A Suspicion Index to aid screening of early-onset Niemann-Pick disease Type C (NP-C)

Niemann-Pick disease Type C (NP-C) [OMIM #257220, NP-C1; #607625, NP-C2] is a severe, autosomal recessive lysosomal lipid storage disorder caused by mutations in NPC1 or NPC2 genes [1]. NP-C has multiple presentations, with a wide range of visceral, neurological and psychiatric symptoms [2, 3].

NP-C can present at any age [1, 4]. Patients who develop symptoms during the early infancy (2 months to 2 years of age) have mainly visceral manifestations, including splenomegaly, hepatomegaly, prolonged unexplained neonatal jaundice, and direct hyperbilirubinaemia, which precede neurological signs [1, 5, 6]. The age at first neurological manifestation and the progression of neurological features usually define disease severity [1]. Neurological and psychiatric presentation varies with age at onset. In infancy, symptoms include delay of motor milestones, language delay, regression of previously achieved developmental level, central hypotonia, ataxia and gelastic cataplexy. Juvenile-onset patients commonly present with problems at school, intellectual decline, vertical supranuclear gaze palsy (VSGP), dysmetria, cerebellar ataxia, progressive dysarthria or dysphagia, and in some cases, seizures. Psychiatric disorders and progressive dementia are common in adolescence and adulthood [1, 5, 6].

The heterogeneous and often nonspecific clinical presentation of NP-C means that diagnosis can be delayed for many years [1, 7, 8]. Typically, a diagnosis is confirmed by biochemical (filipin staining of skin fibroblasts) and genetic analysis (DNA sequencing of the NPC1 and NPC2 genes, the loci that confer 95 % and 5 % of NP-C cases, respectively) [7, 9]; however, rapid biochemical tests utilising biomarkers such as plasma oxysterols or lysosphingolipids are in development, and may improve rates of diagnosis [10‐12].

Miglustat (Zavesca®, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) can slow the progression of irreversible neurological manifestations, and is the only approved treatment for the disease [5, 13, 14]. Patients who begin miglustat therapy at the onset of neurological symptoms may maintain higher levels of neurological function, highlighting the importance of early diagnosis and treatment initiation.

An NP-C Suspicion Index (SI) tool was developed based on a retrospective chart review of NP-C signs and symptoms, to assist clinicians who may be unfamiliar with NP-C in identifying patients who should undergo testing for the disease [15]. Analysis of the NP-C SI discriminatory power by patient age showed high performance in patients aged ≥4 years, but poor performance in patients with early-onset NP-C (aged <4 years) [6]. In the current study, additional data on patients ≤4 years of age were collected to provide a new database, and develop a novel NP-C SI with improved utility in this patient population. This new NP-C SI will be useful to support physicians with no knowledge of NP-C to more easily identify patients with the disease.

This retrospective chart review describes a detailed examination of symptomatology at time of diagnosis in patients with NP-C aged ≤4 years, and has allowed the development of a novel NP-C SI for use in this patient population. A retrospective chart review was necessary as the rarity of NP-C diagnoses does not allow the recruitment of a sufficient number of patients for a prospective study. It is anticipated that the ongoing use of the early-onset NP-C SI in clinical practice will confirm the strength of the statistical analyses and the validity of the early-onset NP-C SI as a clinical aid.

In contrast with the patient cohort used to develop the original NP-C SI, [15] confirming a positive diagnosis in the early-onset NP-C population did not require both filipin staining and genetic testing. Positive filipin staining alone was considered sufficient for diagnosis, as uncertain diagnoses due to variant-staining are very uncommon at this age, being observed more frequently in patients with late-onset NP-C [17].

One of the strengths of the present study is that all patients (NP-C cases, NP-C non-cases and controls) were recruited from the same clinical settings, broadening the universal utility of the NP-C SI in routine clinical practice. The principle weakness of the study is that the resulting NP-C SI is defined by the phenotypes of this particular patient cohort. As such, if the observed frequency of any given symptom is not representative of the incidence within the global early-onset NP-C patient population, the discriminatory power of the NP-C SI could be biased in favour of, or against that symptom when applied in routine clinical practice.

The present study includes a detailed clinical description of the largest cohort of patients aged ≤4 years with NP-C studied to date (Table 1 and Additional file 3: Table S2). This description is in broad agreement with the typical presentation of NP-C in patients within this age group. Patients are usually first identified due to the presence of visceral symptoms, including prolonged unexplained neonatal jaundice, splenomegaly or hepatomegaly in neonates, or developmental delay in patients aged >6 months [1, 7]. Each of these characteristic symptoms is well-represented within this patient cohort. The new early-onset NP-C SI only includes symptoms that were able to discriminate between patients with NP-C and those without NP-C, based on statistical analysis, irrespective of the symptom’s overall prevalence within this patient cohort. This resulted in several of the more typical symptoms, including those related to developmental delay, being excluded from the new NP-C SI. Because of this, the new early-onset NP-C SI will be particularly useful in facilitating screening in young patients presenting with these clinical signs and symptoms, and as an educational tool to assist physicians to identify young patients with NP-C.

This retrospective analysis revealed some unexpected findings in the clinical picture of NP-C. Pulmonary infiltrates, which are more often associated with a diagnosis of NP-C2 (due to mutations in the NPC2 gene) or with aspiration pneumonia in late-stage progressive disease, were unexpectedly common amongst all NP-C cases (13 %). It is likely that the high incidence of pulmonary infiltrates is related to the number of patients with late-stage disease, or with severe forms of early-onset disease [8]. The frequency of gelastic cataplexy was also higher than expected amongst NP-C cases, and presented almost exclusively in older patients within this cohort (mean age of patients with gelastic cataplexy, 35 months).

The strongest and most specific predictor of NP-C in this cohort is family history of the disease, specifically in parents or siblings, which alone is sufficient for high suspicion of NP-C in patients with unclear medical conditions. A history of NP-C in cousins and consanguinity of parents were not strongly related to NP-C cases in this population (Additional file 3: Table S2). The most common signs and symptoms in patients aged ≤4 years were visceral symptoms, consistent with classical descriptions of the disease [1]. These symptoms distinguished well between NP-C cases and controls, but less well between NP-C cases and NP-C non-cases. This may reflect the signs and symptoms that initially lead to NP-C suspicion and referral for testing in NP-C cases and NP-C non-cases. In further agreement with the known progression of the disease, and in keeping with the young mean age of the patient population, CNS symptoms were not as common as visceral signs and symptoms. Despite this, gelastic cataplexy and VSGP, both identified as specific for NP-C during the development of the original NP-C SI, [15] were still found to be highly suggestive of NP-C in this patient cohort.

Ataxia was not highly specific for NP-C in this population, occurring at a similar frequency in NP-C cases as both NP-C non-cases and controls. Ataxia was reasonably common in early-onset NP-C cases (32 %), but was not observed as frequently as in the original NP-C SI cohort (66 % of NP-C cases) [15]. This is likely due to the majority of the patients in this cohort either being too young or being too early in disease progression for CNS signs and symptoms to become apparent [4].

The original NP-C SI tool performed poorly in patients aged <4 years, [6] but the new early-onset NP-C SI has much greater discriminatory power. The cut-off values within the early-onset NP-C SI denoting the boundaries between low (<3 points), moderate (3–5 points) and high likelihood (≥6 points), were determined according to the calculated sensitivity and specificity for each RPS. Despite the relatively low specificity for detection at these cut-off scores, the sensitivity suggests that a high proportion of patients with NP-C will be correctly identified. When the original NP-C SI was applied to the present cohort of early-onset patients, the ROC AUC (0.603) was comparable with the subpopulation of patients aged <4 years used in development of the original NP-C SI (AUC = 0.562) [6]. This finding suggests that the population characteristics are similar.

The newly developed early-onset NP-C SI outperforms the original NP-C SI in identifying patients with NP-C aged ≤4 years. A finding of high likelihood of NP-C should immediately warrant further confirmatory genetic and laboratory testing (e.g. filipin staining), in accordance with the most recent diagnostic guidelines [7]. Clinical use of this novel tool, particularly by physicians with limited knowledge of NP-C, is anticipated to lead to improved detection rates for NP-C, and detection at an earlier age, supporting monitoring of disease progression and natural history, and initiation of therapy at the earliest onset of neurological and/or visceral symptoms. The ability of the early-onset NP-C SI tool to correctly identify NP-C in suspected patients will further validate the tool, and provide supporting evidence for its use in clinical practice.

AUC, area under the curve; CNS, central nervous system; MCRF, Medical Chart Record Form; NP-C, Niemann-Pick disease Type C; ROC, receiver operating characteristic; RPS, risk prediction score; SI, Suspicion Index; VSGP, vertical supranuclear gaze palsy