Background
Niemann-Pick disease type C (NPC, MIM# 257220) is an autosomal recessive lysosomal storage disease caused by
NPC1 (95%) or
NPC2 (5%) gene mutations. If untreated, the prognosis of NPC is severe, with most patients with infantile-, juvenile-, and adult-onset NPC dying by the age of 10 years, before the age of 30 years, and in their mid-30s, respectively [
1].
Disease-specific therapies with miglustat [
2] or intrathecal 2-hydroxypropyl-β-cyclodextrin [
3] are available; therefore, early and accurate diagnosis is critical. However, establishing the diagnosis of NPC is challenging because of its clinical variability. In order to facilitate diagnosis, the NPC Suspicion Index (NPC-SI) was developed, which includes seven key discriminatory features: splenomegaly, neonatal jaundice, gelastic cataplexy, vertical supranuclear gaze palsy (VSGP), cognitive decline, psychotic symptoms, and family history [
4]. NPC-SI assists in the identification of neurologically advanced cases with the key clinical features; however, especially in adult cases, an initial diagnosis of psychiatric illness, such as schizophrenia or depression, is usually made and NPC diagnosis is delayed by several years until the appearance of neurological complications [
5]. Here, we report three cases of NPC; one juvenile-onset sporadic case and two adult sister cases. The latter two were diagnosed at clinical stages with minimum neurological complications, resulting in early therapeutic interventions.
Discussion and conclusions
This case series highlights that patients with NPC may exhibit remarkable phenotypic variability, which in our cases ranged from juvenile-onset progressive neuropsychiatric deterioration to adult psychiatric symptoms clinically indistinguishable from schizophrenia. The phenotypic variability is further supported by previous studies reporting that a substantial number of patients with NPC do not exhibit cardinal symptoms such as VSGP and dysphagia [
9,
10]. Phenotypic heterogeneity was even observed in a case of monozygotic twins [
11]. Meanwhile, the international study on genetic screening for psychiatric patients with neurological symptoms or splenomegaly, known as the ZOOM study, demonstrated that 3 of 250 participants harbored pathogenic mutations in
NPC1 [
12]. Of note, the patient in Case 3 did not show any neurological symptoms at the time of NPC diagnosis. Therefore, the phenotypes of NPC must be more diverse than previously thought, and patients with mild clinical manifestations may remain undiagnosed. Based on these observations, we would like to emphasize that NPC should be considered in the differential diagnosis of a wide variety of disease entities, including juvenile-onset multi-systemic neurological disorders and adult psychiatric disorders such as schizophrenia.
It is of vital importance to accurately diagnose NPC because disease-modifying therapies are available. Furthermore, it is imperative to diagnose it in the early stages, particularly in cases with mild neurological symptoms, because of the severe prognosis of adult NPC, which results in death at a mean age of 38 years [
9] or 33 years [
10], and the difficulty in ameliorating the neurological symptoms even with miglustat, when the disease is at an advanced stage. In contrast, the appearance of psychotic symptoms consistent with schizophrenia or depression precedes the appearance of neurological complications by several years in more than half of the cases [
13], and the effectiveness of miglustat in alleviating the psychotic symptoms [
14] has been reported, further corroborating the importance of early detection. For this purpose, the NPC-SI was invented and revised based on the cardinal features of NPC [
4]. The NPC-SI in this study varied greatly, depending on the extent to which the key features were detected at the time of diagnosis. The NPC-SI showed that there was high likelihood of NPC in all cases, with the recommendation that the patients should be referred to the NPC referral center (institute) for immediate testing, highlighting the clinical usefulness of the NPC-SI. The fact that the mean RPS of adult cases was as high as 179 [
15] implies that most cases were diagnosed at a stage of fully present clinical manifestations. To benefit from the NPC-SI, it is imperative to enhance the awareness of its usefulness in daily clinical settings, particularly in adult neurology.
In Japan, the current initial diagnostic workup for NPC includes a combination of serum oxysterol (7-ketocholesterol) and urinary bile acids, followed by more specific diagnostic procedures including skin biopsy with filipin staining and
NPC1 or
NPC2 gene analysis. In our cases, mild elevation of urine bile acids in Cases 2 and 3 was informative in the initial workup, whereas the oxysterol value in Case 2 was normal (could not be tested in Cases 1 and 3). Additionally, in line with previous reports, cerebrospinal tau proteins were elevated in Case 1 [
16] and the laboratory values of copper metabolism slightly deviated or were close to the lower limit of the normal levels [
17]. Recently, it has been reported that plasma oxysterol (cholestane-3β,5α,6β-triol) is informative in the detection of NPC [
18]. Additionally, lysosphingolipids have been proposed as a potential biomarker for NPC [
19]. Establishing excellent biomarkers for NPC is highly warranted considering that skin biopsy and genetic analyses are time-consuming and expensive procedures.
Finally, we would like to focus on the narcolepsy experienced by the mother of Cases 2 and 3, who shared the c.160_161insG (p.D54GfsX4) mutation. In addition to gelastic cataplexy as one of the key discriminatory features of NPC, sleep problems, such as excessive daytime sleepiness, are known to be related to NPC, presumably via dysfunction of the locus coeruleus [
20]. Regarding partial manifestations in people with
NPC1 gene heterozygosity, a previous report of a family whose proband developed late infantile NPC with compound heterozygous mutations of
NPC1 described that the heterozygous asymptomatic carriers of
NPC mutations, the oldest sister and parents, had foam cells in their bone marrow smears [
21]. Likewise, it is possible that the haploinsufficiency of the
NPC1 gene identified in our pedigree could also cause mild tissue changes resulting in manifesting carriers. Accumulation of familial histories and genetic evidence is necessary to analyze the relationship between narcolepsy and
NPC1 mutation carriers. We hypothesize that
NPC1 might be an extremely rare candidate gene for familial narcolepsy syndrome.
In conclusion, the cases described in this report highlight the clinical variability of NPC and reinforce the importance of early diagnosis of this rare disease to initiate disease-modifying therapy. We would like to emphasize that the exploration of disease-suggestive findings by use of the NPC-SI in patients with schizophrenia would enhance the diagnostic accuracy of NPC.
Acknowledgements
We are grateful to the patients and their families for their invaluable cooperation and for providing blood samples. We thank Prof. Hasegawa T (Department of Pediatrics, Keio University School of Medicine) for the childhood clinical information of Case 2. We also thank Dr. Tajima H (Department of Pediatrics, Nippon Medical School) and Dr. Asayama K (Department of Neuropsychiatry, Nippon Medical School) for referring the patient of Case 2 and providing clinical information including on oxysterol.