**1. Introduction**

#### **1.1. Etiology**

Niemann-Pick disease type C (NPD-C) is a rare autosomal recessive disorder characterized by lysosomal lipid storage in which faulty intracellular lipid transport leads to accumulation of unesterified cholesterol and glycosphingolipids in several neurovisceral tissues [1, 2].

**1.3. Clinical presentation and symptoms of Niemann-Pick disease**

bances as major depression, schizophrenia, or bipolar disorder [4].

be referred to as psychiatric team and special schooling [8, 9].

or hematopoietic stem cell transplantation.

is highly variable.

with neurologic disease many years later [4].

third of patients develop seizures [4].

**1.4. Previous treatments employed**

disorder [10].

Systemic involvement of liver, spleen, or lung, is present in ≥85% of patients, and precedes the development of neurologic symptoms. The age of onset and clinical presentation of NPD-C

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

http://dx.doi.org/10.5772/intechopen.71970

97

*Neonatal and infantile presentations*: Occasionally, ultrasound examination in late pregnancy has detected fetal ascites; infants thus identified typically have a severe neonatal liver disease with jaundice and persistent ascites. Infiltration of the lungs with foam cells can be present. Many infants die at this stage. Of children who survive, many have hypotonia and psychomotor retardation whereas others may have complete resolution of symptoms, only to present

*Childhood presentations*: These patients typically have cerebellar involvement characterized by clumsiness and gait problems progressing to frank ataxia and slow cognitive deterioration Vertical supranuclear ophthalmoplegia is another early manifestation. Progressive dystonia, dysarthria, and dysphagia occur, eventually impairing oral feeding, and approximately one-

*Adolescent and adult presentations*: The clinical presentation is similar to childhood onset with ataxia, supranuclear vertical gaze palsy, cognitive impairment, except that progression is generally much slower. Other adults present with cognitive dysfunction or psychiatric distur-

There is no curative treatment for NPD-C. The disease management is individualized and it consists mainly of symptomatic treatment. Seizures, dystonia, and cataplexy can respond to drugs. Other symptomatic measures like physiotherapy in spasticity, gastrostomy tube placement to prevent aspiration and/or inadequate nutrition in patients with progressive dysphagia, and bronchoalveolar lavage to improve pulmonary function are useful in the disease management. Combination of drug regimens have been shown to lower hepatic and plasma cholesterol but there is no evidence that these results affect the progression of the disease in humans or murine models. Behavioral and speech problems or schooling difficulties should

To date, miglustat is the only disease-specific drug approved in Europe, Canada, and Japan. The drug works by inhibiting the glucosylceramide synthase enzyme that is responsible for the first step in the synthesis of most glycosphingolipids. Miglustat has shown to stabilize key parameters of neurological disease progression in patients of all ages, but it has no effect on the systemic manifestations or intracellular cholesterol accumulation associated with this

There is a persistent search for new treatments to prevent or slow down the progression of NPD-C. Investigational therapies in course are 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD)

NPD-C is caused by mutations in either the *NPC1* or *NPC2* genes. The *NPC1* gene, located on the long arm of chromosome 18 (18q11.2), encodes a large (142 kDa) membrane glycoprotein placed in endosomes and lysosomes. This protein mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. *NPC2* gene, located on the long arm of chromosome 14 (14q24.3), encodes a small (16 kDa) lysosomal protein that binds to cholesterol. NPC1 and NPC2 proteins seem to act in the cooperative transportation of molecules within cells. Recently, it has been shown, the N-terminal domain of NPC1 protein may interact with NPC2 protein to facilitate cholesterol efflux from the late endosome and lysosomes [3, 4].

The majority of patients show mutations in the *NPC1* gene (95%), whereas a much smaller number suffer mutations in the *NPC2* gene, but the resulting phenotypes are clinically indistinguishable. Loss of function of either of these proteins results in an accumulation of cholesterol and other lipids, including sphingomyelin, sphingosine, and gangliosides (GM2 and GM3), within the endosomes and lysosome [3, 4].

#### **1.2. Diagnosis**

The diagnosis of NPD-C requires a combination of clinical, cellular, and molecular criteria. NPD-C is suspected on the basis of the clinical features. Systemic manifestations such as hepatosplenomegaly neonatal, cholestatic jaundice, or splenomegaly can lead to diagnosis, but, due to the heterogeneous clinical phenotype, diagnosis is often delayed for many years or missed altogether [4]. A Suspicion Index tool might be useful as a screen for NPD-C, a risk prediction score ≥70 indicates a strong suspicion for NPD-C [5]. The diagnosis of NPD-C is confirmed by biochemical testing that demonstrates impaired cholesterol esterification and positive filipin staining in cultured fibroblasts obtained from a skin biopsy. Filipin staining demonstrates intense punctate pattern of fluorescence concentrated around the nucleus, consistent with unesterified cholesterol. Molecular genetic testing of *NPC1* and *NPC2* are commercially available and they detect pathogenic variants in approximately 94% of individuals with NPD-C [4].

The filipin assay is unable to provide a firm diagnosis in fibroblasts with "variant" phenotypes that represent one-third of NPD-C cases. Moreover, the assay is invasive and the results can delay for 3 months. Genetic analysis is an important diagnostic tool, though, due to cost considerations, generally applied as a confirmatory rather than screening test. In recent years have been identified promising NPD-C biomarkers. One of these markers, cholestane-3β,5α,6β-triol, which is a cholesterol oxidation product, has emerged as a sensitive diagnostic for NPD-C [6, 7].
