[5] Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).

[citation needed] Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.

[citation needed] In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia.

In Niemann–Pick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell.

In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis.

[23][24] In April 2009, hydroxypropyl-beta-cyclodextrin (HPbCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel,[27] identical twin girls who had Niemann–Pick type C disease.

Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPbCD into their bloodstreams.

Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice[28] and feline[29] models.

[30] In May 2010, the FDA granted hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease.

[citation needed] In December 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND with Dr. Diane Williams, through Asante Rogue Regional Medical Center in Medford, Oregon.

[31] In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients.

[citation needed] In September 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.

[citation needed] In December 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol.

[32] Due to unprecedented collaboration between individual physicians and parents of children affected by NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols.

These include, cholesterol mobilization, neurosteroid (a special type of hormone that affects brain and other nerve cells) replacement using allopregnanolone,[6][44] rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent.

[50] It has been used preclinically, in a mouse model of Niemann-Pick type C, using an adeno-associated virus derived viral vector has been shown to extend lifespan following injection into the lateral ventricles of the neonatal brain.

[51] In a separate proof-of-concept study a similar vector, but with a modified capsid capable of delivering genes to the central nervous system following intravenous injection, was given to Niemann-Pick type C mice at around four weeks of age; this resulted in extended lifespan and improved weight gain.

It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests.

[55][56] Also, studies using diffusion tensor imaging have shown marked reductions in callosal fractional anisotropy, which suggests architectural abnormalities based on the directional flow of water.

[citation needed] Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells.