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.

• Splenomegaly

  Major clinical features included cerebellar ataxia (76%), vertical supranuclear ophthalmoplegia (VSO, 75%), dysarthria, (63%), cognitive troubles (61%), movement disorders (58%), splenomegaly (54%), psychiatric disorders (45%) and dysphagia (37%). [ncbi.nlm.nih.gov]

  She had a facial dysmorphia, cervical bilateral poly-lymphadenopathy and splenomegaly. [ommegaonline.org]

  […] definition Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease (see this term) characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly [orpha.net]

• Falling

  A 10-year-old boy presented to our hospital with a 3-year history of fall attacks triggered by laughing, leading to a generalized loss of muscle tone without loss of consciousness (video). One year later, motor delayed skills started. [ncbi.nlm.nih.gov]

  […] signs/symptoms 2 neonatal presentation: cholestatic liver failure infancy and childhood presentation: hepatosplenomegaly neurological signs / symptoms 2 neonatal and infant presentation: delayed development milestones childhood presentation: ataxia, falls [radiopaedia.org]

  […] problems in walking (ataxia) Difficulty in posturing of limbs (dystonia) Slurred, irregular speech (dysarthria) Learning difficulties and progressive intellectual decline (cognitive dysfunction/dementia) Sudden loss of muscle tone which may lead to falls [npuk.org]

  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. [symptoma.com]

• Developmental Delay

  Signs of NPC include severe liver disease, breathing difficulties, developmental delay, seizures, poor muscle tone, lack of coordination, problems with feeding, and an inability to move the eyes vertically. [nxgenmdx.com]

  Analyzes chromosomes in newborns and infants for changes that can explain certain birth defects or developmental delays. Multiple testing options providing information on the genetic health of your baby during the first and second trimesters. [integratedgenetics.com]

• Progressive Dementia

  A 39-year-old female presented to the Bryan Memory Disorders Clinic at Duke University with a 7-year history of an atypical progressive dementia, mildly impaired vertical gaze, dysarthria and mild ataxia. [ncbi.nlm.nih.gov]

  The neurologic disorders consist of cerebellar ataxia, seizures, dysarthria, dysphagia, dystonia, cataplexy and progressive dementia. [omicsonline.org]

  Static learning impairment and progressive dementia are frequent in NP-C. [2] Psychosis, behavioral disturbances, overt hallucinations and delusions may occasionally be the early features. [2] Phenotypic features such as gait ataxia, dysarthria, supranuclear [annalsofian.org]

  dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor. [en.wikipedia.org]

• Intravenous Administration

  Clinical trials with either intravenous administration of HPBCD or oral administration of arimoclomol are also underway. [medlink.com]

• Respiratory Insufficiency

  insufficiency and airway infections. [ncbi.nlm.nih.gov]

  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. [symptoma.com]

  Fatal lung infiltration with foam cells and a severe respiratory insufficiency is mostly restricted to patients having mutation in the NPC2 gene [2, 5, 6]. Early Infantile Period (Onset at 2 Months to 2 Years of Age). [hindawi.com]

• Dysphagia

  Oropharyngeal dysphagia can be particularly problematic as it can often lead to food or fluid aspiration and subsequent pneumonia. [ncbi.nlm.nih.gov]

  […] such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia [orpha.net]

• Hepatosplenomegaly

  A galactose-free and lactose-free diet resulted in achievement of a normal galactose level, but hepatosplenomegaly and cholestatic signs persisted. [ncbi.nlm.nih.gov]

  Niemann-Pick disease type c (NPD-C or just NPC) is an autosomal recessive lysosomal storage disorder classed under Niemann-Pick disease on account of clinical similarities, namely hepatosplenomegaly and variable involvement of the central nervous system [radiopaedia.org]

• Jaundice

  […] disease Niemann-Pick disease type C Disease definition Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease (see this term) characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice [orpha.net]

  A three-month old Chinese male infant was a victim of neonatal hepatitis presenting with prolonged jaundice, poor body weight gain, progressive hepatosplenomegaly and extremely elevated serum alpha-fetoprotein level. [ncbi.nlm.nih.gov]

  […] a history of neonatal jaundice and 30% who had hepatosplenomegaly during infancy [14]. [hindawi.com]

• Hepatomegaly

  His brother presented at 22 weeks'gestation an isolated hepatomegaly with cholestasis at birth showing favourable evolution. [ncbi.nlm.nih.gov]

  272.7 splenomegaly (cerebroside lipidosis) 272.7 Hepatomegaly (see also Hypertrophy, liver) 789.1 Gaucher's 272.7 Histiocytosis (acute) (chronic) (subacute) 277.89 lipid, lipoid (essential) 272.7 Hyperlipidosis 272.7 hereditary 272.7 Lipidosis 272.7 [icd9data.com]

• Neonatal Jaundice

  […] rare disease Niemann-Pick disease type C Disease definition Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease (see this term) characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal [orpha.net]

  We report the case of a Russian newborn with early-infantile onset Niemann-Pick disease type C who displayed prolonged neonatal jaundice and hepatosplenomegaly. [ncbi.nlm.nih.gov]

• Hearing Impairment

  […] and one (6%) patient had central impairment. [ncbi.nlm.nih.gov]

  Hearing impairment is not uncommon. A cognitive decline is more readily observable in this form of the disease than in early infantile NPC. Juvenile NPC is the classic form of the disease. Onset of neurological symptoms is at six to 15 years. [symptoma.com]

• Hydrops Fetalis

  Pathogenic variants of the NPC1 or NPC2 genes yield highly variable phenotypes with a time course that ranges from fetal onset (i.e., hydrops fetalis) to progressive dementia in adults. NP-C is typically inherited in an autosomal-recessive manner. [ncbi.nlm.nih.gov]

  The presence of perinatal hydrops fetalis or family history of a sibling with fetal ascites is a possible indicator of lysosomal storage disease. It is usually associated with progressive hepatosplenomegaly. [hindawi.com]

  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. [symptoma.com]

• Muscle Weakness

  Cataplexy is the sudden muscle weakness brought on by strong emotions, particularly joking, laughter, or anger. Cataplexy may involve only certain group of muscles or the entire voluntary musculature. [ncbi.nlm.nih.gov]

  Symptoms include: Severe muscle weakness Poor muscle tone Lack of growth and weight gain in infants An enlarged heart, liver, or tongue Tay-Sachs disease: This is caused by a lack of the enzyme hexosaminidases A (Hex-A). [webmd.com]

  There is a gradual decline of motor and intellectual function resulting in a degenerative muscle weakness and floppiness. The severity of the symptoms increases rapidly and life-threatening complications may occur early in childhood. [en.wikibooks.org]

  ] 0003593 Intellectual disability Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ] 0001249 Lymphadenopathy Swollen lymph nodes 0002716 Microcytic anemia 0001935 Muscle weakness Muscular weakness 0001324 [rarediseases.info.nih.gov]

• Ataxia

  Following 12 months of treatment, the patient remained stable with improvements in speech, ptosis, ophthalmoplegia, ataxia, hypotonia and seizures. [ncbi.nlm.nih.gov]

  Both patients were evaluated for dystonia and ataxia using the Dystonia Movement Scale (DMS, maximum score 120) and Scale for the assessment and rating of ataxia (SARA, maximum score 37) before and 18 months after the administration of miglustat. 600mg [mdsabstracts.org]

  falls, poor school performance adolescent and adult presentation: psychiatric illnesses, ataxia Radiographic features are limited, and MRI is the modality of choice. [radiopaedia.org]

• Seizure

  Six patients were caught by focal or generalized seizures from 1 to 4 years after the onset of the disease. [ncbi.nlm.nih.gov]

  Gelastic cataplexy represent the main differential diagnosis of seizures in a patient with NPC. [content.iospress.com]

• Dystonia

  Her symptoms began with dystonia in the right hand at 19 years old and were milder than her brother. [mdsabstracts.org]

  […] prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia, dystonia [orpha.net]

  At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient's 35-year-old sister (Case 3) was diagnosed with schizophrenia. [ncbi.nlm.nih.gov]

  Later that year, her psychosis resolved, but she developed facial dystonia, a shuffling gait and dysarthria, attributed to a tardive syndrome. [jnnp.bmj.com]

• Dysarthria

  Major clinical features included cerebellar ataxia (76%), vertical supranuclear ophthalmoplegia (VSO, 75%), dysarthria, (63%), cognitive troubles (61%), movement disorders (58%), splenomegaly (54%), psychiatric disorders (45%) and dysphagia (37%). [ncbi.nlm.nih.gov]

  […] age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria [orpha.net]

• Neurologic Manifestation

  After 7 and 5 years of miglustat therapy, respectively, both patients remain free of neurologic manifestations. [ncbi.nlm.nih.gov]

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.

• Pulmonary Infiltrate

  In severe cases of type B, progressive pulmonary infiltrates cause major complications. Prenatal screening WBC sphingomyelinase assay Both types are usually suspected by history and examination, most notably hepatosplenomegaly. [msdmanuals.com]

  Additionally, in patients with early-onset disease, or severe NPC2 mutations, pulmonary infiltration with foam cells also occurs. Premature death occurs in all patients with NPC, most of whom have a life expectancy of 10–25 years. [invitae.com]

  NPC2: extensive pulmonary infiltration with foam cells, delayed psychomotor development and respiratory failure, with death in early childhood. [patient.info]

  Patients may also develop respiratory insufficiency due to pulmonary infiltration with foam cells, and this symptom has been proposed to indicate NPC2 mutations. [symptoma.com]

• Enlargement of the Spleen

  Other symptoms include enlarged liver and spleen, and pulmonary difficulties. [ninds.nih.gov]

  Diagnosis Diagnosis of Niemann-Pick disease begins with a thorough physical exam, which can show an early warning sign such as an enlarged liver or spleen. [mayoclinic.org]

• Enlargement of the Liver

  The disease primarily affects the: liver spleen brain bone marrow This leads to enlargement of the spleen and neurologic problems. The disease is broken down into types A, B, C, and E. [healthline.com]

  Accumulation of cholesterol inside lysosomes leads to fatal symptoms, such as progressive nerve degeneration, and enlargement of the liver and spleen. [sciencedaily.com]

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.

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.

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].

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.

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].

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.

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.

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.

1. Crocker AC, Farber S. Niemann-Pick disease: a review of eighteen patients. Medicine (Baltimore). 1958; 37(1):1-95.
2. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010; 5:16.
3. Yang CC, Su YN, Chiou PC, et al. Six novel NPC1 mutations in Chinese patients with Niemann-Pick disease type C. J Neurol Neurosurg Psychiatry. 2005; 76(4):592-595.
4. Vanier MT. Lipid changes in Niemann-Pick disease type C brain: personal experience and review of the literature. Neurochem Res. 1999; 24(4):481-489.
5. Wenger DA, Barth G, Githens JH. Nine cases of sphingomyelin lipidosis, a new variant in Spanish-American Children. Juvenile variant of Niemann-Pick Disease with foamy and sea-blue histiocytes. Am J Dis Child. 1977; 131(9):955-961
6. Winsor EJ, Welch JP. Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D). Am J Hum Genet. 1978; 30(5):530-538.
7. Ridsdale A, Denis M, Gougeon PY, et al. Cholesterol is required for efficient endoplasmic reticulum-to-Golgi transport of secretory membrane proteins. Mol Biol Cell. 2006; 17(4):1593-1605.
8. Peake KB, Vance JE. Defective cholesterol trafficking in Niemann-Pick C-deficient cells. FEBS Lett. 2010; 584(13):2731-2739.
9. Pacheco CD, Lieberman AP. The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev Mol Med. 2008; 10:e26
10. Wraith JE, Baumgartner MR, Bembi B, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab. 2009; 98(1-2):152-165.
11. Yerushalmi B, Sokol RJ, Narkewicz MR, et al. Niemann-pick disease type C in neonatal cholestasis at a North American Center. J Pediatr Gastroenterol Nutr. 2002; 35(1):44-50.
12. Mengel E, Klunemann HH, Lourenco CM, et al. Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet J Rare Dis. 2013; 8:166
13. Tängemo C, Weber D, Theiss S, et al. Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage. J Lipid Res. 2011; 52(4):813-825
14. Lyseng-Williamson KA. Miglustat: a review of its use in Niemann-Pick disease type C. Drugs. 2014; 74(1):61-74.
15. Santos-Lozano A, Villamandos García D, Sanchis-Gomar F, et al. Niemann-Pick disease treatment: a systematic review of clinical trials. Ann Transl Med. 2015; 3(22):360
16. Tamura A, Yui N. Lysosomal-specific cholesterol reduction by biocleavable polyrotaxanes for ameliorating Niemann-Pick type C disease. Sci Rep. 2014; 4:4356.
17. Bremova T, Malinova V, Amraoui Y, et al. Acetyl-dl-leucine in Niemann-Pick type C: A case series. Neurology. 2015; 85(16):1368-1375.
18. Vanier MT. Prenatal diagnosis of Niemann-Pick diseases types A, B and C. Prenat Diagn. 2002; 22(7):630-632.