Other Sphingolipidoses (Niemann-Pick Disease Types A, B, A/B): Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

NPD – Niemann-Pick disease

NPD-A – Niemann-Pick disease type A

NPD-A/B – Niemann-Pick disease type A/B

NPD-B – Niemann-Pick disease type B

ULN – upper limit of normal

BBB – blood-brain barrier

ASMD – acid sphingomyelinase deficiency

LALSD – lysosomal acid lipase deficiency

CT – computed tomography

HRCT – high-resolution computed tomography

HDL – high-density lipoproteins

LDL – low-density lipoproteins

VLDL – very low-density lipoproteins

LSD – lysosomal storage diseases

INR – international normalized ratio

MRI – magnetic resonance imaging

TMS – tandem mass spectrometry

US – ultrasound examination

ERT – enzyme replacement therapy

CNS – central nervous system

EEG – electroencephalography

Lyso-SM (from English Lyso-sphingomyelin) – lyso-sphingomyelin

Lyso-SM509 (from English Lyso-sphingomyelin-509) – lyso-sphingomyelin-509

MCH (from English Mean corpuscular hemoglobin) – mean corpuscular hemoglobin

MCV (from English Mean corpuscular volume) – mean corpuscular volume

OMIM (from English Online Mendelian Inheritance in Man) – Online Mendelian Inheritance in Man project

SMPD1 (from English Sphingomyelin phosphodiesterase) – sphingomyelin phosphodiesterase 1 gene encoding acid sphingomyelinase

Terms and Definitions

Lysosomal storage diseases – a group of inherited monogenic disorders associated with impaired lysosomal function.

Enzyme replacement therapy – treatment involving the lifelong administration of a drug (recombinant enzyme) to patients with an inherited metabolic defect.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Niemann-Pick disease types A, B, A/B (acid sphingomyelinase deficiency, OMIM: # 257200 (NPD-A), # 607616 (NPD-B)) – a rare inherited metabolic disorder from the group of lysosomal storage diseases (LSD), in which pathogenic variants of the SMPD1 gene cause a decrease in the activity of the enzyme acid sphingomyelinase, leading to the accumulation of sphingomyelin and other lipids in organs and tissues: the liver, spleen, bone marrow, lungs, lymph nodes, and central nervous system.

Clinically, three forms of the disease are distinguished: A, B, and A/B. The most common signs of NPD-A are hepatosplenomegaly in infancy, delayed physical and psychomotor development after 6 months of age, followed by regression and loss of acquired skills due to disease progression. Frequent respiratory infections and respiratory failure are also described. NPD-B usually manifests later and in a milder form, with the main difference being the absence of central nervous system involvement or its minimal involvement. Patients with mixed-type NPD A/B show an intermediate clinical picture and, in addition to symptoms characteristic of NPD-B, present with varying degrees of central nervous system impairment, which are not as severe and rapidly progressive as in NPD-A.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Niemann-Pick disease types A, B, A/B (acid sphingomyelinase deficiency) is inherited in an autosomal recessive manner. The presence of biallelic variants of the SMPD1 gene leads to a significant decrease in acid sphingomyelinase activity [1]. This enzyme is necessary for maintaining cellular homeostasis and participates in membrane degradation and turnover. Sphingomyelin, the enzyme's substrate, is one of the main components of the cell membrane. The breakdown of sphingomyelin yields phosphocholine and ceramide [2], [3], [4]. Decreased acid sphingomyelinase activity leads to the accumulation of sphingomyelin and, consequently, the appearance of lipid-loaded cells—usually macrophages, though other specific cells are also affected [5]. Foam cells are present in the adrenal cortex, liver, spleen, respiratory tract, lymph nodes, and bone marrow [1]. The earliest and most pronounced accumulation of sphingomyelin is observed in macrophages of the liver, spleen, lungs, and bone marrow. Sphingomyelin accumulation is also noted in other cell types: hepatocytes and Kupffer cells, skin fibroblasts, vascular endothelial and smooth muscle cells, perineurial cells, Schwann cells, and neutrophils [1]. Less commonly, affected cells are found in the mucous and submucous membranes of the small and large intestines. Lipid-loaded cells ultimately become non-functional and die [1], [5], [6].

The SMPD1 gene, which encodes acid sphingomyelinase, is localized to the chromosomal region 11p15.1-p15.4. Currently, approximately 400 pathogenic variants of the SMPD1 gene have been described in international human mutation databases [7], [8].

1.3 Epidemiology of the Disease or Condition

Niemann-Pick disease types A, B, A/B (acid sphingomyelinase deficiency) is a panethnic ultra-rare disease with an estimated global incidence of approximately 1:100,000 to 1,000,000 newborns. A higher incidence of 1:40,000 is observed in certain ethnic groups [2-5].

Among Ashkenazi Jews, the carrier frequency is estimated to range from ~ 1:100 to 1:200 based on screening for pathogenic variants of NPD-A prevalent in this population. Thus, the projected disease incidence among Ashkenazi Jews ranges from ~ 1:40,000 to 1:200,000 [9, 10].

It is currently estimated that several thousand patients with NPD types A, B, and A/B may live worldwide, based on the number of already diagnosed cases [11]. Data on the incidence of NPD types A, B, and A/B in Russia are currently unavailable.

1.4 Features of Coding the Disease or Condition

ICD-10: E75.2 – Other sphingolipidoses

ICD-11: 5C56.0Y

1.5 Classification of the disease or condition

Niemann-Pick disease types A, B, A/B or acid sphingomyelinase deficiency (ASMD) is a chronic progressive multisystemic disease with a variable age of onset from infancy to adulthood and clinical heterogeneity ranging from mild to perinatally lethal forms [2, 3, 4]. Depending on the clinical course, 3 types of the disease are distinguished:

• Niemann-Pick disease type A – infantile neurovisceral form;

• Niemann-Pick disease type B – chronic visceral form;

• Niemann-Pick disease type A/B – chronic neurovisceral or intermediate form, combining clinical manifestations of types A and B.

1.6 Clinical presentation of the disease or condition

Niemann-Pick disease type A (NPD-A) is the most severe form of acid sphingomyelinase deficiency. It is characterized by severe progressive neurodegenerative manifestations in the first year of life combined with hepatosplenomegaly, developmental arrest, hypotonia, and death, typically by 3 years of age [12, 13].

NPD-A is characterized by the development of hepatosplenomegaly in infancy, loss of psychomotor skills after 6 months of age, and the presence of cherry-red spots in the macula [3, 4]. Most children develop hepatosplenomegaly at 2-4 months of age, followed by the onset of neurological symptoms at an average age of 7 months. Almost all patients exhibit the "floppy infant" symptom complex, irritability, feeding difficulties, sometimes nausea, vomiting, diarrhea, unexplained fever, respiratory disturbances, and sleep disorders. Seizures, nystagmus, and reduced visual acuity may develop. By 10 months, developmental arrest becomes noticeable, followed by rapidly progressive deterioration of psychoverbal and motor development: patients lose the ability to hold their head, sit up, and roll over independently [13]. In the second year of life, marked protein-energy malnutrition and growth retardation become apparent. In the terminal stages of the disease, spasticity up to opisthotonos and bulbar disorders develop, and tendon reflexes disappear. Macular degeneration in the form of a "cherry-red spot" is detected in most patients by 12 months. Corneal opacity and a brownish tint of the anterior lens capsule are occasionally seen. Muscle weakness, impaired sucking, and gastrointestinal disturbances lead to physical growth retardation. All infants develop progressive respiratory symptoms due to the accumulation of Niemann-Pick cells in alveolar septa, bronchial walls, and pleura. Frequent respiratory infections also develop, causing severe bronchopulmonary complications, including respiratory failure. Massive hepatosplenomegaly is typically observed, and most patients show significant liver dysfunction. Abnormal laboratory findings include elevated liver transaminase activity (ALT, AST), low cholesterol and high-density lipoprotein (HDL) levels, and decreased hemoglobin and platelet counts [4].

Niemann-Pick disease type B (NPD-B) can manifest in both childhood and adulthood [1, 2, 4]. Disease manifestations in NPD-B are clinically heterogeneous: ranging from asymptomatic cases to multi-organ involvement. The rate of disease progression can also vary significantly.

Key manifestations of this form of the disease include hepatosplenomegaly, growth retardation, mucocutaneous hemorrhagic syndrome, as well as functional respiratory disorders manifested by recurrent respiratory infections and dyspnea [3].

Splenomegaly is one of the most common manifestations of the disease (observed in over 90% of patients) and serves as an early diagnostic sign. Symptoms of splenomegaly include pain, a feeling of fullness, and early satiety. Splenomegaly can be massive (exceeding normal size by more than 30 times), thereby increasing the risk of rupture and potentially fatal hemorrhage. Splenomegaly can serve as a marker of disease severity due to its correlation with other disease manifestations [4].

Liver damage is associated with the accumulation of sphingomyelin in hepatocytes and Kupffer cells and liver dysfunction, which can progress to fibrosis and liver failure. Hepatomegaly is observed in more than 70% of patients. Liver fibrosis (including minimal, mild, and moderate degrees) and liver cirrhosis are present in 88% of patients. Adult patients with NPD-B are at significant risk for developing liver cirrhosis, portal hypertension, and variceal bleeding. Hepatomegaly may progress to liver cirrhosis, with a risk of developing portal hypertension and ascites. Impaired liver function is observed in 50–75% of patients (typically marked by elevated ALT and AST activity and bilirubin concentration).

With age, pulmonary function often deteriorates in patients due to alveolar infiltration, which clinically becomes noticeable in adolescence or after reaching adulthood. The accumulation of lipid-laden cells in the alveolar septa causes interstitial lesions and impaired gas exchange. Some patients aged 15–20 years develop severe respiratory problems, including reduced $pO_2$ levels, exertional respiratory failure, bronchopneumonia, and the development of cor pulmonale. Signs of interstitial lung disease are observed in more than 80% of patients based on chest X-ray and high-resolution computed tomography (HRCT).

Thrombocytopenia is a characteristic clinical manifestation (observed in more than 50% of patients). Anemia and leukopenia develop in 20–30% of patients. Patients exhibit a variable degree of thrombocytopenia, leukopenia, and anemia. Episodes of bleeding may include recurrent epistaxis, and may also occur as a result of trauma or in the postoperative period (e.g., following dental surgery). More severe bleeding includes subdural hematoma, hematemesis, and hemothorax.

Most patients experience back, limb, or joint pain, as well as growth retardation. Growth retardation is most pronounced in adolescents, who may also exhibit delayed bone age corresponding to delayed onset of puberty.

Most patients have a disrupted lipid profile (persistently low HDL levels in patients of any age against the background of high total cholesterol, triglycerides, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) values). The atherogenic profile likely contributes to an increased cardiovascular risk [1].

An intermediate form of the disease—Niemann-Pick disease type A/B—is distinguished separately, in which somatic manifestations characteristic of NPD-B and described above are observed in combination with neurological disorders characterized by a later onset and slower progression compared to NPD-A [4, 15]. Patients may exhibit a "cherry-red spot" macular degeneration and peripheral neuropathy [3, 4, 14], and in more severe courses—muscular hypotonia, ataxia, spasticity, and cognitive decline.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Please note that, in accordance with the requirements for developing clinical guidelines, each recommendation statement must be accompanied by its recommendation grade and evidence level based on the grading systems for the levels of evidence certainty (LEC) and recommendation credibility levels (RCL). For many statements, the RCL and LEC will be low due to the lack of high-design clinical studies addressing them. Despite this, they are essential elements of patient evaluation for establishing a diagnosis and selecting treatment strategies.

Diagnosis of Niemann-Pick disease types A, B, and A/B is based on a combination of clinical symptoms, medical history, and laboratory testing [4, 14].

Diagnostic criteria: decreased activity of the enzyme acid sphingomyelinase in dried blood spots/leukocytes and the presence of biallelic pathogenic variants in the SMPD1 gene in the presence of clinical symptoms.

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, attention should be paid to any of the following signs:

• a burdened family history (presence of splenectomy or disease-specific symptoms in siblings, confirmed diagnosis in close relatives, cases of infant death in the family, consanguineous marriage);

• delayed physical and/or psychomotor development and/or loss of previously acquired psychomotor skills;

• weakness, increased fatigue;

• enlargement of the abdomen due to splenomegaly or hepatosplenomegaly;

• frequent respiratory infections;

• recurrent bleeding, e.g., epistaxis;

• dyspnea, episodes of breathing difficulty;

• prior splenectomy (total or partial).

Complaints and medical history are also described in the "Clinical Presentation" section.

2.2 Physical Examination

Clinical examination should include measurement of height and body weight, body temperature (A02.30.001 General thermometry), assessment of the musculoskeletal system, detection of signs of hemorrhagic syndrome, with particular attention to palpatory (A01.30.011 Therapeutic palpation) and percussive (A01.30.016 Therapeutic percussion) examination of the liver and spleen, neurological examination, and examination of the respiratory system [11-16].

During the examination, it is necessary to pay attention to the following clinical manifestations of NPD types A, B, and A/B:

- splenomegaly;

- hepatomegaly;

- muscular hypotonia;

- physical growth retardation;

- psychomotor development delay and loss of skills— particularly pronounced in patients with NPD type A, less pronounced in patients with NPD type A/B, while loss of skills is not observed in patients with NPD type B;

- hemorrhagic syndrome;

- dyspnea;

- fatigue;

- "cherry-red spot" macular degeneration (characteristic of NPD type A, less frequent in type A/B).

Detailed physical examination findings are described in the "Clinical Presentation" section.

2.3 Laboratory Diagnostics

Comments: when Niemann-Pick disease types A, B, or A/B (acid sphingomyelinase deficiency) is suspected, enzyme activity testing should be performed. Currently, enzyme activity determination is most frequently performed using dried blood spots via tandem mass spectrometry (TMS). The advantages of this method include minimal requirements for blood collection, shipping, and storage of biological samples, specificity, rapid turnaround time, and the possibility of using the material for re-testing [4, 17, 18].

Comments: The test is performed upon establishing the diagnosis. An initial and follow-up appointment (examination, consultation) with a medical geneticist is necessary to determine the molecular genetic diagnostic strategy and to interpret the obtained results. Molecular genetic diagnostics of Niemann-Pick disease types A, B, and A/B (acid sphingomyelinase deficiency) allows for the detection of causative variants in the SMPD1 gene. In some cases, predicting the severity of acid sphingomyelinase deficiency is possible based on the genotype [10]. In rare cases, causative variants cannot be detected using standard methods as they may fall outside the methodological limitations, which may require additional testing in expert-level laboratories.

Comments: in some cases, determining the blood concentration of Lyso-SM and Lyso-SM509 can serve as a first-line test prior to measuring acid sphingomyelinase enzyme activity or in combination with it for the diagnosis of Niemann-Pick disease types A, B, and A/B (acid sphingomyelinase deficiency). The elevation of Lyso-SM509 in the blood of patients with NPD types A, B, and A/B is less pronounced than in NPD type C.

Comments: the test is performed at least once every 3 months or more frequently, as clinically indicated. Most patients with Niemann-Pick disease types A, B, and A/B (acid sphingomyelinase deficiency) present with thrombocytopenia, and some with anemia, leukopenia, and neutropenia.

Comments: the test is performed at least once every 3 months or more frequently, as clinically indicated. The activities of "liver" enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), as well as total bilirubin, may be elevated in patients with Niemann-Pick disease types A, B, and A/B (acid sphingomyelinase deficiency). An abnormal (atherogenic) lipid profile is common in patients with NPC types A, B, and A/B, with elevated triglycerides and total cholesterol, and decreased HDL cholesterol being the most frequent abnormalities [4].

Comments: biochemical and hematological abnormalities are common in patients with NPC, therefore these tests are necessary both at baseline and at regular intervals during follow-up. The tests are performed at least once every 3 months or more frequently, as clinically indicated [4].

Comments: this test is often prescribed to adult patients with suspected oncological diseases in cases of unexplained splenomegaly. In the bone marrow of patients with NPC types A, B, and A/B, foamy macrophages and/or so-called "blue histiocytes" may be found. However, these cells are non-specific, as they are also encountered in other lysosomal storage diseases, such as acid lipase deficiency or GM1 gangliosidosis, and other conditions. The appearance and staining properties of these cells can lead to a misdiagnosis, as "Gaucher cells," for example, can appear similar [4].

2.4 Instrumental Diagnostics

Comments: these studies are necessary to determine the size of the liver and spleen, the diameter of the portal and splenic veins, the presence of hepatic steatosis, fibrosis, or cirrhosis, and adrenal calcifications, as well as to assess disease progression and subsequently monitor the efficacy of enzyme replacement therapy. The frequency is determined by the patient's condition, but should be at least once a year after diagnosis establishment. To monitor the efficacy of enzyme replacement therapy (ERT), the recommended frequency is: every 6 months at the start of therapy, and then on average once a year. Anesthesia is performed as clinically indicated (combined inhalation anesthesia (including xenon-based anesthesia), combined endotracheal anesthesia).

Comments: in the presence of pulmonary involvement, examinations are performed dynamically, with the frequency determined on an individual basis.

Comments: in the presence of pulmonary involvement, examinations are performed dynamically, with the frequency determined on an individual basis

Comments: the procedure is performed in patients with liver cirrhosis and signs of portal hypertension to assess the grade of esophageal varices and the risk of bleeding.

Comments: liver elastometry is a non-invasive ultrasound method for determining liver parenchyma stiffness. Changes in organ stiffness are a reliable indicator of liver parenchyma alterations and fibrosis progression.

Comments: dual-energy X-ray absorptiometric scanning for measuring bone mineral content (BMC) and bone mineral density (BMD) demonstrates that children exhibit a significant reduction in age-adjusted mean BMC and BMD in the lumbar spine, hip, and femoral neck compared to an age-matched healthy control group. In addition, adults with NPC type B may have osteopenia or osteoporosis at one or more sites according to the World Health Organization BMD classification [34]. Thus, skeletal involvement can be a manifestation of NPC. Patients with NPC types B and A/B may be at an increased risk of clinical complications associated with osteopenia and osteoporosis. Children with NPC may also have low bone density Z-scores. Pathological fractures have been reported in some individuals with severe disease. In this case series, 43% of all patients had a history of one or more skeletal fractures, some of which were pathological. These data indicate that skeletal evaluation, including densitometry of the lumbar spine based on bone age, with the frequency determined by the results and the patient's clinical status, should be part of the clinical evaluation of patients with NPC [4, 34].

2.5 Other Procedures

Comments: patients with NPA, NPB, or NP A/B require initial and follow-up consultations with a clinical nutritionist, neurologist, ophthalmologist, orthopedic traumatologist, cardiologist/pediatric cardiologist, pulmonologist, otolaryngologist-audiologist, psychiatrist, pediatric psychiatrist, gastroenterologist, hematologist/pediatric hematologist-oncologist, pediatrician/general practitioner/family physician, and geneticist, as well as initial and follow-up testing and consultations with a medical psychologist, and with other specialists experienced in managing patients with Niemann-Pick disease type A, B, or A/B, depending on the clinical situation. In life-threatening conditions, the involvement of an anesthesiologist-resuscitologist is required.

2.5.1 Differential diagnosis.

Hepatosplenomegaly is a common symptom in patients with Niemann-Pick disease type A, B, or A/B, with liver involvement being particularly pronounced in NPB, leading to fibrosis and cirrhosis. Elevated liver transaminases in the early stages of the disease often prompt patients to consult gastroenterologists.

The differential diagnosis may include oncological diseases, taking into account splenomegaly and cytopenia, primary liver diseases such as non-alcoholic fatty liver disease, autoimmune diseases, hepatitis B, and cryptogenic cirrhosis, as well as other lysosomal storage diseases causing significant hepatosplenomegaly, including Gaucher disease, lysosomal acid lipase deficiency (LALD), Niemann-Pick disease type C, and mucopolysaccharidoses.

Focal liver lesions and a sudden increase in splenomegaly may indicate infection or the development of portal hypertension [17].

Mixed dyslipidemia is also frequently observed in patients with Niemann-Pick disease type A, B, or A/B and can be detected during laboratory evaluations. The lipid profile is typically characterized by elevated levels of total cholesterol, LDL and VLDL cholesterol, and triglycerides, alongside reduced HDL cholesterol levels [21–23]. A similar lipid profile may also be observed in lysosomal acid lipase deficiency (LALD).

Although some patients with NPA, NPB, or NP A/B may lack respiratory symptoms, the majority have respiratory dysfunction with evidence of interstitial lung disease [24]. In some adult patients, clinical manifestations may be limited solely to pulmonary involvement, broadening the differential diagnostic workup toward infectious, autoimmune diseases, and chronic respiratory disorders such as cystic fibrosis [25]. Pulmonary disease in NPA, NPB, or NP A/B is characterized by a complex of progressive pathophysiological changes, including lipid accumulation in macrophages of the alveolar septa, bronchial walls, and pleura [26].

The differential diagnosis for pulmonary involvement and hepatosplenomegaly encompasses a wide range of conditions, such as Gaucher disease types 2 and 3, cystic fibrosis, alpha-1 antitrypsin deficiency, histiocytosis, sarcoidosis, idiopathic pulmonary fibrosis, alveolar proteinosis, miliary pulmonary tuberculosis, and hemorrhagic vasculitis.

2.5.2. Genetic counseling and comprehensive testing for prenatal diagnosis of child developmental disorders (prenatal diagnosis).

Comments: if both parents are heterozygous carriers of pathogenic variants in the SMPD1 gene, as with other autosomal recessive disorders, the risk of having a child with this disease is 25% for each pregnancy. In families with a child affected by NPA, NPB, or NP A/B, prenatal and preimplantation genetic testing options are available (comprehensive testing for prenatal diagnosis of child developmental disorders (intrauterine) and non-invasive prenatal testing (detection of cell-free fetal DNA in maternal blood)).

It is preferable to perform the study by analyzing DNA extracted from chorionic villus biopsy samples at 9–11 weeks of gestation.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Comments: The medicinal product is intended for intravenous administration, given once every 2 weeks. Infusions should be administered gradually, preferably using an infusion pump [31]. Olipudase alfa is a recombinant human acid sphingomyelinase that reduces sphingomyelin accumulation in the organs of patients with insufficient or impaired function of the enzyme— acid sphingomyelinase, thereby decreasing sphingomyelin accumulation in cells and alleviating disease symptoms. Currently, this is the first and only disease-modifying therapy [32]. The approved indication for olipudase alfa in the Russian Federation is its use as enzyme replacement therapy for the long-term treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency type A/B or B (Niemann-Pick disease type A/B or B) in children and adults [30].

The use of enzyme replacement therapy with olipudase alfa (A16AB25) is not indicated in NPA because the drug does not affect neurological symptoms due to its inability to cross the blood-brain barrier. Since olipudase alfa neither prevents nor exerts an effect on CNS symptoms, it is crucial that families of patients with the neurological form are informed about the risks, benefits, limitations, and lack of effect of the therapy on the CNS. In some countries, indications exist that allow the use of olipudase alfa in all patients with acid sphingomyelinase deficiency, including children with the infantile neurovisceral form (type A).

The rapid metabolism of accumulated sphingomyelin under the action of olipudase alfa leads to the generation of pro-inflammatory breakdown products, which can trigger infusion-associated reactions and/or transient elevations in liver transaminases (ALT, AST). A dose-escalation regimen can minimize most of these adverse events. The drug dose is calculated based on actual body weight for patients with a body mass index (BMI) ≤30 or optimal body weight for patients with a BMI >30.

The initial dose of olipudase alfa is 0.1 mg/kg for adult patients, and the dose should subsequently be increased in accordance with the dose-escalation schedule outlined below in Table 1. The maintenance dose of olipudase alfa in adults is 3 mg/kg every 2 weeks.

Table 1. Dose-escalation schedule for olipudase alfa in adults

The initial dose of olipudase alfa is 0.03 mg/kg for pediatric patients , and the dose should subsequently be increased in accordance with the dose-escalation schedule presented in Table 2. The maintenance dose of olipudase alfa in children is 3 mg/kg every 2 weeks.

Table 2. Dose-escalation schedule for olipudase alfa in children

Comments: performing a splenectomy is inadvisable, as it may lead to the progression of liver disease and increased sphingomyelin accumulation in the lungs, triggering progressive respiratory failure. If splenectomy is necessary due to massive splenomegaly, mass effect symptoms, and severe refractory hypersplenism, partial splenomegaly or partial splenic artery embolization are viable options. If partial or total splenectomy must be performed according to surgical indications, standard postoperative antibiotic prophylaxis and prior vaccination should be utilized [4].

Advanced cases of chronic liver disease (CLD) with fulminant hepatic failure have been reported in several adult patients with NPD [4, 35, 36]. The rate of progression of liver disease is highly variable [35, 36, 37]. Liver failure is a major cause of mortality in patients with NPD [36]. Patients with cirrhosis should be followed by gastroenterologists. Liver transplantation outcomes have been reported in several individuals with type B NPD who exhibited progressive liver dysfunction. In addition to improvements in liver function and dyslipidemia, significant improvements in lung disease and growth parameters were observed in children [4, 36, 37].

Patients may also experience sleep disturbances, increased irritability, chronic pain syndrome, fatigue, behavioral problems, and psychiatric disorders such as anxiety and depression [4]. Treatment plans for these conditions are addressed by the relevant specialists.

3.2 Diet therapy

Comments: patients may lose weight due to dysphagia or side effects of therapy; gastrostomy tube placement if indicated.

3.3 Pain management

Special pain management procedures are not used.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: the presence of pain, weakness, visceral abnormalities, delayed growth and pubertal development can negatively affect the patient's self-esteem, which may require psychological support. It is necessary to help the patient and their family "accept" the diagnosis and adapt to life to maximize their learning potential and independent living in the future.

Comments: furthermore, regular consultations with a physical therapy and rehabilitation medicine physician aim to assess the functional status (level of impairment), which helps evaluate the severity and rate of disease progression

Comments: patients should undergo a comprehensive swallowing evaluation by a medical speech-language pathologist (medical speech-language pathology assessment for dysphagia). Training in dietary modifications and compensatory postures can be beneficial for individuals with dysphagia. The family should be informed about the progressive deterioration of swallowing skills and the increased risk of aspiration as part of ongoing care. Nasogastric tube feeding or surgical tube placement may be considered to increase caloric intake and potentially reduce the risk of aspiration

5. Prevention and Dispensary Observation

5.1 Selective screening of high-risk groups

Comments: screening is performed using laboratory testing methods—determining acid sphingomyelinase activity and/or determining the concentration of lysosphingomyelin (LysoSM) in dried blood spots. Risk groups for screening include patients with the following symptoms: hepatosplenomegaly, hypercholesterolemia, thrombocytopenia, interstitial lung disease.

5.2 Monitoring the condition of patients with Niemann-Pick disease type A, B, A/B

Comments: Patients with NPD type A, B, A/B must be monitored locally in outpatient clinic settings: an annual routine follow-up examination (evaluation, consultation) is required by a pediatrician/general practitioner/family physician, gastroenterologist, hematologist, pediatric oncologist, geneticist, neurologist (in the presence of neurological manifestations), orthopedic trauma surgeon (in the presence of bone abnormalities), ophthalmologist, otolaryngologist-audiologist, and physical therapy physician, on average, annually.

Blood parameters should be monitored every 3 months, and the size of parenchymal organs every 6 months at the start of enzyme replacement therapy (ERT), and subsequently every 12 months. In case of significant clinical complications associated with liver cirrhosis and portal hypertension, blood tests are required every 1 to 3 months and instrumental examinations every 3 to 6 months as indicated. Bone status assessment should be performed every 6 to 12 months, taking into account the patient's baseline data.

ERT should be administered regularly, and when indicated in cases of complicated disease progression, in an inpatient setting; in stable conditions, it should be administered in a day hospital (or outpatient setting as maintenance therapy) once every 2 weeks. All patients must undergo follow-up evaluations to assess ERT outcomes in an inpatient or day hospital setting twice a year at the start of therapy; subsequently, evaluations are performed once a year.

Transaminase ("liver") activity values (ALT, AST) must be obtained prior to treatment initiation and monitored at all dose escalation steps of olipudase alfa. If pre-infusion transaminase activity exceeds the baseline value and is more than 2 times the upper limit of normal (ULN), the olipudase dose may be adjusted (repeating or reducing the previous dose according to the dose escalation schedule) or treatment may be temporarily interrupted depending on the degree of transaminase elevation. If a dose adjustment or treatment interruption is required, when resuming treatment, the dose escalation regimen described above for adults and children respectively must be followed, as well as recommendations for missed doses [4, 30].

The efficacy of olipudase alfa treatment should be monitored by measuring height and weight (in children), liver and spleen volume, pulmonary function, hematological parameters, lipid profile, and other disease biomarkers. Data should be collected for future use and development of treatment guidelines [4].

Comments: the studies are performed at least once every 3 months or more frequently as clinically indicated.

Comments: the study is performed at least once every 3 months or more frequently as clinically indicated. The activity of "liver" enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) may be elevated in patients with Niemann-Pick disease type A, B, or A/B (acid sphingomyelinase deficiency). An abnormal (atherogenic) lipid profile is frequently observed in patients with NPA, NPB, or NPA/NPB, with the most common abnormalities being elevated triglycerides and total cholesterol, alongside decreased HDL cholesterol levels.

Comments: the study is performed at least once every 3 months or more frequently as clinically indicated. To monitor the efficacy of enzyme replacement therapy (ERT), the recommended frequency is: once every 6 months at the initiation of therapy, and subsequently averaging once a year [4].

Comments: frequency averages once every 6 months at the initiation of therapy, and subsequently once a year. The study is required to determine the size of the liver and spleen, measure the diameter of the portal and splenic veins, detect hepatic steatosis, fibrosis, or cirrhosis, identify adrenal calcifications, as well as assess disease progression and subsequently monitor the efficacy of enzyme replacement therapy. To monitor the efficacy of enzyme replacement therapy (ERT), the frequency is: once every 6 months at the initiation of therapy, and subsequently averaging once a year.

Comments: in the presence of pulmonary involvement, examinations are performed dynamically, with the frequency determined on an individual basis.

Comments: in the presence of pulmonary involvement, examinations are performed dynamically, with the frequency determined on an individual basis.

Comments: the procedure is performed in patients with hepatic fibrosis and signs of portal hypertension to assess the degree of esophageal varices and the risk of bleeding.

Comments: liver elastometry is a non-invasive ultrasound method for determining liver parenchyma stiffness. Changes in organ stiffness are a reliable indicator of liver parenchyma alterations and fibrosis progression.

Comments: the study is advisable to perform starting from a bone age of 5 years or in children with a height exceeding 100 cm. Dual-energy X-ray absorptiometry of the lumbar spine is performed based on bone age with evaluation of the Z-score and BMD.

Table 3 outlines the principles of patient monitoring in Niemann-Pick disease type A, B, and A/B.

Table 3. Principles of monitoring in Niemann-Pick disease type A, B, and A/B

6. Organization of Medical Care

Hospitalization of patients is most often carried out in a hematology, pediatric, gastroenterology, or surgery/orthopedic department; treatment may also be conducted in neurology, pulmonology, and other departments depending on the dominant symptoms of the disease.

Routine vaccination in patients with NPA, NPB, or NPA/NPB is carried out in accordance with the National Immunization Schedule.

Required specialist consultations, laboratory and instrumental examinations, and their recommended frequency are presented in Section 5.2.

6.1 Indications for planned hospitalization

1. provision of diagnosis and treatment requiring prolonged (day or round-the-clock) medical observation and monitoring of clinical and laboratory parameters;

2. the need for various types of expert evaluations or medical examinations in a medical institution when they cannot be performed in an outpatient setting (including issuing a federal consilium or medical commission conclusion);

3. a condition requiring active treatment and round-the-clock medical observation;

4. a condition requiring high-tech medical care methods (including monitoring the efficacy of ERT);

5. the inability to provide ERT in outpatient and day-care settings;

6. the need for various expert evaluations or examinations in a medical institution when outpatient performance is not feasible and dynamic observation is required.

6.2 Indications for emergency/urgent hospitalization

1. acute life-threatening conditions and conditions that may develop severe complications requiring emergency treatment, including intensive care, as well as 24-hour medical supervision and special diagnostic and therapeutic procedures.

6.3 Indications for hospital discharge

1. absence of a threat to the patient's life and risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process, no need for prolonged medical supervision (day or inpatient care);

3. the diagnostic and treatment plan has been completed, and recommendations for further follow-up and management have been provided;

4. need to transfer the patient to another medical facility or social care institution.

7. Additional Information

7.1 Outcomes and prognosis

The prognosis in NPA, NPB, and NPA/NPB depends on the severity of clinical manifestations. Pathogenetic therapy initiated in the early stages of the disease ensures a favorable prognosis and improves the quality of life in children with NPD, preventing disability. In NPD type A, the prognosis is poor: death occurs by the age of 3 to 4 years, frequently within the first year of life [33].

Criteria for Evaluating the Quality of Medical Care

Organizational and technical conditions for the provision of medical care

Quality criteria for medical care

References

Appendix A1. Working Group Composition

1. Inga V. Anisimova – Candidate of Medical Sciences, Medical Geneticist, Research Centre for Medical Genetics, Member of the Association of Medical Geneticists

2. Galina V. Baydakova – Candidate of Biological Sciences, Leading Researcher, Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics, Member of the Russian Society of Medical Genetics

3. Aleksandr A. Baranov – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Professor, Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia; Chief Visiting Pediatrician of the Russian Ministry of Health

4. Nato D. Vashakmadze – Doctor of Medical Sciences, Head of the Department of Rare Diseases, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Member of the Union of Pediatricians of Russia, Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Ministry of Health of Russia

5. Sergey V. Voronin – Candidate of Medical Sciences, Chief Medical Officer, Research Centre for Medical Genetics; Chief Visiting Specialist in Medical Genetics of the Russian Ministry of Health in the Far Eastern Federal District

6. Olga S. Gundobina – Candidate of Medical Sciences, Leading Researcher, Gastroenterologist, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Member of the Union of Pediatricians of Russia

7. Elena A. Dobrynina – Candidate of Medical Sciences, Senior Researcher, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Member of the Union of Pediatricians of Russia

8. Ekaterina Yu. Zakharova – Doctor of Medical Sciences, Head of the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics; Member of the Russian Society of Medical Genetics, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM)

9. Elena V. Kaitukova – Candidate of Medical Sciences, Chief Medical Officer, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Ministry of Health of Russia; Member of the Union of Pediatricians of Russia

10. Elena V. Komarova – Doctor of Medical Sciences, Deputy Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Gastroenterologist, Member of the Union of Pediatricians of Russia

11. Sergey I. Kutsev – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics; Chief Visiting Specialist in Medical Genetics of the Russian Ministry of Health, President of the Association of Medical Genetics of Russia

12. Alla E. Lavrova – Doctor of Medical Sciences, Physician of the Highest Qualification Category in Pediatrics, Acting Head of the Institute of Pediatrics, University Clinic of the Privolzhsky Research Medical University, Ministry of Health of Russia; Head of the 2nd Pediatric Department with Medical Rehabilitation, Privolzhsky Research Medical University, Ministry of Health of Russia

13. Olga A. Laisheva – Doctor of Medical Sciences, Professor, Head of the Center for Medical Rehabilitation, Russian Children's Clinical Hospital (branch of Pirogov Russian National Research Medical University, Ministry of Health of Russia), Physician of the Highest Category

14. Svetlana V. Mikhailova – Doctor of Medical Sciences, Head of Department, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University, Ministry of Health of Russia

15. Goar B. Movsisyan – Candidate of Medical Sciences, Senior Researcher, Laboratory of Rare Hereditary Diseases in Children, Medical Genetics Center; Pediatrician, Gastroenterologist, Gastroenterology Department, National Medical Research Center for Children's Health, Ministry of Health of Russia

16. Lyudmila P. Nazarenko – Professor, Doctor of Medical Sciences, Deputy Director for Research and Patient Care, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences; Member of the Association of Medical Geneticists

17. Leyla S. Namazova-Baranova – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatricians of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Ministry of Health of Russia; Chief Visiting Pediatric Specialist in Preventive Medicine, Ministry of Health of Russia

18. Ekaterina A. Nikolaeva – Doctor of Medical Sciences, Professor, Head of the Department of Clinical Genetics, Veltischev Research Institute of Pediatrics, Pirogov Russian National Research Medical University; Member of the Russian Society of Medical Genetics

19. Tatiana M. Pervunina – Candidate of Medical Sciences, Director of the Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre, Ministry of Health of Russia

20. Aleksandr S. Potapov – Doctor of Medical Sciences, Professor, Head of the Gastroenterology Department, National Medical Research Center for Children's Health, Ministry of Health of Russia; Professor, Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia

21. Aleksandr A. Pushkov – Candidate of Medical Sciences, Leading Researcher, Laboratory of Molecular Genetics and Medical Genomics, National Medical Research Center for Children's Health, Ministry of Health of Russia; Member of the Association of Medical Geneticists (contributed to the original version of the document)

22. Svetlana A. Repina – Candidate of Medical Sciences, Medical Geneticist, Research Centre for Medical Genetics; Member of the Russian Society of Medical Genetics, Member of the Association of Medical Geneticists

23. Kirill V. Savostyanov – Doctor of Biological Sciences, Head of the Center for Fundamental Research in Pediatrics, National Medical Research Center for Children's Health, Ministry of Health of Russia; Member of the Association of Medical Geneticists (contributed to the original version of the document)

24. Liliya R. Selimzyanova – Candidate of Medical Sciences, Leading Researcher, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Ministry of Health of Russia; Associate Professor, Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia; Member of the Union of Pediatricians of Russia

25. Olga Ya. Smirnova – Medical Geneticist, Senior Researcher, Department of Standardization and Study of Evidence-Based Medicine Foundations, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Member of the Union of Pediatricians of Russia

26. Nataliya S. Smetanina – Doctor of Medical Sciences, Professor, Deputy Director of the Institute of Hematology, Immunology and Cell Technologies, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Health of Russia; Member of the National Hematological Society

27. Tatiana V. Strokova – Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietotherapy, Clinic of the Federal Research Centre of Nutrition and Biotechnology; Head of the Department of Gastroenterology and Dietology, Faculty of Continuous Professional Education, Pirogov Russian National Research Medical University, Ministry of Health of Russia

28. Dmitry M. Subbotin – Medical Geneticist, Research Centre for Medical Genetics, Member of the Association of Medical Geneticists

29. Andrey N. Surkov – Doctor of Medical Sciences, Head of the Inpatient Pediatric Gastroenterology Department, Head of the Division of Scientific Foundations of Pediatric Gastroenterology, Hepatology and Metabolic Disorders, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Ministry of Health of Russia

30. Marina V. Fedoseenko – PhD in Medical Sciences, Head of the Department for the Development of Scientific Approaches to the Immunization of Patients with Health Deviations and Chronic Diseases, Leading Research Fellow, Pediatrician at the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery; Associate Professor at the Department of Faculty Pediatrics, Faculty of Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Union of Pediatricians of Russia

Representatives of public organizations:

Nelly S. Poghosyan – All-Russian Orphan Disease Society

Sofia A. Glushkova – All-Russian Orphan Disease Society

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• medical geneticists;

• pediatricians;

• general practitioners (family doctors);

• gastroenterologists;

• pediatric hematologists-oncologists;

• hematologists;

• pulmonologists;

• pediatric surgeons;

• trauma and orthopedic surgeons;

• neurologists;

• ophthalmologists;

• endocrinologists;

• medical psychologists;

• medical students, residents, postgraduate students.

Table 1 Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2 Scale for assessing levels of evidence (LE) for methods of prevention, treatment, and rehabilitation, including those based on the use of natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3 Scale for assessing grades of recommendation (GR) for methods of prevention, diagnostics, treatment, and rehabilitation, including those based on the use of natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The clinical guideline update mechanism provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Ministry of Health and Social Development of Russia No. 366n dated April 16, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Pediatric Care"

2. Order of the Ministry of Health of Russia No. 274n dated April 21, 2022 "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases"

3. State Register of Medicines: https://grls.rosminzdrav.ru

Main regulatory legal acts governing the provision of palliative medical care

1. Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 25, 2023) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation"

2. Order of the Ministry of Health of Russia No. 345n, Ministry of Labor of Russia No. 372n dated May 31, 2019 "On Approval of the Regulations on the Organization of Palliative Medical Care, Including the Procedure for Interaction Between Medical Organizations, Social Service Organizations, and Public Associations and Other Non-Profit Organizations Operating in the Health Protection Sphere"

3. Order of the Ministry of Health of Russia No. 348n dated May 31, 2019 (as amended on November 2, 2020) "On Approval of the List of Medical Devices Intended to Support the Functions of Human Organs and Systems Provided for Home Use"

4. Order of the Ministry of Health of Russia No. 505n dated July 10, 2019 "On Approval of the Procedure for Transferring Medical Devices Intended to Support the Functions of Human Organs and Systems from a Medical Organization to a Patient (Their Legal Representative) for Home Use in the Provision of Palliative Medical Care"

Other regulatory and legal documents used in the development of the clinical guidelines:

1. Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 25, 2023) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation";

2. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

3. Order of the Ministry of Health of Russia No. 205n dated May 2, 2023 (as amended on December 4, 2023) "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers";

4. Order of the Ministry of Health of Russia No. 103n dated February 28, 2019 (as amended on June 23, 2020) "On Approval of the Procedure and Timeframes for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition, and the Scientific Validity of Information Included in Clinical Guidelines"

5. Order of the Ministry of Health of Russia No. 804n dated October 13, 2017 (as amended on September 24, 2020, with rev. dated October 26, 2022) "On Approval of the Nomenclature of Medical Services"

Appendix B. Physician Action Algorithms

Algorithm for laboratory diagnosis of acid sphingomyelinase deficiency (Niemann-Pick disease types A, B, A/B)

Appendix C. Patient Information

What is Niemann-Pick disease types A, B, A/B?

Currently, over 50 lysosomal storage disorders are known, one of which is Niemann-Pick disease. Niemann-Pick disease types A, B, and A/B (acid sphingomyelinase deficiency) is a rare inherited metabolic disorder belonging to the sphingolipidosis group. The disease is caused by decreased activity of the acid sphingomyelinase enzyme, which helps break down fats in the body. This leads to their accumulation, which damages various organs, especially the liver and brain. Depending on the severity of symptoms and the age of onset, three types are distinguished: Niemann-Pick disease types A, B, and A/B.

Acid sphingomyelinase deficiency is a very rare disease, with an estimated global prevalence of approximately 1:100,000 to 1,000,000 newborns. In certain ethnic groups (e.g., Ashkenazi Jews), the disease is more common.

How does Niemann-Pick disease types A, B, A/B manifest?

Niemann-Pick disease type A is the most severe form of the disease. Symptoms appear as early as infancy, typically within the first months of life. Children with this type of the disease exhibit severe mental and motor development impairments, feeding problems, liver dysfunction, and significant enlargement of the liver and spleen. Unfortunately, type A frequently leads to early mortality, usually by the age of 3.

Niemann-Pick disease type B has a milder course and typically does not affect the nervous system. Patients with this type may present with hepatosplenomegaly, pulmonary issues, and, occasionally, growth retardation. Symptoms can range from mild to moderate, and many individuals with type B have a normal life expectancy.

Niemann-Pick disease type A/B is an intermediate form characterized by both neurological and systemic manifestations of the disease. Symptoms may include nervous system impairments (ataxia, polyneuropathy), as well as the same signs seen in type B, including hepatosplenomegaly.

Children frequently exhibit irritability, sleep disturbances, insomnia, prolonged crying, and vomiting. The disease has a negative impact on both the patients themselves and their caregivers. This is related to their physical and psycho-emotional state, as well as social isolation.

How is Niemann-Pick disease types A, B, A/B diagnosed?

The "gold standard" of modern diagnostics for Niemann-Pick disease is biochemical methods. To confirm the diagnosis, acid sphingomyelinase activity is determined in dried blood spots or peripheral blood leukocytes. Additionally, the levels of lysosphingomyelin (Lyso-SM) and lysosphingomyelin-509 (Lyso-SM509), which are also specific markers of this disease, are measured simultaneously.

In addition to enzyme assay, molecular genetic testing plays an important role in identifying biallelic pathogenic variants in the SMPD1 gene, which encodes acid sphingomyelinase. This allows not only for confirmation of the diagnosis but also, in some cases, determination of the specific disease type (A, B, or A/B), which is important for predicting disease progression and planning treatment.

A comprehensive study for the prenatal diagnosis of child developmental disorders (prenatal diagnostics) is performed at 9–11 weeks of pregnancy. Testing is conducted on chorionic villus sampling material (the tissue from which the placenta subsequently develops) to detect pathogenic variants in the gene. Based on the analysis performed, a conclusion is reached as to whether the fetus is affected or healthy, and the family makes a decision regarding the pregnancy. Modern technologies also allow for preimplantation genetic testing (preimplantation diagnostics). Fertilization is performed in vitro, after which only those fertilized embryos at the multi-blastomere stage that lack the familial mutation are selected and implanted into the mother's body. This procedure carries its own risks, which can be explained by a genetic counselor.

How is Niemann-Pick disease types A, B, A/B inherited?

The SMPD1 gene, which encodes acid sphingomyelinase, is localized to the chromosomal region 11p15.1-p15.4. Patients harbor alterations in this gene, referred to as "pathogenic variants".

The disease is inherited in an autosomal recessive manner. This means that the disease manifests only if both parents are carriers of the disease ("pathogenic variant") and, although they are not ill themselves, each transmits the altered gene to the child. Most families with a child affected by this disease have not previously encountered such a problem. The risk of recurrence of a child with acid sphingomyelinase deficiency in a family that already has children with this disease is 25% for each pregnancy.

In the same family, the disease does not always manifest identically, and initial symptoms may appear at different ages. A patient's siblings may have acid sphingomyelinase deficiency even if they are asymptomatic at the time of diagnosis. In such cases, diagnostic testing is necessary to initiate therapy as early as possible and prevent complications. They may also be carriers, just like their parents. As for other family members, it is important to inform them that they may be carriers. This means they also carry a risk of having a child with this condition.

All families affected by this disease must undergo medical genetic counseling and receive comprehensive information from a geneticist regarding the risk of recurrence in the family, as well as discuss all questions related to the inheritance of the condition. Attending physicians do not always have the opportunity to speak with the family and discuss the risks and possibilities offered by modern genetics. A geneticist can help determine the risk of having an affected child in a given family, test relatives if necessary, and discuss comprehensive testing for prenatal diagnosis of fetal developmental disorders (prenatal diagnosis) and preimplantation genetic testing (preimplantation diagnosis). In Russia, medical genetic clinics operate in every region.

To undergo comprehensive testing for prenatal diagnosis of fetal developmental disorders (prenatal diagnosis) and preimplantation genetic testing (preimplantation diagnosis), a couple must first be screened for carrier status of pathogenic variants in the SMPD1 gene causing this disease by contacting specialized diagnostic laboratories and medical centers.

How is Niemann-Pick disease types A, B, and A/B treated?

Treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency consists of lifelong enzyme replacement therapy (ERT). Administration of the missing enzyme improves patients' condition and, in some cases, achieves virtually complete resolution of the main clinical manifestations of the disease. ERT is indicated for patients with a confirmed diagnosis of Niemann-Pick disease type B and type A/B who have clinically significant non-neurological manifestations. It is crucial to start ERT as early as possible to prevent severe complications. Supportive symptomatic therapy is also provided depending on the patient's condition.

One ERT product with proven efficacy is registered in the Russian Federation. The main goals of treatment are:

• reduction of splenomegaly and increase in platelet counts;

• regression of pathological changes in affected organs and restoration of their functions;

• improvement of physical development parameters;

• improvement of patients' quality of life.

What monitoring is required for patients with Niemann-Pick disease types A, B, and A/B?

A multidisciplinary approach involving specialists from various fields is necessary for monitoring and management to ensure comprehensive therapy and timely adjustment when needed. Patients with Niemann-Pick disease types A, B, and A/B require regular examinations, including abdominal ultrasound, complete blood count, and blood chemistry panels. Patients should consult their physician regarding the recommended frequency of these tests.

How can family and loved ones help?

Do not forget that treatment success also depends on the family. It is essential to follow recommendations, avoid significant interruptions in therapy, and pay attention to rehabilitation and scheduled check-ups. All family members must be aware that the patient requires enzyme replacement therapy. It is extremely critical to strictly follow all prescriptions for medications prescribed by the physician.

The prognosis depends on the form of the disease and the treatment. With timely initiation of treatment for Niemann-Pick disease types B and A/B, the prognosis is generally favorable.

It is important not to lose hope and to maintain an active and diverse lifestyle as much as possible.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.