1. Genetic testing for Niemann-Pick disease, type C

Niemann-Pick disease, type C

December 01, 2017

Clinical features

Niemann-Pick disease (NPD) is a lipid storage disorder that results from the deficiency of a lysosomal enzyme, acid sphingomyelinase. There are three disorders known as Niemann-Pick disease: types A, B, and C 1. These disorders were initially grouped together because of the significant overlap in clinical symptoms, but they have different genetic causes. NPD types A and B are due to variants in the SMPD1 gene, which causes a deficiency of acid sphingomyelinase (ASM). Niemann-Pick disease type C is due to variants in one of two different genes, NPC1 and NPC2.

Niemann-Pick disease type C is characterized by progressive neurodegeneration with an estimated incidence of at least 1 in 120 000 live births 1, 2. The clinical presentation of NPC is extremely heterogeneous, with an age of onset ranging from the perinatal period until adult age and variable lifespan 1, 3.

Neonatal and infantile presentations of NPC are most commonly nonspecific and may go unrecognized. In rare cases, an ultrasound examination close to the natural end of pregnancy could result in detection of fetal ascites; infants thus identified typically have severe neonatal liver disease with jaundice and persistent ascites.

Infiltration of the lungs with foam cells may accompany neonatal liver disease or occur as a primary presenting feature. Many infants are heavily affected by respiratory and liver dysfunctions. Surviving newborns and infants are severely hypotonic and show delay in psychomotor development. Liver and spleen are enlarged in children with early presenting symptomatic hepatic disease; however many individuals with NPC never have hepatosplenomegaly. The absence of organomegaly never eliminates the diagnosis of NPC.

The classic presentation of NPC is in middle-to-late childhood, with gait disturbance and clumsiness that eventually progress to ataxia. Parents are usually aware of an early manifestation of impaired vertical supranuclear gaze palsy (VSGP). In late stages of the illness, horizontal saccades (specific eye movements) are also impaired. These physical manifestations are accompanied by progressive cognitive impairment, and some children are thought to have primary behavioral disturbances, reflecting unrecognized dyspraxia. However, as the disease progresses, it becomes clear that the child is mentally deteriorating.

In addition to the manifestations outlined above, many children develop dystonia, typically beginning as action dystonia in one limb and gradually spreading to involve all limbs and axial muscles. Speech gradually deteriorates, with a mixed dysarthria and dysphonia. Dysphagia progresses in parallel with the dysarthria, and oral feeding eventually becomes impossible.

Approximately one third of individuals with NPC have partial and/or generalized seizures 3. About 20% of children with NPC have gelastic cataplexy, a sudden loss of muscle tone evoked by a strong emotional stimulus 3. Additional neurological findings in affected children also include mild demyelinating peripheral neuropathy.

Adolescent and adult presentations of NPC is primarily characterized by neurologic disease, but at a much slower rate of progression compared to infantile NPC. Older individuals may also present with apparent psychiatric illness, such as major depression or schizophrenia.

The clinical diagnosis of Niemann-Pick disease type C should be considered in individuals (depending on the age of onset) presenting with the following 1, 3:

  • Fetal ascites or neonatal liver disease, particularly when the latter is accompanied by prolonged jaundice and pulmonary infiltrates
  • Infantile hypotonia without evidence of progression for months to years
  • Vertical supranuclear gaze palsy, followed by progressive ataxia, dysarthria, dystonia, and, in some cases, seizures and gelastic cataplexy, beginning in middle childhood, and progressing slowly over many years
  • Psychiatric presentations, mimicking depression or schizophrenia, with few or subtle neurologic signs, beginning in adolescence or adulthood
  • Enlargement of the liver or spleen, particularly in early childhood.

Traditionally, biochemical testing could demonstrate impaired cholesterol esterification and positive filipin staining. However, this testing is performed in cultured fibroblasts therefore require skin biopsy3. Centogene has developed a biomarker NPC 509 that is highly specific and sensitive for Niemann-Pick disease9.

Approximately 95% of cases are caused by homozygous or compound heterozygous variants in the NPC1 gene on chromosome 18q11, referred to as Niemann-Pick disease type C1 and Niemann-Pick disease type D, also known as the Nova Scotian type. 5% are caused by variants in the NPC2 gene, referred to as type C2 1, 3. Niemann-Pick disease type C2 (NPC2) is caused by homozygous variants in the NPC2 gene on chromosome 14q24, which accounts for the rest 5% cases.

Molecular genetic testing of NPC1 and NPC2 detects pathogenic variants in approximately 94% of individuals with NPC 1. The clinical manifestations of types C1 and C2 are similar because both of these genes are involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes 3.

Most NPC1 cases involve compound heterozygotes for single-nucleotide variants producing missense and nonsense variants; deletions and splice site variants 4, 5. So far there are over 400 pathogenic variants have been described in NPC14, 5, 6. Among them, several hotspot are known: a pathogenic variant leading to a p.Gly992Trp change has been identified in several individuals in the Acadian population of Nova Scotia and in Portugal; a p.Gly992Arg variant has been described in France 6. Individuals homozygous for the p.Gln775Pro variant have severe infantile neurologic illnesses, and those with the p.Cys177Tyr variant have a late-infantile clinical phenotype 5. The p.Ile1061Thr variant accounts for 15-20% of variant alleles in Western Europe and the US, followed by p.Pro1007Ala 6.

Figure 1: Types of NPC1 clinically relevant variants on protein level (CentoMD® 4.1)


Two pathogenic variants common for the NPC2 gene are a homozygous for c.58G>T in exon 1 and a compound heterozygote for c.58G>T and c.332delA 7. So far twenty of different missense, nonsense, and small deletions have been reported in NPC2 7, 4, 5.

Current treatment for NPC is directed toward the specific symptoms apparent in each individual. Symptomatic therapy may be at least partially effective in the management of seizures, dystonia, and cataplexy. Several therapies are currently being studied to assess their long-term safety and effectiveness as potential treatments for individuals with NPC. These therapies include the drugs that are currently in clinical trials (vorinostat, 2-hydroxypropyl-β-cyclodextrin (HPBCD), and arimoclomol) 8.

CENTOGENE offers full sequencing and deletion/duplication testing of the NPC1 and/or NPC2 genes. NPC1 and NPC2 are also part of the following CENTOGENE panels:

  • AllNeuro panel
  • CentoICU™ platinum plus
  • CentoICU™ platinum

Differential diagnosis

The differential diagnosis of NPC1 and/or NPC2-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

Neonatal and infantile presentations:

  • Biliary atresia
  • Congenital infections
  • Alpha-1-antitrypsin deficiency
  • Tyrosinemia
  • Malignancies (leukemia, lymphoma, histiocytosis)
  • Other storage diseases (e.g., Gaucher disease, Niemann-Pick disease type A, Niemann-Pick disease type B)

Childhood presentations:

  • Pineal region or midbrain tumors
  • Hydrocephalus
  • GM2 gangliosidosis
  • Mitochondrial diseases
  • Maple syrup urine disease
  • Absence seizures
  • Idiopathic torsion dystonia, dopa-responsive dystonia
  • Wilson disease
  • Neuronal ceroid-lipofuscinosis

Adolescent and adult presentations:

  • Alzheimer disease
  • Pick disease
  • Frontotemporal dementias
  • Progressive supranuclear palsy
  • Primary psychiatric illnesses.

Testing strategy

To confirm/establish the diagnosis, we offer full NPC1/NPC2 gene sequencing and deletion/duplication gene testing. We also offer a broad selection of NGS panels which are designed for the molecular diagnostics of related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for NPC1/NPC2 gene testing:

Step 1: Measurement of the biomarker NPC509

Step 2: Sequence analysis/pathogenic variant scanning for the NPC1/NPC2 genes. NPC1/NPC2 full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter.

Step 3: Deletion/duplication analysis/pathogenic variants scanning of NPC1/NPC2

Step 4: If no pathogenic variant is identified after analysis of the NPC1/NPC2 genes, panel testing with related genes or further genetic testing of related genes can be done.

Step 5: If no pathogenic variant is identified in any of the panel genes listed, we can offer whole exome sequencing, based on NGS technology.


Referral reasons

The following individuals are candidates for NPC1/NPC2 gene testing:

  • Individuals with a family history of NPC disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling NPC disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of the NPC1/NPC2 genes and related genes should be performed in all individuals suspected of having this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features of Niemann Pick disease C.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the Niemann Pick disease, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


More information on CENTOGENE´s genetic tests for Niemann-Pick disease type C can be found in our genetic test catalogue.