Niemann-Pick Disease – Symptoms and Treatment

Definition of the Disease. Causes of the Illness

Niemann-Pick disease is an inherited degenerative disorder of the nervous system characterized by the accumulation of lipids in the brain, bone marrow, lymph nodes, spleen, and liver. Symptoms of the disease resemble Alzheimer’s disease but progress more aggressively and are much less common. Niemann-Pick disease manifests with various neurological symptoms, often leading to progressive cognitive decline (intelligence, memory, attention, and speech), apathy, indifference, loss of emotions, and possible aggression.

Niemann-Pick disease and Niemann-Pick Type C disease are different conditions. There are three forms of Niemann-Pick disease: A, B, and C. This article focuses on Type C (NPC). The main symptoms of the disease were described in the late 1920s by the German pediatrician Albert Niemann, while another scientist, Ludwig Pick, characterized the cellular level changes.

Niemann-Pick disease is detected in approximately one child per 120,000–150,000 live births. According to the Expert Council on Rare Diseases, as of the beginning of 2019, 37 patients with this condition were registered in Russia, 12 of whom were children. Type C is less commonly identified than other types, possibly due to diagnostic challenges, and the disease may actually be more prevalent than reported. Insufficient attention is given to this type of disease, leading to delayed diagnosis and lack of treatment for patients.

Causes of Niemann-Pick Disease

Niemann-Pick disease is an inherited condition, but identifying the mutated gene is not always possible. The inheritance pattern is autosomal recessive, meaning the disease develops if the mutant gene is present in both parents. However, the parents themselves may not show signs of the disease.

Symptoms of Niemann-Pick Disease Type C

The disease can onset at various ages, from the perinatal period (from the 23rd week of pregnancy to 7 days after birth) to childhood, adolescence, adulthood, and even up to 70 years of age.

The clinical presentation is extremely heterogeneous, meaning there are many symptoms, and they are not specific. All manifestations of the disease can be divided into neurological and systemic (involvement of internal organs – liver, spleen, sometimes lungs). These manifestations occur at different times and progress independently of each other.

Involvement of internal organs appears before neurological symptoms but may be absent or minimal in about 15% of all patients and nearly half of adult patients, at least at the time of diagnosis.

Neurological symptoms arise because cells in the brain gradually die and cease to function properly.

In a typical course, neurological disorders include:

  • Cerebellar ataxia (coordination disorder of movements);
  • Dysarthria (unclear and slurred speech);
  • Dysphagia (swallowing difficulty).

Other common neurological signs include seizures, cataplexy, and dystonia. Cataplexy manifests as sudden loss of muscle tone, leading to falls, while dystonia involves abnormal gait, unnatural head and/or limb positions.

Neurological symptoms are initially subtle and may only manifest as clumsiness, frequent falls, and instability. Developmental delay in speech, intelligence, and sometimes motor skills characterizes the onset of the disease in early and late childhood. The child lags behind peers in mental development, has a smaller vocabulary, unclear or absent speech, inability to run and/or jump, and a “drunken” and unsteady gait. In older children, the disease may start with coordination disorders, such as instability when walking or running and frequent falls.

Patients who develop the disease in adolescence or adulthood often experience psychiatric symptoms, such as psychosis resembling schizophrenia, delusions, auditory or visual hallucinations.

Another characteristic manifestation of Niemann-Pick disease is the limitation of upward eye movement due to the involvement of the structure responsible for this function.

Symptoms are often described by the patient’s relatives rather than the patient themselves. They notice the following signs of the disease:

  • Uncharacteristic rudeness and loss of empathy;
  • Profanity, swearing;
  • Rudeness, familiarity, inappropriate humor;
  • Impulsivity, aggression, and hostility towards others;
  • Increased sexual activity;
  • Deviation from normal behavior;
  • Eating behavior disturbances (overeating, craving for sweets or inedible objects);
  • Neglect of personal hygiene;
  • Slowed speech and diminished vocabulary;
  • Forgetfulness (the patient cannot remember the names of familiar objects);
  • Logoclonia – repeated repetition of the last syllables of words;
  • Echolalia – involuntary repetition of words and phrases after the interlocutor;
  • Walking disturbances – unsteadiness and shuffling leading to falls;
  • Urinary incontinence.

Pathogenesis of Niemann-Pick Disease Type C

Niemann-Pick Disease Type C develops due to mutations in the NPC1 or NPC2 genes (approximately in 95% and 5% of cases respectively). However, in some patients, a genetic defect cannot be identified.

Genetic mutations in Niemann-Pick disease lead to disturbances in intracellular lipid transport, resulting in the accumulation of cholesterol and other substances in the body tissues. These conditions are referred to as sphingolipidoses. In sphingolipidoses, substances accumulate in the body due to the absence or malfunction of enzymes that convert them into other compounds.

In the liver and spleen, cholesterol and sphingomyelin phospholipids mainly accumulate (with concentrations 2–5 times higher than in healthy individuals), along with phosphates, lactosylceramide, glucosylceramide, as well as free sphingosine and sphinganine. In the brain, less cholesterol and sphingomyelin accumulate, with primarily glycosphingolipids accumulating, especially GM2 and GM3.

The abnormal deposition of lipids causes cells to enlarge and eventually die, disrupting the function of the entire organ.

Classification and Stages of Niemann-Pick Disease Type C

In 1958, four forms of Niemann-Pick Disease were identified: A, B, C, and D. However, subtype D, caused by a defect in the NPC1 gene, is no longer distinguished and is considered a subtype C.

Types A and B are caused by a primary deficiency of the enzyme acid sphingomyelinase and present with severe symptoms affecting internal organs with involvement of the central nervous system (Type A) or with preserved CNS function (Type B).

Niemann-Pick Disease Type A typically begins in infants and manifests with hepatosplenomegaly (enlargement of the liver and spleen) and progressive neurological impairment. Patients usually do not survive beyond three years of age.

Niemann-Pick Disease Type B presents with hepatosplenomegaly, growth delay, pulmonary dysfunction with frequent lung infections, elevated cholesterol and lipid levels, and decreased platelet levels (thrombocytopenia). Patients typically survive into adulthood.

Niemann-Pick Disease Type C is a very serious, life-threatening neurological condition. It often goes undiagnosed in infancy as clinical symptoms are nonspecific. Many infants die within the first few months of life.

The disease can be classified based on age of onset:

  • Pre/perinatal form (up to 3 months);
  • Early childhood (3 months to 2 years);
  • Late childhood (2–6 years);
  • Adolescent (6–15 years);
  • Adolescent or adult (older than 15 years).

Complications of Niemann-Pick Disease Type C
With age, Niemann-Pick Disease progresses, and complications often develop over time:

  • Liver involvement may progress to liver failure;
  • Deterioration of lung function can lead to respiratory failure;
  • Progressive nerve cell destruction may cause dementia, seizures, and schizophrenia-like psychosis;
  • Severe thrombocytopenia can lead to internal or external bleeding;
  • Ischemic heart disease and heart valve defects may develop;
  • Bone deformities may occur.
Diagnosis of Niemann-Pick Disease Type C

The diagnosis is based on the patient’s medical history, characteristic symptoms, and the results of laboratory diagnostics, including biochemical and molecular genetic analysis.

The disease can present with a variety of symptoms, making timely diagnosis often challenging.

Scoring Scale Evaluation

Doctors from various specialties often need to rule out Niemann-Pick Disease because its diverse manifestations resemble symptoms of other diseases. To enhance the efficiency of differential diagnosis, an international group of experts has developed a scoring scale to assess the likelihood of Niemann-Pick Disease. This method also helps identify children with characteristic symptoms for further laboratory diagnostics.

During this assessment, the doctor enters the patient’s symptoms into a table observed during examination. To obtain a total score, the results for each category are added up. Some signs (e.g., limited eye movement) are assigned more points, as they indicate a worse prognosis.

The score in points helps evaluate the likelihood of the disease:

  • 70 points: immediate testing is needed to rule out Niemann-Pick Disease.
  • 40–69 points: further observation by a neurologist is required.
  • Less than 40 points: low probability of the disease.

The index is not reliable in children under 4 years old.

Laboratory Diagnostics

Niemann-Pick Disease Type C is a systemic condition that requires comprehensive examination.

Therefore, besides history-taking and physical examination, laboratory diagnostics are performed:

  • Plasma chitotriosidase (CHIT) assay: Used for screening but has low sensitivity and specificity, meaning changes are not exclusive to Niemann-Pick Disease but also seen in other neurodegenerative diseases. It may be used as an additional marker in differential diagnosis.
  • Measurement of CCL18/PARC levels in the blood: This marker is mainly elevated in young patients and serves as an alternative diagnostic method when the first method is not informative. The sensitivity and specificity of this method are not fully studied.
  • Histological methods: Skin biopsy is conducted. Niemann-Pick Disease is indicated by impaired cholesterol transport in cells, determined by staining fibroblasts with filipin. This method is considered the most specific and sensitive.
  • Blood biochemical analysis: Platelets are often slightly reduced, and transaminases (AST and ALT) are elevated. Additionally, levels of low-density lipoproteins (LDL) and high-density lipoproteins (HDL) are typically decreased, while triglycerides are increased. Overall, results of biochemical analysis in patients with Niemann-Pick Disease are usually within the normal range, but this examination helps exclude other pathologies.

DNA Diagnostics: This is the preferred method for confirming the diagnosis. Several common mutations in the NPC1 gene have been described, but often, complete sequencing of the NPC1 and NPC2 genes is required. The test is informative in approximately 94% of cases and can be done at medical-genetic research centers and rare disease (orphan) diagnostic centers.

Genetic testing is necessary for all patients with a preliminary diagnosis. This examination also allows rapid detection of the disease in siblings, identification of carriers among blood relatives, identification of patients with NPC2 mutations who could be candidates for hematopoietic stem cell transplantation. Additionally, DNA diagnostics is a safe method for testing during pregnancy.

Doubtful results of DNA diagnostics and filipin staining do not exclude the possibility of Niemann-Pick Disease. In such cases, with characteristic clinical manifestations, additional examination in orphan disease centers is required.

Differential Diagnosis

Niemann-Pick Disease needs to be differentiated from the following pathologies:

  • Wilson’s disease
  • Sandhoff disease
  • Gaucher disease Type 3
  • Idiopathic neonatal hepatitis
  • Neonatal cholestasis
  • Psychosis
  • Depression
  • Atypical schizophrenia-like psychosis
  • Attention deficit hyperactivity disorder (ADHD)
  • Asperger’s syndrome
Treatment of Niemann-Pick Disease Type C

The earlier treatment begins, the better the outcome, so it’s crucial to detect the disease as early as possible and initiate treatment promptly.

Symptomatic therapy is conducted for Niemann-Pick Disease, aiming to reduce the severity of specific manifestations of the disease. Treatment is tailored based on the clinical manifestations of the disease. For example, tricyclic antidepressants or other central nervous system stimulants help control sudden weakness attacks. Antiepileptic therapy is necessary in case of epilepsy. Anticholinergic drugs and botulinum toxin are often effective for persistent involuntary muscle contractions and tremors.

The only registered drug for treating Niemann-Pick Disease Type C is Miglustat, which reduces cellular cholesterol levels. Unlike medications typically used for high cholesterol, Miglustat penetrates the blood-brain barrier, affecting neurological manifestations of the disease.

Research on medications for Niemann-Pick Disease treatment is ongoing. Clinical trials of Arimoclomol, a drug for treating various neurodegenerative diseases, are currently underway.

Swallowing function must be closely monitored in Niemann-Pick Disease. Swallowing difficulties can lead to feeding problems and the risk of infection. Most patients in the advanced stages of the disease cannot swallow, so they receive nutrition through a gastrostomy—an artificial opening connecting the abdominal wall to the stomach.

Another issue in Niemann-Pick Disease is excessive saliva secretion, which can be managed with medication or injections of botulinum toxin into the salivary glands.

Patients often require joint management by a neurologist and psychiatrist. In the advanced stages of the disease, round-the-clock care is necessary.

Prognosis and Prevention

Various treatment methods, including medications, physiotherapy, speech therapy, and professional support, have been developed to alleviate patients’ conditions. However, the disease remains a severe condition that significantly complicates the lives of patients and their families.

The prognosis and rate of disease progression depend on the age of onset: the earlier the onset, the worse the prognosis and the shorter the lifespan. Most patients die in childhood and young adulthood—between 10 and 25 years old. A more pessimistic prognosis and earlier death are characteristic when neurological symptoms appear in the first few years of life. Bronchopneumonia, arising from swallowing difficulties, is the most common cause of death.

Preventive methods for the disease are not yet developed, but early diagnosis and proper therapy can prolong patients’ lives.