Increasing awareness of Niemann-Pick type C (NP-C) was the focus of the Actelion-sponsored satellite symposium ‘One diagnosis, three presentations, many lives: a biography of Niemann-Pick type C (NP-C)’, held during the 4th Congress of the European Academy of Paediatric Societies (EAPS) in Istanbul, Turkey, October 2012. Delegates attending the symposium had the opportunity to discuss various aspects of the disease with colleagues and NP-C experts.
NP-C is an inherited, genetic, progressive and irreversible neurovisceral lysosomal storage disease (LSD), with a current estimated incidence of 0.85 per 100 000 live births.1,2 NP-C is caused by mutations in NPC1 or NPC2 genes, causing defective intracellular transport and subsequent accumulation of different lipids, including cholesterol, sphingomyelin, multiple glycosphingolipids and sphingosine, as well as alterations to sphingolipid metabolism, resulting in the disease pathophysiology.
Paediatricians can play a crucial role in the prompt identification of children displaying key manifestations of NP-C, in whom further investigation for the disease may be warranted.
Visceral and neurological manifestations presenting during childhood may help provide a differential diagnosis of NP-C. However, such manifestations may not be specific, and the clinical presentation of NP-C differs depending on patient age and age at onset of the disease. Furthermore, the rate of disease progression is influenced by age at onset of neurological manifestations and therefore varies between individuals. Due to its complex heterogeneous presentation, NP-C is often misdiagnosed and underdiagnosed.
The only disease-specific therapy available for patients with NP-C is miglustat (Zavesca® in Europe and Brazaves® in Japan), which was approved for treatment of progressive neurological manifestations in patients with NP-C in Europe in 2009 and in Japan in 2012.3 Treatment with miglustat can stabilise or slow irreversible neurological deterioration in patients with NP-C2, with greater therapeutic benefits observed in late childhood and in juvenile and adult patients.4 It is therefore recommended that patients with NP-C be monitored for the first appearance of neurological manifestations and started on miglustat treatment as soon as these occur.2,5
The symposium Chair, Professor Frits Wijburg of the Department for Inborn Errors of Metabolism, Academic Medical Centre in Amsterdam, The Netherlands, explained the aim of the symposium, which was to discuss the differential diagnosis of NP-C, highlight its various clinical presentations, and provide an overview of the treatment and management of patients with NP-C.
Dr Alasdair Parker, of Addenbrooke’s Hospital, Cambridge, UK, discussed the differential diagnosis of NP-C and how clinicians can efficiently separate rare neurometabolic conditions from ‘developmental delay’, or static neurological and psychiatric disorders. Professor Wijburg followed, explaining that due to the complex symptomatology of NP-C, diagnosis is difficult and often missed or delayed. Professor Wijburg provided the audience with an overview of the heterogeneous clinical presentation of NP-C, including key visceral, neurological and psychiatric manifestations. He also drew the delegates’ attention to the recently published NP-C Suspicion Index tool, which may help identify patients with NP-C. Finally, Dr Charles Lourenço of the Medical Genetics Division, University of São Paulo, Ribeirão Preto, Brazil, presented an overview of the treatment and management of patients with NP-C.
In addition, he presented a case study of a paediatric patient before treatment with miglustat and after eight months and two years of treatment.
- NP-C is a genetic, progressive and irreversible neurovisceral lysosomal lipid storage disease, which often starts with developmental delay
- Increased awareness of NP-C will help clinicians to efficiently separate rare neurometabolic conditions from ‘developmental delay’, or static neurological and psychiatric disorders
- NP-C diagnosis is often delayed or even missed due to the complex heterogeneous presentation of the disease
- The NP-C Suspicion Index tool may help clinicians to identify patients in whom further investigation for NP-C is warranted
- Miglustat can stabilise the progression of neurological manifestations in patients with NP-C, particularly in patients diagnosed in late childhood, and in juvenile and adult patients
- Treatment with miglustat should start as soon as neurological manifestations are detected
A hidden disease: diagnosing NP-C
NP-C is difficult to diagnose. A key neurological manifestation common in early-infantile and late-infantile cases is that of developmental delay. However, developmental delay may also be part of the clinical presentation of other disorders. In order to help clinicians to confirm a differential diagnosis of NP-C, a logical, staged approach to investigation should be undertaken.
Dr Parker discussed differential diagnosis and explained how increased awareness of NP-C may improve the investigation of degenerative disorders such as LSDs. Improved investigation will then help separate them from ‘developmental delay’, static neurological conditions and psychiatric disorders.
Understanding of the epidemiology of LSDs allows clinicians to formulate and carry out a targeted and logical investigation when presented with a child exhibiting developmental delay. This methodical approach will help clinicians to identify the majority of disorders observed in neurology practice. First-line investigations should include obtaining a thorough history, a full clinical examination, and undertaking a magnetic resonance imaging scan.
Obtaining a patient history may be difficult, as parents do not always remember key facts. Therefore, it is important to take into account consanguinity, ascertainment of key milestones, and family history of developmental or neurological disorders. Dr Parker recommended noting neonatal thyroid and phenylalanine levels prior to carrying out a full clinical examination of the patient.
When undertaking clinical examinations, developmental delay/dyspraxia should be separated from the neurological signs. Identification of ataxia, spasticity, dysarthria/dysphagia, dystonia, myoclonus and neuropathy is key to achieving a diagnosis of NP-C. The clinical examination should include monitoring patients’ movements (observing walking, turning, hopping and jumping) and hearing, as well as checking the condition of skin, hair and nails. Monitoring vision, including eye movements, is critical. Vertical supranuclear gaze palsy is a hallmark of NP-C and is characterised in patients with NP-C by paralysis of downward vertical saccades. As noted by Dr Parker, ‘there is no substitute for a good, old-fashioned thorough patient examination, including obtaining a patient’s history’.
In addition to the first-line investigations, subsequent biochemical testing (filipin test) and genetic analysis can help establish a definitive diagnosis of NP-C. Should NP-C be suspected, the nearest specialist NP-C centre should be contacted for further advice.
Early diagnosis of NP-C allows children prompt access to both supportive therapies and disease-specific drugs, such as miglustat.
Presenting NP-C: psychiatric, neurological and visceral symptoms
NP-C has a heterogeneous presentation and, while single manifestations are not specific to the disease, their combination may help prompt clinicians to consider a diagnosis of NP-C.
Professor Wijburg used clinical case studies to highlight the key visceral, neurological and psychiatric symptoms, and the symptom combinations indicative of NP-C. As there is a continuum in NP-C presentations, five subgroups have been identified based on age at onset of neurological manifestations: pre/perinatal, early-infantile, late-infantile, juvenile and adolescent/adult (Figure 1).
Visceral manifestations are most prominent during childhood and include hepatosplenomegaly and isolated splenomegaly. Key neurological manifestations for NP-C include vertical supranuclear gaze palsy, which is a characteristic feature of NP-C. Its presence should always prompt clinicians to consider NP-C. Other neurological manifestations observed during childhood include cerebellar ataxia, dysphagia, gelastic cataplexy, learning disabilities, frequent falls or clumsiness, and behavioural problems.
Psychiatric manifestations, while more often associated with adolescent/adult presentation of NP-C, have also been observed in juvenile cases where manifestations present as behavioural disturbances and catatonia.2 The most common psychiatric manifestations in NP-C include cognitive decline, psychotic symptoms, behavioural problems and schizophrenia-like psychosis.
The recently published NP-C Suspicion Index tool6 was developed by a panel of NP-C experts as a screening tool to assist clinicians who are unfamiliar with the disease with the early identification of patients with NP-C (www.npc-si.com, Figure 2).
Each manifestation was assigned a point score. Additional points were allocated for manifestation combinations and familial history. The tool was validated by a retrospective chart review of 216 patients in Europe and Australia as described in Figure 3. The NP-C Suspicion Index tool is highly sensitive and specific for identifying patients with NP-C >4 years of age (Figure 4), and defines a threshold total risk prediction score of ≥70 points for suspicion of NP-C.
Should NP-C be suspected, diagnostic tests, including filipin staining of cultured skin fibroblasts, analysing the genetic mutations and measuring oxysterol levels in plasma, can help to establish a definitive diagnosis of NP-C. Professor Wijburg highlighted that use of oxysterols as a biomarker for NP-C has real promise in the future to become a rapid, non-invasive and inexpensive diagnostic test for NP-C disease.7
A clinical picture of NP-C: the impact of the symptoms and their treatment
A multidisciplinary approach, combining disease-specific treatment, symptomatic therapy and close community support, is key to improving or maintaining patients’ quality of life and their neurological/mental function. While bone marrow transplantation is not indicated for patients with NP-C1 disease, it appears to have some benefit for patients with NP-C2 disease.8 A clinical trial of cholesterol- lowering therapy did not show any benefits in neurological disease.9
Miglustat (Zavesca®) is a small iminosugar that crosses the blood–brain barrier and reduces sphingolipid accumulation in the brain. Miglustat is the first and only disease-specific therapy approved for the treatment of progressive neurological manifestations in paediatric and adult patients with NP-C.3
Previous studies have shown that miglustat can slow neurological progression in patients with NP-C.4,10 In addition, treatment with miglustat also results in an improved effect on the swallowing function and ability of patients with NP-C (Figure 5).10,11
Dr Lourenço presented a case study of a young patient with NP-C before treatment with miglustat and after eight months and two years of treatment.
Patient case study
Before treatment: Child presented at age six years. At this time she was showing signs of developmental delay and attending a special needs school. Her previous metabolic evaluation revealed only increased levels of lactate in her urine but nothing else abnormal. It took three years for her to be diagnosed with NP-C. Before treatment with miglustat, she was very thin and was being fed via a nasal tube because of severe dysphagia. She showed clear signs of ataxia in her hands and vertical supranuclear gaze palsy. She was deteriorating very quickly; her seizures were difficult to manage with anticonvulsants and she was losing most of her motor and cognitive abilities, becoming more encephalopathic (stopping talking and walking).
Following eight months of treatment with miglustat: The patient had gained weight, although she was showing signs of hypersalivation. There was stabilisation of her neurological manifestations, with maintenance of social interaction and trunk control. Her seizures decreased in frequency and were better managed with use of anticonvulsants. However, she was no longer talking.
Following two years of treatment with miglustat: The patient had stable neurological disease with improved salivation. Although she was still ataxic, her symptoms had not progressed any further.
The availability of miglustat supports the need for earlier diagnosis of patients with NP-C, particularly those patients with early onset of neurological manifestations. These patients often have a poorer prognosis and faster deterioration compared with juvenile or adolescent/adult onset patients.
Improved follow-up of patients with NP-C is also a necessity. Regular patient monitoring should occur and should include neurological assessment using the disability scale.12,13
Symptomatic treatment of clinical manifestations such as dystonia, gelastic cataplexy, spasticity and dysphagia should be tailored to the individual patient’s needs and managed by a multidisciplinary team. Ongoing monitoring of patients with NP-C is required to assess current clinical status and rate of disease progression, and to follow their response to therapy.
NP-C is a genetic, progressive and irreversible lysosomal storage disease, which is characterised by heterogeneous presentation of visceral, neurological and psychiatric manifestations. Due to its complex symptomatology, NP-C is often difficult to detect and diagnose.
Early diagnosis of patients with NP-C must be improved, particularly for those patients with early onset of neurological manifestations, to ensure prompt initiation of disease-specific therapy such as miglustat in order to limit the progression of irreversible neurological damage. The availability of the recently developed NP-C Suspicion Index screening tool may assist clinicians with early identification of patients with NP-C.
Dr Parker, Professor Wijburg and Dr Lourenço have served as speakers for Actelion Pharmaceuticals Ltd. Medical writing assistance was provided by Jayne Blanshard at PHOCUS Services Ltd, a member of the Fishawack Group of Companies, paid for by Actelion Pharmaceuticals Ltd.
- Prevalence of rare diseases: bibliographic data. Orphanet Report Series. Rare Diseases collection. Number 1. (www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_ of_rare_diseases_by_alphabetical_list.pdf; accessed 18 May 2012).
- Patterson MC, Hendriksz CJ, Walterfang M, et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab 2012; 106: 330–344.
- EMEA: Miglustat (Zavesca®) Summary of Product Characteristics (www.ema.europa. eu/ema/index.jspcurl=pages/medicines/human/medicines/000435/human_med_001171.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125; accessed 27 September 2012).
- Pineda M, Wraith JE, Mengel E, et al. Miglustat in patients with Niemann-Pick disease type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab 2009;98:243–249.
- Heron B, Valayannopoulos V, Baruteau J, et al. Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C. Orphanet J Rare Dis 2012;7:36.
- Wijburg FA, Sedel F, Pineda M, et al. Development of a Suspicion Index to aid diagnosis of Niemann-Pick disease type C. Neurology 2012;78:1560–1567.
- Jiang X, Sidhu R, Porter FD, et al. A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma. J Lipid Res 2011;52:1435–1445.
- Bonney DK, O’Meara A, Shabani A, et al. Successful allogeneic bone marrow transplant for Niemann-Pick disease type-2 is likely to be associated with a severe ‘graft versus substrate’ effect. J Inherit Metab Dis 2010;33:1–3.
- Sturley SL, Patterson MC, Balch W, et al. The pathophysiology and mechanisms of NP-C disease. Biochim Biophys Acta 2004; 1685:83–87.
- Patterson MC, Vecchio D, Prady H, et al. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007;6:765–772.
- Fecarotta S, Amitrano M, Romano A, et al. The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann-Pick disease type C after therapy with miglustat. Am J Med Genet A 2011;155A:540–547.
- Iturriaga C, Pineda M, Fernandez-Valero, et al. Niemann-Pick C disease in Spain: clinical spectrum and development of a disability scale. J Neurol Sci 2006;249:1–6.
- Pineda M, Perez-Poyato MS, O’Callaghan M, et al. Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Gen Metab 2010;99:358–366.