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

Abstract

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.

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

“…Recurrent facial nerve palsy has been reported in one patient with CDL (41), while several other publications on CDL (6,(42)(43)(44) lack information on potential neurological symptoms. There are several plausible mechanistic explanations: compression due to cranial sclerosis, as previously suggested (5); basilar invagination due to compromised bone strength, as in OI (45), although no evidence for that was noted in our patients; and neurotoxicity induced by aberrant sphingomyelin metabolism, similar to neuronal damage with incidental cranial nerve palsies in acid sphingomyelinase deficiency (Niemann-Pick disease) (46). In the patients with missense variants, accumulation of SMS2 and production of sphingomyelin in the ER could also lead to a lipid-mediated cellular stress response with adverse effects on neuronal function (47).…”

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

“…The sphingolipid metabolism pathway contains highly bioactive molecules, including ceramide and sphingosine‐1 phosphate, which are important regulators of the inflammatory response . As additional data become available, this will facilitate more mechanistic descriptions of splenomegaly and pulmonary function impairment, including tissue damage and feedback between the organ submodels and the PBPK model. Description of other clinical manifestations, including liver disease, is a third key direction.…”

“…1,2 The consequent cell and tissue damage affects multiple organ systems, and causes heterogeneous disease manifestations, including, but not limited to, hepatosplenomegaly, infiltrative lung disease, hematological abnormalities, and dyslipidemia. 1 ASMD is a serious and potentially fatal disease. It is associated with a spectrum of disease subtypes, ranging from the severe infantile neurovisceral phenotype (Niemann-Pick type A) to the chronic visceral form (Niemann-Pick type B), with an intermediate chronic neurovisceral phenotype (Niemann-Pick type A/B, Niemann-Pick B variant).…”

“…ASM catalyzes the conversion of sphingomyelin, a major constituent of cell membranes, to ceramide. The reduced functional ASM leads to accumulation of sphingomyelin in multiple cell types, including cells of the monocyte‐macrophage lineage and hepatocytes . The consequent cell and tissue damage affects multiple organ systems, and causes heterogeneous disease manifestations, including, but not limited to, hepatosplenomegaly, infiltrative lung disease, hematological abnormalities, and dyslipidemia …”

Changes in PCSK 9 and Apolipoprotein B100 in Niemann-Pick Disease After Enzyme Replacement Therapy with Olipudase Alfa

“…NPD type C is not considered in this study as it has a different causality. ASMD leads to an accumulation of sphingomyelin and large lipid-laden foam cells within the hepatocytes as well as tissues within the lung, spleen, lymph nodes, adrenal cortex and bone marrow [1][2][3] .…”