Niemann-Pick disease

A boy affected by Niemann-Pick disease

Cherry stain

Sphingolipidss

Autosomal recessive hereditary storage disorder, belongs to the so-called lipidoses - lipid metabolic disorders. It arises on the basis of the deposition of sphingomyelin in the macrophages of the reticuloendothelial system - mainly in the liver, spleen and bone marrow.

This is a heterogeneous group of type A, B, Cdiseases, which differ in a metabolic disorder - acid sphingomyelinase deficiency (type A, B) vs. lipid transport disorder (type C).

Acute forms typical for childhood affect the nervous system, chronic forms manifest themselves later in cholestatic liver disease, progressing to cirrhosis. Secondarily, there is an increase in the concentrations of non-esterified cholesterol.

(Acid/lysosomal) sphingomyelinase deficiency

Niemann-Pick disease, type A and B: deficiency of acid sphingomyelinase activity (results from SMPD1 gene mutation, more than 100 mutations are known)

• Type A - the basic features include neurovisceral impairment with death within 1-3 years of age (specifically increased incidence in the ethnic group of Ashkenazi Jews)
  • difficulties appear already in the first weeks of life
  • manifested by vomiting, diarrhea and general failure of the newborn to cachexia; within a few months it progresses to lymphadenopathy and hepatosplenomegaly (rarely to cholestatic icterus)
  • muscle weakness, hypotonia, psychomotor retardation appear, there is a gradual loss of motor functions, spasticity and muscle rigidity; xanthomas and brown-yellow spots may appear on the skin
  • in about half of the patients, a so-called cherry spot appears on the retina
  • patients usually die before the age of 3 years

• type B' - chronic disease (more common in Southern Europe and North Africa), can appear at any time from late childhood to adulthood
  • mostly manifested by splenomegaly or hepatosplenomegaly (more severe liver disease is rare)
  • there is often reticulonodular X-ray infiltration of the lungs associated with interstitial involvement, which may present with varying degrees of exertional dyspnea
  • growth retardation, delayed bone age and puberty also occur
  • intellect and nervous system are not affected
  • adults tend to have a pathological lipid profile, thrombocytopenia and elevated liver transaminase activity
  • there are various severe forms of the disease, mostly with a normal life expectancy
• Diagnosis of Niemann-Pick type A and B disease: is confirmed by determining the deficiency of acid sphingomyelinase activity in leukocytes isolated from peripheral blood or cultured skin fibroblasts; a complementary examination in cases with a confirmed diagnosis is a DNA analysis
• Prenatal diagnosis: in families with enzymatically proven diagnosis, analysis of native and cultured chorionic villi or cultured amniocytes is possible; an additional examination is an analysis of the ultrastructure of the chorionic villi
• Treatment: recombinant enzyme therapy is in preparation

Complex lipid transport disorder

Niemann-Pick disease, type C: defect of transmembrane proteins NPC1, NPC2 - impairment of transport of membrane lipids and cholesterol (defect in gene encoding protein)

• is characterized by accumulation of non-esterified cholesterol in the lysosomal apparatus

• type C - the clinical course is different, symptoms can begin to manifest from birth to adulthood, there is a systemic disability, independent of the neurological
  • among the basic features of the acute type of the disease is a rapid progression of the liver disorder characterized by severe storage, failure to coma and significant splenomegaly
    • neurological symptoms are minimal - hypotonia
    • death occurs around 6 months of age
  • in classic type NPC1 visceral involvement is the first manifestation of the disease (mild hepatosplenomegaly - splenomegaly exceeds)
    • neurological symptoms may develop after several years - ataxia, deepening mental retardation, initially hypotonia, later spasticity with pyramidal manifestations and epileptic seizures; there may also be dystonia and vertical supranuclear ophthalmoplegia
    • the adult type of the disease includes minimal hepatosplenomegaly and schizophrenic syndrome
    • neurovisceral symptomatology is related to significant changes in histiocytes and neurons
  • NPC2 type represents a minor complementary group - symptoms are the same as NPC1, severe lung involvement is often present
• manifestations also depend on the form of the disease:
  • infantile form - faster course with survival up to 5 years
  • juvenile form - may manifest gradually with non-specific disorders of attention, writing and increasing clumsiness, learning problems, ataxia, cognitive dysfunction, gradual development of dysphagia, dysarthia, dystonia, palsy of vertical gaze, dementia
• patients usually live over 30 years, the adult form can only appear after the age of 60
• Diagnosis: is based on evidence of relatively specific storage in bone marrow histiocytes (isotropic accumulation of phospholipids), on evidence of the lack of ability to esterify exogenously supplied LDL cholesterol after its endocytosis in cultured fibroblast lysosomes (insufficiently esterified cholesterol is specifically demonstrated by filipin in the form of an autofluorescent complex); followed by evidence of a mutation in the NPC1 gene
  • decisive for the diagnosis of NPC2 is the proof of a mutation in the NPC2 gene
• Prenatal diagnosis: in families with proven diagnosis is possible by analysis of cultured chorionic villi or cultured amniocytes
• Treatment: therapy is not available
• There is no specific treatment, bone marrow transplant and splenectomy trials and human recombinant enzyme studies are ongoing.

Links

Related Articles

• Lipidosis
• Thesaurisms

Sources

• FERNANDES, John. Diagnostika a léčba dědičných metabolických poruch. 1. edition. Praha : Triton, 2008. ISBN 978-80-7387-096-6.