In animal cells (especially humans), there is an enzyme called acid sphingomyelinase (ASM) (EC 3.1.4.12) which can break the large molecule of sphingomyelin and convert it into smaller structures of ceramide and phosphorylcholine [1]. ASM has three isoforms: isoform I (lysosomal or extracellular) which has catalytic activity and plays a role in breaking down lipid substrates and transporting cholesterol from the lysosomal membrane, and isoforms II and III which have no catalytic activity and are unable to bind to the Zn²⁺ cofactor [2,3]. Any mutation in the gene producing this enzyme leads to Niemann-Pick disease (NPD[k1] ). Following the mutation, the substrate accumulates in the lysosome of different organs, leading to the development of clinical symptoms of the disease [4]. Since the inheritance pattern of NPD is autosomal recessive, this disease has four clinical variants in terms of phenotype: A, B, C, and E, of which the first three types are the most common. The average incidence of NPD (depending on the type) is 1 in 150,000 people and is most common in Ashkenazi Jews [5]. The diagnosis of the disease depends entirely on the type of the disease and the severity of the disease symptoms, but the measurement of ASM levels in the blood of patients and the Philippine test are routinely used [6]. In addition to supportive care, approaches such as enzyme replacement therapy (ERT) [7], substrate replacement therapy (SRT) [8], bone marrow transplantation (BMT) [9], chaperone therapy [10], and gene therapy [11,12] are used to alleviate the symptoms of the disease. Recently, most studies have focused on the last approach.

Clinical variant A (early-onset form) often affects infants neuroviscerally. In this form of the disease, which is the most severe form of NPD (due to missense and frameshift mutations in the SMPD1 gene), there is no sphingomyelinase enzyme in the cell to break down the lipid substrate [13]. Type A often affects children between three months and three years old, and the most common complication of NPA is hepatosplenomegaly, which worsens if left untreated. The most common signs and symptoms of this type of disease include very poor growth of the child, various respiratory infections, lung involvement, visual impairment, and muscle weakness [14,16]. NPA has a poor prognosis and is usually fatal by the age of three. Recent research has shown that there is a direct relationship between clinical symptoms (phenotype) and the genetics of patients (genotype). Thus, one or several different mutations in the SMPD1 gene causes various clinical symptoms. In addition to the latest report by Hosseini et al. [17], some researchers have recently reported cases of NPD type A. For example, studying a 7-month-old Thai girl, Ngoenmak et al. found that she had symptoms similar to NPD type A. In the child, they observed symptoms such as hepatosplenomegaly, neurodevelopmental delay, rough face, cherry red spots, hypotonia, lack of growth, and Mongolian spots. Also, according to the Sanger sequencing results, they found that this patient had a homozygous pathogenic new variant (c.1214T>C (p. Leu 405Pro)) in the SMPD1 gene. Finally, due to a lack of timely diagnosis and treatment, the child died at the age of 4 due to respiratory failure and severe neurological symptoms [17]. Gul et al. found that the 11-month-old baby had NPA by observing signs and symptoms such as lack of growth and developmental delay, abdominal distension, bruising in the lumbar region, hepatosplenomegaly, and spasticity. The child had no symptoms at birth, and symptoms appeared about six months after birth; also, supportive treatments and physical therapy were considered for him [18]. In another study, Shahrani et al. investigated the genotype-phenotype relationship in NPA disease in an eighteen-month-old Saudi child. According to the patient's symptoms and sequencing, they found that the child had a homozygous mutation c.1616A>G (p. Tyr539Cys) on chromosome 11p15.4. The most common signs and symptoms of this disease include hepatosplenomegaly, organomegaly, developmental delay, and neurological defects [19]. It has been shown that no treatment approach can eliminate the symptoms of the disease, but based on the latest study by Hosseini et al. [11], treatment approaches such as ERT, BMT, and gene therapy have been reported to reduce the symptoms of the disease.

Clinical variant B (later-onset form), often referred to as the visceral or juvenile form, occurs before a person reaches puberty. The severity of this form of the disease is less than type A, and like type A, the main cause of this clinical form is a mutation in the SMPD1 gene [14,20]. Unlike type A, children with type B often survive into adulthood, and their lungs are usually severely affected. In addition, hepatosplenomegaly, bronchopneumonia, ataxia, nephropathy, ascites, hypertension, and liver cirrhosis are visible and common in these patients [21-23]. In terms of the incidence in the entire population, it occurs in 1 person per 250,000 people [24]. Based on the latest reports presented by Hosseini et al., therapeutic strategies such as ERT, BMT, and gene therapy were found by studying a 29-year-old pregnant woman with NPB, who was healthy after the delivery of her child; a multidisciplinary team closely monitored her during her pregnancy and performed specialized tests, so the mother was able to give birth to a healthy child [25].In a new study, Ortega et al. reported a specific type of NPB disease with a compound heterozygous mutation in a Caucasian woman. The results of SMPD1 gene sequencing showed the presence of the mutation (c.[84-del-C];[96G>A) which was related to the patient's phenotypic symptoms such as hepatosplenomegaly, wide jaw, closed palpebral fissures, and pulmonary involvement. The difference between this study and previous ones was that most of the previous studies were homozygous mutations, but this study reported compound heterozygous [26]. According to the most recent study (2024), it has been found that NPB disease may be diagnosed simultaneously with some diseases such as Segawa syndrome by DNA sequencing. In this regard, Wu et al. studied a 21-year-old woman who had symptoms such as hepatosplenomegaly and hard skin (persistent symptoms) for several years. Also, CT scan and radiograph images showed pulmonary involvement, thin and low-density trabecular bones, and an open brain cavity. Due to the similarity of the clinical symptoms of Segawa disease and NPB, mutation screening in the genes encoding SMPD1 and TH (c.739 G>A) enzymes is necessary to facilitate the diagnosis between the two diseases [27].

Clinical variant C, also known as the subacute form, is caused by mutations in the NPC1 and NPC2 genes. The mutated enzyme is unable to transport cholesterol out of the cell and the substrate accumulates in the lysosome of the cells. Subtype C1 is more likely to affect people, and its incidence is 1 per 150,000 people in the population. This disease is often seen in the population of Canada (Nova Scotia) [3,24,28,29]. To diagnose this disease, Filipin staining is often used to check the presence of cholesterol and Sanger sequencing to identify mutations in these two genes [30]. Among the common and main signs and symptoms of these two subtypes of the disease, the following can be mentioned: inability to look up and down, difficulty in walking and swallowing, and progressive loss of vision and hearing [31,32]. Based on the latest report published by Hosseini et al. [11], it can be concluded that SRT, BMT, chaperone therapy, and gene therapy can be used to treat C1 and C2 subtypes. Since the last study reported until now, some studies have been conducted recently. For example, in this regard, based on a new statistical study, Bolton et al. reported that among 203 patients with NPC, about 26.4% had form I of the disease. Among these, half of the patients had the NPC1 subtype, and the most common mutation among them was c.3182T>C. According to genotype-phenotype correlation, clinical phenotypes such as hepatosplenomegaly, infants’ jaundice, cognitive impairment, dysarthria, ataxia, vertical supranuclear gaze palsy, dysphagia, seizures, and difficulty swallowing were observed. According to the type of symptoms, therapeutic strategies such as SRT (miglustat) along with the use of anticonvulsants, antidepressants, and antacid drugs were prescribed for the patients [33]. Alipouran et al. were able to identify congenital liver disease in three Iranian families using molecular techniques. They showed that in these three families, two mutations in the SMPD1 gene, c.1718G>C (p. Trp573Ser) (mutated homozygote) and c.1718G>C (p. Trp573Ser) (heterozygote), and one mutation in the NPC1 gene, i.e. c .3175C>T (p. Arg1059Ter) (mutated homozygote) occurred. Mutations in these genes were associated with signs and symptoms such as hepatosplenomegaly, increased LFTs, developmental delay, hypotonia, and in some cases skeletal dysplasia and severe weight loss [34]. As mentioned earlier, there are many therapeutic strategies for the treatment of patients with NPD, aiming to alleviate the symptoms of the disease, and so far, definitive treatment using medicinal compounds has not been approved for these patients. According to this issue, Matsuo et al. administered an intrathecal compound drug containing cyclodextrin (HPBCD) to five patients aged 4-11 years old with NPC, and then the efficacy and safety of the drug were investigated. They found that following the drug injection, the severity of patients' symptoms such as hepatosplenomegaly, jaundice, delirium, gait imbalance, dementia, and developmental delay were reduced significantly [35]. In line with a previous study, during a new clinical trial, Bremovo et al. studied the efficacy and safety of another drug compound called N-acetyl-l-leucine (NALL) in patients with NPC and found that during 12 weeks of continuous use of NALL, the neurological status of the patients improved dramatically. No side effects of the drug were reported in patients [36]. In another study, Nunes et al. investigated the relationship between blood cholesterol levels and brain functions such as cognition and found that increased CYP46A1 protein expression led to decreased cholesterol levels and increased brain function in NPC mice. Therefore, using cell and mouse models (Npc1^tm(I1061T)) as well as gene therapy approaches by AAV vectors improved NPC mouse phenotypes. Hence, following the increase of CYP46A1 expression, hepatomegaly and weight of mice improved, the expression of genes involved in cholesterol homeostasis was moderated, and microgliosis and lysosomal dysfunction in the cerebellum of mice also decreased [37]. Based on the latest case study, Tao et al. reported a new mutation from patients with NPC. They reported a pathogenic missense mutation (c.3452 C>T (p. Ala1151Val)) by studying an eleven-year-old boy with NPC and using the NGS approach. Through genotype-phenotype correlation, this mutation was associated with clinical phenotypes such as the inability to walk, learn, and speak; vertical supranuclear gaze palsy; and dysdiadochokinesia [38]. Table 1 summarizes the preclinical and clinical studies recently conducted in NPC patients.

This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The author declares no competing interests.

The author acknowledges the Molecular Medicine Department of Shiraz University of Medical Sciences. Also, I would like to thank Shiraz University of Medical Sciences, Shiraz, Iran, and the Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.