Niemann-Pick Disease Type C

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2019-12-14
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Summary

Clinical characteristics.

Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.

Diagnosis/testing.

The diagnosis of NPC is confirmed by biochemical testing that demonstrates impaired cholesterol esterification and positive filipin staining in cultured fibroblasts. Biochemical testing for carrier status is unreliable. Most individuals with NPC have NPC1, caused by pathogenic variants in NPC1; fewer than 20 individuals have been diagnosed with NPC2, caused by pathogenic variants in NPC2. Molecular genetic testing of NPC1 and NPC2 detects pathogenic variants in approximately 94% of individuals with NPC.

Management.

Treatment of manifestations: Symptomatic therapy for seizures, dystonia, and cataplexy; a nocturnal sedative to help disordered sleep; physical therapy to maintain mobility as long as possible.

Prevention of secondary complications: Chest physical therapy with aggressive bronchodilation and antibiotic therapy of intercurrent infection; regular bowel program for mobility-impaired individuals to prevent severe constipation and resulting increased seizure frequency and/or increased spasticity.

Surveillance: Swallowing is monitored to allow placement of a gastrostomy tube when aspiration or nutritional compromise is imminent.

Agents/circumstances to avoid: Drugs that cause excessive salivation or that may exacerbate seizures by interacting with antiepileptic drugs; alcohol and other drugs that may exacerbate ataxia.

Genetic counseling.

NPC is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The phenotype (i.e., age of onset and severity of symptoms) usually runs true in families. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.

Diagnosis

Clinical Diagnosis

The 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 infiltrates
  • Infantile hypotonia without evidence of progression for months to years, followed by features outlined in Brady et al [1989]; see VSGP (following)
  • Vertical supranuclear gaze palsy (VSGP), 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 adulthood
  • Enlargement of the liver or spleen, particularly in early childhood

A quantitative scoring system that weights the manifestations of NPC has been developed to assist clinicians in selecting appropriate individuals for further laboratory investigation [Wijburg et al 2012].

Testing

Biochemical. 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].

Oxysterol measurement is likely to replace skin biopsy and will likely prove to be a robust first-line screening and diagnostic test for NPC in the future [Porter et al 2010, Jiang et al 2011].

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 Testing

Genes. 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.

Table 1.

Molecular Genetic Testing Used in Niemann-Pick Disease Type C

Gene 1Proportion of NPC Attributed to Mutation of This Gene 2MethodVariants Detected 3Variant Detection Frequency by Gene and Method 4
NPC190% 5Sequence analysis 6Sequence variants80%-90% 7
Deletion/duplication analysis 8Partial- and whole-gene deletionsUnknown 9
Targeted analysis for pathogenic variantsVary panels differ by laboratoryVary 10
NPC24%Sequence analysis 6Sequence variantsClose to 100%
Deletion/duplication analysis 8Partial- and whole-gene deletionsUnknown; none reported 11
Targeted analysis for pathogenic variantsVariant panels differ by laboratoryVary
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

Percent of individuals with NPC who have at least one identifiable pathogenic variant [Greer et al 1999, Yamamoto et al 1999, Park et al 2003] using a variant scanning testing method

3.

See Molecular Genetics for information on allelic variants.

4.

The ability of the test method used to detect a variant that is present in the indicated gene

5.

Detection rates using sequence analysis may be comparable to those found using scanning for pathogenic variants, which has identified NPC1 variants in 90% of affected individuals [Park et al 2003, Patterson et al 2012].

6.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7.

Most individuals with NPC1 are compound heterozygotes with pathogenic variants unique to their family; to date, pathogenic variants 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].

8.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9.

Few have been reported; the frequency of such variants may be rare.

10.

Of note, individuals with NPC1 from Nova Scotia (previously said to have Niemann-Pick type D) almost uniformly have the p.Gly992Trp variant [Greer et al 1998].

11.

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.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Biochemical 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 pathogenic variants 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 (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Niemann-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, personal communication (2006)].

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 [Walterfang et al 2012b].

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 [Klünemann 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]. Quantitative MRI studies in adults with NPC have found widespread gray and white matter abnormalities [Walterfang et al 2010], and reduction in callosal volume as the disease progresses [Walterfang et al 2011]. In addition, the pontine:midbrain ratio correlates with oculomotor function and disease severity [Walterfang et al 2012a].

Studies of magnetic resonance spectroscopy (MRS) suggested that MRS may be a more sensitive imaging technique in NPC than standard MRI [Tedeschi et al 1998]. A French group has reported improvement in MRS parameters with miglustat therapy [Galanaud et al 2009].

Heterozygotes. A recent report described an NPC1 heterozygote with tremor that the authors attributed to the mutated allele [Josephs et al 2004]. This observation notwithstanding, the question of manifesting heterozygotes must remain moot pending systematic prospective studies.

Genotype-Phenotype Correlations

NPC1. In the approximately 200 pathogenic variants 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 variants and the more common variants in heterozygous state:

  • One international study documented phenotypes associated with a pathogenic variant 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 pathogenic variant had the severe infantile form of NPC [Millat et al 1999].
  • More recently, the same group found that premature-termination-codon variants, variants 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 mutated 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 pathogenic variant showed a severe infantile neurologic form and those homozygous for the p.Cys177Tyr pathogenic variant, a late-infantile clinical phenotype [Fernandez-Valero et al 2005].

NPC2. Of the five pathogenic variants 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 variants had juvenile-onset disease and prolonged survival.
  • Adult-onset disease with frontal lobe atrophy has been described in association with a p.Val39Met variant in NPC2 [Klünemann et al 2002].
  • Neonatal or infantile onset and death in early childhood were reported in children homozygous for p.Gln45Ter, p.Cys47Ter, 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].

Nomenclature

The older literature on NPC is bedeviled by the large number of terms used to describe individuals now known to have the disease. These include juvenile dystonic idiocy, juvenile dystonic lipidosis, juvenile NPC, neurovisceral lipidosis with vertical supranuclear gaze palsy, Neville-lake disease, sea-blue histiocytosis, lactosylceramidosis, and DAF (downgaze paralysis, ataxia, foam cells) syndrome.

The term Niemann-Pick disease type D describes a genetic isolate from Nova Scotia that is biochemically and clinically indistinguishable from NPC and that also results from mutation of NPC1.

The terms NPC1 and NPC2 are now preferred because they accurately describe the mutated genes responsible for the phenotype.

Prevalence

The prevalence of NPC has been estimated at 1:150,000 in western Europe. The incidence of NPC in France has been calculated at about 1:120,000, based on the number of postnatally diagnosed cases in a ten-year period versus the number of births during that same time period. When prenatal cases that did not result in a live-born infant were included, a slightly higher incidence of 1:100,000 was found [Vanier 2010]. The prevalence of NPC in early life is probably underestimated, owing to its nonspecific presentations. The overall prevalence is likely higher than the calculated incidence, owing to relatively prolonged survival in those with later-onset disease, although no comprehensive data are available.

Acadians in Nova Scotia, individuals of Hispanic descent in parts of Colorado and New Mexico, and a Bedouin group in Israel represent genetic isolates with a founder effect.

Differential Diagnosis

Neonatal 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), 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.

Management

Clinical management guidelines for Niemann-Pick C have been published [Patterson et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 advanced
  • Consideration of EEG and sleep studies if the history suggests seizures or sleep disturbances
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No curative 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 Complications

Chest 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.

Surveillance

General pediatric evaluations, with special attention to pulmonary function, swallowing, bowel habit, and mood (for occult depression), are appropriate at six-month intervals 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 Avoid

Drugs 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Inhibition of glycosphingolipid synthesis by n-butyldeoxynojirimycin has been shown to delay onset and prolong survival in both murine and feline models of NPC [Zervas et al 2001, Stein et al 2012]. A prospective trial of the same agent showed evidence of stabilization or benefit in some individuals [Patterson et al 2007]. Subsequent clinical studies have supported a role of miglustat in stabilizing NPC [Pineda et al 2009, Wraith & Imrie 2009, Patterson et al 2010, Pineda et al 2010, Wraith et al 2010, Fecarotta et al 2011, Di Rocco et al 2012, Héron et al 2012, Chien et al 2013]. The agent has been approved for the management of neurologic manifestations of NPC in several countries, not including the United States.

Laboratory studies of cellular and murine models of NPC have raised the possibility of small-molecule therapies to interdict pathways triggering apoptosis and related routes to cell death and dysfunction [Patterson & Platt 2004]; to date, these have not proceeded to clinical trials.

Preliminary studies of neurosteroid replacement therapy with allopregnanolone in NPC mice suggested similar improvements in survival to those seen with n-butyldeoxynojirimycin, provided that the steroid is administered early in postnatal life [Mellon & Griffin 2002]. Subsequent studies have shown that the active agent was the vehicle, hydroxypropyl beta cyclodextrin, which has shown dramatic effects in the murine model of NPC [Abi-Mosleh et al 2009, Davidson et al 2009, Ramirez et al 2010, Rosenbaum et al 2010, Ward et al 2010, Vance & Peake 2011, Peake & Vance 2012].

Studies in tissue culture have demonstrated that direct or indirect overexpression 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.

Treatment of certain NPC fibroblast cell lines with an HDAC inhibitor produced marked reduction of cholesterol storage [Pipalia et al 2011]; a clinical trial is being considered.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

In 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.