Niemann-Pick Disease, Type C (Supraoptic Vert Ophthalmopleg)

Niemann-Pick disease type C is a neurovisceral disorder caused by mutations in two genes that encode for proteins involved in intracellular lipid trafficking. Consequently, a broad range of lipids is stored in endosomes and lysosomes. Symptom onset usually occurs in childhood.

Presentation

In about half of all patients, neonatal cholestatic icterus and progressive hepatosplenomegaly are the initial signs of NPC [11]. They manifest shortly after birth and commonly resolve spontaneously within a few months, although hepatosplenomegaly may also persist for variable periods of time. Hepatic insufficiency may cause hydrops fetalis. Patients may also develop respiratory insufficiency due to pulmonary infiltration with foam cells, and this symptom has been proposed to indicate NPC2 mutations. Few patients die from liver failure or respiratory failure before developing any neurological symptoms. These patients are sometimes diagnosed with acute neonatal NPC, but there is no consensus regarding this classification. In general, the following forms of the disease are distinguished:

  • Onset of neurological symptoms in early infancy, i.e., in patients aged two months to two years. Parents may claim their children not to reach motor developmental milestones. Upon physical examination, generalized hypotonia may be identified as a clinical manifestation of this disease. Furthermore, neurological examination usually reveals vertical supranuclear gaze palsy and abnormal saccadic eye movements. As the disease progresses, neurological symptoms worsen. Patients may develop spasticity and impaired motor skills.
  • In late infancy (generally defined as age two to six years), children are already able to walk. Accordingly, neurological deficits result in ataxia, frequent falls and general clumsiness. Additionally, dysarthria, dysphagia, cataplexy and seizures may be noted. Gaze palsies are similar to those observed in younger patients. Hearing impairment is not uncommon. A cognitive decline is more readily observable in this form of the disease than in early infantile NPC [12].
  • Juvenile NPC is the classic form of the disease. Onset of neurological symptoms is at six to 15 years. Dystonia causes ataxia, and dysarthria and dysphagia constitute both physical and psychological burdens. Cataplexy, seizures and gaze palsies may also be observed. Patients often present with learning disability, problems concentrating and paying attention, and behavioral disorders.
  • Psychiatric symptoms and dementia usually predominate adult-onset NPC. Dystonia, ataxia, dysarthria and dysphagia are also common while cataplexy, seizures and gaze palsy are rare.

Workup

Thorough anamnesis and physical examination may prompt a suspicion of NPC if the treating physician is aware of the disease. In fact, NPC has repeatedly been mistaken for idiopathic diseases because it never entered the list of potential diagnoses [11]. The examination of an NPC patient should comprise general, neurological and ophthalmological studies. Patients are to be tested for motor reflexes, muscle tone, strengths, movements of eyes, head, arms and legs, and cognitive development. Functional tests yield more conclusive results than neuroimaging studies, since the latter often only reveal non-specific symptoms like leukodystrophy or atrophy of brain structures.

Histopathological analysis may further support a tentative diagnosis of NPC. In this context, staining of cultured fibroblasts with filipin is generally considered to be most specific. Fibroblasts are obtained from skin biopsy specimens. In about 80% of NPC patients, intense fluorescence reflects cholesterol enrichment. Of note, the absolute intensity of fluorescence does not necessarily correlate with disease severity [13].

Detection of NPC1 or NPC2 mutations are diagnostic of the disease, but genetic screens are complicated by the size of NPC1 and the fact that several gene variants have been associated with the disease. Thus, caution has to be taken when ruling out NPC based on such diagnostic measures. Target-oriented genetic studies are of great value though to identify carriers in affected families, and can also be employed in prenatal diagnostics.

Treatment

To date, N-butyldeoxynojirimycin is the only drug approved for NPC treatment [14]. It is commonly known as miglustat and has been shown to delay neurodegeneration [15]. Thus, life quality can be maintained for longer periods of time and the risk of mortality due to neurological deficits like dysphagia is reduced. The compound's efficacy is highest in patients suffering from adult-onset NPC. Its effects are mediated by an inhibition of glycosphingolipid synthesis.

Few studies indicate possible benefits of other compounds, e.g., of hydroxypropyl-β-cyclodextrin and acetyl-dl-leucine [16] [17]. The former may enhance clearance of cholesterol and other lipids accumulated in endosomes and lysosomes, which may possibly contribute to prolonging life expectancy. Application of acetyl-dl-leucine improves the patient's quality of life and reduces ataxia.

Prognosis

NPC is a progressive disorder and currently, no effective treatment is available. NPC leads to premature death, and the life expectancy of an individual patient depends on their age at the onset of neurological symptoms. If NPC manifests in early infancy, death usually occurs before the patient reaches the age of five. Onset in late infancy is associated with death before puberty, whereas patients diagnosed with juvenile NPC may live beyond the age of 30 [10]. The most common cause of death is aspiration pneumonia due to dysphagia.

Etiology

NPC is a genetic disorder inherited with an autosomal recessive trait. It may be provoked by mutations in either of two genes that have been named after their association with the disease, namely NPC1 and NPC2. About 95% of NPC patients show NPC1 mutations, the remainder tests positive for dysfunctional NPC2 variants [3]. NPC1 is located on the long arm of chromosome 18, NPC2 is situated on the long arm of chromosome 14. Both gene products are involved in lipid trafficking:

  • Lipids are released from low-density lipoproteins in the lumen of endosomes and lysosomes, and bind to the small soluble protein encoded by NPC2. This protein carries the lipids to a membrane-bound transporter.
  • This transporter consists of a large glycoprotein with 13 putative membrane-spanning domains and is encoded by NPC1. It mediates the egress of cholesterol and other lipids through the membrane bilayer of endosomes and lysosomes.

Because NPC1 and NPC2 are part of the same pathway, dysfunction of either of both proteins leads to the disruption of a single chain of events. Consequently, mutations of both genes ensue the same consequences, namely the accumulation of lipids in late endosomes and lysosomes. In detail, unesterified cholesterol, sphingomyelin, glycolipids, free sphingosine and sphinganine accumulate in liver and spleen, and glycosphingolipids predominate in the central nervous system [4].

Epidemiology

The overall incidence of NPC has been calculated to be minimum 1 in 120,000 live births [2]. However, this likely is an underestimation since considerable shares of rapidly fatal infantile cases are assumed to remain undiagnosed. Gender and racial predilections have not been reported so far, but it may be assumed that incidence rates are higher in ethnic groups of increased consanguinity [5] [6].

Classical NPC corresponds to the juvenile onset form, which is less severe than early and late infantile-onset NPC. Still, NPC may be diagnosed at any age. Early infantile NPC usually manifests within the first few months of life, and in late infantile NPC, symptom onset may be delayed until children attend school. Patients who develop first symptoms in childhood or puberty are diagnosed with juvenile NPC, and adults may present with mild forms of the disease until beyond their fifties.

Sex distribution
Age distribution

Pathophysiology

NPC is a lysosomal storage disease, i.e., lipids accumulate within endosomes and lysosomes, which causes progressive enlargement of those cell organelles. Histopathologically, marked cytoplasmic vacuolization becomes apparent. Eventually, enlarged organelles may mechanically interfere with cell and tissue function. Moreover, defective organelles no longer fulfill their function with regards to cellular metabolism, and lipids that are retained in endosomes and lysosomes are not available for biosynthetic pathways that functionally depend on these molecules. Under physiological conditions, cholesterol is exported from endosomes and lysosomes, and is subsequently transported to the endoplasmic reticulum (ER) and the plasma membrane. In this context, depletion of cholesterol in ER membranes has been shown to hinder the transport of secretory membrane proteins from this cell organelle to the Golgi apparatus [7].

With regards to the involvement of organ systems, development of neurological deficits is most characteristic of NPC. Neurons are directly affected by disruption of lipid trafficking and primarily accumulate glycosphingolipids like gangliosides GM2 and GM3 instead of unesterified cholesterol. In fact, cholesterol contents of brain tissues decreases with age in NPC patients [8]. The precise mechanism underlying this observation are poorly understood. Differences between neurological and non-neurological consequences of NPC may be partially explained by the isolation of the CNS behind the blood-brain barrier. Nevertheless, several aspects imply a pathogenetic role of cholesterol in the CNS, wherein the majority of cholesterol is contained in myelin, and late myelination occurs during the first few weeks of life. This scenario is consistent with severe, early infantile NPC. Histopathological analysis of tissue samples obtained from NPC patients reveals swollen somata and neuronal loss [9].

Prevention

NPC is inherited following an autosomal recessive mode. It may be challenging to identify the precise gene defect in an individual patient, but if successful, their family members may be tested for that same gene variant. Similar tests may also be conducted prenatally [18]. Both chorionic villus sampling and amniocentesis may be carried out to this end, with the former assumed to yield better results. In contrast, population-wide screens to identify carriers of NPC1 or NPC2 mutations are not feasible due to the complex sequence of NPC1 and high costs.

Studies regarding treatment of NPC with drugs like miglustat are still in its very early stages and to date, no recommendations can be given regarding the administration of such compounds to prevent the onset of neurological symptoms in patients known to be affected by the disease.

Summary

Niemann-Pick disease type C (NPC) is a lysosomal storage disease. It has first been described by Crocker and Farber, who proposed to distinguish NPC from other forms of Niemann-Pick disease due to distinct clinical and histopathological features [1].

NPC is inherited with an autosomal recessive trait and is caused by mutations in the NPC1 or NPC2 genes. Both genes encode for proteins involved in intracellular lipid transport. Thus, in case of functional deficits of those proteins crucial for lipid trafficking, cholesterol and other lipids cannot be exported from late endosomes and lysosomes leading to accumulation within these cell organelles. Eventually, this metabolic disorder may interfere with cell, tissue and organ function. In NPC patients, degeneration of the central nervous system (CNS) is the main manifestation of symptoms. However, lipid accumulation is by no means restricted to the CNS and NPC is generally deemed as a neurovisceral disorder.

Progressive neurodegeneration and hepatosplenomegaly are the hallmarks of NPC. However, the age of patients at symptom onset varies and is related to certain predominant neurological deficits. Accordingly, distinct forms of NPC have been defined [2].:

  • Early infantile NPC, development of motor skills is delayed
  • Late infantile, gait disorders result in frequent falls
  • Juvenile, clinically similar to the late infantile form, patients may not be able to cope with school
  • Adult, often marked by psychiatric disorders and ataxia

All forms of NPC are associated with progressive neurodegeneration and premature death, wherein treatment options are highly restricted. An early onset of neurological symptoms usually indicates an increased severity of the disease.

Patient Information

Niemann-Pick disease (NPC) type C is a rare genetic disorder. Due to mutations in genes NPC1 or NPC2, intracellular lipid trafficking is disturbed. NPC1 and NPC2 encode for proteins that bind and transport cholesterol and other lipids, and if these proteins are dysfunctional, lipids accumulate within cell organelles known as lysosomes. Virtually every tissue in the human body depends on lipid metabolism, since molecules like cholesterol are part of the cellular plasma membranes. Accordingly, multiple organs may be affected by NPC. Indeed, the majority of patients initially develops jaundice and hepatosplenomegaly, while neurological symptoms dominate the clinical picture during later stages of the disease. Jaundice and hepatosplenomegaly usually develop shortly after birth, but the onset of neurological deficits may be delayed until adulthood. Depending on the age at symptom onset, delayed development of motor skills, gait disturbances, frequent falls, problems speaking and eating, seizures and psychiatric disorders may indicate NPC. The disease is associated with progressive neurodegeneration and to date, few drugs are available to delay that pathophysiological process. Unfortunately, mortality is high, particularly if neurological symptoms manifest in infancy.

Self-assessment

References

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