Hepatosplenomegaly is evident at the time of diagnosis in majority of ASMD patients, with clinically significant liver disease in as high as 40% of patients with chronic forms (5, 13, 14, 17, 21).

Hepatomegaly in ASMD is related to massive infiltration of hepatic sinusoidal spaces by sphingomyelin-laden hepatic macrophages (Kupffer cells) and lysosomal sphingomyelin accumulation in hepatocytes (7).

Liver disease is commonly noted in chronic ASMD patients, as associated with liver failure, cirrhosis or need for liver transplant in some individuals (11). Liver failure, in addition to respiratory disease, is the leading cause of mortality in chronic forms of ASMD (14).

Splenomegaly is also one of the most common disease manifestations (13, 17, 18). Although infiltration of lipid-laden macrophages is the initial cause of splenomegaly (2, 22), more rapid progression of splenomegaly with spleen volumes >20 multiples of normal is considered to occur in relation to worsening portal hypertension resulting from the progression of fibrotic liver disease, and to increase the risk of bleeding, splenic rupture, and mortality (7, 14, 15). Spleen volume is considered to be a surrogate marker of disease severity as correlated with other disease parameters (i.e., hepatomegaly, growth, lipid profile and hematologic parameters) along with-it significant impact on patient quality of life (QoL) by compromising respiratory function and limiting daily activities via massive abdominal distension (5, 11, 13, 15, 17, 23, 24).

Pulmonary involvement refers to one of the key characteristics of the multisystem manifestation of sphingomyelin storage, with radiographic evidence of infiltrative lung disease (ILD) in most patients with ASMD (25–27). The progressive restriction of lung volumes and impaired gas exchange occurs due to accumulation of lipid-laden macrophages in the alveolar septa, bronchial walls, and pleura (7, 28). Hence, in patients with functional pulmonary disease, in accordance with the restrictive lung disease and impaired gas exchange secondary to ILD, the decrease in forced vital capacity and in the percent diffusion capacity of carbon monoxide (DLCO) are commonly noted (5, 15).

Notably, lung-only involvement—without organomegaly—has also been reported in adult ASMD patients (29) as well as the absence of overt respiratory symptoms despite identification of typical reticulonodular patterns of infiltration on chest radiography (26). In addition, dissociation between the extent of ILD on imaging and the degree of lung compromise on pulmonary function test has frequently been noted (26). Accordingly, identification of markedly abnormal imaging findings is possible in case of only mild to moderately impaired gas exchange as well as the detection of mildly abnormal imaging findings in case of marked gas exchange impairment (DLCO <60% of predicted value) (26). Therefore, imaging studies are considered not to be sufficient in the assessment of pulmonary disease in ASMD type B and suggested to be interpreted as accompanied with the functional testing and the clinical status (5). The infiltrative pulmonary process is typically progressive and strongly related to disease burden and severity of sequela (11, 14, 15, 17, 27, 30, 31), while respiratory infections and respiratory failure account for the major causes of mortality in patients (pediatric and adult) with chronic forms of ASMD (5, 11, 14, 15).

Most patients with ASMD have an atherogenic lipid profile including low HDL cholesterol (HDL-C) and elevated levels of LDL-C, VLDL-C and triglyceride (3, 13, 18, 32). A similar lipid profile is also noted in lysosomal acid lipase deficiency (LALD), and low levels of HDL-C also occur in patients with Gaucher disease, while more severe decreases occur in ASMD patients (6). In addition, accelerated atherosclerosis with hypertrophy of medial and intimal smooth muscle cells in distal branches of coronary arteries (32) as well as established coronary artery or heart valve disease (in ∼10% of patients) (11) have been reported in chronic visceral ASMD patients.

Pediatric and adult patients with chronic visceral ASMD commonly suffer from joint and limb pain, while lower bone mineral content (BMC) and bone mineral density (BMD) in spine, hip, and femur in the pediatric setting, and osteopenia or osteoporosis in adult ASMD patients have also been reported (7, 13, 24).

Growth delay is considered likely in children and adolescents with chronic visceral ASMD, along with delayed skeletal age, short stature, low weight, and delayed puberty (7, 13, 23).

Growth delay is most pronounced in adolescents accompanied with delayed bone age and delayed puberty, whereas the height is in low normal range in most adults (≥18 years of age) (5, 13). Hence, while short stature is a cause of concern in the adolescence age, final adult heights approach normal values, suggesting the likelihood of a period of catch-up growth in late adolescence and/or early adulthood in patients chronic visceral ASMD (5, 13).

The neurological symptoms are considered to be predominant, absent and variable (ranging from mild hypotonia and hyporeflexia to severe involvement including loss of motor function and cognitive decline) in patients with infantile neurovisceral, chronic visceral and chronic neurovisceral ASMD, respectively (7).

In a study among patients with infantile neurovisceral ASMD, hepatosplenomegaly was reported to be identifiable at 2–4 months of age, while developmental arrest followed by rapidly progressing neurodegeneration started from 7 months of age along with failure to thrive by 10 months of age, respiratory symptoms by 9 months of age, irritability and macular cherry-red spots detectable by 12 months of age and death by 27 months of age (8). Hydrocephalus and magnetic resonance imaging (MRI) findings of delayed myelination, widening of the anterior horn of the left ventricle and an arachnoid cyst was also reported (8).

The childhood vs. infantile period in chronic neurovisceral ASMD has been associated with later onset and slower progression neurological symptoms (7). In chronic neurovisceral ASMD, normal developmental milestones persist at least during the first 2 years of life along with a range of symptoms from mild hypotonia and hyporeflexia to severe involvement (i.e., loss of motor function and cognitive decline) (5, 7, 19, 33). The presence of macular cherry-red spots and Q292K mutation is linked to neurological involvement in patients with chronic ASMD (19, 20, 33).

The present expert panel considers the most common presenting symptoms and signs in both pediatric and adult patients with ASMD to include hepatosplenomegaly, elevated transaminases, jaundice, thrombocytopenia, progressive pulmonary dysfunction, dyspnea, and pulmonary infections. Cherry-red maculae, developmental delay, feeding problems, failure to thrive and hypotonia in the pediatric age, while fatigue, limb/joint pain, neuropsychiatric symptoms, and low BMD in the adult age are also amongst the manifestations (Table 2).

For ASMD subtypes, the participating experts consider the developmental delay to be specific to ASMD type A and fatigue to be more common in ASMD type B, while hepatosplenomegaly, abnormal liver function tests, pulmonary dysfunction and cherry-red macula are considered to be prevalent in both types (Figure 1).

Frequent misdiagnosis or delayed diagnosis remains a challenge in clinical practice due to lack of awareness of LDSs, including ASMD, among physicians (34–36).

The participating experts consider the suspicion of the disease by clinicians as the key factor in establishing the diagnosis of ASMD, given the availability of appropriate blood-based enzymatic diagnostic testing and genetic sequencing. In addition, while general practitioners and family medicine, general pediatricians, internists, and neurology specialists are also involved in the patient journey as first-admission or referring physicians before the diagnosis of ASMD, the pediatric/adult gastroenterology and hematology specialists seem to have the greatest potential to come across a patient with ASMD deficiency presenting with hepatosplenomegaly and thus in preventing the diagnostic delay by referring these patients directly to pediatric metabolic disease specialists for confirmation of diagnosis, follow-up and treatment. Of note, pediatric metabolic disease specialists in Turkey are assigned to take care of both pediatric and adult patients (Table 3).

Although DBS assay is readily available for any physician who suspect presence of a LSD in his/her patient, given the likelihood of false-negative/positive test findings on DBS assay the diagnosis should be confirmed or ruled out by enzyme assay in leukocytes or by molecular analysis.

Increased awareness among gastroenterologists and hematology specialists, as the most consulted specialists, as well as non-disease-expert physicians seems to be the key factor in consideration of ASMD.

Misdiagnosis of ASDM at the time of initial presentation is likely due to rarity of disease and the heterogeneity of clinical manifestations (5, 7). Diagnostic guidelines have been published for infantile (neurovisceral), childhood (chronic neurovisceral and chronic visceral) and later-onset (chronic visceral) ASMD, in accordance with the most prevalent symptoms at initial presentation, the associated symptoms predictive of ASMD, the differential diagnoses, and the diagnostic testing paradigms (6) (Tables 2, 3).

The proposed diagnostic algorithm is provided in Figure 2.

Specifically, ASMD should be considered in the diagnosis of patients presenting with hepatosplenomegaly. Presence of at least two of the following in a patient presenting with hepatosplenomegaly refers to high index of suspicion (Figure 2): •

Cherry-red maculae

Infectious diseases including CMV infection, other LSDs including Gaucher disease, hematological disorders, NPD type C, other genetic neurological disorders and LALD should be considered in the differential diagnosis of a patient presenting with hepatosplenomegaly (Figure 2).

The participating experts consider preparation of simple “red flag” cards based on the most frequent symptoms of the disease that would remind the physicians to consider ASMD in differential diagnosis of a patient with unexplained hepatosplenomegaly as well as implementation of awareness raising projects via ASMD-based educational and informative meetings may help to improve disease awareness among physicians.

Enzyme assay in leukocytes to quantify ASM activity is the gold standard for the diagnosis of ASMD. Enzyme assay in DBS has been used as an easy and rapid method to “screen” patients with suspected ASMD, the possible false negative/positive results with this method necessitated confirmation with enzyme assay in leukocytes.

Molecular testing, generally DNA sequence analysis of the SMPD1 gene is generally referred after coming across a low ASM activity either in DBS or leukocytes (1, 38–42).

While ASMD is a pan-ethnic genetic disease, phenotypic differences are likely given that many mutations are private and others are found preferentially in specific ethnic groups (5). Hence, demonstration of missing or significantly diminished enzyme activity is of critical importance, given the existence of many unique mutations or genetic variants of unknown significance (VUS) and most genetic variants are not pathogenic (6).

Infantile neurovisceral ASMD (type A) is associated with p.R498l, p.L304P, and p.P333Sfs*52 variants [homoallelic for p.R498l, p.L304P and p.P333Sfs*52 (Ashkenazi founder mutations)]. Chronic neurovisceral ASMD (type A/B) is associated with p.Q294K and p.W393G variants. Chronic visceral ASMD (type B) is associated with p. ΔR610, p.P323A, p.P330R, and p.W393G variants [homo- or heteroallelic p. ΔR610, p.P325A, and p.P332R (neuroprotective); p.W393G]. For unknown genotype/phenotype correlations, clinical assessment is needed to determine phenotype (6).

Newborn screening for ASMD is feasible by testing the enzymatic activity in DBS, and confirming this with enzyme assay in leukocytes. Genetic analysis is also a frequently referred analysis but high incidence of novel “VUS” changes sometimes makes the interpretation difficult (43, 44). Newborn screening was carried out at in Illinois using multiplexed tandem mass spectrometry for five different LSDs including Niemann-Pick A/B disease. Of the 219.973 infants screened, two were found to have Niemann-Pick A/B showing that NBS provides the potential for early diagnosis and treatment (45).

The clinical and laboratory assessments highly suggestive of ASMD include histological tests that are performed to assess sphingomyelin accumulation (presence of characteristic large, lipid-laden foam cells present in the liver, spleen, lymph nodes, airways, and bone marrow), liver function tests (elevated transaminases) as primary effect of decreased ASM activity where inflammation and fibrosis are secondary effects, the lipid profile (low HDL cholesterol with high levels of LDL cholesterol and triglycerides), pulmonary function and lung imaging, skeletal radiographs, bone density measurement and clinical neurological and ophthalmological examinations, including direct ophthalmoscopy to assess presence of cherry-red spots (1, 6, 7, 42).

The potential biomarkers regarding the burden of the disease useful in diagnosis as well as in monitoring the treatment responses include sphingomyelin and its derivatives, macrophage markers, exercise tolerance markers and QoL (6, 7, 37, 42).

Patients with chronic visceral and chronic neurovisceral ASMD require appropriate follow up and monitoring of multisystem manifestations for optimizing outcomes of ASMD by an interdisciplinary clinical team throughout childhood and adulthood (7).

The proposed monitoring strategy in ASMD patients are provided in Table 4 (7). The participating experts consider periodic assessment of the following parameters in chronic ASMD patients: •

Weight and linear growth and nutritional assessments in children (every 6–12 months)

In ASMD, QoL is mainly influenced by fatigue, dyspnea, and pain due to organ involvement (liver failure, severe splenomegaly, abdominal distension, compromised growth, compromised respiratory function with decreased DLCO, limited physical activity), while the disease is also suggested to negatively affect body image, self-esteem, and relationships with peers (13, 15, 17, 42, 56, 57). Accordingly, while not meet the definition of a standard biomarker, QoL questionnaires such as the Short Form 36 Health Survey (also known as SF36) or Health Assessment Questionnaire (HAQ) are considered useful tool in periodic assessment of QoL for disease monitoring (42).

Currently, the mainstay of therapy in ASMD is supportive symptom targeted approach to reduce morbidity and disease complications, and improve patient QoL (7).

The most common causes of disease-related morbidity and mortality are respiratory and liver failure in ASMD (1), while more pronounced visceral disease and the neurodegenerative phenotype are considered to contribute to earlier death in these patients (5, 11, 14).

Accordingly, the present expert panel considers pulmonary disease (infiltrative lung disease, respiratory infections, or insufficiency), liver disease (cirrhosis) and hematologic disease (thrombocytopenia, hemorrhage, splenic rupture, injury, postoperative hemorrhage, splenic vein tear, and gastrointestinal bleeding/varices bleeding) as the main causes of premature death in chronic ASMD (11, 13, 14, 17, 22). Hence, in patients with chronic visceral and chronic neurovisceral ASMD the treatment goals should include reducing splenomegaly and improving liver function and respiratory status, with the ultimate goal of decreasing serious morbidity and mortality (14). The proposed treatments, interventions and lifestyle modifications based on organ-specific involvement are provided in Table 4.

Treatment options for liver disease are limited including symptom management in patients with end-stage liver disease (control of edema and ascites, prevention of esophageal varices bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis, vaccinations and nutritional maintenance), while liver transplantation is performed in several ASMD patients depending on the degree of complications resulting from cirrhosis (7).

No satisfactory treatment options are available for splenomegaly and splenectomy is generally contraindicated due to risk of liver disease exacerbation and progressive respiratory insufficiency. While in cases with massive splenomegaly, compression symptoms, and severe unsustainable hypersplenism, particularly in case of planned bone marrow transplantation, or in cases of emergency surgery for splenic trauma, necrosis, or rupture then partial splenectomy is a potential option (7).

While transfusions may be needed in extreme cases of bleeding, interventions such as nasal packing and cauterization are more commonly applied for patients with frequent or severe nose bleeds (7). Although reduction in liver and spleen size has been reported after bone marrow transplantation, complications secondary to the transplant procedure may be severe (1, 58).

Treatment options for pulmonary involvement are limited with use of oxygen therapy and bronchodilator for symptomatic pulmonary disease, prevention of first-and second-hand exposure to tobacco smoke, appropriate management of pulmonary infections along with administration of preventative vaccinations for pediatric and adult patients (7).

In neurological forms, educational support and physical therapy are performed on demand (7). Family counseling and the early involvement of palliative care teams are recommended for individualization of therapy and improved QoL in infantile neurovisceral ASMD patients. Nutritional support, physiotherapy, and spasticity management are amongst the other interventions (7).

Treatment and lifestyle changes include dietary modifications for adolescents and adults, lipid-lowering therapy for dyslipidemia, interventions (i.e., weight bearing exercise) to prevent/delay bone loss, physical therapy for joint and limb pain, as well as no restriction of dietary fat and cholesterol to ensure adequate caloric intake and optimal growth in children with severe growth restriction (7).

Supportive services (patient, and disease support groups, social services, family counseling) may offer improved quality of care and QoL (7). Genetic counseling is important to inform patients and families on the autosomal recessive inheritance pattern, carrier status, and potential impact on future offspring and siblings. When both SMPD1 pathogenic variants are identified in a family, carrier testing for at-risk relatives and prenatal diagnosis are possible. Prenatal diagnosis is also likely via testing for ASM enzyme activity (7).

Nonetheless, two registrational trials for olipudase alfa, the first etiology-specific treatment for ASMD in children and adults (7, 12, 15), revealed that 52-week olipudase alfa treatment was well-tolerated along with significantly improved disease pathology across a range of clinically relevant endpoints [pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height] in children with chronic ASMD (59) as well as associated with significant improvement in clinically relevant endpoints (DLCO, spleen and liver volumes, liver function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics) compared with placebo in adults with chronic ASMD (60).

Basically, the metabolic disease specialists provide the medical care for patients with ASMD, while primary care providers and other specialists (e.g., pediatricians, hematologists, gastroenterologists, cardiologists, pulmonologists) can also be part of a team approach to patient care (7). The participating experts emphasize the consultation and communication between physicians involved in ASMD management to enable the familiarity with the routine care for the multisystem impact of the disease (7), while consider the rarity of pediatric metabolic disease specialists, availability of only symptomatic treatment, progression of liver and pulmonary disease, complication related to thrombocytopenia, presence of limited available evidence on progression, clinically significant events and mortality are the main challenges in the management of ASMD. While ERT is likely to become available for patients with ASMD soon, it is also unlikely to reverse the neurological impairment, emphasizing the need for future research that addresses widespread enzyme delivery to the brain, and novel alternatives to enzyme infusions such as gene therapy and small molecule approaches (1, 7).