DiagnosisClinical DiagnosisThe diagnosis of Niemann-Pick disease type C (NPC) should be considered in individuals presenting with the following [Vanier 1997]:Fetal ascites or neonatal liver disease, particularly when the latter is accompanied by prolonged jaundice and pulmonary infiltratesInfantile hypotonia without evidence of progression for months to years, followed by features outlined in Brady et al [1989] (see VSPG)Vertical supranuclear gaze palsy (VSPG), followed by progressive ataxia, dysarthria, dystonia, and, in some cases, seizures and gelastic cataplexy, beginning in middle childhood, and progressing slowly over many years. Rarely, such presentations may begin later in childhood or in adulthood.Psychiatric presentations, mimicking depression or schizophrenia, with few or subtle neurologic signs, beginning in adolescence or adulthoodEnlargement of the liver or spleen, particularly in early childhoodTestingBiochemical. Definitive diagnosis of NPC requires demonstration of abnormal intracellular cholesterol homeostasis in cultured fibroblasts [Pentchev et al 1985]. These cells show reduced ability to esterify cholesterol after loading with exogenously derived LDL-cholesterol. Filipin staining demonstrates an intense punctate pattern of fluorescence concentrated around the nucleus, consistent with the accumulation of unesterified cholesterol:Classic. Most individuals have zero or very low esterification levels with a classic staining pattern.Variant. About 15% of individuals have intermediate or 'variant' levels of cholesterol esterification and a less distinctive staining pattern. More precise characterization of the biochemical defect in this group can be achieved by the use of BODIPY-lactosylceramide to identify lipid trafficking abnormalities [Sun et al 2001]. Histology. Other tests, including tissue biopsies and tissue lipid analysis, which were essential for diagnosis before recognition of the biochemical defect in NPC, are now rarely needed. These tests include examination of bone marrow, spleen, and liver, which contain foamy cells (lipid-laden macrophages); sea-blue histiocytes may be seen in the marrow in advanced cases. Electron microscopy of skin, rectal neurons, liver, or brain may show polymorphous cytoplasmic bodies [Boustany et al 1990].Molecular Genetic TestingGenes. Two genes are associated with Niemann-Pick disease type C (NPC):NPC1. From complementation studies and linkage analysis, it is concluded that the majority of individuals with NPC harbor mutations in NPC1.NPC2. It is assumed that the remaining individuals with the NPC phenotype have mutations in NPC2. NPC2 mutations have been detected in 4% of individuals with NPC [Park et al 2003].Evidence for further locus heterogeneity. No direct evidence exists for other loci; however, in some individuals with the typical clinical and biochemical phenotype, mutations have not been found in NPC1 or NPC2.Clinical testingSequence analysis. Detection rates using sequence analysis may be comparable to those found using mutation scanning, which has identified NPC1 mutations in 90% [Park et al 2003] and NPC2 mutations in 4% of individuals with NPC:Most individuals with NPC1 are compound heterozygotes with mutations unique to their family; to date, mutations in one or both NPC1 alleles cannot be identified in a substantial number of cases [Greer et al 1999, Yamamoto et al 1999, Park et al 2003].Of note, individuals with NPC1 from Nova Scotia (previously said to have Niemann-Pick type D) almost uniformly have the p.Gly992Trp mutation [Greer et al 1998].The majority of identified mutations are missense alterations, raising the question of whether some of these could be benign polymorphisms or variants rather than pathogenic mutations.Deletion/duplication analysis. No large insertions or deletions have been reported in NPC2. Based on the high sensitivity of the NPC2 sequencing test, a screening test for large deletions/duplications is expected to have a very low yield.Table 1. Summary of Molecular Genetic Testing Used in Niemann-Pick Disease Type CView in own windowGene SymbolProportion of NPC Attributed to Mutations in This Gene ^{1Test MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 2Test AvailabilityNPC190%Sequence analysisSequence variants 380%-90%ClinicalDeletion/duplication analysis 4Partial- and whole-gene deletionsUnknown 5NPC24%Sequence analysisSequence variants 3Close to 100%ClinicalDeletion/duplication analysis 4Partial- and whole-gene deletionsUnknown 61. Percent of individuals with NPC who have at least one identifiable mutation [Greer et al 1999, Yamamoto et al 1999, Park et al 2003] using a mutation scanning testing method.2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.5. Few have been reported; the frequency of such mutations may be rare.6. No large insertions or deletions have been reported in NPC2. Based on the high sensitivity of the NPC2 sequencing test, a screening test for large deletions/duplications may have a very low yield.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyEstablishing the diagnosis in a probandBiochemical testing demonstrating abnormal intracellular cholesterol homeostasis in cultured fibroblasts is the mainstay of diagnosis and may be supported by ultrastructural changes on skin or rectal biopsy.Molecular genetic testing is used primarily to confirm the diagnosis in individuals with variant biochemical findings.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in NPC1 or NPC2.}

Natural HistoryNiemann-Pick disease type C (NPC) may present at any age.Neonatal and infantile presentations. The presentation of NPC in early life is nonspecific and may go unrecognized by inexperienced clinicians. On occasion, ultrasound examination in late pregnancy has detected 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 (pulmonary failure secondary to impaired diffusion).Many infants succumb at this stage. Of those who survive, some are hypotonic and delayed in psychomotor development, whereas others may have complete resolution of symptoms, only to present with neurologic disease many years later. Liver and spleen are enlarged in children with symptomatic hepatic disease; however, children who survive often 'grow into their organs,' so that organomegaly may not be detectable later in childhood. Indeed, many individuals with NPC never have organomegaly. The absence of organomegaly never eliminates the diagnosis of NPC.Another subgroup of children has minimal or absent hepatic or pulmonary dysfunction and presents primarily with hypotonia and delayed development. Children in this group usually do not have vertical supranuclear gaze palsy (VSGP) at the onset but acquire this sign after a variable period, when other evidence of progressive encephalopathy supervenes.Childhood presentations. The classic presentation of NPC is in middle-to-late childhood, with clumsiness and gait disturbance that eventually become frank ataxia. Many observant parents are aware of impaired vertical gaze, which is an early manifestation. VSGP first manifests as increased latency in initiation of vertical saccades, after which saccadic velocity gradually slows and is eventually lost. In late stages of the illness, horizontal saccades are also impaired. The physical manifestations are accompanied by insidiously progressive cognitive impairment, often mistaken at first for simple learning disability. Some children are thought to have primary behavioral disturbances, reflecting unrecognized dyspraxia in some instances. 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 of the 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. Epilepsy may be refractory to medical therapy in some cases. Seizures usually improve if the child's survival is prolonged, this improvement presumably reflecting continued neuronal loss. About 20% of children with NPC have gelastic cataplexy, a sudden loss of muscle tone evoked by a strong emotional (humorous) stimulus. This can be disabling in those children who experience daily multiple attacks during which injuries may occur.Mild demyelinating peripheral neuropathy has been described in a child with otherwise typical late-infantile NPC [Zafeiriou et al 2003]. This finding is likely a rare manifestation of NPC because prospective nerve conduction studies in a cohort of 41 affected individuals participating in a clinical trial of miglustat have identified only one case to date [Patterson 2006, personal communication].Polysomnographic and biochemical studies have demonstrated disturbed sleep and variable reduction in cerebrospinal fluid hypocretin concentration in individuals with NPC, suggesting that the disease could have a specific impact on hypocretin-secreting cells of the hypothalamus [Kanbayashi et al 2003, Vankova et al 2003].Death from aspiration pneumonia usually occurs in the late second or third decade.Adolescent and adult presentations. Adolescents or adults may present with neurologic disease as described in the preceding section, albeit with a much slower rate of progression. The author has seen one individual who survived into the seventh decade, having first developed symptoms 25 years earlier. Older individuals may also present with apparent psychiatric illness [Imrie et al 2002, Josephs et al 2003], sometimes appearing to have major depression or schizophrenia. The psychiatric manifestations may overshadow neurologic signs, although the latter can usually be detected with careful examination. An adult presenting with bipolar disorder has been described [Sullivan et al 2005].A German report describes two individuals with adult-onset dementia associated with frontal lobe atrophy and no visceral manifestations, as is common in adult-onset disease [Klunemann et al 2002].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. Increased signal in the periatrial white matter, reflecting secondary demyelination, may also occur. In one adult, areas of confluent white matter signal hyperintensity mimicked multiple sclerosis [Grau et al 1997].Limited studies of magnetic resonance spectroscopy (MRS) suggest that MRS may be a more sensitive imaging technique in NPC than standard MRI [Tedeschi et al 1998].Heterozygotes. A recent report described an NPC1 heterozygote with tremor that the authors attributed to the mutant allele [Josephs et al 2004]. This observation notwithstanding, the question of manifesting heterozygotes must remain moot pending systematic prospective studies.

Genotype-Phenotype CorrelationsNPC1. In the approximately 200 mutations described in NPC1 [Scott & Ioannou 2004, Fernandez-Valero et al 2005], genotype-phenotype correlation is limited because most affected individuals are compound heterozygotes; and correlation of the trafficking defects demonstrable in culture and the clinical phenotype is poor. Nonetheless, some correlations have been possible for homozygous mutations and the more common mutations in heterozygous state:One international study documented phenotypes associated with a mutation leading to a p.Ile1061Thr change in the Hispanic population in the upper Rio Grande Valley in the southwestern US, and in the UK and France. No individuals with this mutation had the severe infantile form of NPC [Millat et al 1999].More recently, the same group found that premature-termination-codon mutations, mutations involving the sterol-sensing domain, and p.Ala1054Thr in the cysteine-rich luminal loop of NPC1 are associated with early-onset disease and classic biochemical changes [Millat et al 2001b].All mutant alleles that correlate with the biochemical 'variant' phenotype are clustered in the cysteine-rich luminal loop [Millat et al 2001b].A study of 40 unrelated individuals of Spanish descent suggested that those homozygous for the p.Gln775Pro mutation showed a severe infantile neurologic form and those homozygous for the p.Cys177Tyr mutation, a late-infantile clinical phenotype [Fernandez-Valero et al 2005].NPC2. Of the five mutations identified by Millat et al [2001b], all but c.190+5G>A were associated with a severe phenotype, characterized by pulmonary infiltrates, respiratory failure, and death by age four years:The two individuals with splice site mutations had juvenile-onset disease and prolonged survival.Adult-onset disease with frontal lobe atrophy has been described in association with a p.Val39Met mutation in NPC2 [Klunemann et al 2002].Neonatal or infantile onset and death in early childhood were reported in children homozygous for p.Gln45*, p.Cys47*, and p.Cys99Arg, whereas prolonged survival into middle adult life has been seen in those homozygous for p.Val39Met and p.Ser67Pro [Chikh et al 2005].

Differential DiagnosisNeonatal and infantile presentations include 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), and infections (e.g., TORCH). A study from Colorado found that 27% of infants initially diagnosed with idiopathic neonatal cholestasis and 8% of all infants with cholestasis had NPC [Yerushalmi et al 2002]. Although this cohort may have been enriched by a local Hispanic genetic isolate, the importance of Niemann-Pick disease type C (NPC) as a cause of jaundice in infants is appropriately emphasized.Childhood presentations include pineal region or midbrain tumors causing dorsal midbrain syndrome, hydrocephalus, GM2 gangliosidosis, mitochondrial diseases, maple syrup urine disease, attention-deficit disorder, learning disabilities, absence seizures, other dementing illnesses, idiopathic torsion dystonia, dopa-responsive dystonia, Wilson disease, amino acidurias and organic acidopathies (e.g., glutaric aciduria type 1) (see The Organic Acidemias: An Overview), pseudodementia (depressive disorder), neuronal ceroid-lipofuscinosis, subacute sclerosing panencephalitis (see Mitochondrial DNA-Associated Leigh Syndrome and NARP), HIV encephalopathy, sleep disorders, syncope, and periodic paralysis (see Hyperkalemic Periodic Paralysis Type 1, Hypokalemic Periodic Paralysis).Adolescent and adult presentations include Alzheimer disease, Pick disease (an adult-onset disorder with dementia associated with characteristic neuronal inclusions called Pick bodies, not related to Niemann-Pick disease), frontotemporal dementias, Steele-Richardson-Olzewski syndrome (also known as progressive supranuclear palsy), late-onset lysosomal storage diseases, syphilis, HIV dementia, and primary psychiatric illnesses.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Niemann-Pick disease type C (NPC), the following evaluations are recommended:Assessment of ability to walk and transfer, manage secretions, and communicate (language, speech, and hearing)For individuals with hepatosplenomegaly, complete blood count and tests of hepatic function.MRI of the head; usually performed in the course of the workup and usually normal until the disease is advancedConsideration of EEG and sleep studies if the history suggests seizures or sleep disturbancesTreatment of ManifestationsNo definitive therapy for NPC exists.Symptomatic therapy may be at least partially effective in the management of seizures, dystonia, and cataplexy.If disordered sleep is identified, a nocturnal sedative may be indicated. In complex cases, formal evaluation by a sleep specialist should be considered.Bronchoalveolar lavage has been described as effective in improving function in one child with pulmonary infiltrates [Palmeri et al 2005].General supportive care, including respite for primary caregivers, is crucial to the maintenance of the family unit in the face of this devastating illness.Prevention of Secondary ComplicationsChest physical therapy with aggressive bronchodilation and antibiotic therapy for intercurrent infection appears beneficial, although no systematic study has been performed.Individuals whose mobility is compromised should have a regular bowel program to prevent severe constipation, which may present as increased seizure frequency or increased spasticity in some impaired individuals with NPC.Physical therapy is indicated to maintain mobility as long as possible.Swallowing must be monitored to allow consideration of gastrostomy tube placement when aspiration or nutritional compromise is imminent.SurveillanceGeneral pediatric evaluations, with special attention to pulmonary function, swallowing, bowel habit, and mood (for occult depression) at six-month intervals are appropriate for most juvenile and adult affected individuals. Sleep disturbances are common in NPC; the affected individual or caregiver should be questioned regarding sleep hygiene as a part of regular evaluation.Annual psychometric testing may be helpful in arranging appropriate school or work placement.Teenagers and adults with motor or sensory impairments who are driving should be monitored at six- to 12-month intervals to ensure that they do not present a risk to themselves or others.Agents/Circumstances to AvoidDrugs that cause excessive salivation or that may exacerbate seizures directly by interacting with antiepileptic drugs should be avoided.Alcohol as well as many drugs exacerbate ataxia and should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationInhibition of glycosphingolipid synthesis by n-butyldeoxynojirimycin has been shown to delay onset and prolong survival in a murine model of NPC [Zervas et al 2001], and a therapeutic trial of the same agent is presently in progress in humans. Preliminary data show evidence of stabilization or benefit in some individuals [Patterson et al 2007].Recent laboratory studies of cellular and murine models of NPC raise the possibility of small-molecule therapies to interdict pathways triggering apoptosis and related routes to cell death and dysfunction [Patterson & Platt 2004].Preliminary studies of neurosteroid replacement therapy with allopregnenolone in NPC mice suggest similar improvements in survival to those seen with n-butyldeoxynojirimycin, provided that the steroid is administered early in postnatal life [Mellon & Griffin 2002]. Confirmatory studies are in progress [Mellon et al 2008].Studies in tissue culture have demonstrated that direct or indirect over-expression of the GTPase Rab 9 reverses the NPC phenotype [Choudhury et al 2002, Walter et al 2003]. Although not yet applicable in human trials, this finding suggests the existence of alternate pathways for mobilization of endosomal cargoes that are potential targets for small-molecule therapies.Screening of a library of more than 44,000 compounds led to identification of a compound that corrects the NPC phenotype in cell culture [Liscum et al 2002]. It is not known if further development of this compound as a potential therapy is planned.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherIn the C57 murine model of NPC, all treatment modalities, including bone marrow transplantation, combined bone marrow and liver transplantation, and aggressive cholesterol-lowering therapy, have proven ineffective.Although a trial of cholesterol-lowering agents showed that the amount of free cholesterol in the liver of individuals with NPC could be reduced by the administration of cholestyramine, lovastatin, and nicotinic acid [Patterson et al 1993], there is no evidence that this approach modifies the neurologic progression of NPC.Liver transplantation in humans corrects hepatic dysfunction but does not ameliorate the neurologic disease.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Niemann-Pick Disease Type C: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNPC118q11​.2Niemann-Pick C1 proteinNPC1 homepage - Mendelian genes
NPC-dbNPC1NPC214q24​.3Epididymal secretory protein E1NPC2 homepage - Mendelian genes
NPC-dbNPC2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Niemann-Pick Disease Type C (View All in OMIM) View in own window 257220NIEMANN-PICK DISEASE, TYPE C1; NPC1 601015NPC2 GENE; NPC2 607623NPC1 GENE; NPC1 607625NIEMANN-PICK DISEASE, TYPE C2Molecular Genetic PathogenesisThe central defect in NPC is in intracellular trafficking of lipids, as opposed to the lysosomal hydrolase deficiency characteristic of the classic lysosomal storage diseases (LSDs). Notwithstanding, all LSDs are marked by the accumulation of multiple lipid species in the lysosomes, and secondary trafficking impairment occurs in disorders with primary hydrolase deficiencies. In NPC, cholesterol accumulates in great excess in the lysosomes and may lead to a deficiency in membrane cholesterol. Given the critical role of cholesterol in maintaining membrane order, this downstream deficiency could conceivably play a role in membrane dysfunction, and possibly in the triggering of apoptosis [Mukherjee & Maxfield 2004].Glysosphingolipid accumulation is characteristic of the neuropathology of NPC; animal studies have demonstrated that GM2 accumulation is associated with ectopic dendritogenesis and meganeurite formation, which — together with the formation of neurofibrillary tangles (cholesterol dysregulation) and neuroaxonal dystrophy — are likely anatomic substrates for neurologic dysfunction [Walkley & Suzuki 2004].Trafficking studies suggest that NPC2 binds cholesterol in the luminal space of the late-endosome/lysosome and transports it to the delimiting membrane. NPC resides in the membrane of the late endosomes and is shuttled between that compartment and the plasma membrane and other internal sites. It remains to be determined how these two molecules interact, how they sense the presence and concentration of lipids, and why NPC1 accompanies its vesicular cargo to its destination [Liscum & Sturley 2004].NPC1Normal allelic variants. NPC1 contains 25 exons, varying in size from 74 to 788 bp, spread over 47 kb [Morris et al 1999]. More than 50 exonic polymorphisms have been described; the most prevalent are listed in Table 2 [Millat et al 2005].Pathologic allelic variants. Approximately 200 mutations have been described in NPC1 [Scott & Ioannou 2004, Fernandez-Valero et al 2005].A study of 143 unrelated individuals with NPC identified 121 different mutations in 251 of 286 disease alleles, an overall detection rate of 88% [Park et al 2003]. Cases negative for mutations showed a high proportion of equivocal results in complementation studies, raising the possibilities of (1) a third complementation group for NPC or (2) nonspecificity of NPC biochemical testing. The region between amino acids 1038 and 1253 (which includes the Patched 1 domain) and the region in amino acids identical to the NPC1 homolog NPC1L1 were hot spots for mutations.Most affected individuals are compound heterozygotes for point mutations producing missense (~70% of mutations overall) [Millat et al 2005] and nonsense mutations; deletions and splice site mutations have also been reported.A mutation leading to a p.Gly992Trp change has been identified in several individuals in the Acadian population of Nova Scotia [Greer et al 1998] and in Portugal; a p.Gly992Arg mutation has been described in France [Fernandez-Valero et al 2005] (Table 2).A Spanish report found that individuals homozygous for the p.Gln775Pro mutation had a severe infantile neurologic illness, and those with the p.Cys177Tyr mutation had a late-infantile clinical phenotype [Fernandez-Valero et al 2005].The p.Ile1061Thr mutation accounts for 15%-20% of mutated alleles in Western Europe and the US, followed by p.Pro1007Ala [Millat et al 2005].Table 2. Selected NPC1 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesNormalc.709C>Tp.Pro237SerNM_000271​.3
NP_000262​.1c.1926C>Gp.Ile642Metc.2572A>Gp.Ile858Valc.2793C>Tp.Asn93c.3797G>Ap.Arg1266GlnPathologicc.530G>Ap.Cys177Tyrc.2324A>Cp.Gln775Proc.2974G>Tp.Gly992Trpc.2974G>Cp.Gly992Argc.2974G>Ap.Gly992Argc.3019C>Gp.Pro1007Alac.3160G>Ap.Ala1054Thrc.3182T>Cp.Ile1061ThrSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The NPC1 protein product is an integral membrane protein with 13 transmembrane domains, which appears to be localized to a late endosomal compartment. Its function is as yet imperfectly understood, but it clearly plays a central role in modulating intracellular sorting of cholesterol and glycosphingolipids [Neufeld et al 1999]. Wojtanik and Liscum [2003] have shown that in the cells of individuals with NPC1, LDL cholesterol traffics directly through endosomes to lysosomes, bypassing the plasma membrane, and is trapped there because of dysfunctional NPC1. NPC1 appears to serve this function, at least in part, by maintaining the small size of cholesterol-containing lipid droplets in the cell [Wiegand et al 2003]. Strauss et al [2002] have suggested that NPC1 may act cooperatively with NPC2 and MLN64 in an ordered sequence to effect intracellular sterol movement. Sterol storage in fibroblasts correlates with oxysterol levels; administration of oxysterols corrects the phenotype in cells with the p.Ile1061Thr mutation, suggesting that NPC1 and NPC2 regulate intracellular sterol homeostasis via oxysterols [Frolov et al 2003]. Domains 3-7 of the NPC1 protein have homology to the sterol-sensing domains of SCAP and HMG CoA reductase, and other domains are homologous to the Drosophila morphogen patched [Carstea et al 1997]. Studies in cultured fibroblasts have shown that specific point mutations in the sterol-sensing domain can induce either loss of function (p.Pro692Ser) or gain of function (p.Asp787Asn, p.Leu657Phe) in trafficking to the plasma membrane and ER [Millard et al 2005]. The overrepresentation of pathogenic mutations in these domains further emphasizes their key roles in the function of the protein (see NPC1, Pathologic allelic variants). NPC1 appears to mediate fatty acid transport in E. coli; but this is not the case in human NPC fibroblasts, where fatty acid trafficking is normal [Passeggio & Liscum 2005].Abnormal gene product. Deficiency of the NPC1 gene product leads to a complex pattern of intracellular lipid storage, including excess unesterified cholesterol, GM2 and GM3 gangliosides, lactosylceramide, glucosylceramide, and lysobisphosphatidic acid. The accumulation of these substrates is thought to reflect impaired intracellular trafficking mediated by the NPC1 and NPC2 proteins respectively [Watari et al 1999, Liscum & Sturley 2004, Mukherjee & Maxfield 2004].NPC2Normal allelic variants. NPC2 has five exons and a single transcript of 0.9 kb in all tissues. It has been mapped to 14q24.3 [Chikh et al 2004].Pathologic allelic variants. Two individuals were originally described with mutations in NPC2 [Naureckiene et al 2000]. One individual was homozygous for c.58G>T in exon 1, and the other was a compound heterozygote for c.58G>T and c.332delA. A comprehensive study of eight families with NPC2 found five mutations in the 16 mutant alleles identified (p.Glu20*, p.Glu118*, c.27delG, c.190_5G>A, p.Ser67Pro) [Millat et al 2001a]. Except for c.27delG, the mutations were all homozygous. More recent studies have identified a total of 13 disease-causing mutations, including five missense mutations and six that code for a premature stop codon [Chikh et al 2005].Table 3. Selected NPC2 Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.58G>Tp.Glu20*NM_006432​.3
NP_006423​.1c.115G>Ap.Val39Metc.133C>Tp.Gln45*c.141C>Ap.Cys47*c.199T>Cp.Ser67Proc.295T>Cp.Cys99Argc.332delAp.Asn111Ilefs*5c.352G>Tp.Glu118*c.27delGp.Ala12Argfs*23c.190+5G>A
(IVS2+5G>A)--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The NPC2 protein product is a 132-amino acid glycoprotein that is expressed in all tissues examined, with the highest concentrations being found in epididymal fluid as well as in testis, kidney, and liver. NPC2 protein is soluble, binds cholesterol, and is able to partially reverse the lipid accumulation in NPC2 fibroblasts when added to the medium in culture. Added NPC2 has no effect on NPC1 fibroblasts in culture [Naureckiene et al 2000]. Different isoforms varying from 19 to 23 kd are distributed in a tissue-specific fashion, reflecting variable glycosylation [Vanier & Millat 2004]. Only the Asn58 residue needs to be glycosylated to ensure accurate targeting. NPC2 protein binds the mannose-6-phosphate receptor, and, in contrast, is not dependent on the presence of cholesterol for lysosomal targeting. NPC2 mainly colocalizes with LAMP1 but is also distributed to LAMP1-negative organelles [Vanier & Millat 2004].