Niemann-Pick disease type C: Clinical Guidelines

List of Abbreviations

ALT — alanine aminotransferase

AST — aspartate aminotransferase

VVS — vertical supranuclear gaze palsy

HPLC-MS/MS — high-performance liquid chromatography tandem mass spectrometry

GGT — gamma-glutamyl transferase

GC-MS — gas chromatography-mass spectrometry

NPC PI — NPC probability index

CT — computed tomography

HDL — high-density lipoproteins

LDL — low-density lipoproteins

LSM 509 — lyso-sphingomyelin 509

INR — international normalized ratio

MRI — magnetic resonance imaging

NPC — Niemann-Pick disease type C

PT — prothrombin time

PI — prothrombin index

SDE — saccadic eye movements

SRT — substrate reduction therapy

US — ultrasound

ALP — alkaline phosphatase

MLPA — multiplex ligation-dependent probe amplification

Terms and Definitions

Substrate reduction therapy is the lifelong administration of a drug that affects the metabolism of accumulated substrates in patients with metabolic disorders.

Lysosomal storage diseases — a group of hereditary monogenic disorders associated with impaired lysosomal function.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Niemann-Pick disease type C (NPC) is a rare inherited multisystem disorder. Characteristic neurological manifestations of NPC include oculomotor disorders in the form of impaired saccadic eye movements (SEM) or vertical supranuclear gaze palsy (VSGP), cerebellar disorders (ataxia, dysmetria), dystonia, dysarthria, dysphagia, and gelastic cataplexy. Patients also frequently experience seizures and develop epilepsy [1–7, 19, 20]. Neurological symptoms typically onset in childhood, although an increasing number of cases are identified and diagnosed in adulthood due to late-onset neurological and psychiatric symptoms. The distribution of patients by age of neurological manifestation (early childhood, late childhood, juvenile, and adolescent/adult onset) can be useful for assessing disease progression and treatment response. In September 2012, updated recommendations developed during a regular meeting in Paris, France by a group of international experts were published, and guidelines on selective screening, diagnosis, and treatment of NPC were updated in 2018 [8, 19, 20].

Patient selection for diagnostics is carried out based on selective screening — identifying a group of patients who have clinical symptoms characteristic of this disease (visceral, neurological, psychiatric) for further laboratory testing [20].

In the presence of a corresponding clinical picture, the diagnosis is confirmed by biochemical and molecular genetic methods [4, 8, 19, 20].

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

The disease is caused by pathogenic variants in the NPC1 (in 95% of cases) or NPC2 (about 4% of cases) genes, which lead to impaired intracellular lipid transport and the accumulation of cholesterol and glycosphingolipids in the brain and other tissues. The inheritance pattern is autosomal recessive [13].

The NPC1 and NPC2 genes encode cell membrane proteins responsible for the transport of cholesterol and lipids into the cell. NPC1 belongs to the gene family encoding membrane-bound sterol-sensing proteins. In cell models, NPC1 defects have been shown to impair the intracellular transport (efflux) of free cholesterol taken up by cells with low-density lipoprotein fractions. Intra-lysosomal accumulation of cholesterol inhibits sphingomyelinase activity and leads to the accumulation of sphingomyelin in the cells of parenchymal organs (liver, spleen, kidneys) and the nervous system. Microscopic examination of all organs reveals "foamy" cells, the so-called Niemann-Pick cells. When specific stains are used, the cytoplasm of histiocytes acquires a sea-blue color («sea-blue histiocytes») due to the deposition of lipopigments or ceroid. However, these cells are not as typical for NPC as they are for types A and B [1, 12].

1.3 Epidemiology of the Disease or Condition

The disease is panethnic. The prevalence of the disease averages 0.66–0.83 per 100,000 live newborns [13].

1.4 Features of Coding the Disease or Condition

E75.2 — Other sphingolipidoses.

1.5 Classification of the disease or condition

NPC belongs to lysosomal storage diseases, a subgroup of sphingolipidoses. The classification of NPC is based on the age of disease manifestation [12, 13]. Currently, the following forms of NPC are accepted: perinatal (onset at <3 months of age), early infantile (3 months to 2 years of age), late infantile (2 to 6 years of age), juvenile (6–15 years of age), and adolescent/adult (older than 15 years) [3, 12, 13].

1.6 Clinical presentation of the disease or condition

NPC is a multisystem disease. Clinical manifestations that indicate a possible diagnosis of NPC include visceral, neurological, and psychiatric symptoms. The severity of clinical manifestations of NPC at different ages is presented in Appendix A3.2.

A variable clinical course of NPC is often observed among siblings, despite identical genotype and biochemical phenotype [8, 12, 13]. Patients born with a severe perinatal form may have siblings with the onset of neurological manifestations in childhood or adolescence.

Neurological manifestations.

Neurological disorders in NPC often develop gradually, debuting with non-specific symptoms such as decreased muscle tone (central hypotonia) or frequent falls and clumsiness in cases of onset in older childhood.

In cases of NPC onset in early and late infancy, speech development delay or arrest typically occurs, and in some cases, regression of speech skills with or without delayed overall cognitive and/or motor development [3, 5, 8, 13, 19, 45].

Starting from late infancy and older, one or more cerebellar symptoms are frequently observed. Typical neurological manifestations of NPC include gait disturbance, cerebellar ataxia, dystonia, dysmetria, dysdiadochokinesia, dysarthria and dysphagia, gelastic cataplexy, epileptic seizures, and sensorineural hearing loss [1–8, 13, 19].

Cerebellar ataxia is a frequent manifestation in cases of adult-onset disease.

Dystonia is associated with striatal involvement and often manifests as focal dystonia affecting the hands and face. Generalized dystonia may manifest as gait disturbances and abnormal postures. Acute myoclonus or myoclonic tremor may develop as the disease progresses or sometimes occur in the early stages of NPC development.

Dysphagia may appear in the early stages of the disease or develop later and presents a serious challenge for clinical management, as it severely impairs the ability to eat independently in the later stages of the disease, increasing the risk of aspiration and, consequently, severe pulmonary infections. Dysphagia may begin with simple choking or coughing during meals, usually when consuming liquids.

Oculomotor disturbances are a hallmark of NPC, observed in 81% of patients according to a large-scale retrospective study [9], typically beginning in late infancy with saccadic eye movement (SEM) abnormalities. SEM abnormalities may be missed during clinical examination if spontaneous eye movements are not assessed. This symptom is detected in almost all patients with NPC upon proper examination, and the true prevalence of this symptom is likely underestimated. Vertical eye movements are affected first, followed by horizontal saccade impairments [3, 8, 12, 13, 16, 29]. Initially, only spontaneous saccadic movements are impaired, while slow smooth pursuit eye movements may remain normal. Over time, these impairments progress to complete vertical supranuclear gaze palsy [13, 19], starting with a progressive decrease in saccadic velocity (although saccadic latency remains normal), leading to complete paralysis of saccadic eye movements. The vestibulo-ocular reflex is often preserved for a long time, confirming the fact that gaze palsy is truly supranuclear in nature.

Cataplexy is a relatively specific and frequent neurological sign of NPC, observed overall in more than half of patients. It is less frequently observed in early childhood and is more commonly noted in cases of late infantile and juvenile onset [3, 13, 19]. Cataplexy manifests as a sudden loss of muscle tone in the legs or, occasionally, in the jaw or neck, and is triggered by emotions such as laughter (gelic cataplexy). This sign is easily missed and often misdiagnosed as secondary falls due to ataxia or as atonic epileptic seizures.

Epileptic seizures are less frequently observed in patients with early infantile or adult onset [13, 19] than in cases with late infantile and juvenile onset. Patients with NPC may experience any type of epileptic seizure (partial/focal, generalized, absence, myoclonic, tonic-clonic); seizures can vary significantly in intensity and frequency.

Sensorineural hearing loss is frequently encountered in clinical practice [12, 13, 46, 47].

Peripheral neuropathy is a rare complication in patients with NPC that may be observed in infantile forms. It has never been observed in cases with juvenile or adult onset [12, 13, 19].

Cognitive impairment.

Cognitive decline is observed in virtually all patients with adolescent/adult-onset NPC from a certain point in the disease progression, but is rarely recognized in childhood during the early stages of NPC [1, 7, 13, 19].

Patients with late infantile and juvenile onset exhibited poor school performance and learning difficulties.

Cognitive impairment in NPC primarily begins with frontostriatal/frontal-subcortical disorders and is characterized by a decline in executive function and verbal memory, as well as reduced information processing speed.

As NPC progresses, patients experience a more pronounced deterioration in cognitive function, leading in many cases to severe dementia with gross dysregulatory syndrome and memory impairment [15, 19, 23, 27].

Psychiatric manifestations.

Patients with adolescent/adult-onset NPC often present with psychiatric manifestations; patients with juvenile onset who had a history of behavioral abnormalities and other manifestations have also been reported to present later for psychiatric illnesses [15].

Behavioral problems, learning disabilities, expressive language disorder, and attention-deficit/hyperactivity disorder are frequently observed in patients with juvenile onset [1, 2, 7, 13, 19].

Psychosis with schizophrenia-like features is a frequent symptom in adolescent/adult NPC patients, reported in up to 25% of cases. Clinical manifestations are often indistinguishable from schizophrenia, featuring typical auditory hallucinations, delusions, thought and behavioral disorders; markers of organic psychosis may also be observed, including visual hallucinations, cognitive impairment, and resistance to psychotropic therapy [19, 20].

Catatonia may also be observed, most commonly in patients with early-onset disease. It is often treatment-refractory and may be considered a sign of organic mental illness [12, 13, 19].

Other severe psychiatric manifestations, including depression, bipolar disorder, and obsessive-compulsive disorder, have been reported [8, 9, 13, 15, 24].

Adults over the age of 30 more frequently present with a dysregulatory syndrome characterized by impairments in inhibition, planning, and organization, as well as reduced self-awareness/insight and cognitive flexibility, which appear prior to memory impairment and deficits in other cognitive domains [19].

Visceral manifestations. Visceral symptoms of NPC include lesions of the liver, spleen, lungs, and other organs.

Manifestations of NPC in the neonatal period are noted in 45–65% of cases. The earliest clinical manifestation, regardless of the clinical form of the disease, is cholestasis syndrome, though isolated splenomegaly or hepatosplenomegaly may also be noted. Additionally, a mild-to-moderate increase in blood alanine aminotransferase and aspartate aminotransferase activity (cytolysis syndrome) has been described in a number of patients. Furthermore, cases of non-immune hydrops fetalis, ascites, and fetal hepatosplenomegaly have been reported. The combination of cholestasis with a significant degree of splenomegaly in the absence of portal hypertension signs is considered pathognomonic. In most cases, signs of cholestasis in this disease resolve spontaneously by the 6th–8th month of life, while hepatosplenomegaly persists for a long time [17]. In 10% of cases with early NPC manifestation, the course is fulminant, with the development of liver failure and death within the first year of life [17, 19, 20].

A history of neonatal cholestasis, hepatosplenomegaly, or isolated splenomegaly is frequently noted in patients with early and late childhood onset.

In patients with older-onset disease, hepatosplenomegaly/isolated splenomegaly is usually asymptomatic and often clinically unrecognized, which necessitates abdominal ultrasound in cases of suspected NPC. According to available data, approximately 15% of all NPC patients and nearly half of adolescent/adult-onset patients lack hepatomegaly or splenomegaly [15]. However, these data do not reflect the true prevalence of hepatosplenomegaly because abdominal ultrasound was frequently not performed [15].

While splenomegaly is almost universally observed in NPC, hepatomegaly is less frequently observed in adults [19]. In patients with neurodegenerative or psychiatric disorders, the presence of isolated splenomegaly in the absence of portal hypertension and liver disease strongly suggests the diagnosis of NPC [19].

Pulmonary involvement in the form of foamy macrophage infiltration is associated with pulmonary alveolar proteinosis and is typically observed exclusively in early-onset patients or those with NPC2 gene mutations, unlike patients with NPC1, in whom respiratory complications usually arise due to recurrent aspiration and infections [13, 19, 48].Visceral manifestations, when present, always precede neurological symptoms. Moreover, the age of onset of visceral symptoms is not correlated with the age of onset of neurological manifestations; neurological symptoms may appear many years or even decades after the appearance of visceral symptoms.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of NPC is established based on a combination of: anamnestic data, clinical findings, and laboratory test results (biochemical and molecular genetic analysis). Clinical diagnosis is aided by the NPC high-risk questionnaire/scoring scales presented in Appendices G1 and G2.

2.1 Complaints and Anamnesis

NPC symptoms can develop at different age periods. Taking a detailed medical history can help the physician identify early manifestations of NPC. In the neonatal period, NPC patients may exhibit prolonged jaundice, cholestasis, and hepatosplenomegaly, which may resolve with age. Subsequently, such patients may present with neurological or psychiatric symptoms [13, 19].

Cases of stillbirth and unexplained intrauterine fetal death may be observed in the family [13, 19].

Prior to the development of prominent neurological manifestations, clumsiness and frequent falls due to oculomotor disturbances are noted in the early stages of the disease [13, 15, 19].

2.2 Physical Examination

2.3 Laboratory Diagnostics

Comments: according to published data, elevated levels of cholesterol oxidation products (cholestane-3,5,6-triol and 7-ketosterole) in individuals with pathogenic variants in the NPC1 and NPC2 genes are a sensitive and specific marker for NPC screening. The levels of these metabolites are not elevated in patients with other neurodegenerative diseases. These compounds can be determined using gas chromatography-mass spectrometry (GC-MS) or high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) [3, 8, 19, 20].

Comments: laboratories performing the testing must establish their own reference ranges for these metabolites. It should also be noted that non-compliance with sample storage and transportation requirements causes false-positive results [8, 19, 20, 33]. The rules for blood collection on a standard filter paper card are provided in Appendix A3.3. These compounds can be detected using GC-MS or HPLC-MS/MS [3, 8, 19, 20].

Comments: NPC disease is caused by pathogenic/likely pathogenic variants in the NPC1 and NPC2 genes. 95% of cases are associated with nucleotide substitutions in the NPC1 gene (locus 18q11–q12), about 4% of cases with variants in the NPC2 gene (locus 14q24), and in approximately 1% of cases, the molecular genetic defect cannot be identified. More than 300 nucleotide substitutions and about 60 different polymorphic variants have been described in the NPC1 gene. Several relatively common variants in the NPC1 gene are known, located in exons 20–22 (p.Ile1061Thr, p.Ser954Leu, and p.Pro1007Ala), but in most cases, complete sequencing of the coding exons of the NPC1 and NPC2 genes is required. The informative value of such testing is about 94%. Next-generation sequencing (NGS) methods—gene panel analysis or clinical/whole exome sequencing—may also be used.

Multiplex ligation-dependent probe amplification (MLPA) is used to detect large gene rearrangements.

In some cases, there are objective difficulties in interpreting the results of molecular genetic analysis, and the diagnosis can be established based on the combination of clinical, biochemical, and instrumental findings.

Patients in whom only one pathogenic/likely pathogenic variant in the NPC1 or NPC2 gene is identified should be thoroughly evaluated, and the opinion regarding the diagnosis or carrier status should be made collegially.

The search for pathogenic/likely pathogenic variants (especially for the NPC1 gene) can be difficult and may require combined DNA and cDNA studies, as well as sequencing of promoters and deep intronic regions, as large rearrangements, deletions, and duplications may be located in these areas. Multiplex ligation-dependent probe amplification (MLPA) can be useful for identifying these regions.

In some cases, the diagnosis of Niemann-Pick disease type C can be established based on a characteristic clinical presentation, elevated biomarker levels, and the presence of a single pathogenic variant.

Comments: levels of total hemoglobin, red blood cells, white blood cells, platelets, hematocrit, erythrocyte sedimentation rate (ESR), and differential leukocyte count (leukocyte formula) are evaluated.

Comments: evaluation includes determination of blood aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, gamma-glutamyl transferase activities, total bilirubin, conjugated (direct) bilirubin, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, albumin, glucose, creatinine, total protein, sodium, potassium, total calcium, and fibrinogen levels. In rare cases, the development of liver failure reveals a decrease in blood parameters reflecting the synthetic function of the liver: albumin, fibrinogen, laboratory parameters assessed to evaluate the extrinsic pathway of blood coagulation, cholesterol, etc. [3, 8, 13, 17, 19, 20]. At an older age, laboratory changes may be absent, or a moderate increase in blood ALT, AST, and triglycerides, along with a decrease in LDL and HDL, may be observed [3, 19, 20]. Thrombocytopenia caused by hypersplenism may develop at any age [3, 19, 20].

Comment: it is necessary to determine activated partial thromboplastin time (APTT), thrombin time, prothrombin time in blood or plasma, and blood fibrinogen level.

Comment: during follow-up, the test is performed, on average, once a year

Comment: patients with NPC may develop neurogenic bladder, recurrent urinary tract infections, nocturia, and incomplete bladder emptying.

2.4 Instrumental Diagnostics

Comments: magnetic resonance imaging (MRI) of the brain with contrast enhancement may be performed. Brain magnetic resonance imaging (MRI) in patients with late-onset neurological forms of NPC often reveals cerebral and/or cerebellar atrophy, as well as high signal intensity in the periventricular white matter on T2-weighted and FLAIR images in patients with early childhood onset. Other brain areas predominantly affected according to neuroimaging data include the hippocampus, thalamus, and striatum. In addition, thinning of the corpus callosum and some reduction of the midbrain on the midsagittal slice are frequently observed. Proton magnetic resonance spectroscopy () is currently used for research purposes in the diagnosis and monitoring of certain other inborn errors of metabolism. For the diagnosis of NPC in clinical practice, this technique is not widely used [8, 19, 20, 40].

Comment: video-EEG monitoring may be performed if necessary. A neurologist's consultation is required to prescribe antiepileptic therapy.

Comments: also used to detect signs of hepatocellular carcinoma. If available, liver elastometry is additionally performed [47].

Comments: the number of nerves examined is determined by the clinical situation.

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment: allows simultaneous measurement of signal intensities of N-acetylaspartate (NA), choline-containing compounds (Cho), creatine and phosphocreatine (Cre), and lactate (Lac). Patients with NPC show a decrease in the NA/Cre ratio in the frontal and parietal cortex, and an increase in the Cho/Cre ratio in the frontal cortex and centrum semiovale. A correlation was also found between NPC clinical staging scores and abnormalities in results. demonstrates diffuse brain involvement in patients with NPC, consistent with the pathological features of the disease. is an objective and sensitive tool for the neurological evaluation of patients with NPC [40].

Comment: the following tests may also be performed to assess hearing: otoacoustic emission testing, auditory brainstem response (short-latency auditory evoked potentials), and auditory steady-state response (ASSR test).

Comment: characteristic neurological manifestations of NPC are impaired saccadic eye movements or vertical supranuclear gaze palsy.

Comment: patients may experience frequent recurrent lower respiratory tract infections and diffuse interstitial lung infiltration.

Examinations may be performed dynamically if clinically necessary (suspicion of pulmonary involvement).

Comment: lung volumes in patients with clinical signs of Niemann-Pick disease type C usually remain normal in the presence of pulmonary interstitium involvement.

2.5 Other Procedures

Visceral symptoms characteristic of NPC (neonatal jaundice, isolated splenomegaly, or hepatomegaly) and neurological signs (e.g., loss or delay of developmental motor milestones, cerebellar symptoms) occur in several other inborn errors of metabolism, including Sandhoff disease, Gaucher disease type 2 and 3, Niemann-Pick disease type A and B, Tay-Sachs disease, and lysosomal acid lipase deficiency [1, 3, 8, 12, 13, 19, 20].

In newborns and infants with visceral symptoms of Niemann-Pick disease type C, differential diagnosis is carried out with a broad group of other diseases manifesting with cholestasis syndrome, including biliary atresia and metabolic disorders: galactosemia, alpha-1 antitrypsin deficiency, tyrosinemia type 1, citrullinemia type 2, progressive familial intrahepatic cholestasis type 3, mitochondrial disorders, Alagille syndrome, and other hereditary liver diseases [3, 17, 19].

In Wilson's disease and certain other metal storage disorders, liver cirrhosis can also be associated with late-onset neurodegeneration [3, 8, 19].

In adolescence or early adulthood, patients with NPC frequently present with psychotic symptoms, bipolar disorder, depression, atypical schizophrenia-like disorders, and/or other psychiatric symptoms including attention deficit disorder, Asperger-like features, and dysregulatory syndrome [1, 14, 16, 24, 28].

Cognitive decline, ataxia, movement disorders, and vertical supranuclear gaze palsy can be observed in patients with adult-onset neurodegenerative disorders such as Huntington's disease, Gerstmann-Sträussler-Scheinker syndrome, or progressive supranuclear palsy. However, the first two disorders have an autosomal dominant inheritance pattern, and progressive supranuclear palsy typically begins in the fifth to seventh decades of life. None of these disorders is associated with visceromegaly [3, 8, 19, 20].

Comments: light microscopy can identify characteristic foamy cells in various tissues, but these changes are not specific to Niemann-Pick disease type C. Bone marrow biopsy: if this test is available, bone marrow aspiration may reveal foamy cells. It should be kept in mind that bone marrow infiltration by foamy cells correlates with disease severity and may be minimal in patients at early stages of the disease. Multiple bone marrow cores are required to rule out sampling error; less invasive procedures should be performed first.

Comment: a consultation with a general practitioner (family physician) is also possible.

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

Treatment of NPC includes disease-modifying (pathogenetic) and symptomatic therapy. It should be taken into consideration that the efficacy of pathogenetic therapy largely depends on the age at treatment initiation and helps slow down disease progression, but does not halt it completely. The standard video protocol provided in Appendix G3 can be used for clinical assessment of motor functions during therapy.

3.1 Pathogenetic treatment

Comments: disease-modifying treatment can be prescribed and adjusted by a medical geneticist, internist/pediatrician, general practitioner (family physician), neurologist, or another specialist experienced in treating patients with Niemann-Pick disease type C.

Comments: for patients aged 4–12 years with neurological manifestations, the dose of miglustat** is calculated based on body surface area (Appendix A3.4); for patients aged 12 years and older with neurological manifestations, the recommended dose of miglustat** is 200 mg 3 times daily to achieve a therapeutic effect. Miglustat** (N-butyl-deoxynojirimycin; NB-DNJ) is a small iminosugar molecule that acts as a competitive inhibitor of the enzyme glucosylceramide synthase, which catalyzes the first committed step in glycosphingolipid (GSL) biosynthesis. Miglustat** can cross the blood-brain barrier and has been shown to reduce GSL accumulation in the brain, slow down the progression of neurological symptoms, and prolong survival in preclinical studies. It may also indirectly regulate intracellular calcium homeostasis associated with sphingosine accumulation — a hypothesized trigger in the pathogenesis of NPC1 — by influencing glucosylceramide concentration.

The observed safety and tolerability profile of miglustat** in NPC is approximately the same as in type 1 Gaucher disease and is generally similar in pediatric and adult/young patient populations. The most frequently reported adverse events were mild to moderate diarrhea, flatulence, weight loss, and tremor.

Gastrointestinal adverse events and mild-to-moderate weight loss (generally observed in 50% of patients) tended to decrease over time with continuous therapy and were successfully managed [9-11, 22]. Clinical trial data on miglustat** are summarized in Appendix A3.5 [22]. Due to the neurodegenerative nature of NPC, disease stabilization or a reduction in the rate of disease progression are the most realistic goals achievable with long-term disease-specific therapy.

A visible positive clinical outcome in patients with NPC may be observed after 6 months to 1 year. In cases of slowly progressive forms of the disease (e.g., in patients with adult-onset disease), treatment effects may take an even longer time to manifest [3, 8-11, 19, 23].

In cases of severe neurological impairment already present at the time of diagnosis, particularly in young patients, there is a lower probability that miglustat** will provide significant therapeutic benefit.

Comment: prolonged diarrhea and abdominal pain may occur. Treatment is symptomatic; antispasmodic therapy may be prescribed according to indications.

Comments: the advisability of continuing miglustat** treatment in patients with severe progressive impairments resulting in profound neuropsychiatric disability is not clear-cut and requires further discussion.

The decision to modify or discontinue miglustat** therapy should be based on individual patient characteristics and made jointly by a metabolic disease specialist, parents, and family members [3, 18, 19].

3.2 Symptomatic treatment

There are no randomized controlled trials regarding the symptomatic therapy of NPC. All recommendations below reflect the expert opinion of specialists from various countries.

Comments: see Appendix A3.6

Comments: The issue of nutritional support and/or treatment of dysphagia should be addressed as early as possible, with the following measures recommended: softer or thicker food, tube feeding, A16.16.034 Gastrostomy / A16.16.034.001 Video-endoscopic gastrostomy / A16.16.034.003 Laparoscopic gastrostomy (to ensure adequate fluid and calorie intake).

Comment: neurologist consultation is required.

Comments: psychosis is often treatable with antipsychotic medications, although some NPC patients show no treatment response or even a paradoxical worsening.

Comments: drugs are prescribed in the absence of contraindications

Comments: regular monitoring for neurological manifestations should be performed in patients diagnosed via sibling screening or based on visceral symptoms, and treatment should be considered at the earliest signs of the onset of neurological disorders [3,8,19].

3.3 Dietary therapy

Comments. When using miglustat** in NPC patients, diarrhea, abdominal pain, and flatulence may occur due to the blockade of the enzyme that breaks down di- and oligosaccharides during the first weeks of therapy, followed by expansion of the diet with foods listed in the "RESTRICT" column (Appendix A3.7). At the initial stage of substrate reduction therapy, it is advisable to prescribe probiotics, which reduce the risk of gastrointestinal problems and improve bowel function.

The diet is prescribed in three consecutive stages:

1. Strict diet with exclusion of disaccharides;

2. Expanded diet with the gradual introduction of foods containing disaccharides;

3. Practically normal diet, with the exception of poorly tolerated foods.

The duration of each stage varies from several weeks to several months. Following the diet helps reduce the side effects of miglustat** and ensures an adequate intake of essential substances and energy for normal bodily functioning [3,18].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: the following can be considered: exercise therapy for central nervous system and brain diseases, exercise therapy using apparatus and exercise machines for central nervous system and brain diseases, correction of motor dysfunction using biofeedback, aids for the restoration of postural-tonic functions, dynamic propriocorrection.

Comments: Remedial and pedagogical intervention is determined based on the severity and duration of the disease, the structure of health disorders, the degree of underdevelopment of cognitive activity, the type of emotional response, and the behavioural characteristics of the child. The inclusion of remedial and pedagogical support in the complex of rehabilitation measures provides an additional assessment of mental development dynamics as one of the important indicators of health status, increases the effectiveness of therapeutic interventions, and reduces the economic burden of this pathology through the socialisation of patients and the preservation of the psychological potential of able-bodied family members.

The following may be performed: medical and speech therapy procedure for dysphagia, medical and speech therapy procedure for dysarthria, medical and speech therapy tonal-rhythmic procedure, medical and speech therapy procedure using interactive information technologies, etc.

5. Prevention and Dispensary Observation

5.1. Dispensary follow-up

The schedule for follow-up examinations of patients with NPC is given in Appendix A3.8. Depending on the specific course of the disease, the frequency of follow-up examinations may be determined individually by the attending physician.

Comment: hemoglobin, erythrocyte, leukocyte, and platelet counts, hematocrit evaluation, erythrocyte sedimentation rate determination, and differential leukocyte count (leukocyte formula) are performed; frequency as clinically indicated.

Comments: it is necessary (determination of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, gamma-glutamyl transferase activity in the blood, determination of total bilirubin, conjugated (direct) bilirubin, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, albumin, glucose, creatinine, total protein, sodium, potassium, total calcium, and fibrinogen in the blood); in rare cases, the development of liver failure reveals a decrease in blood parameters reflecting the synthetic function of the liver: albumin, fibrinogen, laboratory parameters determined to assess the extrinsic blood coagulation pathway, cholesterol, etc. [3, 8, 13, 17, 19, 20]. At an older age, laboratory changes may be absent or a moderate increase in ALT, AST, triglycerides, and a decrease in LDL and HDL may be observed [3, 19, 20]. Thrombocytopenia caused by hypersplenism may be observed at any age [3, 19, 20]. Frequency as clinically indicated.

Comment: it is necessary to determine activated partial thromboplastin time, thrombin time in the blood, prothrombin (thromboplastin) time in the blood or plasma, and the fibrinogen level in the blood. Frequency as clinically indicated.

Comments: contrast-enhanced magnetic resonance imaging of the brain may be performed. Brain magnetic resonance imaging (MRI) in patients with NPC with late-onset neurological disorders often reveals cerebral and/or cerebellar atrophy, as well as a high-intensity signal from the periventricular white matter of the brain on T2-weighted and FLAIR images in patients with early childhood disease onset. Other brain areas predominantly affected according to neuroimaging include the hippocampus, thalamus, and striatum. In addition, thinning of the corpus callosum and some reduction of the midbrain area on the midsagittal slice are often observed. H-MRSI (proton magnetic resonance spectroscopy) is currently used for the diagnosis and monitoring of certain other inherited metabolic disorders for research purposes. This technique is not widely used for the diagnosis of NPC in clinical practice [8, 19, 20]. Frequency as clinically indicated.

Comment: electroencephalography with video monitoring can be performed if necessary.

Comments: also used to detect signs of hepatocellular carcinoma. If available, liver elastometry is additionally performed [47].

For adults — Recommendation grade C (Level of evidence — 5).

For children — Recommendation grade C (Level of evidence — 4).

Comments: the number of nerves examined is determined by the clinical situation.

Comment: the following tests may also be performed to assess hearing: otoacoustic emission testing, auditory brainstem response (short-latency auditory evoked potentials), and auditory steady-state response (ASSR test).

For adults — Recommendation grade C (Level of evidence — 5).

For children — Recommendation grade C (Level of evidence — 4).

Comment: characteristic neurological manifestations of NPC are impaired saccadic eye movements or vertical supranuclear gaze palsy.

For adults — Recommendation grade C (Level of evidence — 5).

For children — Recommendation grade C (Level of evidence — 4).

Comment: patients may experience frequent recurrent lower respiratory tract infections and diffuse interstitial lung infiltration.

Comment: lung volumes in patients with clinical signs of Niemann-Pick disease, type C in the presence of pulmonary interstitium involvement most often remain normal.

Comment: allows simultaneous measurement of signal intensities of N-acetylaspartate (NA), choline-containing compounds (Cho), creatine and phosphocreatine (Cre), and lactate (Lac). Patients with NPC show a decrease in the NA/Cre ratio in the frontal and parietal cortex, and an increase in the Cho/Cre ratio in the frontal cortex and centrum semiovale. A correlation was also found between NPC clinical staging scores and abnormalities in results. demonstrates diffuse brain involvement in patients with NPC, consistent with the pathological features of the disease. is an objective and sensitive tool for the neurological evaluation of patients with NPC [40].

Comments: in families with an identified patient carrying the mutation, pre-implantation and prenatal diagnosis are available. Prenatal diagnosis can be performed using direct or indirect DNA diagnostic methods for families with a known genotype.

Comment: an examination and consultation (dispensary check-up) by a general practitioner (family physician) is also possible.

5.1. Vaccination

Comments: vaccination should preferably be administered by or under the supervision of specialists experienced in managing patients with metabolic disorders.

Additionally, for patients with Niemann-Pick disease type C, consider the administration of the 23-valent pneumococcal polysaccharide vaccine, as well as vaccination against meningococcal infection, varicella, and novel coronavirus infection (COVID-19) [60].

6. Organization of Medical Care

Patients with Niemann-Pick disease type C may receive any type, condition, and form of medical care provided by the legislation of the Russian Federation, as clinically indicated.

Indications for planned hospitalization in a medical organization:

- Provision of diagnostics and treatment requiring round-the-clock medical supervision.

- A condition requiring active treatment and round-the-clock medical supervision;

- A condition requiring high-tech treatment methods;

- The need for various types of expert evaluations or examinations in a medical organization when outpatient assessment is impossible and dynamic observation is required (including issuing a federal medical board conclusion).

Indications for emergency/urgent hospitalization:

- Acute illnesses, exacerbations of chronic conditions, poisoning, and injuries; conditions requiring intensive care and transfer to critical care or intensive care units, as well as round-the-clock medical observation and specialized diagnostic and treatment procedures.

Indications for discharge from a medical organization:

- Absence of a threat to the patient's life;

- Absence of a risk of complications requiring urgent treatment;

- Stabilization of the patient's condition and key clinical and laboratory parameters regarding the underlying disease;

- No further need for continuous physician supervision and round-the-clock medical care for the underlying disease;

- The need to transfer the patient to another hospital or social care facility.

7. Additional Information

Early diagnosis and the prompt initiation of disease-modifying and symptomatic treatment can significantly impact the prognosis and clinical outcome [13,20,23].

Despite the availability of disease-modifying therapy, the prognosis for Niemann-Pick disease type C remains unfavorable. The rate of disease progression and life expectancy in NPC patients are extremely variable.

Timely initiation of disease-modifying therapy (substrate reduction therapy) can improve patient prognosis [8-13,19,23,27].

Patients who develop severe epilepsy generally have a worse prognosis and shorter life expectancy compared to those without epileptic seizures [19].

Criteria for Evaluating the Quality of Medical Care

Quality of care criteria for primary health care in adults and children with Niemann-Pick disease type C (ICD-10 code: E75.2)

Quality of care criteria for specialized medical care in adults and children with Niemann-Pick disease type C (ICD-10 code: E75.2)

References

Appendix A1. Working Group Composition

1. Sergey I. Kutsev — Academician of the RAS, Doctor of Medical Sciences, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, President of the Association of Medical Geneticists

2. Sergey N. Illarioshkin — Academician of the RAS, Doctor of Medical Sciences, Professor, Deputy Director for Research, Head of the Brain Research Department at the Research Center of Neurology

3. Alexander A. Baranov — Academician of the RAS, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery (NC C2), Professor of the Department of Pediatrics and Pediatric Rheumatology at the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatric specialist of the Russian Ministry of Health

4. Leila S. Namazova-Baranova — Academician of the RAS, Professor, Doctor of Medical Sciences, President of the Union of Pediatrists of Russia; Past President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery (NC C2), Head of the Department of Faculty Pediatrics at the Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Chief freelance pediatric preventive medicine specialist of the Russian Ministry of Health

5. Anisimova Inga Vadimovna — Candidate of Medical Sciences, Head of the Department of Medical Care Organization, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

6. Nato D. Vashakmadze — Doctor of Medical Sciences, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions at the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery (NC C2), Professor of the Department of Faculty Pediatrics at the Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pediatrists of Russia

7. Natalia V. Zhurkova — PhD, Leading Researcher, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists

8. Ekaterina Yu. Zakharova — Doctor of Medical Sciences, Head of the Laboratory of Hereditary Metabolic Diseases at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM)

9. Sergey A. Klyushnikov — Candidate of Medical Sciences, Leading Research Fellow, Neurologist at the 5th Neurological Department of the Research Center of Neurology, Member of the Russian Society of Neurologists, Association of Medical Geneticists, Movement Disorder Society, and European Huntington's Disease Network (Euro-HD Network). Leading Specialist for Huntington's Disease at the REGISTRY Euro-HD Network Research Center (based at the Research Center of Neurology). Chairman of the Russian Huntington's Disease Association.

10. Lyudmila M. Kuzenkova — Doctor of Medical Sciences, Head of the Department of Psychoneurology and Psychosomatic Pathology at the National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the Union of Pediatrists of Russia.

11. Svetlana V. Mikhailova — Doctor of Medical Sciences, Head of Department at the Russian Children's Clinical Hospital of the Ministry of Health of the Russian Federation.

12. Alexander V. Pashkov — Candidate of Medical Sciences, Head of the Department of Otorhinolaryngology and Audiology at the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery (NC C2)

13. Tatyana Yu. Proshlyakova — Candidate of Biological Sciences, Senior Research Fellow at the Laboratory of Hereditary Metabolic Diseases, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Geneticists.

14. Tatyana V. Podkletnova — Candidate of Medical Sciences, Senior Research Fellow at the Laboratory of Rare Hereditary Diseases in Children, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Member of the Union of Pediatrists of Russia.

15. S.A. Repina — Candidate of Medical Sciences, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists of Russia.

16. Valeria V. Sviridova — Medical Geneticist at the Medical Care Organization Department, Research Centre for Medical Genetics named after Academician N.P. Bochkov; Junior Research Fellow at the Mutagenesis Laboratory, Research Centre for Medical Genetics named after Academician N.P. Bochkov

17. Liliya R. Selimzyanova — Candidate of Medical Sciences, Head of the Department of Standardization and Study of Evidence-Based Medicine Fundamentals at the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery (NC C2), Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Associate Professor at the Department of Faculty Pediatrics, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pediatrists of Russia

18. Semyachkina Alla Nikolaevna — Doctor of Medical Sciences, Chief Research Fellow at the Department of Clinical Genetics, Moscow Research Institute of Pediatrics and Pediatric Surgery of the Ministry of Health of Russia, Member of the Association of Medical Geneticists (AMG)

19. Olga Ya. Smirnova — Medical Geneticist, Senior Research Fellow at the Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Child Health of the Petrovsky National Research Centre of Surgery (NC C2), Member of the Union of Pediatrists of Russia, Member of the Association of Medical Geneticists

20. Subbotin Dmitry Mikhailovich — Medical Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

21. Surkov Andrey Nikolaevich — MD, Head of the Gastroenterology Department for Children at the Children's Hospital, Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology, and Metabolic Disorders at the Research Institute of Pediatrics and Child Health in Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, member of the Union of Pediatrists of Russia

22. Marina V. Fedoseenko — Candidate of Medical Sciences, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Status 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 (NC C2), Associate Professor at the Department of Faculty Pediatrics, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pediatrists of Russia

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

Appendix A2. Methodology for Developing Clinical Guidelines

These guidelines are intended for use by medical organizations and institutions of federal, territorial, and municipal healthcare management systems, compulsory and voluntary medical insurance systems, and other medical organizations of various legal forms engaged in the provision of medical care.

These guidelines establish the types, scope, and quality indicators of medical care for patients with NPC and were reviewed within the framework of the 3rd All-Russian Scientific and Practical Congress with International Participation "Orphan Diseases" (May 31, 2018 – June 2, 2018) and the 21st Congress of Pediatricians of Russia with International Participation "Current Problems of Pediatrics" on February 15–17, 2019.

These clinical guidelines were developed based on a systematic review of the 1992–2019 literature from the Medline (PubMed version), Embase (Dialog version), and Cochrane Library databases, using established protocols and modern international clinical guidelines for the diagnosis, treatment, and management of patients with metabolic diseases (Tarekegn Geberhiwot et al. Consensus clinical management guidelines for Niemann-Pick disease type C: Orphanet Journal of Rare Diseases (2018) 13:50; Patterson Marc C. et al. Recommendations for the detection and diagnosis of Niemann-Pick disease type C. An update. Neurol Clin Pract 2017;7:1–13) [50].

NPC is a rare hereditary disease, which precludes large-scale cohort and randomized controlled trials; therefore, the creation of diagnostic and therapeutic protocols relies solely on expert case studies published over the past two decades.

The evaluation of levels of evidence and grades of recommendation was carried out in accordance with Tables 1, 2, and 3.

Target audience for these clinical guidelines:

1. General practitioners (family physicians);

2. Pediatricians;

3. General practitioners;

4. Medical geneticists;

5. Laboratory geneticists;

6. Neurologists;

7. Ophthalmologists;

8. Functional diagnostics physicians;

9. Psychiatrists;

10. Pediatric psychiatrists;

11. Adolescent psychiatrists;

12. Medical psychologists;

13. Gastroenterologists;

14. Hematologists;

15. Medical students;

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on 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

Appendix A3.1 Documents and resources used in the preparation of clinical guidelines

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 185 dated March 22, 2006 "On mass screening of newborns for hereditary diseases",

2. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 "On approval of the Procedure for providing pediatric care"

3. Order of the Russian Ministry of Health No. 274n dated April 21, 2022 "On approval of the Procedure for providing medical care to patients with congenital and (or) hereditary diseases"

4. State Register of Medicinal Products: https://grls.rosminzdrav.ru

5. Order of the Russian Ministry of Health No. 205n dated May 2, 2023, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers".

6. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

7. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

8. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services".

9. Order of the Ministry of Health of the Russian Federation No. 1094n dated November 24, 2021 "On approval of the Procedure for prescribing medicinal products, prescription forms for medicinal products, the Procedure for issuing said forms, their accounting and storage, forms of prescriptions containing appointments of narcotic drugs or psychotropic substances, the Procedure for their manufacture, distribution, registration, accounting and storage, as well as the Rules for issuing prescription forms, including in the form of electronic documents"

10. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On approval of criteria for assessing the quality of medical care"

11. List of specialized medical nutrition products for disabled children for 2024, approved by Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023. Order No. 500 dated June 14, 2016 "On organizing selective screening"

12. Order of the Russian Ministry of Health No. 721n dated November 9, 2012, "On Approval of the Standard of Specialized Medical Care for Children with Niemann-Pick Disease Type C".

Appendix A3.2 Severity of clinical manifestations of NPC at different ages

Appendix A3.3 Rules for collecting biological material for diagnostics using dried blood spots

Algorithm of actions for medical personnel during blood sample collection

• wash hands (hygienic level), put on gloves;

• wash the patient's hands (the infant's heel, if blood is collected from the heel);

• wipe the puncture site with a sterile wipe moistened with 70% alcohol, blot with a dry sterile wipe; - puncture with a sterile single-use lancet;

• remove the first drop of blood with a sterile dry swab;

• gently press to obtain a second drop of blood;

• apply the test card perpendicularly to the drop of blood and saturate it completely through with blood;

• apply 6–8 drops to the test form in a similar manner; the appearance of the blood spots should be identical on both sides.

• dry the test card in a horizontal position on a clean, grease-free surface for at least 4 hours without heat treatment and direct sunlight;

• package the test cards in a clean envelope so that the blood spots do not touch.

Specifics during infusion therapy

Some patients may receive infusion therapy or blood component transfusions, which can affect test results. For example, blood plasma transfusions may yield false-negative results since the enzymes being determined are present in both plasma and blood cells. It is recommended to collect blood for enzymatic and DNA diagnostics no earlier than 6-7 days after a blood plasma transfusion and 7-10 days after a blood component transfusion.

Blood collection is not permitted:

• immediately after the patient undergoes infusion therapy;

• immediately after an exchange blood transfusion.

Storage and transportation of biological material

Dried blood spot samples can be stored in a regular refrigerator chamber at +4 °C prior to shipment. The storage period prior to shipment must not exceed 7 days. Storing them longer or at a higher temperature may reduce enzyme activity even within the normal range, leading to false-positive results.

Appendix A3.4 Recommended doses of miglustat** depending on body surface area

Appendix A3.5 Clinical studies of miglustat** in Niemann-Pick disease type C

Appendix A3.6 Symptomatic treatment of disorders in patients with Niemann-Pick disease type C

Appendix A3.7 Food groups to exclude/restrict/consume without restriction during the first weeks of miglustat** therapy

Appendix A3.8 Frequency of follow-up examinations in patients with Niemann-Pick disease type C

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Niemann-Pick disease type C

Causes of the disease

Niemann-Pick disease type C (NP-C) is a rare, inherited disorder. In this disease, the intracellular transport and distribution of a specific substance, cholesterol, is impaired. Cholesterol is a complex and vital substance responsible for a wide range of functions in the body. It is both essential and extremely treacherous. Cholesterol metabolism is extremely complex—its synthesis alone requires about 100 sequential reactions. For the most part, it is transported in the blood not in a pure form, but in complex compounds of 2 types: low-density lipoproteins (LDL) and high-density lipoproteins (HDL). An incorrect ratio of these compounds, as well as a high total cholesterol level, can lead to serious cardiovascular diseases. However, cholesterol is an essential substance as it plays a very important role in cellular metabolism. It is a necessary component of all cell membranes and participates in the production of all hormones, including testosterone, estrogen, and cortisol. It is also essential for the brain and supplies the body's tissues with antioxidants. Cholesterol delivered by the blood in the form of LDL enters special vesicles within the cell after LDL binds to its receptors on the membrane, and then LDL is transported to cell organelles—lysosomes. Afterwards, LDL is digested; several enzymes and proteins participate in these reactions, including NPC1 and NPC2 proteins, and the released cholesterol enters the cytoplasm through the lysosomal membrane. Several rare inherited disorders associated with impaired cholesterol metabolism are known. Some of these are associated with impaired metabolism inside cell organelles—lysosomes: acid lipase deficiency, Niemann-Pick disease type C. Other diseases are caused by impairments in the uptake and circulation of cholesterol in the blood—familial hypercholesterolemia.

Niemann-Pick disease type C is a very rare disorder with an incidence of 1:120,000 to 1:150,000 live births, associated with mutations in the NPC1 and NPC2 genes.

Inheritance

NP-C is inherited in an autosomal recessive manner. An affected child inherits one altered gene (a gene with a mutation in its sequence) from each parent. In families where parents are carriers of the disease, the risk of having an affected child is 25% for each pregnancy. Therefore, if a child is born with the disease, it does not mean that all children will be affected.

Clinical manifestations of NP-C

NP-C can begin at any age. Depending on the age of onset of the first symptoms, several forms are distinguished: neonatal (manifestation up to three months), early infantile (three months to two years), late infantile (two to six years), juvenile (6–15 years), and adult (over 15 years).

Main symptoms of the disease:

• Prolonged jaundice in the neonatal period

• Hepatosplenomegaly (enlargement of the liver) or moderate splenomegaly (enlargement of the spleen)

• Mental Retardation

• Extrapyramidal symptoms

• Ataxia

• Cataplectic attacks

• Vertical supranuclear gaze palsy

Age of onset, severity of manifestations, and rate of progression are also variable and may differ among patients.

When the disease begins in early childhood, psychomotor developmental delay, hepatomegaly, and splenomegaly are observed. When the disease begins at an older age, neurological symptoms such as gait disorders, dysphagia, and muscle tone abnormalities come to the fore. Most patients also experience cognitive impairment, and psychiatric symptoms may occur in some cases.

How the diagnosis is established

Doctors may suspect the disease based on clinical symptoms. Then, laboratory tests and instrumental examinations are performed. Because different diseases are very similar in their clinical manifestations, it is necessary to confirm the diagnosis using laboratory methods. Confirmatory diagnosis of NP-C involves determining the concentration of specific metabolites in dried blood spots or blood plasma (oxysterols, lysosphingomyelin-509). Further DNA testing is recommended thereafter (if metabolites were elevated).

Treatment, monitoring, and scheduled examinations

Currently, substrate reduction therapy has been developed for this disease, which helps reduce neurological manifestations and slow down disease progression.

This medication does not cure the disease, but many of its manifestations can be slowed down and mitigated.

When using this drug, a diet must be followed to reduce the risk of gastrointestinal side effects. The table shows foods whose consumption should be limited.

Food groups to be excluded/restricted/consumed without restriction in the first weeks of therapy

Monitoring, scheduled examinations, and tests

Various tests and scales exist to assess the patient's condition and the effect of enzyme therapy and physical therapy. It is very important not to refuse these examinations because they help doctors objectively assess the patient's condition, justify treatment, or introduce changes into rehabilitation and habilitation programs. The table lists the main examinations for patients with NP-C and their frequency.

Frequency of follow-up examinations for patients with Niemann-Pick disease type C

Medical Genetic Counseling

It is very important for families with an NP-C patient to consult a geneticist. Treating physicians do not always have the opportunity to talk with the family and explain all the risks and opportunities that modern genetic services can provide. A geneticist can advise on the potential risk of having another affected child in the family, arrange testing for relatives if necessary, and discuss the options of prenatal and preimplantation genetic diagnosis.

Prenatal diagnosis is performed at 9–11 weeks of pregnancy. Enzyme activity and gene mutation analysis are performed on cells isolated from chorionic villi (the tissue from which the placenta subsequently develops) to determine whether the fetus is affected or healthy. Modern technologies also allow for preimplantation genetic diagnosis: in vitro fertilization is performed, after which only those fertilized embryos (at the several-blastomere stage) that lack the familial mutation are selected and implanted (transferred) into the mother's body. This procedure carries specific risks, which a geneticist can explain. 

Where to receive diagnosis and treatment in Russia

There are many centers in our country that help patients with NP-C and other rare diseases. In each region, specific clinics are also designated to provide enzyme replacement therapy. Once a diagnosis is established, you should check with your regional geneticist to find out where to go for scheduled care and emergency assistance if needed.

Learn more

There are many organizations worldwide that can help you find answers to any other questions related to NP-C:

International Rare Diseases Portal www.orpha.net

EURORDIS, the European organization representing patients with various rare diseases: www.eurordis.org 

Public organizations and foundations in Russia

NP-C is included in the list of orphan diseases whose treatment is funded from regional budgets, giving patients the opportunity to receive treatment in Russia. Public organizations can help patients obtain treatment, raise public awareness about rare diseases, and promote legislative initiatives in the field of orphan diseases. Information about such non-profit associations can be found on the internet.

Family support 

Of course, much depends on the doctor—how much they know about your disease, how correctly they prescribe treatment, and how well they explain the principles of therapy. But do not forget: the success of treatment depends equally on the family. It is essential to follow recommendations, never lose hope under any circumstances, and become an expert in your own disease. Read literature, communicate with other families, and do not hesitate to ask questions. Even if you cannot completely defeat the disease, changing life for the better and making your loved one happy is entirely within your power!

Individuals with a mild form of the disease need to learn how to be independent from their families. Do not let children and adolescents become isolated. They need friends, social interaction, and independent living skills.

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

Appendix G1. NPC diagnosis probability index in children under 4 years of age

Russian title: NP-C suspicion index in children under 4 years of age

Original title (if applicable): The NPC-suspicion index in patients aged <4 years.

Source (official developer website, validation publication): Pineda, M., Mengel, E., Jahnová, H. et al. A Suspicion Index to aid screening of early-onset Niemann-Pick disease Type C (NP-C). BMC Pediatr 16, 107 (2016) doi:10.1186/s12887-016-0641-7 [61].

Type (underline):

- assessment scale

- score

- questionnaire

- other

Purpose: clinical diagnostics — assessing the probability of NP-C diagnosis in patients under 4 years of age.

Content (template): each symptom characteristic of NP-C is assigned a specific score based on its significance in diagnosing the disease.

Key (interpretation): a total score of more than 6 indicates a high probability of the diagnosis.

Figure 1. NP-C suspicion index in children under 4 years of age

Note: Symptoms of ataxia and intellectual disability are additional and are only taken into account if the core symptoms are present (gelastic cataplexy, vertical supranuclear gaze palsy, splenomegaly).

Appendix G2. NPC diagnosis probability index in children over 4 years of age

Russian title: NP-C suspicion index in patients over 4 years of age

Original title (if applicable): The NPC-suspicion index.

Source (official developer website, validation publication): Wijburg FA, Sedel F, Pineda M, Hendriksz CJ, Fahey M, Walterfang M, et al. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. Neurology. 2012;78:1560–7 [62].

Type (underline):

- assessment scale

- score

- questionnaire

- other

Purpose: clinical diagnostics — assessing the probability of NP-C diagnosis in patients over 4 years of age.

Content (template): each symptom characteristic of NP-C is assigned a specific score based on its significance in diagnosing the disease.

Key (interpretation): Niemann-Pick disease type C is considered highly probable with a total score of more than 70.

Figure 2. NP-C suspicion index in patients over 4 years of age

Appendix G3. Standard video protocol for clinical assessment of motor functions

Russian title: Video protocol for motor function assessment in NP-C

Original title (if applicable): Standard video protocol for clinical assessment

Source (official developer website, validation publication): James E. Wraith, Matthias R. Baumgartner, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C, Molecular Genetics and Metabolism, 2009, Volume 98, Pages 152-165 [63]. Type (underline):

- assessment scale

- index

- questionnaire

- other (video protocol for motor function assessment)

Purpose: clinical diagnostics — evaluation of motor functions prior to therapy and during treatment.

Content (template): video recording of key symptoms characteristic of NP-C.

Key (interpretation): helps document key clinical manifestations of NP-C and evaluate the dynamics of their changes during treatment.

Video protocol

1) Speech (30–45 s)

· Say a phrase, for example, "Hello, today is a wonderful day" (3 times)

2) Hand movements

· Opening and closing fists (5–10 times each)

· Finger-to-thumb opposition sequentially with each finger

· Finger-to-nose test with eyes open (5–10 times on each side)

3) Standing and barefoot walking

· Standing: feet together (15 s)

· Standing: tandem stance, one foot in front of the other (15 s)

· Walking + normal U-turn (15 s)

· Tandem walking (heel-to-toe) (15 s)

4) Writing/drawing (dominant hand)

· Write a phrase, e.g., "Today is a wonderful day." For young children: make a drawing or draw a spiral

· Copy a page

5) Eye movements

· Spontaneous eye movements: up, down, right, left (two cycles)

· Eye tracking (following a finger): up, down, right, left (twice, speed assessment)

Note: Infants are unlikely to be able to perform some of the tests mentioned above; video recording must be performed with the consent of a parent or legal guardian for pediatric patients, or with the consent of the patient if he/she is an adult.