Niemann-Pick disease is a rare hereditary disease characterized by the accumulation of lipids in various organs and tissues, which leads to a violation of their functions. A distinctive feature is a pronounced clinical polymorphism. The most common are focal neurological symptoms, delayed neuropsychiatric development, hepatomegaly and splenomegaly. The diagnosis uses the determination of the activity of specific enzymes, histological studies, cerebral tomography, molecular genetic analysis. Symptomatic, substrate-reducing therapy is used for treatment.
ICD 10
E75.2 Other sphingolipidoses
General information
Niemann-Pick disease (NPD, sphingomyelinosis, sphingomyelin lipidosis) belongs to the group of lysosomal accumulation diseases. Nosology was first described by the German pediatrician A. Niemann in 1914, and in 1930 the German pathologist L. Pik published pathomorphological data. There are 3 types of the disease, differing in pathogenesis, epidemiology, and the nature of the course. The prevalence of types A and B among the general population is 1 case per 250,000 people, type C – 1 per 120-150 000 population. Ashkenazi Jews have type A much more common, according to various data 1:40 000-1:100 000.
Causes
The origin of all varieties of Niemann-Pick disease is based on genetic mutations. Types A and B are caused by a mutation of the SMPD-I gene located at the 11p15.4-p15.1 locus. This gene encodes the enzyme acidic sphingomyelinase. The cause of type C is mutations of the NPC1 (locus 18q11-q12) and NPC2 (locus 14q24) genes. These genes encode carrier proteins involved in the transport of cholesterol and other lipids inside the cell. Pathology is inherited by autosomal recessive type.
Pathogenesis
The mechanisms of disease development at the pathogenetic level in different types of Niemann-Pick disease differ somewhat. As a result of a genetic mutation in NPD-A, there is almost complete insufficiency of acidic sphingomyelinase, which leads to a rapid accumulation of sphingolipids in the central nervous system and other internal organs.
This is accompanied by the rapid development of severe neurological symptoms and a fatal outcome already in early childhood. Another type of mutation of the same gene in type B causes only a 20% decrease in the functional activity of sphingomyelinase. Therefore, the deposition of lipids occurs mainly in the cells of the reticuloendothelial system (liver, spleen).
In Niemann-Pick type C disease, different classes of lipids accumulate in cells due to disruption of the work of transporter proteins – non-esterified cholesterol, sphingomyelin, glycosphingolipids. The nervous system and internal organs are affected. Cholesterol aggregations cause a secondary decrease in the activity of sphingomyelinase by suppressing its synthesis.
Classification
In clinical practice, there are 3 main types of NPD:
1 Type A (classic infantile). The most severe form. It is characterized by early onset, progressive course, rapid onset of death.
2 Type B (visceral). Typically more moderate course, late debut. Neurological symptoms are practically absent.
Type 3 C. The most common type with extremely diverse symptoms. Depending on the age of the beginning of the manifestation , it is divided into the following forms:
- neonatal – up to 3 months;
- early infancy – from 3 months to 2 years;
- late infancy – from 2 to 6 years;
- youth (juvenile) – from 6 to 15 years;
- adult – over 15 years old.
Symptoms
Type A
The first signs appear almost from birth – this is an increase in the liver, spleen, lymph nodes. From 4-6 months, the child’s appetite decreases, nausea and vomiting join. Such basic skills as the ability to hold your head, walking, speech, are significantly delayed. In the second year of life, muscle spasticity is formed. With deep neurodegenerative brain damage, respiratory and palpitation disorders develop, which is the main cause of death.
Type B
Neurological symptoms are not characteristic of this variety. The main symptoms are hepatosplenomegaly, generalized lymphadenopathy, frequent respiratory infections. The defeat of the respiratory system is the greatest threat to life. Infiltration of the alveoli leads to the formation of interstitial lung pathology by the age of 20-25, so patients experience serious breathing problems.
Type C
This type of Niemann-Pick disease is characterized by a wide range of clinical symptoms. Most often, the disease debuts from the age of 7-12. In addition to the delay in general development, there is a decrease in overall muscle tone, gait disorders, coordination of movements, falls often occur. A specific neurological sign is the restriction of eye movement when looking up and down.
Another pathognomonic, but rare symptom is considered to be gelastic cataplexy – a sudden loss of muscle tone in the legs, arms or neck, which is provoked by emotions, such as laughter. The child has difficulty pronouncing words or sounds, speech becomes slurred, illegible. Involuntary painful spasms of the muscles of the face or hands are possible. Due to impaired swallowing, choking often occurs when eating.
Tonic-clonic, generalized epileptic seizures often occur. The child’s ability to learn and memorize deteriorates significantly, and recently acquired skills are quickly lost. In 25% of patients, acute psychoses with hallucinations occur. Sometimes depression, bipolar, obsessive-compulsive disorder (OCD) are noted. Hepatosplenomegaly with cholestasis is characteristic of the symptoms of internal organ damage.
Complications
The disease is characterized by a large number of complications. The most dangerous are respiratory or cardiac arrest due to damage to the deep structures of the brain. In the neonatal form of type C NPD, hepatic and respiratory insufficiency progresses rapidly, and the likelihood of developing fetal dropsy is high.
Due to a decrease in the tone of the muscles of the pharynx, food may enter the respiratory tract (aspiration). Infiltrates in the lungs contribute to the occurrence of pneumonia, an increase in pressure in the vessels of the small circle of blood circulation, the formation of a pulmonary heart (right ventricular heart failure). The deposition of lipids in the liver tissue can lead to cirrhosis of the liver.
Diagnostics
Pediatricians and neurologists are involved in the curation of patients with NPD. During physical examination, neurological examination is important – assessment of muscle tone, tendon reflexes, cerebellar tests. It is necessary to differentiate Niemann-Pick disease with Gaucher, Tay-Sachs, Wilson-Konovalov disease. To clarify the diagnosis, additional research methods are prescribed:
- Routine laboratory tests. In the AOC, there is often a decrease in the number of platelets, less often – hemoglobin, erythrocytes, leukocytes. The biochemical analysis of blood shows an increase in the concentration of hepatic transaminases (ALT, AST), bilirubin, cholesterol.
- Specific laboratory tests. In types A, B of NPD, a decrease in the level of acidic sphingomyelinase is detected in leukocytes. In type C, the activity of chitotriosidase, the content of cholesterol oxidation products – 7-ketosterol, and cholestane-3,5,6-triol are sharply increased in the blood.
- Tomographic methods. CT or MRI of the brain visualizes atrophy of the cerebral cortex and cerebellum, thinning of the corpus callosum, moderate ventricular expansion.
- Histological studies. When a skin biopsy is stained with filipin, intensely luminous areas are observed, concentrated around the nuclei, which are clusters of non-esterified cholesterol. Infiltration by foamy cells (Niemann-Pick cells), azure histiocytes is noted in the bone marrow aspirate.
- DNA diagnostics. The most accurate research method that can reliably confirm Niemann-Pick disease is molecular genetic testing, which determines mutations of the SMPD–1, NPC-1, NPC-2 genes.
Treatment
Conservative therapy
All patients are required to be hospitalized in a hospital. Specific therapy of NPD-A and NPD-B has not yet been developed, only symptomatic treatment is being carried out. To interrupt the initial link in the pathogenesis of NPD-C, a substrate-reducing therapy is prescribed – the drug miglustat, which blocks the initial stages of the synthesis of glycosphingolipids.
Thus, the accumulation of sphingolipids in tissues is significantly reduced. Thanks to the use of miglustat, it is possible to slow down the progression and regression of neurological symptoms. Preparations for symptomatic therapy of all types of Niemann-Pick disease are as follows:
- Anticonvulsants. To prevent epileptic seizures, anticonvulsants are prescribed – carbamazepine, valproic acid, lamotrigine.
- Psychotropic drugs. In order to correct mental disorders, neuroleptics (chlorprotixen), selective serotonin reuptake inhibitors (fluoxetine) are used.
- Holinoblockers and muscle relaxants. For patients with dystonia and muscle spasms, it is advisable to use biperiden, baclofen, tizanidine.
- Choleretic. To combat intrahepatic cholestasis, ursodeoxycholic acid is an effective drug.
- Antidiarrheal drugs and antispasmodics. With the development of dyspeptic symptoms while taking miglustat, loperamide and drotaverine are additionally prescribed.
- Statins. Atorvastatin or rosuvastatin is used to reduce cholesterol levels in the blood.
Surgical treatment
Surgical interventions were successful only in the case of Niemann-Pick-B disease. Bone marrow stem cell transplantation in some patients reduces the degree of visceral symptoms – hepatosplenomegaly, interstitial lung damage. In hypersplenism with pancytopenia, splenectomy is performed. The development of cirrhosis of the liver with severe hepatic insufficiency is an indication for liver transplantation.
Experimental treatment
Research is continuing to find effective methods of treating Niemann-Pick disease. In experiments on laboratory mice, the activity of sphingomyelinase increased in cells under the influence of gene therapy. Currently, the drug 2-hydroxypropyl-betacyclodextrin and NPD type B replacement enzyme therapy are at the stage of clinical trials.
Palliative care
At a late stage of the disease with a neglected neurodegenerative process, measures are taken to alleviate the patient’s condition. With a pronounced swallowing disorder, it may be necessary to provide probe feeding or the imposition of a gastrostomy in order to provide the patient with a sufficient amount of nutrients and fluid.
Prognosis and prevention
In most cases, the prognosis for life with Niemann-Pick disease is unfavorable. Relatively benign is considered type B, in which the nervous system is not affected. With type A, life expectancy is 1-4 years, with type C – about 10-20 years from the moment of diagnosis. The most common causes of death are lesions of the brain structures that regulate respiratory and cardiac activity.
Less often, death occurs from severe respiratory tract infections, liver failure. The main method of primary prevention is prenatal diagnosis in the early stages of pregnancy. In chorionic villi, molecular genetic tests determine the presence of NPC1, NPC2, SMPD-1 mutations; in amniocytes, the activity of sphingomyelinase is studied.
