INTRODUCTION:

Niemann-Pick Disease is one of a group of lysosomal storage diseases that affect metabolism and that are caused by genetic mutations. There are three most commonly recognized forms are Niemann-Pick Types A and B and Niemann-Pick Disease Type C (NPC). Niemann-Pick Disease affects all segments of the population with cases reported in North America, South America, Europe, Africa, Asia, and Australia. However, a higher incidence of NPD has been found in certain populations: Ashkenazi Jewish population, French Canadian population of Nova Scotia, Maghreb region of North Africa, Spanish-American population of southern New Mexico and Colorado. Niemann-Pick Type C (NPC) is very different than Type A or B, present in infants, children, or adult. NPC Patients are not able to metabolize cholesterol and other lipids properly within the cell.¹

Definitions:

Niemann-Pick disease type C is an inherited condition in which the body cannot properly metabolize cholesterol and fats, resulting in an excess of these substances in the body.²

NPC is an inherited neurodegenerative disease that causes increased damage to the nervous system over time. This condition is referred to as a “lipid storage disease” that is caused by the body’s inability to process and remove abnormal amounts of cholesterol or other lipids (fats) from the body.³

Niemann-Pick disease type C (NPC) is a rare, inherited neurodegenerative disorder caused by an intracellular lipid-trafficking defect.⁴

Incidences/prevalence:

The true prevalence of NP-C is difficult to assess, because of insufficient clinical awareness combined with the relative difficulty of biochemical testing. Estimates of birth prevalence ranging between 0.66 and 0.83 per 100,000 were proposed for France, the United Kingdom and Germany based on the diagnoses made in the lab of the author over the period 1988 to 2002.⁵ However, very different figures of 0.47, 0.35 and 2.20 per 100,000, respectively, were reported in studies from Australia (20 cases between 1980-1996), The Netherlands (25 cases between 1970-1996) and Northern Portugal (9 cases 1985-2003).⁶The low incidence found for Australia and the Netherlands might be explained by a non- exhaustively of the diagnoses in the years of birth of many patients. The wide clinical spectrum of NP-C was not recognized until the early 1990s, especially regarding rapidly fatal infantile cases, and no specific laboratory testing was available until the mid-1980s. Most families (about 95%) belong to the NP-C1 group. Two NP-C1 isolates have been described. The first one, in French Acadians originating from Normandy and originally established in Nova Scotia, was initially described as Niemann-Pick disease type D; it is characterized by the NPC1 p.G992W mutation [1, 17, and 24]. Another isolate was described in Hispanics from southern Colorado and New Mexico with their roots in the Upper Rio Grande valley of the USA, carrying the NPC1 p. I1061T mutation.⁷

When both parents are carriers of the abnormal gene, there is:

· a 1 in 4 chance that a child will have the disease

· a 1 in 2 chance that a child will be a carrier

· a 1 in 4 chance that a child will not have the disease and will not be a carrier. ⁸

Etiology/Causes:

· Approximately 95% of Niemann–Pick type C cases are caused by Genetic mutations in the NPC1 gene, referred to as type C1

· 5% are caused by mutations in the NPC2 gene, referred to as type C2.⁹

Pathophysiology:

The primary biological defect in Niemann-Pick type C disease (NP-C) is impaired intracellular lipid transportation that leads to toxic accumulation of lysosomallipids.¹⁰ in peripheral tissues such as the skin; it is predominantly unesterified cholesterol that accumulates. ¹¹However, in the liver and spleen, several different types of lipid accumulate including unesterified cholesterol, glyspingolipids, phospholipids and sphingomyeline. Glycosphingolipid accumulation primarily occurs in the central nervous system (CNS), including the brain. In normal cells, low density lipoprotein (LDL) cholesterol enters cells via endocytosis at the LDL receptor and is delivered to the late-stage endosomes and lysosomes where it is hydro lyzed and released as free cholesterol (see Figure below).¹²Unesterified cholesterol is then transported to the plasma membrane and the endoplasmic reticulum (ER) for recycling within the cell. In NP-C, the LDL-cholesterol becomes trapped within the lysosomes, resulting in considerably reduced transport of unesterified cholesterol.¹³the end result is accumulation of lipids to toxic levels, which causes damage to cells and tissues, leading to the symptoms of NP-C.

Fig. Cholesterol transport in normal and in NP-C cells

Clinical manifestations:

Niemann-Pick type C disease (NP-C) is characterized by a variety of highly variable clinical manifestations that can be classified as visceral (systemic), neurological or psychiatric. The most common symptoms are as follows.

Visceral or systemic symptoms:

· Hepatomegaly

· Splenomegaly

· Prolonged neonatal jaundice

· Pulmonary infiltrates (in NPC2 mutations or early onset NP-C)

· Fetal hydrops

· Fetal ascites

· Neonatal cholestasis.

Neurological or psychiatric symptoms:

· Vertical supranuclear gaze palsy (VSGP)

· Ataxia, clumsiness or frequent falls

· Dysphagia

· Dysarthria

· Dystonia

· Gelastic cataplexy

· Acquired and progressive spasticity

· Hypotonia

· Delayed developmental milestones

· Seizures (partial or generalized)

· Myoclonus

· Deafness

Psychiatric symptoms:

· Early-onset psychosis

· Prominent visual hallucinations

· Treatment-resistant psychiatric symptoms

· Pre-senile cognitive decline and/or dementia

· Disruptive or aggressive behavior in adolescence or adulthood

· Cognitive dysfunction.¹⁴

Diagnostic evaluations:

Niemann-Pick Type C (NPC) is a rare and extremely variable condition and therefore may not be recognized by some health care providers. Most common diagnostic evaluations are as follows,

Initial Clinical Assessments:

NP-C Patients Differ from Other Lysosomal Storage Diseases. Due to complex and unspecific clinical symptoms, the diagnosis is relatively difficult in cases lacking the typical symptoms. In order to properly diagnose, one should seek a combination of signs and symptoms for early detection such as the splenomegaly and psychosis, or the ataxia with dysarthria.¹⁵

A Full Medical History:

Might include organomegaly, history of splenectomy, neurological manifestations, abnormal muscle tone or posture, ataxia, dystonia, dysphagia, seizures, cataplexy, behavioral problems (agitation, hyperactivity, sleep disorders, visual hallucination or depression)and neuropsychiatric manifestations (psychosis, schizophrenia) where early warning signs.

Clinical Examination:

A comprehensive clinical examination should consider vital signs, body weight, height and head circumference, neurological examination, and ultrasound of liver and spleen. Clinical assessment of the disease progression can be evaluated by video record.

Skin biopsy:

This procedure requires the removal of a small piece of skin that is sent to a special laboratory where cells are cultured and then tested for the capacity to process cholesterol.¹⁵

Blood test:

Only measures the products of cholesterol processing.

DNA testing:

May also be recommended if the cultured skin cells reveal abnormal processing of cholesterol. A DNA test will look for mutations in one of two genes NPC1 and NPC2 that could be causing abnormal function of proteins involved in processing of cholesterol and other lipids.

Bone marrow aspiration:

It could be useful in highly suspicious cases (prior to a specific biochemical test) which show the cholesterol loaded foam cells.

Specific Diagnostic Tests:

The primary biomarker diagnostic test is the Filipin test. It is the most sensitive and specific test. It is a fibroblast culture of living cells from a skin biopsy.¹⁵

Molecular Genetic Testing:

Pathogenic variants in two genes are known to cause Niemann-Pick disease type C (NPC):NPC1 and NPC2.

Evidence for further locus heterogeneity. No direct evidence exists for other loci; however, in some individuals with the typical clinical and biochemical phenotype, pathogenic variants have not been found in NPC1 or NPC2.

Imaging:

MRI of the brain is usually normal until the late stages of the illness. At that time, marked atrophy of the superior/anterior cerebellar vermis, thinning of the corpus callosum, and mild cerebral atrophy may be seen.¹⁶

Medical management:

No curative therapy for NPC exists.

Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialist in neurology, pulmonology, gastroenterology, psychiatric, orthopedics, nutrition, physical therapy. Standard medications used to treat symptoms can be used in NPC patients. Treatment is primarily supportive, aimed at symptom management, and includes control of seizures, provision of nutritional support, prevention and treatment of aspiration pneumonia, treatment of psychiatric manifestations and supportive treatment of liver disease.¹²

· Seizures, including myoclonic seizures, generally respond at least partially to anti-epileptic drugs until a fairly advanced stage of the disease.

· Cataplexy can usually be controlled by clomipramine, imipramine, and protriptyline.

· Anti-cholinergic agents have been reported to improve dystonia and tremor in some patients.

· Physiotherapy is useful in the management of spasticity and the prevention of contractures.

· Melatonin may be helpful to treat insomnia.

· Patients with a slow disease course may benefit from individualized education programs.

· Proper management of infections and of feeding difficulties (gastrostomy tubes) is essential at an advanced stage of the disease.

· Diet softening and thickening and Gastrostomy is useful for Dysphagia

· Oral atropine Heavy drooling of saliva

· Tricyclic anti-depressants or CNS stimulants may be used to treat Cataplexy

· Anticholinergic drugs like Trihexyphenydil, benzodiazepines and Gamma-amino butyric acid to treat Dystonia

· Positive airway pressure is used for Sleep apnea.¹⁷

· Spasticity is managed by Physiotherapy.¹⁷Histone deacetylase inhibitors is used for stabilizing NPC1 missense mutant proteins, reducing cholesterol accumulation, and preventing the rapid degradation of mutant NPC1 proteins.¹⁸

· Patients with dysphagia become malnourished and are at risk of silent aspiration, requiring a softening and thickening of food and antibiotics to avoid aspiration pneumonia. Some patients need gastrostomy to maintain daily caloric intake. Heavy drooling of saliva can be controlled by small doses of oral atropine. Diarrhea associated with miglustat therapy can be managed with antidiarrheal and diet modification.¹⁹

Disease-Specific Treatment:

Miglustat (N-butyldeoxynojirimycin; NB- DNJ; Zavesca, Actelion pharmaceutical Ltd.) is the only disease-specific oral therapy approved to treat progressive neurological manifestation of NP-C. A small water-soluble, iminosugar molecule reversibly inhibits glycosphingolipid synthesis. It has beneficial effects on lipid trafficking defects, reducing the neurotoxic accumulation of glucosylceramide, lactosylceramide, and gangliosides GM2 and GM3 in the brain and delaying the progression of neurological symptoms of NP-C but it has no effect on the systemic manifestation.²⁰

Tissue and organ transplantation:

Bone marrow transplantation or liver transplantation may also be effective although there is a regression of hepatosplenomegaly and lung infiltration.²⁰

NURSING CONSIDERATIONS:

Genetic Counseling:

Genetic Counseling is the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. This process integrates:

· The interpretation of family and medical histories to assess the chance of disease occurrence or recurrence;

· Education about inheritance, testing, management, prevention, resources, and research;

· Counseling to promote informed choices and adaptation to the risk or condition.

Nurses are health professionals with specialized graduate degrees and experience in the areas of medical genetics and counseling. Genetic counselors provide,

· Supportive counseling to families,

· Serve as patient advocates, and

· Refer individuals and families to community or state support services.

· They serve as educators and resource people for other health care professionals and for the general public.

· Some counselors also work in administrative capacities.

· Many engage in research activities related to the field of medical genetics and genetic counseling.

· Information about Niemann-Pick disease types A, B, and C for health care providers, and for family and friends

· Middle and high school curriculum supplement about Niemann-Pick disease

· Information about bone marrow transplantation and stem cell transplantation

· Approaches to care of the caregiver

· Hospice and respite care resources

· Grief Support information

· Teens and chronic illness, and transition to adult care.21

REFERENCES:

1. Marc Patterson, MD Mayo Clinic Rochester, Minnesota Initial Posting: January 26, 2000; Last Update: July 18, 2013.

2. https://www.counsyl.com/services/family-prep-screen/diseases/niemann-pick-disease-type-c/

3. Alzheimer’s Society UK, Rarer Causes of Dementia Factsheet http://www.alzheimer.ca/~/media/Files/national/Other-dementias/rarer_dementias_niemann_pick_e.pdf

4. Marc C. Patterson, M.D. For Medical Professionals Clinical updates. http://www.mayoclinic.org/medical-professionals/clinical-updates/neurosciences/treating-rare-disease-niemann-pick-disease-type-c

5. Patterson MC, Vanier MT, et. all: Niemann-Pick disease type C: a lipid trafficking disorder. The Metabolic and Molecular Bases of Inherited Disease New York: Edited by: McGrawHillScriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, 8, 2001, 3611-3634.

6. Meikle PJ, Hopwood JJ, Clague AE, Carey WF: Prevalence of lysosomal storage disorders. JAMA. 1999, 281: 249-254. 10.1001/jama.281.3.249.

7. Wenger DA, Barth G, Githens JH: Nine cases of sphingomyelinlipidosis, a new variant in Spanish-American Children. Juvenile variant of Niemann-Pick Disease with foamy and sea-blue histiocytes. Am J Dis Child. 1977, 131: 955-961.

8. Available from-http://nnpdf.org/the-disease/diagnosis/

9. Mellon SH, Gong W, Schonemann MD (March 2008). "Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease". Brain Research Reviews57 (2):410–20. Available from-https://www.counsyl.com/services/family-prep-screen/diseases/niemann-pick-disease-type-c/

10. Wraith JE, Imrie J. Understanding Niemann-Pick disease type C and its potential treatment. UK Blackwell Publishing, 2007.

11. Patterson MC. A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C Neurologist 2003; 9: 301-10.

12. Vanier MT. Niemann-Pick disease type C Orphanet J Rare Dis 2010; 5:16.

13. Mukherjee S, Maxfield FR. Lipid and cholesterol trafficking in NPC BiochimBiophysActa 2004; 1685: 28-37.

14. Patterson MC, Hendriksz CJ, Walterfang M, et al, on behalf of the NP-C Guidelines Working Group. Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update. Mol Genet Metab 2012. 106(3):330-344.

15. HannaAlobaidy. Hindawi Publishing Corporation International Journal of Pediatrics Volume 2015, Article ID 816593, 10 pages. Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician

16. Marc Patterson, MD Mayo Clinic Rochester, Minnesota Initial Posting: January 26, 2000; Last Update: July 18, 2013.

17. Kandt RS, Emerson RG, Singer HS, Valle DL, Moser HW. Cataplexy in variant forms of Niemann-Pick disease. Ann Neurol. 1982 12((3)): 284-8.)

18. N.H.Pipalia, C. C. Cosner, A. Huangetal, “Histonedeacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts,” Proceedings of the National Academy of Sciences of the United States of America, vol.108, no.14, pp.5620–5625, 2011.

19. M.T.Vanier,“Niemann-Pick disease type C,”Orphanet Journal of RareDiseases,vol.5,no.1,article16,2010

20. Saneifard H. MD. Iran J Child Neurol. 2015 Autumn vol 9 no 4 suppl.1

21. Available from-http://nnpdf.org/genetic-counseling/

Received on 04.04.2017 Modified on 20.04.2017

Int. J. Adv. Nur. Management. 2017; 5(3): 265-269.

DOI: 10.5958/2454-2652.2017.00058.0