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Niemann–Pick type C: a potentially treatable disorder?
  1. Ammar Kheder1,
  2. Camilla Scott2,
  3. Simon Olpin2,
  4. Marios Hadjivassiliou1
  1. 1Academic Department of Neurosciences, Royal Hallamshire Hospital, Sheffield, UK
  2. 2Department of Clinical Chemistry, Sheffield Children's Hospital, Sheffield, UK
  1. Correspondence to Professor Marios Hadjivassiliou, Academic Department of Neurosciences, Royal Hallamshire Hospital, Glossop Rd, Sheffield S10 2JF, UK; m.hadjivassiliou{at}


Niemann–Pick disease refers to a group of autosomal recessive lipid storage disorders associated with a variable degree of neurological manifestations in addition to other organ involvement. Niemann–Pick disease is divided into types A–C. Of interest to neurologists is Niemann–Pick type C because of the association with neurological manifestations that are not confined to childhood. The clinical presentation of Niemann–Pick type C is variable, depending on age at onset. Neurological symptoms vary with age: hypotonia, delay in developmental motor milestones, falls, seizures, learning difficulties, ataxia with cognitive deficits and psychosis. The definitive diagnosis of Niemann–Pick type C requires demonstration of abnormal intracellular cholesterol trafficking using the filipin test. Therapeutic interventions are few but one that is of interest is miglustat, which has been approved for specific treatment of the neurological manifestations. It showed improvement in horizontal saccadic eye movement and a trend towards improvement or stabilisation in swallowing, hearing and walking. Niemann–Pick type C should be considered in patients with early-onset ataxia associated with progressive learning/cognitive difficulties even in the absence of vertical gaze palsy.


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Niemann–Pick disease refers to a group of autosomal recessive lipid storage disorders associated with variable degrees of neurological and other organ involvement (usually visceral).

A defect in cellular trafficking leads to lysosomal lipid accumulation in cells of different organs. Several lipids accumulate in the liver and spleen, including glycosphingolipids, phospholipids and sphingomyelin. Glycosphingolipid accumulates primarily in the central nervous system, causing the neurological manifestations.

The name recognises its first clinical description by the German paediatrician Albert Niemann and its pathological characterisation by Ludwig Pick.1 ,2

Niemann–Pick disease is divided into types A–C.3 Type A is the infantile form with a high incidence among Ashkenazi Jews. Type B is less severe than A and is associated with visceral involvement and survival into adulthood.4 Niemann–Pick types A and B result from mutations on the same gene (SMPD1).

Niemann–Pick type C is of interest to neurologists because of its neurological manifestations that are not confined to childhood. Most patients presenting late (juvenile/adult form) typically have cerebellar involvement and a slowly progressive cognitive decline. Vertical supranuclear gaze palsy can be an early and useful diagnostic sign. Niemann–Pick type C is caused by mutations in either one of two genes, NPC1 and NPC2. It is not possible to distinguish clinically between these two genetic defects.

Niemann–Pick type C can present in infants, children or adults with an estimated prevalence of 1:150 000.5 There are currently about 100 cases in the UK.

Clinical cases

Case 1

This 25-year-old man was referred for a second opinion. He had noticed difficulty with his writing from the age of 15 years, primarily due to tremor of his hand.

He subsequently developed problems with balance when walking. He had a few falls but did not require any walking aid. The tremor in his arms had evolved into clumsiness and his speech was becoming affected. His family commented on some cognitive decline but not bad enough to impair his ability to work as a night guard. There was no relevant family history.

On examination, his mini-mental state examination was normal. There was a full range of eye movements but non-sustained nystagmus on lateral gaze. There was limb ataxia and he could only tandem walk with support. His reflexes were normal and plantars were flexor.

He had already undergone extensive investigations, including genetic testing for the common inherited ataxias, all of which were normal. His MRI of brain showed mild cerebellar (vermian) atrophy (figure 1). White cell enzymes showed elevated chitotriosidase. The combination of early-onset ataxia with cognitive involvement and elevated chitotriosidase raised the possibility of Niemann–Pick type C. Skin biopsy with filipin staining showed that 90% of all cells had cholesterol accumulation (figure 2). DNA analysis showed he was a compound heterozygote for NPC1 mutation (c.1133T>C/c.3591+4del). Following referral to the inherited metabolic disease centre, he started treatment with miglustat; while taking this, his condition remains stable.

Figure 1

MRI from case 1 showing mild vermian cerebellar atrophy (arrow). The MR brain appearances in Niemann–Pick type C are non-specific and occur in several different ataxias.

Figure 2

Fluorescence microscopy showing a positive filipin test with skin fibroblasts from patient 2. The arrows point to strongly fluorescent cholesterol-filled perinuclear vesicles using fluorescence microscopy.

Case 2

This 29-year-old woman attended for a further opinion. She had normal developmental milestones. At the age of 6 years, she had episodes of severe dizziness but recovered fully between attacks. During her teenage years she became clumsy and could not participate in sports. She began to struggle at school. Assessments at the time suggested elements of dyslexia and dyspraxia. She managed to graduate from a normal school with some extra support. In her early 20s she developed slurred speech, worsening gait difficulties and a tendency to fall. She also presented with symptoms of urinary frequency. At the time, there was no relevant family history.

On examination, eye movements showed mildly restricted upgaze, broken pursuit and nystagmus on lateral gaze. She had significant gait ataxia and could not tandem walk. There was no suggestion of a peripheral neuropathy. She was emotionally labile.

Initial investigations including α-fetoprotein, serum vitamin E, genetic testing for spinocerebellar ataxia genes 1, 2, 3, 6, 7, 12, 17 and Friedreich's ataxia were all negative. MR scan of brain showed cerebellar atrophy. White cell enzymes were normal and chitotriosidase was not elevated. Muscle biopsy showed no evidence of mitochondrial disease. Cultured fibroblasts from skin biopsy showed cholesterol accumulation by filipin staining in 70% of the cells. Genetic testing confirmed the diagnosis of Niemann–Pick type C. She was a compound heterozygote for NPC1 mutation (c.3022A>C p.lle1061Thr). She was referred to the inherited metabolic disease centre and started on miglustat.

Case 3

This 28-year-old woman—the younger sister of patient 2—was initially assessed in the ataxia clinic when she attended with her sister. She reported no balance problems. She was able to work as a secretary and had no history of trouble at school. Examination showed subtle signs of cerebellar dysfunction with mild gait ataxia. She was re-referred while her sister was undergoing investigations following an acute episode of psychosis requiring psychiatric input. During treatment with antipsychotics as an inpatient she was noted to be very clumsy, unsteady and with slurred speech. While undergoing inpatient psychiatric treatment, her sister was diagnosed with Niemann–Pick type C. As a result, she was also genetically tested for the condition and proved to be positive, with the same genetic defect as her sister.

Clinical features, diagnosis and management

The clinical presentation of Niemann–Pick type C varies with age at onset. Neurological symptoms also vary with age: hypotonia, delayed developmental motor milestones (early infantile period), ataxia, falls, seizures, learning difficulties (late infantile and juvenile period) and ataxia with cognitive deficits often follow a new onset of psychosis (adult form). In the perinatal and early infantile period there is often a history of jaundice (with hepatosplenomegaly) that often resolves spontaneously. This can be a useful diagnostic clue. Life expectancy is variable, with some patients living only a few days and others till their seventh decade. The majority of patients die before 25 years of age.6 The average age at death for patients presenting in adulthood is 38 years. Most patients presenting late (juvenile/adult form) have cerebellar involvement and slowly progressive cognitive decline. Vertical supranuclear gaze palsy is an early and useful sign. Dystonia sometimes occurs and about half of the patients develop seizures.

MRI is not particularly useful for the diagnosis, typically showing symmetrical cerebellar atrophy, a feature of many different ataxias.

Plasma chitotriosidase (a non-specific enzyme of storage diseases) can help to alert clinicians to the possibility of Niemann–Pick type C, but it is neither sensitive nor specific. Only one of the three cases described here had elevated chitotriosidase.

The definitive diagnosis of Niemann–Pick type C requires the demonstration of abnormal intracellular cholesterol trafficking. The filipin test is currently the most sensitive and specific assay, and is the key diagnostic test for Niemann–Pick type C before embarking on genetic testing.7 Filipin is a fluorescent antibiotic, which reacts with unesterified cholesterol giving a strongly fluorescent, stable cholesterol–filipin complex suitable for in situ detection. It requires the use of cultured skin fibroblasts. Skin fibroblasts are first delipidated and then exposed to a low-density lipoprotein (LDL)-enriched medium, after which the cells are fixed and stained with filipin. About 90% of Niemann–Pick type C cases show strongly fluorescent cholesterol-filled perinuclear vesicles on fluorescence microscopy. If the clinical suspicion is high and this test is negative, genetic testing is justified, as 10% of Niemann–Pick type C patients test negative on filipin staining.

Niemann–Pick type C has two disease gene loci: the NPC1 and NPC2 genes. About 95% of patients have NPC1 gene mutations, encoding the NPC1 protein; this is a large membrane glycoprotein predominantly located within the late endosomal membrane but is also transiently associated with lysosomes and the trans-Golgi network. It plays a role in LDL cholesterol intracellular trafficking, plasma levels and distribution.8 ,9 Disrupting this trafficking allows lipid accumulation with resulting neurological and hepatic manifestations.10

NPC2 gene mutations and abnormalities of other as yet unidentified genes account for the remaining 5% of cases.

Management is largely supportive. This includes antiepileptic drugs for patients with seizures and botulinum toxin injections for those with dystonia. Physiotherapy may help the ataxia. Early diagnosis may help to identify special schooling needs for those patients with learning difficulties.

There are few therapeutic interventions but one merits further discussion: miglustat inhibits glycosphingolipids biosynthesis, decreases lipid storage and normalises lipid trafficking in B lymphocytes.11 In a randomised controlled study of 29 patients with Niemann–Pick type C aged ≥12 years, horizontal saccadic eye movement improved in those treated with miglustat 200 mg three times daily for 12 months versus those receiving standard care. There was also a trend towards improvement or stabilisation of clinically relevant secondary outcome measures, including swallowing, hearing and walking.12

An international, multicentre, observational cohort study evaluated neurological disease progression retrospectively in patients treated with miglustat in clinical practice (n=66), using a modified disease-specific disability scale.13 While most patients had impaired function and disease progression before miglustat therapy, most remained stable or improved during treatment, and there was a significant reduction in the annual rate of progression in composite disability scores.

The most frequently reported adverse events were mild or moderate diarrhoea, flatulence, weight loss and tremor. Gastrointestinal adverse events and mild-to-moderate weight loss (50% of patients, overall) tend to decrease over time.

The Health Technology Assessment NIHR programme recently reviewed these studies and any case reports using miglustat in Niemann–Pick type C.14 The panel estimated the cost of caring for an adult patient with Niemann–Pick type C as £3800 per year. The mean annual cost of the use of miglustat was £94 108. Using a longitudinal regression modelling of the costs, the panel found no significant association between time on miglustat and either total National Health Service, social-care and hospital-care costs, or non–hospital care costs for patients with Niemann–Pick type C. The panel acknowledged that any analysis of the association between the use of miglustat and clinical outcome were hampered by both the small numbers recruited (due to the rarity of the disease) and the lack of data regarding key outcomes for those that participated. In the case of our three patients, all have been referred to the National service for Niemann–Pick disease and are all currently on miglustat. Their condition remains stable.

An important message is that in patients with early-onset ataxia associated with progressive learning/cognitive difficulties, clinicians should consider Niemann–Pick type C even in patients without vertical gaze palsy. This is even more important now that there is a potential treatment.



  • Contributors AK and MH wrote the manuscript and reviewed of literature. CS and SO reviewed the manuscript and provided the figure of positive filipin test. All authors have read and approved the final manuscript.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed, This paper was reviewed by Kathryn Peall, Cardiff, UK.

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