Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update

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Abstract

Niemann–Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues. Characteristic neurological manifestations of NP-C include saccadic eye movement (SEM) abnormalities or vertical supranuclear gaze palsy (VSGP), cerebellar signs (ataxia, dystonia/dysmetria, dysarthria and dysphagia) and gelastic cataplexy. Epileptic seizures are also common in affected patients. Typically, neurological disease onset occurs during childhood, although an increasing number of cases are being detected and diagnosed during adulthood based on late-onset neurological signs and psychiatric manifestations. Categorization of patients according to age at onset of neurological manifestations (i.e. early-infantile, late-infantile, juvenile and adolescent/adult-onset) can be useful for the evaluation of disease course and treatment responses. The first international guidelines for the clinical management of NP-C in children and adults were published in 2009. Since that time a significant amount of data regarding the epidemiology, detection/diagnosis, and treatment of NP-C has been published. Here, we report points of consensus among experts in the diagnosis and treatment of NP-C based on a follow-up meeting in Paris, France in September 2011. This article serves as an update to the original guidelines providing, among other things, further information on detection/diagnostic methods, potential new methods of monitoring disease progression, and therapy. Treatment goals and the application of disease-specific therapy with miglustat are also re-evaluated.

Highlights

► Niemann–Pick disease type C (NP-C) is a rare inherited neurovisceral disease. ► The first international guidelines for managing NP-C were published in 2009. ► This article serves as an update to the original guidelines.

Introduction

Niemann–Pick disease type C (NP-C) is a rare inherited neurovisceral disease characterized by progressive, disabling neurological symptoms and premature death in most patients. Estimated to occur in 1 case in every 120,000 live births [1], [2], [3], [4], [5], NP-C generally arises sporadically in a panethnic pattern, although genetic isolates have been identified that show a higher than average incidence of the disease [6], [7].

NP-C is caused by autosomal recessive inheritance of mutations in either of two genes, NPC1 (in 95% of cases) or NPC2 (in approximately 4% of cases) [5], [8], [9], [10], [11]. Mutations in either causal gene result in impaired processing and utilization of endocytosed cholesterol, with subsequent intracellular accumulation of unesterified cholesterol and alterations of sphingolipid metabolism [12], [13], [14], [15].

Clinical presentations of NP-C are extremely heterogeneous, featuring a range of systemic and neurological signs that are not specific to the disease, arise at different ages, and progress at different rates [5], [16], [17], [18]. As a result, the diagnosis of NP-C can be a prolonged and complicated process [19], [20]. Patients typically present with one or more neurological signs during childhood [5], [17], [18], although very early-onset patients are often diagnosed based on isolated systemic manifestations [21], [22]. An increasing number of cases are being detected and diagnosed during adulthood [5], [16], [23], [24].

The age at onset of neurological manifestations has a major influence on disease progression and prognosis. In general, patients with neurological onset early in life deteriorate faster and die sooner [5], [16], [17], [18], [25]. Categorization of patients by age at onset of neurological manifestations in a number of studies has led to the definition of early-infantile, late-infantile, juvenile and adolescent/adult-onset disease forms [5], [18], [26]. These categories are useful for the evaluation of disease course and responses to therapy, and aid in clinical management and genetic counseling.

A variety of symptomatic treatments can alleviate neurological manifestations [27]. The appropriate application of such therapies can have an important influence on patient quality of life. Clinical experience with miglustat (Zavesca®; Actelion Pharmaceuticals), currently the only approved disease-specific therapy for children and adults with NP-C, is increasing. Miglustat was approved for the treatment of progressive neurological deterioration in children and adults with NP-C in Europe in 2009 [28], and has since been approved in a number of other countries [29], [30], [31], [32], [33]. Data on the use of miglustat in clinical practice settings has been published in a number of cohort studies and case reports/series [34], [35], [36], [37], [38], [39].

The first international recommendations for the clinical management of NP-C were prepared in 2009 based on consensus among a panel of experts at a meeting in Paris [26]. The following article serves as an update, modifying the original recommendations with a comprehensive review after a second meeting of an NP-C Guidelines Working Group in September, 2011. New data on the epidemiology, differential diagnosis, and detection/screening of NP-C are presented, with updated recommendations for treatment initiation. Findings from further clinical experience with both symptomatic and disease-specific therapies, and information on potential new methods for monitoring disease progression and response to therapy are also included.

Section snippets

Disease nomenclature

  • NP-C, in which the primary biochemical defect is impaired intracellular transport of endocytosed cholesterol, is caused by mutations in both alleles of either one of the two genes, NPC1 or NPC2.

  • NP-C is distinct and separate from Niemann–Pick disease types A and B (NP-A and NP-B), where the underlying defect is primary acid sphingomyelinase (ASM) deficiency due to mutations in the SMPD1 gene. NP-A, NP-B and intermediate types are now more accurately termed ASM-deficient Niemann–Pick disease [40].

Clinical signs and symptoms

  • NP-C is a neurovisceral condition; clinical features that indicate a possible diagnosis of NP-C involve systemic, neurological and psychiatric symptoms.

  • Broadly accepted age-at-onset subgroups are: pre/peri-natal (onset at age < 3 months), early-infantile (at age 3 months to < 2 years), late-infantile (at age 2 to < 6 years), juvenile (at age 6–15 years), and adolescent/adult (at age > 15 years) [26].

  • Fig. 1 is a graphical representation of the occurrence of clinical manifestations by age [5]. The

Prognosis

  • All patients with NP-C die prematurely, although rates of disease progression and life expectancy vary greatly. The majority of patients die between 10 and 25 years of age [5]. In very rare cases, patients can survive into the sixth or even seventh decade of life [73], some of whom have not exhibited neurological abnormalities at the time of their evaluation [7], [84], [85].

  • In general, patients with onset of neurological manifestations in early childhood deteriorate faster, and death occurs

Differential diagnosis and initial detection methods

  • Patients with NP-C may present many clinical practice settings, but should always be referred to regional or national care centers specializing in inherited metabolic disorders [26].

  • General physicians should be aware that neurological disease onset in NP-C is insidious, often starting with subtle findings ranging from clumsiness and poor school performance to psychological disturbances.

  • Delays between initial appearance of possible neurological dysfunction and further investigations, or referral

Diagnosis

  • Laboratory diagnostic tests for NP-C are complex and can be difficult to interpret due to a variety of methodological factors.

  • Diagnostic testing to confirm NP-C, following screening and differential diagnosis, should therefore be conducted by, or in consultation with, regional or national care centers specializing in the diagnosis of inherited metabolic disorders [26].

Treatment

  • Progressive neurological manifestations in NP-C have a profound effect on the quality of life of both patients and their carers/family [132]. The correct, early identification of NP-C and the appropriate application of symptomatic and disease-specific therapies can dramatically improve quality of life for all those affected.

  • In the absence of any curative treatment, quality of life represents a legitimate treatment goal in the management of NP-C [27], and can be addressed by 1) rigorous

Disease monitoring

  • Clinical evaluations following screening and confirmed diagnosis of NP-C should address each of the key neurological symptom types (see 5.3 Detection methods, 6 Diagnosis).

  • While it is most important to monitor 1) neurological function and 2) quality of life based on clinical judgment, the regular application of other ‘ancillary’ tests may be helpful, depending on their availability.

  • Primary reasons for applying these tests are to provide objective support for key clinical observations, and to

Potential future therapies

  • A number of experimental strategies have been or are still being assessed for their potential use in the treatment of NP-C.

Acknowledgments

This report and the expert meeting on which it is based were supported by Actelion Pharmaceuticals Ltd. Matthew Reilly, associated with InTouch Medical Ltd, provided medical writing support in the preparation of this manuscript, paid for by Actelion Pharmaceuticals Ltd. All authors read, contributed to and approved this manuscript. The decision to submit this article to peer review, for publication, was reached by consensus among all of the authors.

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    NP-C Guidelines Working Group: Baumgartner M, Bembi B, Bonnot C, Burlina A, Correll C, Covanis A, Dionisi-Vici C, Gama C, Hendriksz CJ, Klünemann H, Lachmann R, Lobo A, Lourenço C, Mengel E, Ory D, Patterson M, Pineda M, Sedel F, Topçu M, Vanier MT, Walterfang M, Wijburg F, Wraith JE.

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