Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective

Abstract

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM) enzyme, leading to the accumulation of varying degrees of sphingomyelin. Lipid storage leads to foam cell infiltration in tissues, and clinical features including hepatosplenomegaly, pulmonary insufficiency and in some cases central nervous system involvement. ASM enzyme replacement therapy is currently in clinical trial being the first treatment addressing the underlying pathology of the disease. Therefore, presently, it is critical to better comprehend ASMD to improve its diagnose and monitoring. Lung disease, including recurrent pulmonary infections, are common in ASMD patients. Along with lung disease, several immune system alterations have been described both in patients and in ASMD animal models, thus highlighting the role of ASM enzyme in the immune system. In this review, we summarized the pivotal roles of ASM in several immune system cells namely on macrophages, Natural Killer (NK) cells, NKT cells, B cells and T cells. In addition, an overview of diagnose, monitoring and treatment of ASMD is provided highlighting the new enzyme replacement therapy available.

Health insurance literacy and health services access barriers in Niemann–Pick disease: the patient and caregiver voice

“…Niemann-Pick disease (NPD) is a group of rare, autosomal recessive, highly heterogeneous, neurovisceral, progressive lysosomal disorders that are often life-threatening [12,13]. NPD types A and B, also known as acid sphingomyelinase deficiency (ASMD), manifest as a continuum of phenotypes with varying severity and occur due to the abnormal accumulation of sphingomyelin in different organs such as the spleen, liver, lung, and bone marrow [13][14][15]. In severe forms, the nervous system is also involved [13,14].…”

“…In severe forms, the nervous system is also involved [13,14]. Infantile neurovisceral (acute) ASMD (type A) is the most severe, rapidly progressive form, and patients do not survive beyond 2 to 3 years [13,[15][16][17]. Chronic neurovisceral (intermediate form, type A/B) and chronic visceral (type B) ASMD are slowly progressive forms with symptom onset occurring from childhood through adulthood [14].…”

Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine

“…Sphingomyelinase (encoded by SMPD1) breaks down SM into ceramide and phosphocholine. Mutations in SMPD1 cause accumulation of SM in the CNS, leading to dementia, ataxia, and slurred speech as seen in Niemann-Pick disease type A and B [150][151][152] (Fig. 3).…”

Acid sphingomyelinase deficiency: The clinical spectrum of 2 patients who carry the Q294K mutation and diagnostic challenges

“…ASMD is caused by mutations in the SMPD1 gene, which encodes acid sphingomyelinase (ASM). Reduced ASM activity leads to the progressive accumulation of sphingomyelin and other related lipids in organs [ 2 ].…”

“…To date, more than 200 SMPD1 sequence variants have been associated with ASMD [ 2 ]. The range of mutations and other genetic and epigenetic factors results in a spectrum of disease trajectories and severity.…”