetectable muscle myophosphorylase activity on muscle biopsy, and a novel homozygous frameshift p.Lys42Profs*48 PYGM mutation.

Conclusions: This report expands the phenotype and genotype of McArdle disease and suggests that PYGM mutations should be looked for in patients with very late-onset myopathy with no previous history of exercise intolerance. Muscle Nerve 57: 157-160, 2018.
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http://dx.doi.org/10.1002/mus.25588DOI Listing
January 2018

Antenatal manifestations of inborn errors of metabolism: biological diagnosis.

J Inherit Metab Dis 2016 09 8;39(5):611-624. Epub 2016 Jul 8.

Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et de Pathologie Est CHU de Lyon, Lyon, France.

Inborn errors of metabolism (IEMs) that present with abnormal imaging findings in the second half of pregnancy are mainly lysosomal storage disorders (LSDs), cholesterol synthesis disorders (CSDs), glycogen storage disorder type IV (GSD IV), peroxisomal disorders, mitochondrial fatty acid oxidation defects (FAODs), organic acidurias, aminoacidopathies, congenital disorders of glycosylation (CDGs), and transaldolase deficiency. Their biological investigation requires fetal material. The supernatant of amniotic fluid (AF) is useful for the analysis of mucopolysaccharides, oligosaccharides, sialic acid, lysosphingolipids and some enzyme activities for LSDs, 7- and 8-dehydrocholesterol, desmosterol and lathosterol for CSDs, acylcarnitines for FAODs, organic acids for organic acidurias, and polyols for transaldolase deficiency. Cultured AF or fetal cells allow the measurement of enzyme activities for most IEMs, whole-cell assays, or metabolite measurements. The cultured cells or tissue samples taken after fetal death can be used for metabolic profiling, enzyme activities, and DNA extraction. Fetal blood can also be helpful. The identification of vacuolated cells orients toward an LSD, and plasma is useful for diagnosing peroxisomal disorders, FAODs, CSDs, some LSDs, and possibly CDGs and aminoacidopathies. We investigated AF of 1700 pregnancies after exclusion of frequent etiologies of nonimmune hydrops fetalis and identified 108 fetuses affected with LSDs (6.3 %), 29 of them with mucopolysaccharidosis type VII (MPS VII), and six with GSD IV (0.3 %). In the AF of 873 pregnancies, investigated because of intrauterine growth restriction and/or abnormal genitalia, we diagnosed 32 fetuses affected with Smith-Lemli-Opitz syndrome (3.7 %).
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http://dx.doi.org/10.1007/s10545-016-9947-8DOI Listing
September 2016

Molecular analysis in a GALNS study cohort of 15 Tunisian patients: description of a novel mutation.

Diagn Pathol 2016 Jun 17;11(1):51. Epub 2016 Jun 17.

Department of Biology, Laboratory of Biotechnologies and Valorization of Natural Resources. IBN Zohr University, School of Sciences, BP 8106, Agadir, Morocco.

Background: Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal recessive disease caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). The purpose of this study was to analyze the GALNS mutations and the haplotypes associated.

Methods: Mutation screening of the GALNS gene was performed by direct sequence analysis using DNA samples from 15 unrelated Tunisian MPS IVA patients. We also analyzed the haplotypes associated with the novel mutation and with the other reported GALNS mutations.

Results: We have identified an unreported missense mutation p.D288G (c.863A > G) in one patient, the most frequently c.120 + 1G > A (IVS1 + 1G > A) mutation in eleven MPS IVA patients and three previously reported mutations p.G66R, p.A85T and p.R386C on the other MPS IVA patients. All the studied patients were homozygous for these identified mutations. Bioinformatics analysis predicted the novel mutation as being probably pathogenic. These findings with the unobserved p.D288G mutation in controls subjects, suggested that it is a disease-causing mutation, which was correlated with the severe phenotype observed in the patients. We have found that the two GALNS unreported and reported mutations, respectively p.D288G and p.R386C, were associated with a common and specific haplotype.

Conclusion: Our results were in agreement with previous reports from Tunisia, suggesting, on one hand the genotype/phenotype correlations in MPS IVA patients and the other hand the haplotype analyses were useful for determination of mutation origin in Tunisian population.
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http://dx.doi.org/10.1186/s13000-016-0498-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912732PMC
June 2016

Genetic basis of cystinosis in Tunisian patients: Identification of novel mutation in CTNS gene.

Meta Gene 2015 Sep 25;5:144-9. Epub 2015 Jul 25.

The Auvergne-Loire Regional Branch of the French National Blood System EFS/GIMAP-EA 3064, 42100 Saint Etienne, France.

Nephropathic cystinosis (NC) is an autosomal recessive disorder characterized by defective transport of cystine across the lysosomal membrane and resulting in renal, ophthalmic, and other organ abnormalities. Mutations in the CTNS gene cause a deficiency of the transport protein, cystinosin. This study was performed to investigate mutations of the CTNS gene in three Tunisian families with NC. Polymerase chain reaction (PCR), ARMS multiplex PCR and direct sequencing were performed for molecular characterization of the CTNS gene in 3 unrelated Tunisian patients and their parents. Based on family history, prenatal diagnosis (PND) was performed in fetal DNA isolated from chorionic villi obtained at 10-12  weeks of gestation. None of the patients showed the most common 57-kb deletion in heterozygous or homozygous status. One patient was homozygous for the previously reported mutation c.1515G > A (p.G308R). One patient presented the novel gross deletion of 20,327 bp. One was homozygote for the previously reported mutation c.771_793del (p.Gly258Serfs*30). In addition, eight polymorphisms were identified in the 3 patients and their parents. The prenatal diagnosis in one family showed that the fetus DNA was heterozygous for the c.771_793del (p.Gly258Serfs*30) mutation. This study expands the mutational and population spectrum of NC, representing the first molecular diagnosis of NC in Tunisian population. The mutation screening of the CTNS gene was used for prenatal diagnosis to prevent and/or limit this inheritable disease in our country where the families are particularly large and have a high rate of consanguinity.
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http://dx.doi.org/10.1016/j.mgene.2015.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528043PMC
September 2015

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

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

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

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

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

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

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

Glycogen Storage Disease Type IV and Early Implantation Defect: Early Trophoblastic Involvement Associated with a New GBE1 Mutation.

Pediatr Dev Pathol 2016 Nov/Dec;19(6):512-515. Epub 2014 Dec 9.

1 Service d'Anatomie et Cytologie Pathologiques-Hôpital d'Enfants Armand Trousseau-AP-HP, Paris, France.

A 29-year-old primigravida presented with a spontaneous miscarriage at 8 weeks of gestation. There was no consanguinity in the family. Aspiration was performed. Pathological examination showed immature villi with numerous slightly yellow intracytoplasmic inclusions within the early implantation stage cytotrophoblastic cells. Inclusions were periodic acid-Schiff and Alcian blue positive and partially positive with periodic acid-Schiff with amylase. Diagnosis of Glycogen storage disease type IV (GSD IV) was made. Genetic analysis of glycogen branching enzyme 1 gene (GBE1) was performed in parents and showed a novel deletion of 1 nucleotide, c.1937delT, affecting the mother and a mutation affecting a consensus splice site, c.691+2T>C, in the father. At time of subsequent pregnancy, genetic counseling with GBE1 gene analysis was performed on throphoblastic biopsy and showed a mutated allele, c.1937delT, inherited from the mother. The mother gave birth to a healthy, unaffected female newborn. Our findings demonstrate that GSD IV may affect early pregnancies, leading to trophoblastic damage and early fetal loss. Diagnosis can accurately be made on pathological examination and should be further documented by genetic analysis.
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http://dx.doi.org/10.2350/14-09-1557-CR.1DOI Listing
June 2017

Modeling changes in biomarkers in Gaucher disease patients receiving enzyme replacement therapy using a pathophysiological model.

Orphanet J Rare Dis 2014 Jun 30;9:95. Epub 2014 Jun 30.

INSERM, IAME, UMR 1137, INSERM, F-75018 Paris, France.

Background: Gaucher disease (GD) is a rare recessively inherited disorder caused by deficiency of a lysosomal enzyme, glucocerebrosidase. Accumulation of glucosylceramide or glucosylsphingosine in macrophages leads to increased production of ferritin and chitotriosidase and to decreases in hemoglobin concentration and platelet count, which are used as blood biomarkers. GD is treated by enzyme replacement therapy (ERT) or, sometimes by substrate reduction therapy. However, no physiological model for analysis of biomarkers change during ERT has been proposed. We aimed to develop a pathophysiological model to analyze biomarker's response to ERT and several covariates impact.

Methods: Changes in blood ferritin, chitotriosidase, hemoglobin and platelets were analyzed in French GD Registry patients receiving imiglucerase/alglucerase as ERT. We used simplified exponential pathophysiological model, with initial concentration, biomarkers amplitude of variation and rate constant of normalization during ERT. Changes in four biomarkers were analyzed separately and then all four together from initiation to discontinuation of ERT, or until the end of follow-up. Several covariates were tested, including age at ERT initiation, splenectomy, sex, genotype (N370S/N370S), and ERT dose.

Results: An exponential model gave a good data fit. The four biomarkers analysis showed that the rate of nomalization was the same for all biomarkers, with a half-life of 0.5 years. Predicted values of biomarkers at ERT's steady state were 40% and 10% of initial concentrations, for ferritin and chitotriosidase, respectively, and 120% and 200% for hemoglobin and platelets, respectively. We found that 3 covariates had an effect on initial concentration or on amplitude of variation in ferritin, hemoglobin and platelets: women and patients under 15 years of age had lower ferritin and hemoglobin concentrations, and patients under 15 years of age had higher platelet count. Splenectomized patients had higher ferritin concentrations and platelet count and lower amplitude of variation of hemoglobin.

Conclusion: We report the first dynamic model of biomarker changes in GD. It enabled us to estimate that 95% of biomarker response to ERT was achieved in 2 years, but with high inter-patient variability. We also found that with the current treatment, normalization of chitotriosidase and ferritin will occur in about 65% of patients.
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http://dx.doi.org/10.1186/1750-1172-9-95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094900PMC
June 2014

Cirrhosis and liver failure: expanding phenotype of Acid sphingomyelinase-deficient niemann-pick disease in adulthood.

JIMD Rep 2015 10;15:117-21. Epub 2014 Apr 10.

Service de Médecine Interne-Rhumatologie, Hôpital de la Croix Saint Simon, 125 rue d'Avron, 75020, Paris, France,

Acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) includes the severe neuronopathic type A, the non-neuronopathic type B, and rare intermediate cases. Here we report on such an atypical type B patient who died at 31 years of age from liver failure. This male subject was first seen in a paediatric department at the age of 3 years because of significant hepatosplenomegaly. Foam cells in bone marrow, interstitial pneumonitis, a slight facial dysmorphy and normal psychomotor development were additional findings. Acid sphingomyelinase studies in lymphocytes (and later SMPD1 gene studies [c.151_154delGACT; c.1341-21_1341-18delAATG]) established the diagnosis of ASMD. Between the ages 6-27, he developed growth retardation, peripheral neuropathy, kyphoscoliosis, alopecia, and aortic valve insufficiency requiring valve replacement. Surgery for bilateral inguinal hernias was performed twice, when the patient was 10 and 21 years of age, respectively. At the age of 28, he was noted to have hepatosplenomegaly and follow-up investigations revealed ascites and gastric varices. Liver biopsy showed cirrhosis without areas of necrosis (A6 in Child-Pugh classification). He developed haematemesis and worsening encephalopathy leading to his death at age 31. In conclusion, cirrhosis should be considered as a possible complication of ASMD in adult patients, even if hepatic tests are normal.
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http://dx.doi.org/10.1007/8904_2014_306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270874PMC
December 2014

Abnormal glycogen in astrocytes is sufficient to cause adult polyglucosan body disease.

Gene 2013 Feb 21;515(2):376-9. Epub 2012 Dec 21.

AP-HP, Department of Neuropathology, Hospital La Salpêtrière, Paris, France.

Background: A 45-year old woman of Cambodian ethnic background presented with fatal respiratory failure due to a severe diaphragmatic dysfunction. Two years before, she had developed early onset of urinary symptoms.

Methods And Results: Neuroimaging showed atrophy of the spine and medulla as well as a leukodystrophy affecting both supra- and infra-tentorial regions. At autopsy, polyglucosan bodies (PB) were seen in several peripheral tissues, including the diaphragm, and nervous tissues such as peripheral nerves, cerebral white matter, basal ganglia, hippocampus, brainstem and cerebellum. Immunohistochemistry and electron microscopy of the brain revealed an exclusive astrocytic localization of the PB. The diagnosis of adult polyglucosan body disease (APBD) was confirmed by enzymatic and molecular studies.

Conclusion: Storage of abnormal glycogen in astrocytes is sufficient to cause the leukodystrophy of APBD. Since brain glycogen is almost exclusively metabolized in astrocytes, this observation sheds light on the pathophysiology of APBD. In addition, this is the first report of an APBD patient presenting with a subacute diaphragmatic failure.
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http://dx.doi.org/10.1016/j.gene.2012.12.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126849PMC
February 2013

Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice.

Nephrol Dial Transplant 2013 Mar 12;28(3):505-17. Epub 2012 Dec 12.

Department of Internal Medicine,Regional Hospital Jan Yperman, Ypres, Belgium.

Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism resulting in the accumulation of glycolipids including globotriaosylceramide in cells of various tissues resulting in end-organ manifestations. Initially, FD is typically characterized by angiokeratoma and recurrent episodes of neuropathic pain in the extremities occurring during childhood or adolescence. Most affected patients also exhibit a decreased ability to sweat. Later in life, FD results in left ventricular hypertrophy, proteinuria, renal failure and stroke. These later disease manifestations are non-specific and also common in diabetes, hypertension and atheromatosis and thus for most practitioners do not point into the direction of FD. As a consequence, FD is under-diagnosed and screening of high-risk groups is important for case finding, as is a thorough pedigree analysis of affected patients. In the nephrology clinic, we suggest to screen patients for FD when there is unexplained chronic kidney disease in males younger than 50 years and females of any age. In men, this can be performed by measuring α-galactosidase A activity in plasma, white blood cells or dried blood spots. In women, mutation analysis is necessary, as enzyme measurement alone could miss over one-third of female Fabry patients. A multidisciplinary team should closely monitor all known Fabry patients, with the nephrologist screening kidney impairment (glomerular filtration rate and proteinuria) on a regular basis. Transplanted Fabry patients have a higher mortality than the regular transplant population, but have acceptable outcomes, compared with Fabry patients remaining on dialysis. It is unclear whether enzyme replacement therapy (ERT) prevents deterioration of kidney function. In view of the lack of compelling evidence for ERT, and the low likelihood that a sufficiently powered randomized controlled trial on this topic will be performed, data of all patients with FD should be collected in a central registry.
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http://dx.doi.org/10.1093/ndt/gfs526DOI Listing
March 2013

Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review.

J Inherit Metab Dis 2013 Sep 30;36(5):859-68. Epub 2012 Nov 30.

Department of Neurology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris and University Pierre&Marie Curie, Paris, France.

Krabbe disease usually presents as a severe leukodystrophy in early infancy and childhood. From a series of 11 patients and 30 cases previously reported in the literature we describe the clinical, radiological, electrophysiological and genetic features of adult Krabbe disease. Patients diagnosed after the age of 16 years were included in this study. They were further divided into three groups depending on age at symptoms onset: (1) childhood onset cases (n = 7); (2) adolescence onset cases (n = 6) and adult onset cases (n = 28). Overall, 96 % of patients in the adult-onset group presented with signs of pyramidal tracts dysfunction. Spastic paraparesis or tetraparesis became prominent in all cases. A peripheral neuropathy was present in 59 % of cases and was most often demyelinating (80 %). Other clinical signs encompassed dysarthria (31 %), cerebellar ataxia (27 %), pes cavus (27 %), deep sensory signs (23 %), tongue atrophy (15 %), optic neuropathy (12 %), cognitive decline (12 %). Cerebrospinal fluid protein concentration was moderately increased in 54 % of patients. Patients in the adolescent- and childhood-onset groups had similar presentations but were more likely to display optic neuropathy (33 % and 57 %) and cerebellar ataxia (50 % and 57 %). In the adult-onset group, the disease progressed slowly over more than 10 years, but a rapid course was observed in two patients. Abnormalities of brain MRI was similar in the three groups and included high signals of cortico-spinal tracts (94 % of cases), hyper-intensities of optic radiations (89 %) and hyper-intensities or atrophy of the posterior part of the corpus callosum (60 %). No clear genotype-phenotype relationship could be demonstrated.
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http://dx.doi.org/10.1007/s10545-012-9560-4DOI Listing
September 2013

Acute but transient neurological deterioration revealing adult polyglucosan body disease.

J Neurol Sci 2013 Jan 10;324(1-2):179-82. Epub 2012 Nov 10.

AP-HP, Service de neurologie, Hôpital Avicenne, Bobigny, France.

Adult polyglucosan body disease (APBD) is a metabolic disorder usually caused by glycogen branching enzyme (GBE) deficiency. APBD associates progressive walking difficulties, bladder dysfunction and, in about 50% of the cases, cognitive decline. APBD is characterized by a recognizable leukodystrophy on brain MRI. We report here a novel presentation of this disease in a 35-year old woman who presented with an acute deterioration followed by an unexpected recovery. Enzymatic analysis displayed decreased GBE activity in leukocytes. Molecular analyses revealed that only one mutated allele was expressed, bearing a p.Arg515His mutation. This is the first observation reporting acute and reversible neurological symptoms in APBD. These findings emphasize the importance of searching GBE deficiency in patients presenting with a leukodystrophy and acute neurological symptoms mimicking a stroke, in the absence of cardiovascular risk factors.
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http://dx.doi.org/10.1016/j.jns.2012.10.015DOI Listing
January 2013