Niemann-Pick disease (lipoid histiocytosis, non-leukemic reticulosis, sphingomyelin lipidosis, sphingomyelinosis, phosphatidosis) refers to a group of rare hereditary pathologies affiliated with leptin, since the main sign of the disease is accumulation of lipids in human organs and tissues with their dysfunction. The peculiarity of the pathology is the polymorphism of the clinic. About the main symptoms, diagnosis and correction of the disease you will learn from the article.
- General information.
- Classification and symptoms.
- Prognosis and prevention.
Lipoid histiocytosis is a pathology from the group of lysosomal accumulation diseases. The disease was first described by German pediatrician A. Niemann at the beginning of the last century. Two decades later, German pathologist L. Pick gave a pathomorphological description of the syndrome. Since the significance of both discoveries is difficult to overestimate, the disease is named after these two doctors.
There are three types of pathological changes, which differ in the mechanism of development, epidemiology and course of the disease. The prevalence of type A and B is 1: 250,000, type C – 1 per 120-150,000 population. In Ashkenazi Jews, type A is common with a frequency of 1:40,000 to 1:100,000.
Genetic mutations are thought to be the main trigger for Niemann-Pick disease. Types A and B are associated with the SMPD-I gene, which is localized at locus 11p15.4-p15.1. This gene controls the enzyme acid sphingomyelinase. Type C is affiliated with a mutation of the NPC1 genes, which are located at loci 18q11-q12 and NPC2 at locus 14q24. These genes control proteins that transport cholesterol and other lipids inside the cell. The disease is inherited autosomal recessively.
The mechanisms of type A, B, and C pathology are different. In type A, a genetic mutation develops that leads to an almost complete deficiency of acid sphingomyelinase. This leads to the accumulation of sphingolipids in the CNS and other internal organs, which is accompanied by the rapid development of fatal neurological symptoms and death in early childhood.
In type B, a similar situation occurs only in 20% of cases, so fat accumulation occurs in the reticuloendothelium: liver, spleen. Type C leads to impaired protein transport and accumulation of lipids of different classes in the cells, which involves lesions of the nervous system and internal organs. Cholesterol, in turn, suppresses the synthesis and activity of sphingomyelinase.
Leptin plays a subordinate role in such pathogenesis, since it is a product of adipose tissue and is a priori involved in lipid metabolism, but does not take part in the mechanism of development of such complex processes on its own.
Classification and symptoms
In practice, there are three types of lysosomal pathology:
- Infantile or classic type A – the most severe variant with early onset of the pathology, progressive course, and fatal outcome.
- Visceral or type B – characterized by a later onset and a moderate course without neurological symptoms.
- The most common type C , which is characterized by polymorphic symptoms. It is distinguished: neonatal form – up to 3 months of age; early infant form – up to 2 years of age; late infant form – up to 6 years of age; juvenile – up to 15 years old; the adult form – older than 15 years.
The symptoms of Niemann-Pick disease vary by type:
- Type A demonstrates symptoms from birth – hepato- and splenomegaly, enlarged lymph nodes. From about six months of age, the child’s appetite decreases (here the role of leptin is obvious), there is constant nausea, head holding, speech, walking skills are retarded, by two years of age spastic muscle condition is formed. With degeneration of the brain, breathing and heartbeat are impaired, leading to fatal outcome.
- Type B is not associated with neurological symptoms, hepato- and splenomegaly, lymphadenitis, frequent acute respiratory infections, acute respiratory infections prevail. The maximum threat comes from the respiratory system: infiltrated alveoli provoke interstitial lung pathology by the age of 20, so patients have big problems with the respiratory system.
- Type C is polymorphic, debuting from 7 years of age and in addition to lagging in general development is characterized by muscle atony, impaired gait, loss of coordination of movements, falls. Restriction of upward and downward eye movements, as well as a sudden loss of muscle tone in the limbs, neck during laughter or emotional tension are considered specific signs. Babies have difficulty pronouncing sounds, speech becomes slurred, involuntary painful spasms of the facial muscles or hands occur, swallowing is disturbed and choking when eating. Epileptic seizures not infrequently develop, cognitive abilities and memory deteriorate. In a quarter of cases, acute psychosis and hallucinations develop. Depressive states and bipolar disorders are sometimes encountered. Hepatosplenomegaly with bile stagnation in the biliary system becomes the leading symptom of internal organ damage.
Lipoid histiocytosis has many complications. The most dangerous are respiratory or cardiac arrest due to damage to the brain centers. Type C demonstrates rapidly progressive hepatic and respiratory failure, and the risk of fetal dropsy is high. Low muscle tone of the pharynx promotes aspiration of food, infiltrates in the lungs provoke pneumonia, high pressure in the small circle of circulation forms the pulmonary heart. Impaired lipid metabolism with leptin resistance leads to liver cirrhosis.
In order to make a correct diagnosis, patients must be examined by a neurologist in addition to the pediatrician: muscle tone, tendon reflexes, cerebellar tests. The pathology should be differentiated from Gaucher disease, Tay-Sachs disease, Wilson-Conovalov disease.
To clarify the diagnosis, the following tests are performed:
- OAC and biochemical testing;
- specific laboratory tests for sphingomyelinase (type A), chitotriosidase (type C) levels, cholesterol oxidation products;
- imaging – CT or MRI – of the brain, which reveals atrophy of the large hemisphere and cerebellar cortex, thinning of the corpus callosum, and enlargement of the ventricles;
- histology of bone marrow aspirate, skin biopsy;
- molecular genetic testing to detect gene mutations.
The therapy of the disease is complex and includes:
- Conservative correction with obligatory hospitalization in a hospital. There is no specific treatment, to block the development of the pathology at the very beginning is prescribed substrate-reducing therapy: Miglustat, which interrupts the synthesis of glycosfingolipids. Minimization of sphingolipids in tissues prevents neurological symptoms. In addition to Miglustat, anticonvulsants (Lamotrigine), psychotropics (Chloroprotixen, Fluoxetine), choline blockers and muscle relaxants (Baclofen), choleretic agents (ursodeoxycholic acid), antidiarrheals, antispasmodics (Loperamide, Drotaverine), statins (Atorvastatin) are used.
- Surgical intervention in the form of bone marrow stem cell transplantation, splenectomy, liver transplantation.
- Experimental therapy – the drug 2-hydroxypropyl-betacyclodextrin and BNP type B enzyme replacement therapy are at the clinical trial stage.
- Palliative correction is used in neglected cases (gastrostomy).
Prognosis and prevention
In most cases, the prognosis for life is unfavorable. Type B is relatively benign without neurological symptoms. In type A, life expectancy does not exceed 4 years, in type C – 20 years. The cause of fatal outcome is respiratory and cardiac arrest, less often – severe respiratory failure of infectious genesis. Prevention of the disease consists in prenatal diagnosis at an early gestational stage.