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Niemann-Pick Disease

Niemann Pick Disease

Niemann-Pick disease (NPD) is an autosomal recessive disorder, observed most frequently in Ashkenazi Jews, where there is a deficiency of the lysosomal enzyme sphingomyelinase, leading to accumulation of sphingomyelin in cells of the monocyte-macrophage system and reticular endothelial cells.


Presentation

Patients with type A NPD appear normal at birth but start to display signs, such as hepatosplenomegaly, in early infancy. In type A NPD less than 5% or sphingomyelinase activity is observed and along with hepatosplenomegaly, patients display a failure to thrive, feeding problems, interstitial lung disease resulting in recurrent respiratory tract infections, motor and intellectual developmental delays followed by regression, irritability, cherry-red macula, pancytopenia, progressive neurodegeneration and eventually death by age two or three. Progressive hepatosplenomegaly is usually apparent by three months and mild hypotonia may appear by 6 months leading to loss of tone and deep tendon reflexes (previously achieved milestones may be lost). Psychomotor skills of type A patients do not progress beyond the 12 month level (eg. sit with assistance). The final stage of type A NPD is characterized by spasticity and rigidity. Although uncommon, some patients present unilateral tremors and ipsilateral hemiparesis [8].

Patients with type B NPD have 5-10% of normal sphingomyelinase activity and display more variable severity of symptoms, clinical findings and age of onset than type A. Hepatosplenomegaly is a hallmark of both types of NPD and lymphadenopathy may occur in patients with type B. Patients with type B NPD have minimal neurologic involvement but pancytopenia is common. Pulmonary involvement may be observed in type B NPD patients which is detected on chest radiographs as diffuse reticular or finely nodular infiltration. Severe pulmonary complications may arise in patients with type B NPD due to progressive pulmonary infiltrates. It is common for type B NPD patients to survive into adulthood and often it is hard to distinguish these patients from patients with Gaucher disease type 1. Growth retardation may be observed in patients with moderate-to-severe type B NPD [7] [8].
Mildly affected patients may have minimal disease manifestations and hepatosplenomegaly may not be detected until adulthood.

Easy Bruising
  • There is easy bruising. Typical cells (called Niemann-Pick cells) that have a foamy appearance due to their storage of sphingomyelin are found in the bone marrow, spleen and lymph nodes. These unusual cells help in establishing the diagnosis.[medicinenet.com]
Splenomegaly
  • RESULTS: Common disease-related morbidities included splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), and pulmonary disease (75.0%).[ncbi.nlm.nih.gov]
  • Hepatosplenomegaly, was detected at 6 weeks of age; the splenomegaly resolved following CBSCT. Recovery was complicated by graft-versus-host disease.[ncbi.nlm.nih.gov]
  • Comments: This patient with Niemann-Pick disease was a 12 y/o boy with progressively worsening splenomegaly causing respiratory difficulty and anorexia. The splenectomy specimen showed firm, pale, red-brown parenchyma.[webpathology.com]
  • It usually presents with splenomegaly, first noted in childhood.[patient.info]
  • Patients with splenomegaly have increased risk of splenic rupture, therefore, contact sports should be avoided.[symptoma.com]
Anemia
  • NPC1-depleted embryos presented with thrombocytopenia and mild anemia as studied by flow cytometry and real-time QPCR for specific blood cell markers.[ncbi.nlm.nih.gov]
  • Other examples include the defective gene that causes sickle cell anemia. Like Niemann-Pick, sickle cell anemia is a recessive disease; to have it, you must receive two defective genes: one from your mother and the other from your father.[geneticliteracyproject.org]
  • Caused by deficiency of sphingomyelinase, resulting in accumulation of sphingomyelin in the reticuloendothelial system, mental and physical retardation, enlarged liver and spleen, anemia, and blindness.[icd10data.com]
  • Niemann-Pick disease: A biochemical disorder affecting a lipid (fat) called sphingomyelin, resulting usually in progressive enlargement of the liver and spleen (hepatosplenomegaly), "swollen glands" (lymphadenopathy), anemia and mental and physical deterioration[medicinenet.com]
Death in Childhood
  • Abstract Niemann-Pick disease type A (NPA) is a rare lysosomal storage disorder characterized by severe neurological alterations that leads to death in childhood.[ncbi.nlm.nih.gov]
Cough
  • Pulmonary involvement was discovered incidentally during the evaluation of a dry cough and exertional dyspnoea which occurred in the context of an acute febrile, self-limiting illness.[ncbi.nlm.nih.gov]
  • Although many NPD-B patients are asymptomatic, more severely affected patients may exhibit cough, shortness of breath, and recurrent respiratory infections. 12 Cyanosis, clubbing, rales, and rhonchi may be present on physical examination in such patients[pediatrics.aappublications.org]
  • […] interstitial lung disease. 8 Chest radiographs in affected patients reveal interstitial infiltrates with reticulonodular changes and areas of ground-glass density that may be out of proportion to clinical findings. 16 Severely affected patients may exhibit cough[nature.com]
Dry Cough
  • Pulmonary involvement was discovered incidentally during the evaluation of a dry cough and exertional dyspnoea which occurred in the context of an acute febrile, self-limiting illness.[ncbi.nlm.nih.gov]
Failure to Thrive
  • Type A NPD is a fatal disorder in young children characterized by failure to thrive, hepatosplenomegaly and progressive neurodegeneration resulting in death by age three.[symptoma.com]
  • It is characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course culminating in death by 3 years of age. There is no known effective treatment.[ncbi.nlm.nih.gov]
  • We describe an 11-month-old Palestinian baby boy with hepatosplenomegaly, hypotonia, delayed motor development, laryngomalacia, bilateral cherry-red spots, and failure to thrive.[ncbi.nlm.nih.gov]
  • The disease is characterized by hepatosplenomegaly, failure to thrive, and rapidly progressive neurodegeneration. Death occurs by age 2 or 3 yr. Patients with type B have sphingomyelinase activity within 5 to 10% of normal.[msdmanuals.com]
  • Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, mental retardation, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms.[uniprot.org]
Hepatosplenomegaly
  • Patients with type A NPD appear normal at birth but start to display signs, such as hepatosplenomegaly, in early infancy.[symptoma.com]
  • Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no central nervous system signs.[ncbi.nlm.nih.gov]
  • Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs.[ncbi.nlm.nih.gov]
  • Hepatosplenomegaly, was detected at 6 weeks of age; the splenomegaly resolved following CBSCT. Recovery was complicated by graft-versus-host disease.[ncbi.nlm.nih.gov]
  • Type B patients also have hepatosplenomegaly and progressive alterations of their lungs, but there are usually no central nervous system signs.[ncbi.nlm.nih.gov]
Hepatomegaly
  • Although neurodegeneration defines the disease's severity, in most patients it is preceded by hepatic complications such as cholestatic jaundice or hepatomegaly.[ncbi.nlm.nih.gov]
  • He was first admitted to the hospital at 2 months because of vomiting, refusal to feed, lethargy, hepatomegaly and mild transaminasaemia. Liver biopsy at 12 months showed lipid accumulation and fibrosis.[ncbi.nlm.nih.gov]
  • The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood.[ncbi.nlm.nih.gov]
  • RESULTS: Common disease-related morbidities included splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), and pulmonary disease (75.0%).[ncbi.nlm.nih.gov]
  • Later on, hepatomegaly with developmental delay was observed. Parents also noticed unexplained frequent falls without any sign of seizure.[slideshare.net]
Xanthoma
  • Xanthoma tuberosum References Millat et al., (2005) Mol Genet Metab 86:220-232 Park et al., (2003) Hum Mut 22:313 Verot et al., (2007) Clin Genet 71:320-30 Sevin et al., (2007) Brain 130:120-133 Fernandez-Valero et al., (2005) Clin Genet 68 :245-254[genedx.com]
  • Tendon xanthoma Triglyceride storage disease with ichthyosis Xanthoma tendinosum Clinical Information Autosomal recessive disorder caused by deficiency of the enzyme glucocerebrosidase featuring the pathological storage of glycosylceramide in mononuclear[icd9data.com]
Muscle Weakness
  • Symptoms include: Severe muscle weakness Poor muscle tone Lack of growth and weight gain in infants An enlarged heart, liver, or tongue Tay-Sachs disease: This is caused by a lack of the enzyme hexosaminidases A (Hex-A).[webmd.com]
  • There is a gradual decline of motor and intellectual function resulting in a degenerative muscle weakness and floppiness. The severity of the symptoms increases rapidly and life-threatening complications may occur early in childhood.[en.wikibooks.org]
  • Symptoms include: Severe muscle weakness Poor muscle tone Lack of growth and weight gain in infants An enlarged heart , liver, or tongue Tay-Sachs disease: This is caused by a lack of the enzyme hexosaminidases A (Hex-A) .[webmd.com]
Withdrawn
  • All immune suppression was withdrawn 18 months after transplantation, and his respiratory illness has resolved. He walked independently at 24 months and is continuing to reach development milestones after receiving his transplant.[ncbi.nlm.nih.gov]

Workup

NPD may be suspected due to familial history along with identification of hepatosplenomegaly upon physical examination. Diagnosis may be confirmed pre or postnatal, using a sphingomyelinase assay on amniocentesis or chorionic villus sampling and white blood cells (WBCs), respectively. The hallmark of NPD is characteristic lipid-laden foam cell on bone marrow examination, although, genetic tests are needed for definitive diagnosis [10]. Along with hepatosplenomegaly patients often display pancytopenia (secondary to splenomegaly), elevated transaminase, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Patients with type B NPD commonly have reduced high-density lipoprotein (HDL-C) fraction and these patients often display hypertriglyceridemia. Pulmonary reticulonodular patterns of infiltration and calcified nodules may be observed in chest radiographs of NPD patients with or without pulmonary symptoms. Patients often display decreased oxygen diffusion, restrictive lung disease and exercise intolerance. A lag in bone age of up to two and a half years may be observed in NPD type B patients. Myocardial dysfunction and valvular heart disease can be diagnosed with an echocardiogram (ECHO), which are especially prevalent in NPD patients with underlying coronary artery disease [10].

Clinical laboratories are equipped to identify the four most common SMPD1 mutations responsible for NPD. Three common mutations have been identified in type A NPD patients (L302P, R495L and fsP330) and one common allele in type B (deltaR608). Another less common mutation, Gln294Lys, is associated with a milder form of type B NPD. Patients with the Gly294Lys mutation may not show decreased sphingomyelinase function in tests where the artificial substrate is used [9]. Mutation analysis is available for rare or specific gene mutations which can provide useful information for genotype-phenotype correlations and prenatal diagnosis for family members.

Treatment

No specific treatments are available for patients with type A NPD and current treatment modalities focused on symptom management. Novel therapies, such as bone marrow, stem cell transplants and enzymatic replacement, are currently being tested as a treatment option for patients with NPD [11] [12]. Liver and amniotic cell transplantation have been attempted in infants with type A NPD with minimal success.

Adults with type B NPD that have elevated cholesterol should receive treatments to lower cholesterol levels to normal range. If statins are used, liver function should be monitored. Patients with type B NPD that experience acute bleeding secondary to an overactive spleen and thrombocytopenia may require blood transfusions. Affected individuals with pulmonary disorders, including interstitial lung disease, may be administered oxygen or bronchopulmonary lavage (although this has mixed results). Bone marrow transplants have shown some success in treating type B NPD patients by reducing hepatosplenomegaly, increasing peripheral blood counts and decreasing lung infiltration, however, this is not recommended for patients with neurological symptoms.

Prognosis

Type A NPD is extremely serious and is characterized by failure to thrive, hepatoslenomegaly, interstitial lung disease, cherry-red macula, progressive neurodegeneration and eventually death by age three. Children with type A NPD appear normal at birth. Severity of symptoms, clinical findings and age of onset for patients with Type B NPD are typically more variable than type A and symptoms are often milder, including neurological signs which may be absent [7].
Patients are usually diagnosed during early childhood or infancy when physicians notice hepatoslenomegaly upon physical examination. Patients with type A NPD exhibit neurodegeneration beginning at three months of age and death by three years of age. Patients with type B NPD often survive into adulthood [7] [8].

Etiology

NPD is a sphingolipidosis characterized by a deficiency in sphingomyelinase caused by an autosomal recessive gene. Sphingomyelinase deficiency leads to lysosomal accumulation of sphingomyelin. The sphingomyelinase gene is located on chromosome 11 (11p15.1 to p15.4). The primary cell types affected by this disease are cells in the monocyte-macrophage system along with reticuloendothelial cells.

Type A NPD is extremely serious and is characterized by failure to thrive, hepatoslenomegaly, interstitial lung disease, cherry-red macula, progressive neurodegeneration and eventually death by age three. Type B NPD is regarded as a milder form of the disease, without neurological signs, that has a later-onset, however, there is much overlap between type A and B. A number of mutations have been identified to cause NPD, including deletions and substitutions.

Epidemiology

NPD is an autosomal recessive disorder that affects more commonly Ashkenazi Jews, people of Turkish decent and individuals who reside in the Maghreb region of North Africa and Saudi Arabia, however, it does occur rarely in all races and geographical locations [2] [3] [4]. Males and females are affected equally by both types of NPD. The onset and severity of type A and type B NPD vary from early onset and death by age three to later onset and survival into adulthood, respectively.

Sex distribution
Age distribution

Pathophysiology

NPD is caused by an autosomal recessive mutation of the Sphingomyelin Phosphodiesterase 1 (SMPD1) gene located on chromosome 11 (11p15.1-p15.4) that results in sphingomyelinase deficiency [5] [6]. Genomic studies have revealed that three mutations (L302P, 1bp del fsP330, R496L) are responsible for 90% of type A NPD cases and the deltaR608 mutation is most commonly found in type B NPD. Patients with NPD demonstrate less than 10% of sphingomyelinase activity compared to unaffected individuals. Sphingomyelinase deficiency leads to the accumulation of sphingomyelin in cells of the monocyte-macrophage system as well as reticuloendothelial cells. Systemic manifestations are observed in both type A and type B, including progressive lung disease, hepatosplenomegaly, short stature, and pancytopenia, whereas, neurodegenerative signs are primarily observed in patients with type A [7].

Prevention

Dietary supplements are often needed for pediatric patients with type B NPD who experience early satiety due to hepatosplenomegaly. High calorie supplements may be beneficial. Patients with splenomegaly have increased risk of splenic rupture, therefore, contact sports should be avoided. If trauma occurs in NPD patients with hyperslenism, immediate medical care should be administered to address risk of splenic rupture and intracranial bleeding.

Summary

Type A and B Niemann-Pick disease (NPD) result from an autosomal recessive gene that causes a deficiency in the enzyme sphingomyelinase which leads to a sphingolipidosis associated with the accumulation of sphingomyelin. Type A NPD is a fatal disorder in young children characterized by failure to thrive, hepatosplenomegaly and progressive neurodegeneration resulting in death by age three. There is much overlap between type A and B NPD, however, type B is generally less severe. Type C NPD is an unrelated disorder associated with abnormal cholesterol storage. The occurrence of NPD is 1 in 248,000 [1].

Patient Information

Niemann-Pick disease (NPD) is a genetic disorder associated with a deficiency of the enzyme, sphingomyelinase, which results in the accumulation of sphingomyelin or cholesterol in tissues. There are different forms of NPD, based on the level of sphingomyelinase deficiency, with the most severe form (type A) found to occur most commonly in Jewish patients and the milder form (type B) occurring in any ethnic group (although rarely). Patients with type A NPD experience severe growth complications and neurologic problems starting in infancy and typically don’t survive past age three. Usually, patients with type B NPD survive into adulthood and do not experience neurologic symptoms. Patients with type B NPD may develop fatty growths and areas of dark pigmentation on the skin, enlarged liver, spleen and lymph nodes and in some cases possess intellectual disabilities.

Some tests can be performed, including amniocentesis and chorionic villus sampling, to diagnose certain forms of NPD in a developing fetus. Diagnosis can be achieved after birth through analysis of tissue samples, including liver and blood, and genetic tests. There is no cure for NPD and in severe cases children die early from central nervous system dysfunction or infection. New therapies are being developed that are showing promise in preclinical studies but none have been approved for treatment of NPD.

References

Article

  1. Vanier MT, Rousson R, Garcia I, et al. Biochemical studies in Niemann-Pick disease. III. In vitro and in vivo assays of sphingomyelin degradation in cultured skin fibroblasts and amniotic fluid cells for the diagnosis of the various forms of the disease. Clin Genet. 1985; 27(1):20-32.
  2. Cho YU, Chae JD, Lee WM, et al. A Case of a Korean Adult Affected by Type B Niemann-Pick Disease: Secondary Sea-blue Histiocytosis and Molecular Characterization. Korean J Lab Med. 2009; 29(2):97-103.
  3. Rodriguez-Pascau L, Gort L, Schuchman EH, et al. Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. Hum Mutat. 2009; 18
  4. Simonaro CM, Desnick RJ, McGovern MM, et al. The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations. Am J Hum Genet. 2002; 71(6):1413-9.
  5. Camoletto PG, Vara H, Morando L, et al. Synaptic vesicle docking: sphingosine regulates syntaxin1 interaction with Munc18. PLoS ONE. 2009; 4(4):e5310.
  6. Jenkins RW, Canals D, Hannun YA. Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signal. 200; 21(6):836-46.
  7. Ambrosio C, Serra S, Alexandre M, et al. Arthralgia, bone pain, positive antinuclear antibodies and thrombocytopenia...diagnosis: Niemann-Pick disease. Acta Reumatol Port. 2009; 34(1):102-5.
  8. Vykuntaraju KN, Lokanatha H, Shivananda. Niemann-Pick disease type A presenting as unilateral tremors. Indian Pediatr. 2012; 49(11):919-20.
  9. Wasserstein MP, Aron A, Brodie SE, et al. Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. J Pediatr. 2006; 149(4):554-9.
  10. Hervé A, Marchand-Adam S, Fabre A, et al. Niemann-Pick disease type B identified following an episode of bronchopneumonia. Rev Mal Respir. 2008; 25(7):861-6.
  11. Alizon C, Beucher AB, Gourdier AL, et al. Type B Niemann Pick disease: clinical description of three patients in a same family. Rev Med Interne. 2010; 31(8):562-5
  12. Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. 2007; 30(5):654-63. Epub 2007 Jul 12.

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Last updated: 2019-07-11 21:05