Diagnostic Tests for Niemann-pick Disease Type C (Np-c) a Critical Review

Niemann Pick Disease Type C

NORD gratefully acknowledges Forbes D. Porter, MD, PhD, Senior Investigator, Clinical Director; Simona E. Bianconi, Medico, Staff Clinician; and An N. Dang Do, MD, PhD, Staff Clinician; National Found of Child Health and Man Evolution, Programme in Developmental Endocrinology and Genetics, Section on Molecular Dysmorphology, for assist in the preparation of this report.

Synonyms of Niemann Choice Disease Type C

• NPC
• NPD-C

Subdivisions of Niemann Pick Illness Blazon C

• Niemann Pick disease type 1C
• Niemann Pick disease type 2C

Full general Give-and-take

Summary

Niemann-Pick disease blazon C (NPC) is a rare progressive genetic disorder characterized past an inability of the body to ship cholesterol and other fat substances (lipids) inside of cells. This leads to the aberrant accumulation of these substances within various tissues of the body, including brain tissue. The accumulation of these substances amercement the affected areas. NPC is highly variable and the age of onset and specific symptoms can vary from one person to another, sometimes even amongst members of the aforementioned family. NPC can range from a fatal disorder within the first few months after birth (neonatal menstruation) to a tardily onset, chronic progressive disorder that remains undiagnosed well into adulthood. Nearly cases are detected during childhood and progress to crusade life-threatening complications by the 2nd or third decade of life. NPC is caused by mutations in the NPC1 gene (NPC type 1C) or the NPC2 gene (NPC type 2C) and is inherited in an autosomal recessive manner.

Introduction

NPC belongs to a larger group of more than 50 disorders known as lysosomal storage disorders. Lysosomes are membrane-spring compartments inside cells. They incorporate enzymes that break down big molecules such every bit proteins, carbohydrates and fats into their edifice blocks. Abnormal functioning of a transport protein leads to the accumulation of cholesterol and other fatty substances in various tissues of the body, including encephalon tissue. NPC used to be grouped together with two other disorders, named Niemann-Pick disease blazon A and Niemann-Pick disease type B. Nevertheless, researchers accept determined that the underlying defect in types A and B involves mutations in the SMPD1 factor and deficiency of the enzyme acrid sphingomyelinase, which does not occur in NPC. Niemann-Choice disease types A and B are now considered a distinct disorder called acid sphingomyelinase deficiency. NORD has a separate report in the Rare Disease Database on this disorder. Niemann-Pick illness type D is an obsolete term for a condition in a group of individuals in Nova Scotia, Canada who have NPC due to a specific founder mutation of the NPC1 gene. This course is clinically indistinguishable from NPC. Additional terms take been used in the past to describe NPC including DAF (down gaze palsy, ataxia, foam cells) syndrome, juvenile dystonic lipidosis, lipid histiocytosis, and sea blue histiocyte illness. These terms are at present considered obsolete.

Curlicue back up to restore default view.

Signs & Symptoms

Individuals with NPC tin have onset of symptoms at different ages that have been grouped historically equally: perinatal (soon before and after birth), early on infantile (3 months to < two years), late infantile (2 to < 6 years), juvenile (vi to < 15 years), and adult (fifteen years and greater). NPC affects neurologic and psychiatric functions, as well as various internal organs (visceral). Symptoms arise at different times and follow independent progression. Visceral symptoms are more typically seen in individuals presenting at a younger age. Neurologic and psychiatric symptoms often occur slowly over time, and thus feature more prominently in individuals presenting in the later age groups.

Because NPC is a highly variable disorder, it is of import to annotation that affected individuals will non have all of the symptoms described below and that every private instance is unique. Some children will develop severe, life-threatening complications early in life; others have a mild affliction that may go undiagnosed well into adulthood. Parents should talk to their child'southward physician and medical team about the specific symptoms and overall prognosis.

In perinatal NPC, the accumulation of fluid in the fetal belly (fetal ascites) may be present and persist after nativity. These infants often take prolonged severe interruption or suppression of the flow of bile from the liver (cholestasis). Features of cholestasis include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) or spleen (splenomegaly) is present in a high percent of afflicted individuals in this age group. Lipid-containing (foam) cells may accumulate in the lungs, resulting in lung disease. Liver and lung disease tin progress to crusade life-threatening complications during this period. Surviving individuals will develop neurological symptoms at a later on age.

In the early on infantile period, afflicted individuals may present with abnormal enlargement of the liver or spleen equally the simply noticeable symptom (isolated hepato-/splenomegaly), and that may remain the only symptom for many years. In other cases, additional symptoms develop including lack of muscle tone (hypotonia) ofttimes past 1 or two years of age. Affected individuals may also feel delays in the conquering of skills requiring the coordination of mental and physical activities (delayed psychomotor development).

A characteristic early finding in children with NPC is harm of the ability to expect upward and down (vertical supranuclear gaze palsy or VSGP). Specifically, affected children lose their ability to rapidly move their eyes up and down. To recoup, they may blink their eyes, jerk their heads, or make abnormal movements. Somewhen, vertical eye movements are lost, and side to side (horizontal) middle movements are also affected.

Hearing loss tin occur in some individuals with NPC. Affected individuals may develop loftier frequency sensorineural hearing loss, in which transmission of sensory inputs from the auditory nerves to the brain is impaired. Up to 74% of individuals develop clinically significant hearing loss in at least one ear. Hearing loss may be the first problem seen in adults.

The classic presentation of NPC occurs during middle to late childhood with clumsiness or difficulty in drawing and writing, frequently noted by teachers and parents. VSGP may be first reported during this fourth dimension from a conscientious neurological test or observations by the parents. Other neurological abnormalities may be the offset apparent symptoms, specifically lack of muscle coordination (cerebellar clutter). Children with cerebellar ataxia often have difficulties with residuum and trouble with walking (unsteady gait). They may fall often and exist considered clumsy. Affected children may also experience progressive difficulty speaking (dysarthria), resulting in slurred and eventually unintelligible voice communication. Children may lose previously acquired voice communication skills. Difficulty swallowing (dysphagia) may besides develop and tin become progressively worse, so that modifications such equally thickening fluids or using special utensils may exist recommended. Somewhen a feeding tube may be required to maintain adequate diet. The dysphagia tin atomic number 82 to trouble swallowing saliva and other secretions. This may consequence in the inhalation of foreign materials into the airways and lungs (aspiration pneumonia).

During this time, affected individuals may too develop slowly progressive damage of intellectually ability (cognitive impairment) that can initially exist mistaken for learning disabilities. Furthermore, psychiatric disturbances and the progressive loss of memory and intellectual ability (dementia) tin develop.

Additional neurologic findings can include drooling, epileptic seizures, and cataplexy. Cataplexy is characterized by a sudden loss of muscle tone and strength that can crusade a sudden head drop, a weak, rubbery awareness in the legs, or in severe cases collapse. Cataplexy is ofttimes caused by strong emotions, typically laughter, in individuals with NPC (gelastic cataplexy). Dystonia, a large group of movement disorders, is also common. Dystonia is generally characterized by involuntary muscle contractions that strength the body into abnormal, sometimes painful, movements and positions (postures). Some individuals may develop a tremor marked by rhythmic, jerking movements (myoclonic tremor). Sleep disturbances or irregularities such as narcolepsy or sleep apnea take also been reported.

Adolescent or developed onset of NPC may be associated with a similar neurological presentation as in babyhood onset. However, the rate of progression is oft much slower. Specific manifestations may vary, but tin include cerebellar ataxia, dysarthria, dysphagia, cognitive impairment, and other movement disorders such every bit dystonia or tremor. VSGP is invariably present, but can exist difficult to appreciate initially. Although systemic symptoms are more common in infancy or babyhood, they tin can also occur in individuals with boyish or adult onset NPC. Isolated splenomegaly may be the presenting symptom in some adolescents or adults.

Psychiatric problems that have been described in individuals with adolescent onset of NPC include learning difficulties, behavioral problems, difficulty with expressive linguistic communication, and attending deficit-hyperactivity disorder. Psychotic or manic episodes may occur in some affected individuals. Adults greater than 30 years of age may experience impairment of executive functions (dysexecutive syndrome) characterized by problems with circuitous thinking and reasoning tasks such as difficulty with organisation and planning.

In some cases, older adults may first be misdiagnosed with dementia or psychiatric illness such as major depression or schizophrenia. Individuals take been described in the medical literature with other psychiatric manifestations such every bit obsessive-compulsive disorder, bipolar disorders, and hallucinations.

Post-obit a long term gradual neurological reject decease often results from aspiration pneumonia and subsequent respiratory failure, or intractable epilepsy not responding to medical intervention.

Causes

Individuals with NPC have mutations in ane of two genes, NPC1 or NPC2. Approximately 95% of affected individuals have mutations in NPC1. Genes provide instructions for producing proteins that play a critical office in many functions of the body. Mutations in a factor may lead to the production of a poly peptide that has reduced or aberrant functions, or to the absence of the protein. Depending upon the functions of the particular protein, this can affect many organ systems of the trunk, including the brain.

Investigators have adamant that the NPC1 gene is located on the long arm (q) of chromosome 18 (18q11.ii). The NPC2 gene is located on the long arm of chromosome 14 (14q24.3). Chromosomes, present in the nucleus of human cells, carry the genes that contain genetic data for each individual. Human body cells normally have 46 chromosomes, 23 inherited from each parent. Pairs of corresponding chromosomes are numbered from 1 through 22, and the sex chromosomes are designated 10 and Y. Males have one Ten and i Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q."

Genetic diseases are determined by the combination of the pair of genes for a particular trait received from the begetter and the mother. Recessive genetic disorders occur when an individual inherits an abnormal (mutated) gene for the same trait from each parent. If an individual receives one normal gene and one mutated gene, the person will be a carrier for the disease, merely usually volition not show symptoms. For a couple who are both carriers the risk with each pregnancy for them to accept an affected child is 25%, a child who is a carrier is l%, and a kid who is unaffected and is non a carrier is 25%. In recessive genetic disorders such as NPC the gamble is the same for male and female person offspring.

The exact function of the NPC1 and NPC2 proteins is not fully understood. Researchers exercise know that the protein products of these genes are involved in the movements (trafficking) of large molecules within cells. When NPC1 or NPC2 cistron is mutated bereft levels of functional poly peptide products are fabricated. This causes aberrant accumulation of cholesterol in the peripheral tissues of the torso such every bit the liver and spleen, and accumulation of cholesterol and glycosphingolipids (complex compounds consisting of fatty material and carbohydrates) in the encephalon. The accumulation of these materials causes the various observable symptoms of NPC.

Affected Populations

NPC affects males and females in equal numbers, and can affect individuals of whatsoever indigenous background (pan ethnic). NPC is estimated to occur in 1 in 100,000-120,000 alive births. However, many cases go misdiagnosed or undiagnosed, making it difficult to determine the disorder'southward true frequency in the general population.

Diagnosis

Niemann-Choice disease blazon C is diagnosed based on characteristic symptoms obtained from a thorough clinical evaluation (see under Signs and Symptoms), and confirmed by a diversity of specialized tests. Proper diagnosis of NPC requires physicians to suspect the diagnosis based upon symptoms, and to follow up with appropriate laboratory tests to evaluate the function of the protein or the presence of accumulated byproducts (biochemical tests), and to place mutations in the NPC1 or NPC2 gene (gene sequencing).

Many physicians take piffling feel with NPC. Thus, affected individuals and families often face a meaning delay in diagnosis. Clinical experts on NPC have developed a Suspicion Index Tool to aid physicians unfamiliar with the disorder to diagnose NPC (Wraith JE, 2014). This tool creates a run a risk prediction score based on the specific manifestations present in an individual, cleaved down into visceral, neurological, and psychiatric categories. The original tool was effective in diagnosing individuals over the historic period of 4 years. Afterwards the aforementioned group derived a version that improved on diagnosing NPC in children younger than 4 years (Pineda M et al, 2016). Further study and refinement of the Suspicion Index Tool is necessary to decide its usefulness in clinical practice.

Clinical Testing and Workup
Traditionally the confirmation of an NPC diagnosis was done by staining the affected individual'due south peel cells (fibroblasts) for level of cholesterol aggregating (filipin staining). Testing for the cells' ability to modify cholesterol (cholesterol esterification test) has too been used for diagnostic purpose. Recently, blood-based testing for biomarkers (oxysterols, lysosphingolipids, bile acid metabolites) and molecular gene sequencing of NPC1 and NPC2 have replaced these traditional methods. Outside of the neonatal period, the combination of biomarkers and gene sequencing has improved the detection rate (sensitivity) and accuracy (specificity) of diagnosing NPC. In cases where the test results are equivocal, experts in the NPC field should be consulted to hash out their estimation.

Standard Therapies

Handling
Treatment of NPC may require the coordinated efforts of a squad of specialists. Pediatricians, neurologists, ophthalmologists, pulmonologists, gastroenterologists, and other healthcare professionals may demand to systematically and comprehensively program an affected child's treatment. Psychosocial back up for the entire family is essential as well. Genetic counseling would do good affected individuals and their families.

Electric current treatment is directed toward the specific symptoms apparent in each individual. Difficulty swallowing (dysphagia) should be monitored and evaluated regularly for the chance of aspiration. Swallowing difficulties may offset exist managed by softening solids and thickening liquids. A oral communication therapist can work with the individual to optimize swallowing function. Eventually, a gastronomy tube may be required to encounter acceptable caloric needs. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the straight intake of food or medicine.

Seizures often respond, at to the lowest degree partially, to anti-seizure medications (antiepileptics). Somewhen, in an avant-garde stage of the disease, seizures may no longer reply to such medications (refractory seizures). Cataplexy may exist treated by specific drugs including tricyclic antidepressants and primal nervous system stimulants such equally clomipramine, protriptyline or modafinil. Drugs that cake the neurotransmitter acetylcholine (anticholinergic agents) have been effective in treating dystonia and tremor. Botulinum toxin injections can be used to care for severe dystonia. Drugs accept too been used to treat various psychiatric illnesses, such every bit antipsychotic medications to treat psychosis and antidepressants to treat mood disorders.

Sleep abnormalities observed in NPC are diverse. Many individuals suffer from poor sleep quality due to fragmented myoclonus during tedious wave slumber. Full sleep time, and time spent in different stages of sleep (REM and slow wave) may be decreased. Some individuals may suffer from insomnia which can exist linked to underlying psychiatric diseases, such as anxiety or low. When hypotonia is severe, especially in combination with enlarged adenoids and tonsils, disordered breathing with long respiratory pauses during sleep (obstructive sleep apnea) may occur. This diagnosis oft requires an overnight sleep study. If the obstructive sleep apnea is severe, the patients may demand a machine supplying continuous positive air force per unit area (CPAP) with a mask to continue the airways open up during sleep. Insomnia and other sleep bug should exist treated with melatonin, and if needed nocturnal sedatives.

Diverse services that may exist benign to affected patients include an individualized educational plan encompassing concrete therapy, spoken communication therapy and occupational therapy. Parents, siblings, and other family members of affected individuals may discover support, resources for respite care, and data on NPC through their principal pediatrician and the various professional and parent organizations listed below.

Studies accept shown that miglustat (Zavesca®) may exist able to tiresome the progression of neurological symptoms associated with NPC. Miglustat blocks the synthesis of glycosphingolipids, one of the substances that accumulates in the encephalon of individuals with NPC. The U.Southward. Food and Drug Administration (FDA) has not approved miglustat for the treatment of individuals with NPC, although the drug is canonical for the treatment of another lysosomal storage illness known as Gaucher disease. Miglustat has been used off-characterization in the U.S. to treat individuals with NPC. Miglustat is bachelor for the handling of NPC in Australia, Canada, New Zealand, and several countries in Asia, Europe, and South America as Zavesca®, and in Japan equally Brazaves®.

NPC affects the processing of cholesterols produced within neurons, and not those outside of the cells. Thus, diets depression in fats and cholesterols do not touch the neurological disease form.

Investigational Therapies

Several therapies have been studied or are currently being studied to assess their long-term safety and effectiveness as potential treatments for individuals with NPC. These therapies include vorinostat, two-hydroxypropyl-β-cyclodextrin (HPBCD), and arimoclomol. HPBCD, specifically VTS270, and arimoclomol are currently in stage two/3 clinical trials beingness studied for their effectiveness in treating NPC.

Information on electric current clinical trials is posted on the Net at www.clinicaltrials.gov. All studies receiving U.Due south. regime funding, and some supported by private industry, are posted on this regime web site.
For information about clinical trials existence conducted at the NIH Clinical Center in Bethesda, Medico, contact the NIH Patient Recruitment Part:

Toll-gratuitous: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resource/news-patient-recruitment/

For information nearly clinical trials sponsored past private sources, in the main, contact:
www.centerwatch.com

For more data well-nigh clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.european union/

Resources

RareConnect offers a safe patient-hosted online customs for patients and caregivers afflicted past this rare affliction.  For more than data, visit www.rareconnect.org.

NORD Fellow member Organizations

• National Niemann-Option Affliction Foundation, Inc.
  • 401 Madison Artery
  • Suite B
  • Fort Atkinson, WI 53538-0049
  • Telephone: (920) 563-0930
  • Toll-free: (877) 287-3672
  • Email: [email protected]
  • Website: http://world wide web.nnpdf.org

Other Organizations

• Ara Parseghian Medical Enquiry Foundation
  • 4729 E Sunrise Dr.
  • Suite 327
  • Tucson, AZ 85718-4535 USA
  • Phone: (520) 577-5106
  • Email: [email protected]
  • Website: http://www.parseghian.org
• Genetic and Rare Diseases (GARD) Data Center
  • PO Box 8126
  • Gaithersburg, Doctor 20898-8126
  • Telephone: (301) 251-4925
  • Cost-complimentary: (888) 205-2311
  • Website: http://rarediseases.info.nih.gov/GARD/
• Hide & Seek Foundation for Lysosomal Affliction Inquiry
  • 6475 East Pacific Coast Highway Suite 466
  • Long Embankment, CA 90803
  • Phone: (877) 621-1122
  • Email: [electronic mail protected]
  • Website: http://world wide web.hideandseek.org
• Instituto de Errores Innatos del Metabolismo
  • Pontificia Universidad Javeriana Ed. Jesús Emilio
  • Ramírez (53) Laboratorios 305A - 303
  • Bogota, Colombia
  • Phone: (571) 320-8320
  • Email: [electronic mail protected]
  • Website: http://www.javeriana.edu.co/ieim/programas_ieim.htm
• Metabolic Support Britain
  • Unit 11-12 Gwenfro
  • Engineering Park, Croesnewydd Rd
  • Wrexham, Wales LL13 7YP Uk
  • Telephone: 0124420758108452412173
  • Email: [email protected]
  • Website: https://www.metabolicsupportuk.org/
• Niemann Pick Affliction Type C
• Niemann-Pick Disease Grouping (UK)
  • Suite 2, Vermont Business firm
  • Concur
  • Tyne and Vesture, NE37 2SQ Uk
  • Phone: 4401914150693
  • Email: [email protected]
  • Website: http://www.niemannpick.org.uk
• Vaincre Les Maladies Lysosomales
  • ii Ter Artery
  • Massy, 91300 France
  • Phone: 169754030
  • Email: [email protected]
  • Website: http://world wide web.vml-asso.org

References

TEXTBOOKS
Patterson MC. Niemann-Selection Disease, Type C. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:485.
Journal Manufactures

Mengel E, Pineda Thou, Hendriksz CJ, Walterfang 1000, Torres JV, Kolb SA: Differences in Niemann-Pick disease Type C symptomatology observed in patients of different ages. Molecular genetics and metabolism 2016; available online Dec. vi. In press.

Papandreou A, Gissen P: Diagnostic workup and management of patients with suspected Niemann-Pick type C disease. Therapeutic advances in neurological disorders 2016;9(iii):216-229.

Pineda M, Mengel E, Jahnova H, Heron B, Imrie J, Lourenco CM, van der Linden V, Karimzadeh P, Valayannopoulos V, Jesina P et al: A Suspicion Index to assistance screening of early on-onset Niemann-Selection disease Type C (NP-C). BMC pediatrics 2016;16:107.

Vanier MT, Gissen P, Bauer P, Coll MJ, Burlina A, Hendriksz CJ, Latour P, Goizet C, Welford RW, Marquardt T et al: Diagnostic tests for Niemann-Pick disease type C (NP-C): A disquisitional review. Molecular genetics and metabolism 2016;118(4):244-254.

Walkley SU, Davidson CD, Jacoby J, Marella PD, Ottinger EA, Austin CP, Porter FD, Vite CH, Ory DS: Fostering collaborative enquiry for rare genetic illness: the instance of niemann-pick blazon C illness. Orphanet journal of rare diseases 2016;xi(ane):161.

Santos-Lozano A, Villamandos Garcia D, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Garatachea N, Nogales Gadea Thousand, Lucia A: Niemann-Option disease treatment: a systematic review of clinical trials. Annals of translational medicine 2015; iii(22):360.

Wraith JE, Sedel F, Pineda One thousand, Wijburg FA, Hendriksz CJ, Fahey One thousand, Walterfang M, Patterson MC, Chadha-Boreham H, Kolb SA: Niemann-Pick type C Suspicion Index tool: analyses by age and association of manifestations. Journal of inherited metabolic disease 2014;37(1):93-101.

Patterson MC, Mengel East, Wijburg FA, Muller A, Schwierin B, Drevon H, Vanier MT, Pineda M: Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet journal of rare diseases 2013; viii:12.

Jiang X, Sidhu R, Porter FD, Yanjanin NM, Speak AO, te Vruchte DT, Platt FM, Fujiwara H, Scherrer DE, Zhang J et al: A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Choice C1 affliction from human being plasma. Periodical of lipid research 2011;52(7):1435-1445.

INTERNET
Patterson M. Niemann-Pick Disease Type C. 2000 Jan 26 [Updated 2013 Jul 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1296/ Accessed Feb 9, 2017.
Vanier TM. Niemann-Pick Disease Type C. Orphanet Journal of Rare Diseases. 2010;v:6. Available at: http://www.ojrd.com/content/5/1/16 Accessed February 9, 2017.

Patterson MC. Overview of Niemann-Pick Affliction. UpToDate, Inc. Aug 02, 2016. Bachelor at: http://world wide web.uptodate.com/contents/overview-of-niemann-choice-disease Accessed February 9, 2017.

Years Published

1986, 1988, 1990, 1993, 1997, 1999, 2000, 2003, 2004, 2005, 2006, 2014, 2017

The information in NORD's Rare Disease Database is for educational purposes only and is non intended to supervene upon the communication of a md or other qualified medical professional person.

The content of the website and databases of the National Arrangement for Rare Disorders (NORD) is copyrighted and may non be reproduced, copied, downloaded or disseminated, in any mode, for whatsoever commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD'southward copyright.

National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100

whitacreestion.blogspot.com

Source: https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/

Share this post