Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, is an autosomal recessive genetic disorder caused by different SMPD1 mutations. Historically, ASMD has been classified as Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). NPD A is associated with a uniformly devastating disease course, with rapidly progressing psychomotor degeneration, leading to death typically by the age of 3 years, most often from respiratory failure. In contrast, the clinical phenotype and life expectancy of patients with NPD B may vary widely. Almost all patients have hepatosplenomegaly and an atherogenic lipid profile, and most patients have interstitial lung disease with progressive impairment of pulmonary function and hematologic abnormalities including cytopenias. Other common clinical manifestations include liver dysfunction, heart disease, skeletal abnormalities and growth delays. Some patients with ASMD who survive beyond early childhood have intermediate phenotypes (variant NPD B) characterized by combinations of non-neurologic and mild to severe neurologic symptoms. The physical and psychosocial burden of illness in patients with NPD B is substantial. Common symptoms include shortness of breath, joint or limb pain, abdominal pain, bleeding and bruising. The disease often leads to chronic fatigue, limited physical or social activity and difficulties in performing daily activities or work. Many patients die before or in early adulthood, often from pneumonia/respiratory failure or liver failure. Available treatments are limited to symptom management and supportive care. An enzyme replacement therapy currently in clinical development is expected to be the first treatment addressing the underlying pathology of the disease. Early diagnosis and appropriate management are essential for reducing the risk of complications. While knowledge about ASMD is evolving, more evidence about ASMD and the natural history across the disease spectrum is needed, to improve disease recognition, timely diagnosis and appropriate disease management.

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Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)

Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. Ceramide is a heterogeneous lipid entity determined by the length of the fatty acyl chain linked to its carbon backbone sphingosine, which can be generated either by de novo synthesis from serine and palmitoyl-CoA in the endoplasmic reticulum or via sphingomyelin (SM) hydrolysis by sphingomyelinases (SMases). Unlike de novo synthesis, SMase-induced SM hydrolysis represents a rapid and transient mechanism of ceramide generation in specific intracellular sites that accounts for the diverse biological effects of ceramide. Several SMases have been described at the molecular level, which exhibit different pH requirements for activity: neutral, acid or alkaline. Among the SMases, the neutral (NSMase) and acid (ASMase) are the best characterized for their contribution to signaling pathways and role in diverse pathologies, including liver diseases. As part of a Special Issue (Phospholipases: From Structure to Biological Function), the present invited review summarizes the physiological functions of NSMase and ASMase and their role in chronic and metabolic liver diseases, of which the most relevant is nonalcoholic steatohepatitis and its progression to hepatocellular carcinoma, due to the association with the obesity and type 2 diabetes epidemic. A better understanding of the regulation and role of SMases in liver pathology may offer the opportunity for novel treatments of liver diseases.

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Sphingomyelinases and Liver Diseases.

Biochemical and imaging parameters in acid sphingomyelinase deficiency: Potential utility as biomarkers.

Acid sphingomyelinase deficiency (ASMD), due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, is divided into infantile neurovisceral ASMD (Niemann-Pick type A), chronic neurovisceral ASMD (intermediate form, Niemann-Pick type A/B) and chronic visceral ASMD (Niemann-Pick type B). We conducted a long-term observational, single-center study including 16 patients with chronic visceral ASMD. 12 patients were diagnosed in childhood and 4 others in adulthood, the oldest at the age of 50. The mean time of follow-up was approximately 10 years (range: 6 months – 36 years). Splenomegaly was noted in all patients at diagnosis. Hepatomegaly was observed in 88% of patients. Moderately elevated (several-fold above the upper limit of normal values) serum transaminases were noted in 38% of patients. Cherry-red spots were found in five Gypsy children from one family and also in one adult Polish patient, a heterozygote for p.delR610 mutation. Dyslipidemia was noted in 50% of patients. Interstitial lung disease was diagnosed in 44% of patients. Plasmatic lysosphingomyelin (SPC) was elevated in all the patients except one with p.V36A homozygosity and a very mild phenotype also presenting with elevated plasmatic SPC-509 but normal chitotriosidase activity. The most common variant of SMPD1 gene was p.G166R. We found a previously unreported variant in exon 2 (c.491G > T, p.G164 V) in one patient. Chronic visceral ASMD could constitute a slowly progressing disease with a relatively good outcome. The combined measurement of lysosphingomyelin (SPC) and lysospingomyelin-509 (SPC-509) is an essential method for the assessment of ASMD course.

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Chronic visceral acid sphingomyelinase deficiency (Niemann-Pick disease type B) in 16 Polish patients: long-term follow-up.

Clinical relevance of endpoints in clinical trials for acid sphingomyelinase deficiency enzyme replacement therapy

Resume Introduction Le deficit en sphingomyelinase acide est une maladie de surcharge lysosomale autosomique recessive allant d’une forme neuro-viscerale severe de l’enfant, la maladie de Niemann-Pick A, a une forme chronique viscerale evoluant jusqu’a l’âge adulte, la maladie de Niemann-Pick B (NP-B). Methodes Etude retrospective multicentrique francaise de patients adultes suivis entre 1985 et mars 2015 pour une maladie de NP-B. Recueil des donnees cliniques et paracliniques a partir des dossiers medicaux. Resultats Vingt-huit patients (19 hommes, 9 femmes) ont ete analyses. Seize patients ont ete diagnostiques avant l’âge de 10 ans. Les principaux symptomes au diagnostic etaient l’hepatosplenomegalie et l’atteinte pulmonaire interstitielle. Une thrombopenie etait notee dans 24 des 28 cas (plaquettes Conclusion La maladie de NP-B associe une hepatosplenomegalie et une atteinte pulmonaire interstitielle. Un diagnostic precoce permet de reduire les complications et d’eviter les procedures inappropriees (par exemple splenectomie). A l’heure actuelle, la prise en charge repose principalement sur un traitement symptomatique, mais un essai de phase 2/3 de traitement enzymatique substitutif est en cours.

Déficit en sphingomyélinase acide (maladie de Niemann-Pick B) : une étude rétrospective multicentrique de 28 patients adultes

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Introduction Le deficit en sphingomyelinase acide conduit a une forme severe de l’enfant (Niemann-Pick A) et a une forme evoluant jusqu’a l’âge adulte (Niemann-Pick B [NP-B]) avec dans ce cas, absence d’atteinte neurologique. Nous rapportons 28 cas de NP-B. Patients et methodes Etude retrospective nationale. Les donnees cliniques, biologiques et d’imagerie ainsi que l’âge au diagnostic ont ete recueillis. Dans la perspective d’un essai therapeutique de phases 2–3 evaluant la sphingomyelinase acide recombinante, les criteres d’inclusion de l’ensemble de ces patients ont ete evalues. Resultats Vingt-huit patients (19 hommes, 9 femmes) ont ete inclus. Le diagnostic a ete fait dans 16 cas avant l’âge de 10 ans. Le diagnostic le plus precoce a ete fait a l’âge de 6 mois. Une patiente a ete diagnostiquee a l’âge de 73 ans. Les symptomes au diagnostic etaient : association d’une hepatosplenomegalie et d’une atteinte pulmonaire interstitielle dans la moitie des cas, splenomegalie seule dans 5 cas, splenomegalie associee a une atteinte pulmonaire dans 3 cas. Le diagnostic etait confirme dans chaque cas par un deficit en sphingomyelinase acide. L’analyse genetique complete a ete realisee dans 14 cas, avec anomalie genetique de type p.R610del sur 16 des 28 alleles etudies. Six patients etaient homozygotes pour cette mutation. Une consanguinite familiale etait notee dans 8 cas. Lors de la derniere evaluation, la taille de la rate etait mesuree a 18,6 cm de plus grand axe (12–25), la taille moyenne du foie etait a 18,3 cm (13–22). Ces deux donnees etaient disponibles chez 20 patients. L’atteinte pulmonaire aux dernieres nouvelles etait definie par une capacite pulmonaire totale a 88 % de la theorique (65–114) chez 16 patients, par un transfert du CO (DLCO) evalue chez 18 patients a 50 % (17–80). Un patient est decede d’une insuffisance respiratoire probable vers l’âge de 50 ans. Les autres donnees cliniques incluaient : retard staturo-ponderal et/ou puberte retardee (n = 3), hernie inguinale avec chirurgie avant 40 ans (n = 5), remplacement valvulaire aortique (n = 2), pneumothorax recidivant necessitant une chirurgie (n = 2), osteoporose chez 3 hommes âges de moins 40 ans. Le diagnostic differentiel chez les patients a inclus une miliaire tuberculeuse, une maladie de Gaucher, un syndrome de Silverman (hematomes multiples). Le taux de prothrombine (TP) etait disponible chez la majorite des patients, seulement deux patients ont eu un TP  Les examens biologiques notaient par ailleurs : frequence de l’hypergammaglobulinemie polyclonale (n = 6), gammapathie monoclonale de type MGUS (n = 5), cryoglobulinemie (n = 1), elevation de la chitotriosidase (n = 11, avec dans 2 cas augmentation nette au cours du temps). Des examens histologiques/cytologiques ont apporte une aide au diagnostic : myelogramme (n = 2), lavage bronchiolo-alveolaire (n = 2), biopsie pulmonaire (n = 2), ponction biopsie hepatique (n = 4) permettant le diagnostic chez un enfant de 4 ans, montrant chez 3 adultes une steatose/fibrose avec surcharge macrophagique. Conclusion La maladie de NP-B doit etre evoquee devant l’association atteinte pulmonaire interstitielle et hepatosplenomegalie. Le diagnostic est d’autant plus probable qu’il existe une consanguinite familiale. Les patients ont par ailleurs un profil atherogene avec abaissement du HDL cholesterol. La maladie de NP-B peut etre grave avec trois deces precoce. Le traitement etait jusqu’a maintenant symptomatique. Parmi les 25 patients evalues en vue d’un essai therapeutique, seuls 13 sont susceptibles de participer. Les criteres de non-inclusion sont : projet de grossesse (n = 3), troubles psychiatriques (n = 3), oxygenotherapie (n = 1), plaquettes   a 70 % (n = 1), absence de couverture sociale (n = 1), absence de disponibilite (n = 2), splenectomie totale (n = 1).

G. Besson

Papers

Déficit en sphingomyélinase acide (maladie de Niemann-Pick B) : une étude rétrospective multicentrique de 28 patients adultes

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Maladie de Niemann-Pick B : à propos de 28 cas chez l’adulte