Niemann-Pick disease is also known as Niemann-Pick disease. The inherited disease belongs to the lysosomal storage diseases.
What is Niemann-Pick disease?
Niemann-Pick disease is a disorder belonging to the group of sphingolipidoses. These are metabolic diseases that manifest largely in the central nervous system. Within the sphingolipidoses, the disease belongs to the lysosomal storage diseases. These are characterized by malfunctions in the lysosomes. In English-speaking countries, the term Lysosomal Storage Diseases (LSDs) is used for these diseases. In Niemann-Pick disease, sphingomyelin storage occurs in the liver, bone marrow, spleen, and brain. The disease was named after its discoverers Albert Niemann and Ludwig Pick. First described in 1914, Niemann-Pick disease occurs rather rarely. About one newborn per 8000 births develops lysosomal storage disease. However, this includes not only Niemann-Pick disease, but also conditions such as Hunter syndrome and Sanfilippo syndrome.
Causes
Niemann-Pick disease is inherited in an autosomal recessive manner. In autosomal recessive inheritance, the defective allele is located on a homologous chromosome or on an autosome. Only homozygous trait carriers develop the disease. This means that the genetic material of a cell must have two identical copies of the defective gene on both chromosomes for the disease to occur. Niemann-Pick syndrome is caused by a genetic enzyme defect. The enzyme sphingomyelinase is affected. Sphingomyelinase is responsible for the cleavage of sphingomyelin. The enzyme defect leads to increased storage of sphingomyelins in the lysosomes of the spleen, bone marrow, brain and liver. Lysosomes are cell organelles that contain digestive enzymes. They digest non-cellular material such as pathogens or cellular debris. They also play an important role in programmed cell death (apoptosis). Animal studies have shown that the expression of myelin gene regulatory factor (MRF) is significantly reduced by mutation in the NPC-1 gene. The protein MRF is a so-called transcription factor. It plays a role in gene coding in the formation and protection of myelin sheaths. Myelin sheaths surround nerve fibers and ensure rapid transmission of stimuli. Presumably, the neurological deficits that occur in Niemann-Pick disease are due to defective differentiation of oligodendrocytes. These cells belong to the glial cells. Their cell processes coat the cell processes of the nerve fibers as myelin sheaths. Thus, the defective differentiation of the oligodendrocytes leads to a missing or insufficient myelination. In Niemann-Pick type C disease, cholesterol metabolism is also impaired. Here, in addition to sphingomyelins, cholesterols and other metabolites accumulate in the body cells.
Symptoms, complaints, and signs
Niemann-Pick disease can be divided into three forms:
- Type IA is also called the acute infantile neuropathic form. The disease begins at three months of age and is manifested by weakness in drinking and developmental abnormalities of individual tissues and organs.
Leading symptom is a swelling of the liver (hepatomegaly). This may also occur in combination with a swelling of the spleen (splenomegaly). In addition, the lymph nodes are palpable and there is brownish discoloration of the skin. Neurological deterioration begins in the second year of life. Affected infants become deaf, blind, and lose social contact. The prognosis is infaust, meaning that all children with Niemann-Pick type IA disease die within two years. This form is the most common variant of the disease.
- TYPE IS is also known as the chronic visceral form. It is a mild course with liver swelling and pulmonary infiltrates. There is no central nervous system involvement. The life expectancy of patients is only slightly limited.
- In type C of Niemann-Pick disease, neonatal jaundice occurs. The skin and sclerae of affected newborns are yellow in color due to deposits of the pigment bilirubin. A supranuclear gaze palsy is also typical for this variant of the disease.This results in progressive paralysis of the eye muscles with double vision or disturbances of balance.
Cerebellar ataxia with disturbances in movement coordination can also be observed. During the course of the disease, patients often develop dysphagia. This can lead to aspiration pneumonia. The onset of disease in type C is highly variable. The first symptoms may appear in infants, children, or not until adolescence or adulthood.
Diagnosis and course of the disease
Prenatal diagnosis is possible if the risk of disease is known. If Niemann-Pick disease is suspected, white blood cells are collected from the bone marrow. These appear vacuolated. This means that the leukocytes are riddled with cavities. Vacuolated foam cells are also found. This phenomenon is called “sea-blue histiocytosis”. In the cultures of leukocytes and fibroblasts, the deficient activity of the enzyme sphingomyelinase can be detected. In one in two children with Niemann-Pick disease, a red macular spot is seen on ocular funduscopy.
Complications
Depending on the type, Niemann-Pick disease is associated with a number of complications. In TYPE IS, liver swelling and pulmonary infiltrates, collections of foreign bodies in the lungs, can occur. The life expectancy of those affected is slightly reduced and the quality of life is sometimes severely impaired. In type C, the first symptoms may appear in infancy. This can lead to severe developmental disorders, often associated with cerebellar ataxia with disturbances in movement coordination. During the course of the disease, swallowing disorders sometimes occur, leading to aspiration pneumonia and other complications. Affected individuals sometimes show symptoms of respiratory distress associated with cough with sputum, increased body temperature, and blue discoloration of the skin and mucous membranes. Such cyanosis, in turn, is associated with severe complications. In TYPE IA there is early weakness of drinking and developmental disorders of organs and tissues. Swelling of the liver is usually associated with swelling of the spleen, which causes severe physical impairment in affected individuals. Thus, there is an increased incidence of infections, the gastrointestinal tract becomes inflamed, and the body’s functions rapidly decline. Affected infants usually become deaf and blind within two years before eventually dying from the severe complications of Niemann-Pick disease.
When should you see a doctor?
Niemann-Pick disease is an inherited condition that takes a progressive course. Parents who notice that their child has recurrent jaundice and muscle symptoms should contact the pediatrician. If motor developmental delays or mental behavioral problems are also present, a serious condition is suspected and must be diagnosed and treated. The parents or guardians should visit a specialized center for rare metabolic diseases. Children who have Niemann-Pick syndrome require ongoing medical treatment due to increasing physical and mental problems. Unusual symptoms or a sudden increase in typical symptoms must be reported to the appropriate physician. The same applies if the child no longer tolerates the prescribed medication or otherwise shows deviations from the usual behavior. Routine treatments such as medication adjustment and physical examinations may be performed by the primary care physician. For the most part, people with Niemann-Pick disease must be treated by specialists in metabolic diseases. Individual symptoms are treated by neurologists, orthopedists, and speech therapists. Physical and occupational therapists are also involved in treatment. In addition, a therapist may be involved for psychological symptoms such as depression or delusions. Because of the wide range of possible symptoms, Niemann-Pick disease most often requires treatment by a team of physicians.
Treatment and therapy
There is currently no known causal therapy. However, there is evidence that specific cyclodextrins may relieve the symptoms of the disease. Cyclodextrins are cyclic oligosaccharides that are commonly used as solvents in drug manufacturing. Niemann-Pick type C disease is treated with miglustat.Miglustat is a drug approved in the European Union exclusively for the treatment of Niemann-Pick disease and for the treatment of Gaucher disease type 1. The drug is an iminosugar and an n-butyl derivative of moranolin.
Prospect and prognosis
The prognosis of Niemann-Pick disease is unfavorable. The disease is a genetic defect. Current law prohibits scientists from interfering as well as altering human genetics. Although the disease can be diagnosed before birth, no cure is possible based on the legal requirements. Doctors and physicians are still focusing on the development of adequate medical care after the birth of the affected person. Currently, the treatment consists of initiating a drug therapy to support the patient’s metabolism in the best possible way. Already in the developmental process of the patient, optimizations are thus possible, which contribute to an improvement of the overall situation. Without treatment, the quality of life of the affected person is greatly reduced. In addition, the development of life-threatening conditions may occur, as the disease is accompanied by swelling of internal organs as well as respiratory distress. The risk of an emergency situation is significantly increased without treatment. Long-term therapy is therefore indicated, regardless of the intensity of the individually occurring symptoms. Patients require daily care as well as support in coping with everyday life. Depending on the type of disease present, the patient may die prematurely within the first few years of life if the course of the disease is unfavorable.
Prevention
Niemann-Pick disease is inherited in an autosomal recessive manner. There is currently no effective prevention.
Follow-up
In most cases, the person affected by Niemann-Pick disease has only a few and also limited measures of aftercare available to him or her. For this reason, the patient must see a physician at the first signs and symptoms to prevent other complications or symptoms from developing. The earlier a doctor is contacted, the better the further course of the disease usually is, so that a doctor should be consulted already at the first symptoms or signs. If the patient wishes to have children, genetic testing and counseling should be performed in any case to prevent a recurrence of Niemann-Pick disease. Most patients are usually dependent on taking various medications. Patients should always ensure that the correct dosage is taken and that the medication is taken regularly in order to provide lasting relief from the symptoms. If there are any uncertainties or questions, a doctor should always be consulted first. Many patients are also dependent on the help and support of their own families in their daily lives. Above all, depression and other psychological complaints can be alleviated by this.
Here’s what you can do yourself
The options for self-help are extremely limited in Niemann-Pick disease. In particular, type IA does not offer sufficient options to bring about an improvement in the situation. Despite all efforts, the life expectancy of the affected child is very low. In everyday life, the focus should therefore be on making the time spent together as pleasant as possible. Making leisure time enjoyable is important for building closeness, cohesion and stability. The disease is an enormous challenge for patients as well as for their relatives. Building up mental strength is particularly important in coping with adversity. For this reason, psychological support is essential for everyone involved. For many it is furthermore a help if the possibility of an exchange to other affected persons can take place. Therefore, contacting established self-help groups can be beneficial. In joint discussions, an exchange takes place on the basis of mutual understanding. Communication can help with processing. In addition, tips for coping well are given. Mental techniques and relaxation exercises promote the reduction of stressors. Since situations of excessive demands and thus vegetative problems often occur, the training sessions can help to reduce stress. The handling of the overall situation should thus be improved.
