Handbook of Genetic Counseling/Niemann-Pick Disease

Niemann-Pick Disease


  • Acknowledge any prior phone contact
  • Assess their knowledge and understanding about Niemann-Pick disease
  • Assess their concerns and ask what they want to discuss today


  • Elicit medical history
  • Elicit family history
  • Construct pedigree

Natural HistoryEdit

What is Niemann-Pick disease?Edit

  • A group of rare inherited disorders of fat metabolism (three main types with subdivisions)
  • Type A (acute infantile form) and Type B (chronic, non-neurological form): caused by excessive amounts of a fatty substance (sphingomyelin) that accumulates in the brain, central nervous system, and several visceral organs (liver, spleen, lungs). This is due to a deficiency of the enzyme sphingomyelinase, which breaks down the fat from the cell membrane products created by the normal turnover of cell death.
  • Type C (biochemical form): is a lipid storage disorder that results in the accumulation of excessive amounts of cholesterol within the cells of the liver, spleen, and brain. This is due to the cell's inability to transport the cholesterol properly during esterification reactions. It causes progressive deterioration of the nervous system.

What are the symptoms?Edit

  • Type A: this is the most common form of the disease (80%). Most of the infants appear normal at birth, and then develop symptoms by 6-12 months. 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. The fat accumulation is so severe that it may represent 2-5% of the body weight.
  • the fat accumulation in various parts of the body occurs in the developing fetus
  • hepatosplenomegaly
  • lymphadenopathy
  • abnormalities of the nervous system (profound MR)
  • poor feeding
  • edema and distention - abdominal swelling
  • vomiting and diarrhea
  • failure to thrive
  • pyrexia - fever
  • macula - bright red spots in the eyes (50%)
  • jaundice
  • Type B: begins in infancy or early childhood. These symptoms progress more slowly and there is minimal nervous system *involvement
  • hepatosplenomegaly
  • bright red spots in the eyes
  • increased susceptibility to lung infections
  • slow growth rate
  • Type C: the disease may strike anytime from early infancy to adulthood, but usually affects school-age children
  • fetal ascites or neonatal liver disease
  • jaundice at birth
  • infantile hypotonia
  • developmental delay
  • hepatosplenomegaly
  • vertical supranuclear gaze palsy (VSGP) - difficulty with upward or downward eye movements
  • ataxia - unsteady gait, clumsiness, difficulty walking
  • dystonia - difficulty in the posturing of limbs
  • dysarthria - slurred, irregular speech {these two eventually become disabling,
  • dysphagia - difficulty swallowing making oral feeding impossible}
  • dementia - learning disorders and progressive intellectual decline
  • cataplexy - sudden loss of muscle tone, causing abrupt falls
  • seizures and tremors accompanying movement

What is the prognosis?Edit

  • Type A: death usually occurs by 4 years of age
  • Type B: the earliest diagnosed patients are now middle-aged without neurological impairment
  • Type C: death usually occurs in the late 2nd or 3rd decade (aspiration pneumonia is often the cause)

Genetic EtiologyEdit

Mode of InheritanceEdit

  • autosomal recessive
  • both parents carriers: ¼ affected, 2/4 carriers, ¼ unaffected
  • males and females affected in equal numbers
  • this means that no family history of the disease is the norm

Chromosome locationEdit

  • Type A and Type B: SMPD1 (ASM) gene on locus 11p15.1-15.4
  • Type C: NPC1 gene is on locus 18q11-q12
  • NPC2 gene is on locus 14q24.333

Molecular geneticsEdit

  • Type A: in non-Jewish populations, many different mutations have been detected in Jewish populations, 1/3 of the people have a R496L point mutation
  • Type B: in non-Jewish populations, many different mutations have been detected in Jewish populations, a 3 base pair deletion ΔR608 is either homozygous or heterozygous with R496L
  • it's not possible to predict the severity by enzyme testing
  • Type C: 95% of patients have mutations in the NPC1 gene (clinical tests available)
  • 5% of patients have mutations in the NPC2 gene (research basis only)
  • the exact gene defect is not known, as mutation scanning has identified most patients as compound heterozygotes with mutations unique to their family (over 100 mutations so far)
  • the individuals with Nova Scotia ancestry (Type D) almost uniformly have a G992W mutation on NPC1


  • The phenotype (age of onset and severity of symptoms) usually runs true in families
  • Type C: "classic" patients have zero or very low esterification levels with a positive staining pattern, while "variant" patients (about 15%) have intermediate levels of cholesterol esterification and a less distinctive staining pattern

Incidence and Carrier FrequencyEdit

  • Type A: identified in people of all races
  • higher incidence in: Ashkenazi Jew ancestry (between 1:20,000 and 1:30,000)
  • carrier frequency: 1:90 to 1:100
  • Type C: rare, with 300 reported cases in the United States and 1 in a million worldwide
  • affects all populations with a prevalence 1:150,000 (est. in western Europe)
  • no accurate info. on true incidence or carrier frequency
  • higher incidence in: French Canadians in Nova Scotia (Type D)
  • Hispanic ancestry in NM and CO (Rio Grande River)
  • Bedouin group in Israel {Founder Effect}



  • Type A and Type B: blood testing - enzyme assay confirms a deficiency of the enzyme sphingomyelinase in the leukocytes (and a biopsy of the bone marrow will show abnormal foam cells)
  • Type C: biochemical test - skin biopsy taken and the fibroblasts are tested for their ability to handle cholesterol (esterification studies to test impaired cell transport and filipin fluorescent staining studies to test cell storage)

biochemical testing is used to diagnose; molecular genetic testing is primarily used to confirm diagnosis in "variant" patients

  • {Note: The diagnosis of often delayed because many clinicians do not realize that the absence of organomegaly doesn't rule out storage diseases and because "routine" tests for metabolic disease, such as urine screens and lysosomal enzyme panels, are normal in NPC.}


  • Type A: partial deficiency in sphingomyelinase activity in cultured fibroblasts indicates the heterozygote state
  • Type C: carrier detection is not yet reliable using standard biochemical tests molecular analysis of the NPC1 gene may be used if proband mutations have been identified


  • Type A and Type B: available by amnio or CVS to measure the enzyme activity
  • Type C: prenatal diagnosis available through amniocentesis or CVS for pregnancies at 25% risk
  • biochemical testing is the proband has a "classical" biochemical phenotype, but not if the proband has a "variant" *biochemical phenotype
  • molecular genetic testing if the proband as identified mutations in the NPC1 gene


  • Type A: Genzyme Genetics: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/niemann-pick-disease-type-a-testing.aspx
  • Carrier testing for Ashkenazi Jewish individuals
  • Prenatal diagnosis for carrier couples with identified mutations
  • Genzyme's Niemann-Pick disease type A mutation analysis tests for 3 mutations for a 95% carrier detection rate in the Ashkenazi Jewish population.
  • Specimen Requirements:
    • 1. Blood: ACD-A (yellow-top) or EDTA (lavender-top) tube. Adult: 10 ml whole blood; 30 ml whole blood if ordering multiple tests. Turnaround Time: 10-14 days.
    • 2. Mouthwash: Please Note: Patient should not eat, drink, smoke or chew gum for at least one hour prior to collection. (See specimen kit for detailed instructions). Mouthwash samples can be sent when ordering up to two tests. When ordering more than two tests, blood samples are required. 10 ml of Scope® mouthwash that has been swished vigorously for at least 1 minute. Collect in orange-top 50 ml polypropylene tube. Turnaround Time: 10-14 days.
    • 3. Prenatal: Please Note: Call a laboratory genetic coordinator prior to obtaining any prenatal specimens. Prenatal testing is recommended only for carrier couples with identified mutations. In some circumstances, specimens from other family members may be required. All prenatal specimens (including cord blood) must be accompanied by a maternal blood or mouthwash specimen for analysis of possible maternal cell contamination. Discard first 2 ml; then 10 ml amniotic fluid in 15 ml orange-top polypropylene tube, 10-15 mg chorionic villi in laboratory-provided screw-top tubes with sterile transport medium or one T-25 flask of confluent fetal cells. Additional specimen must be obtained for back-up culture at one of our cytogenetics laboratories or another facility. If additional testing is desired, more amniotic fluid is needed. For example, chromosome analysis requires an additional 15-25 ml (see Cytogenetics – Amniotic Fluid Chromosome Analysis test page: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/amniotic-fluid-testing.aspx) and AFAFP requires an additional 2 ml (see Amniotic Fluid Alpha-Fetoprotein - AFAFP test page: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/afafp-test.aspx). Turnaround Time: 10-14 days (when cell culture required, add ~2 weeks).
  • Baylor DNA Diagnostic Laboratory
    • Ashkenazi Jewish background only (a negative test lowers the carrier risk from 1:100 to 1:1240)
    • diagnosis confirmation
    • carrier identification
    • prenatal diagnosis
    • direct DNA analysis: 3 mutations (R496L, L302P, fsP330)
    • $200 per sample
    • 92% detection accuracy
    • prenatal specimen: 30 cc amniotic fluid >15 weeks gestation
    • >5 mg chorionic villi with 2 T25 flasks
    • postnatal specimen: whole blood in EDTA (purple top) tube

adult - 14 cc; child - 6 cc; infant - 2-3 cc

  • Type A and Type B: Dr. Wenger's Lysosomal Diseases Testing Lab, Philadelphia
    • carrier testing
    • 8-10 cc heparinized whole blood at room temp.
    • clinical history and pedigree included
    • $150
  • Type C: Dr. Wenger's Lysosomal Diseases Testing Lab, Philadelphia
    • cholesterol esterification studies
    • $1000
  • Adelaide Women's and Children's Hospital, Australia
    • cholesterol esterification in fibroblasts
    • $305
  • Mayo Clinic
    • biochemical testing only, no mutation

Surveillance, Management, and TreatmentEdit

  • Treatment is symptomatic and supportive
  • Type A: bone marrow transplantation is being tested
  • Type B: a splenectomy may relieve pressure in the abdomen; clinical trials are being done for enzyme replacement therapy
  • Type C: clinical studies are being done to determine if a reduction of cholesterol in cells through diet and drugs will help delay the neurological progression; liver transplantation corrects hepatic dysfunction, but doesn't help the neurological disease

Differential DiagnosesEdit

  • neonatal/infantile presentations: biliary atresia, congenital infections, alpha-1-antitrypsin deficiency, tyrosinemia, malignancies, Gaucher disease, infections (TORCH)
  • childhood presentations: pineal region or midbrain tumors, hydrocephalus, GM2 gangliosidosis, mitochondrial disease, maple syrup urine disease, ADD, LD, absence seizures, idiopathic torsion dystonia, Wilson disease, amino acidurias, pseudodementia, HIV encephalopathy
  • adolescent/adult presentations: Alzheimer disease, Pick disease, frontotemporal dementias, Steele-Richardson-Olzewski syndrome, syphilis, HIV dementia, psychiatric illnesses

Psychosocial IssuesEdit

  • adjusting to a child with significant medical problems
  • death of a child
  • pregnancy termination
  • guilt of "giving" this to their child
  • sibling survivor guilt
  • emotional support system/respite care for primary caregivers

Patient Resources and Support GroupsEdit

  • National Niemann-Pick Disease Foundation
North 1590 Fairview Lane
Ft. Atkinson, WI 53538
  • Just For The Kids of N.P.C. Inc.
1990 JE-TO Lake E. Drive
Danville, Indiana 46122
  • Genetic Alliance
35 Wisconsin Circle, Suite 440
Chevy Chase, MD 20815


  • www.geneclinics.org
  • NORD
  • www.ninds.nih/gov
  • Genetic Disorders Among the Jewish People
  • Emery & Rimoin's Principle & Practices of Medical Genetics

External linksEdit


The information in this outline was last updated in 2002.