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Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database

  • Jackie Imrie1Email author,
  • Lesley Heptinstall2,
  • Stephen Knight2 and
  • Kate Strong3
BMC Neurology201515:257

https://doi.org/10.1186/s12883-015-0511-1

Received: 23 September 2015

Accepted: 28 November 2015

Published: 15 December 2015

Abstract

Background

Niemann-Pick disease type C (NP-C) is a rare neurovisceral lipid storage disorder characterised by progressive, disabling neurological symptoms and premature death in most patients. During the last decade, national cohort studies have accrued a great deal of data on the symptomatology and natural history of NP-C.

Methods

In an observational cohort study, we present a substantial update based on the clinical presentation and follow-up of all known UK-based patients with a confirmed diagnosis of NP-C who have been tracked on an electronic database at the Department of Genetic Medicine, University of Manchester, UK. Patients were stratified according to accepted age-at-neurological-onset categories. Data on patients’ clinical signs and symptoms, medical history and genetic studies are summarised using descriptive methods.

Results

A total of 146 patients with NP-C were included, representing the full known UK NP-C cohort, as observed from database information between 1999 and the end of 2011: 72 patients (49 %) were alive at the end of the observation period. Among a total of 116 patients (79 %) who possessed at least one identified, disease-causing NP-C gene mutation, 114 (98 %) had NPC1 and two (2 %) had NPC2 mutations. Overall, 53/194 (27 %) identified mutations were novel. Six patients (4 %) had an early, non-neurological neonatal onset form of NP-C. The numbers (%) of patients with accepted age-at-neurological onset forms were: 8 (5 %) early-infantile onset, 51 (35 %) late-infantile onset, 42 (29 %) juvenile onset, and 25 (17 %) adolescent/adult onset. Fourteen patients diagnosed based on visceral symptoms and/or sibling history, confirmed in most cases by genetic analysis, did not have any neurological manifestations at last follow up (11 patients with mean [SD] age at last follow up 2.5 [1.8] years: 3 with mean [SD] age at death 20.8 [15.9] years). A total of 51 patients (35 %) received miglustat therapy. The mean (SD) overall treatment duration up to the end of the observation period was 2.6 (2.3) years.

Conclusions

This UK cohort is the largest national NP-C cohort reported to date, and confirms the wide phenotypic variability of the disease, as reported in other countries. Further analyses are required to assess the impact of miglustat therapy on neurological disease progression.

Keywords

Niemann-Pick disease type C Natural history NPC1/NPC2 Miglustat

Background

Niemann-Pick disease type C (NP-C) is a rare neurovisceral lipid storage disorder characterised by progressive, disabling neurological symptoms and premature death in most patients [13]. It is caused by autosomal recessive inheritance of mutations in either of two genes (NPC1 and NPC2), and has been estimated to affect one case in every 100,000–120,000 live births [1, 2, 4].

The clinical presentation of NP-C is highly heterogeneous, necessitating a multidisciplinary diagnostic process that takes into account clinical assessments, histological and electron microscopic tests, and biochemical and molecular genetic laboratory studies [1, 5]. Clinical work-up requires detection and recognition of numerous non-specific systemic and neurological signs and symptoms. While ancillary testing helps to narrow the differential diagnosis, final confirmation of NP-C requires demonstration of characteristic intralysosomal accumulation of unesterified cholesterol (based on filipin staining in cultured skin fibroblasts) and/or the identification of one or more disease-causing mutations in either the NPC1 or NPC2 genes [1, 2]. The demonstration of abnormal cholesterol homeostasis with impaired low-density lipoprotein (LDL)-induced cholesterol esterification can also provide supportive data in cases with an uncertain biochemical phenotype, but is rarely performed now [5, 6]. Newer screening and diagnostic tools have recently been developed. The NP-C suspicion index (SI) allows more rapid detection of patients who warrant further testing for NP-C [79]. Laboratory measurements of plasma oxysterols (particularly cholestane-3β,5α,6β-triol and 7-ketocholesterol) [1012], and certain sphingolipids such as lyso-sphingosine [13, 14], have shown promise in allowing more rapid diagnosis in patients with suggestive clinical signs and symptoms. The increasing application of these newer measures is expected to increase the efficiency of diagnosis in NP-C.

Previous studies in cohorts of NP-C patients from France, Spain, Portugal and the USA have accrued data describing the biochemical and clinical phenotypes, genetics and natural history of NP-C [1517]. NP-C has historically been considered a childhood-onset disease, but patients with late-onset symptoms are increasingly being detected due to the wider application of biochemical and genetic diagnostic techniques. In 2007, a retrospective case note review documented clinical signs and symptoms and subsequent disease course based on 94 NP-C patients diagnosed in the UK between 1999 and 2006 [15]. Data were available from approximately even numbers of patients with neonatal-onset (n = 33), childhood-onset (n = 31) and adolescent/adult-onset disease (n = 30), and a detection rate of 4–5 new cases per year between 1990 and 1999 was reported [15].

Major efforts have been made in the last decade to further consolidate clinical data from all known NP-C patients diagnosed and managed in the UK. This report provides an update of information from the UK NP-C database based on data collected between 1999 and the end of 2011, including a further 52 patients since the previous report in 2006 [15].

Methods

The UK NP-C database

We reviewed retrospective data for all UK-based patients with NP-C whose details were stored in a database maintained by the Niemann-Pick Disease Clinical Nurse Specialist at the Department of Genetic Medicine, University of Manchester, UK. All data were collected during clinical visits forming part of ongoing long-term care. The database contained information from all UK patients with a diagnosis of NP-C that had been confirmed using filipin staining, causal gene mutation analysis and/or esterification studies between 1999 and the end of 2011 (data cut-off). All patients were either referred or self-referred to the Nurse Specialist or Support Group.

Diagnostic information

Laboratory diagnostic data for all patients are included from at least one of three laboratories in the UK and/or France that provide the required specialised testing. Diagnostic Laboratories in the UK and Lyon, France were involved independently in submitting information on cases they diagnosed to the database.

In general diagnostic information included findings from skin biopsy analyses (filipin staining and cholesterol esterification assays) from all UK patients with: 1) clinical symptoms suggestive of NP-C and; 2) raised plasma chitotriosidase (routinely checked alongside white-cell enzymes if laboratory analyses hinted at a possible lysosomal storage disease). NPC1 gene sequencing analyses were conducted in all patients with positive filipin staining and/or cholesterol esterification findings, and some sibling cases. Patients in whom NPC1 mutations were not identified, or on whom complementation studies have not been performed, underwent further investigations and NPC2 gene sequencing.

Clinical manifestations

During the observation period, information on key signs and symptoms of NP-C were recorded up to the last clinical follow up (i.e., last clinic visit and/or update of medical records in the database) in line with international guidelines for the diagnostic assessment and follow-up of the disease [1]. The following data types were included whenever possible: oculomotor signs (e.g. vertical supranuclear gaze palsy [VSGP]), neurological manifestations (e.g., cerebellar signs [ataxia, dysarthria, dysphagia, dyskinesia], seizures/cataplexy); spasticity; childhood developmental status (e.g. psychomotor delay and/or regression, learning disabilities); cognitive loss/problems, psychiatric abnormalities (e.g., psychosis, behavioural abnormalities); and systemic symptoms (e.g., hepatosplenomegaly, lung disease or neonatal cholestatic disease). Information on miglustat therapy was also included, where available, for all treated patients.

Ethical data reporting

All information was accessed in accordance with applicable laws and ethical requirements for the study period concerned, and all study procedures, including informed consent for molecular genetic analyses, were conducted in line with ethical standards of the responsible institutional ethics committees and the Helsinki Declaration (1975) and subsequent revisions. All patients and/or their kin provided written informed consent for publication of individual clinical details, as presented in this report. Data reported previously for patients included in this cohort, based on publications by Lachmann et al. [18], Patterson et al. [19], and Patterson et al. [20], are identified where relevant.

Data analysis

In recognition of international guidelines for the management of NP-C, patients are assessed based on neonatal presentation of NP-C (characterised mainly by systemic symptoms [splenomegaly, hepatomegaly, neonatal cholestatic disease and liver failure], and hereafter referred to as the ‘neonatal’ form), and as per accepted age subgroups based on onset of neurological manifestations (i.e., early infantile- [<2 years], late infantile- [2 to <6 years], juvenile- [6–15 years] and adolescent/adult-onset [>15 years]). Patients with a confirmed diagnosis but, as yet, no neurological symptoms, were also included in a ‘non neurological’ category.

All data analyses were exploratory in nature, and no statistical analyses of differences between patient subgroups were performed. Data are presented using descriptive statistics (mean, SD, median and range for continuous variables, and n (%) for categorical values). Patients for whom no numerical data values were available were treated as having ‘missing values’.

Results

Overall cohort characteristics

This UK cohort comprised a total of 146 NP-C patients born between 1954 and 2009, among whom 77 (53 %) were female and 69 (47 %) male. Patient demographics and general characteristics per patient subgroup are summarised in Table 1. Among a total of 112 patients (77 %) who possessed at least one identified, disease-causing NP-C gene mutation, 110 (98 %) had NPC1 mutations and two (2 %) had NPC2 mutations. In patients where genetic analyses did not reveal any known or identifiable novel mutations, diagnoses were based on filipin staining and ancillary methods combined with clinical examination findings and medical history.
Table 1

Patient demographics and general characteristics per age-at-onset subgroup

 

Neonatal onset (N = 6)

Early infantile onset (N = 8)

Late-infantile onset (N = 51)

Juvenile onset (N = 42)

Adolescent/adult onset (N = 25)

Gender, n (%) female

3 (50)

7 (88)

28 (55)

25 (60)

10 (40)

Age, years:

     

At neurological onset

     

 na

8

50

40

18

 Mean (SD)

1.1 (0.7)

4.1 (1.2)

9.4 (2.6)

24.2 (8.8)

At diagnosis

     

 na

4c

7c

49

39

24

 Mean (SD)

0.1 (0.1)

1.3 (1.5)

4.6 (5.5)

11.5 (7.4)

29.3 (9.3)

At last follow upb

     

 na

19

21

17

 Mean (SD)

11.6 (8.9)

20.2 (9.0)

39.5 (9.2)

At death

     

 na

6

8

30

19

8

 Mean (SD)

0.19 (0.22)

5.6 (2.0)

13.4 (6.7)

25.9 (8.9)

33.7 (6.2)

Number (%)d with NP-C genetic information

1 (17)

8 (100)

41 (80)

36 (86)

16 (64)

Number (%)d treated with miglustat

2 (25)

17 (33)

20 (48)

12 (48)

aNumber of patients with available data; blast follow up (data cut-off at end-2011) in living patients only; cage at diagnosis not relevant for two neonatal patients and one early-infantile patient who were diagnosed post-mortem; dpercentages calculated relative to total number of patients per treatment subgroup

Six patients (4 %) had the visceral neonatal form of NP-C. The numbers (%) of patients per accepted age-at-neurological onset category were: early-infantile onset (n = 8 [5 %]), late-infantile onset (n = 51 [n = 35 %]), juvenile onset (n = 42 [29 %]); and adolescent/adult onset (n = 25 [17 %]). A total of 14 patients (10 %), most of whom were detected due to early visceral symptoms and three of whom had a sibling history of NP-C, had no neurological symptoms and are categorised herein as having non-neurological disease.

The overall mean (SD; range) ages at neurological onset and diagnosis were 8.8 (8.1; 0–40) years and 10.4 (11.5; 0–49.5) years, respectively. In general, age at diagnosis tended to increase in line with age at onset of neurological manifestations (Table 1): NP-C was diagnosed most quickly among patients with infantile onset, with the greatest delays to diagnosis recorded among patients with adolescent/adult onset. A total of 43 patients (29 %) were siblings who were also affected by NP-C. Based on all patients with available data, the mean time period between neurological disease onset and diagnosis was 1.73 (5.80) years, while this period among the sibling subgroup was 1.25 (4.75) years. In many cases, confirmation of a diagnosis of NP-C in one sibling led to a more rapid diagnosis in either younger or older siblings.

Overall, 72/146 (49 %) patients were alive at data cut-off. Among patients with available data, the mean age at last follow up (i.e., the latest clinical assessment before data cut-off at the end of 2011) ranged from 11.6 years in the late-infantile onset subgroup to 39.5 years in the adolescent/adult-onset subgroup. Mean ages at death among the age-at-onset subgroups ranged from 0.19 years among neonatal patients to 33.7 years in the adolescent/adult-onset subgroup. In non-neurological NP-C patients , the mean age at last follow-up among 11 living patients was 2.5 years (range 0.5–6.1). The mean age at death among three non-neurological patients who died was 20.8 (15.9) years (range 4.9–36.7).

Neurological and psychiatric manifestations: overall cohort

The large majority of patients had at least one neurological manifestation commonly associated with NP-C at last follow up. A total of 19 patients (13 %) had no recorded manifestations, five of whom had the neonatal form of the disease.

Figure 1 summarises the prevalence of individual neurological symptoms per age at onset subgroup. Overall, developmental delay (during childhood) and/or cognitive deterioration were recorded in the greatest proportion of patients up to last follow up (in 119/146 patients [82 %]). In order of incidence, other common neurological signs were: ataxia (in 110 patients [76 %]), VSGP (103 patients [71 %]), dysarthria (99 patients [68 %]), dysphagia (93 patients [64 %]) and seizures/cataplexy (72 patients [50 %]).
Fig. 1

Occurrence of neurological and psychiatric manifestations per patient subgroup Percentages calculated based on numbers of patients with available data

Psychiatric disturbances were recorded in a total of 17 (12 %) patients. As could be expected, all cases in whom psychiatric disturbances were recorded were in the juvenile-onset or adolescent/adult-onset subgroups (incidence per subgroup 8/42 patients [19 %] and 9/25 patients [36 %], respectively).

Visceral symptoms: overall cohort

Visceral symptoms of NP-C were recorded most frequently in patients with the neonatal visceral form of NP-C and in the early infantile-onset and non-neurological subgroups, and least frequently among adolescent/adult-onset patients (Fig. 2). Prolonged neonatal jaundice with or without neonatal liver disease was by far the most common visceral symptom, occurring in all neonatal onset, 6/8 (75 %) early-infantile onset, 29/51 (57 %) late-infantile onset, and 14/42 (33 %) juvenile-onset patients. Only one adolescent/adult-onset patient had a recorded history of neonatal jaundice. Organomegaly (hepatosplenomegaly in most cases) also tended to occur less and less frequently as age at neurological onset increased. All patients in whom no neurological manifestations have yet been recorded had a history of at least one visceral symptom, most commonly prolonged neonatal jaundice (in 5/14 [36 %] patients).
Fig. 2

Occurrence of visceral symptoms per patient subgroup Percentages calculated based on numbers of patients with available data

Clinical symptomatology and outcomes in age-at-onset subgroups

Neonatal onset patients

All six patients with the neonatal form of NP-C had liver disease at or soon after birth (mean [SD] age 0.19 [0.22] years), with organomegaly also apparent in four cases and foetal ascites present in two (Table 2). Hepatosplenomegaly was also recorded in four cases. Patients with the severe neonatal-onset form of NP-C have been reported in other national cohorts to have a short lifespan [2, 16], and the same was true in this UK cohort. Two cases were stillborn and the other four died within 1–7 months of birth. Liver disease was the most frequently recorded cause of death (three patients), and one patient died due to failure to thrive and chest infection. One patient (patient 1) had a record of developmental delay from birth.
Table 2

Patients with neonatal NP-C

Patient number/Gender

Sibship

Date of birth

Age at diagnosis

Age at last FU/deatha

Neonatal LD

HS/S

Seizures/cataplexy

VSGP

Dev. delay

Ataxia

Swallowing problems

Psychiatric disturbance

Slurred speech

Miglustat?

Age at 1st miglustat start

Miglustat duration

Genetic mutations

1/M

2000

4 m

4 ma

PJ LD

HS

From birth

No

2/F

a

2001

PM

0a

FA

No

3/F

a

2002

PM

0a

FA

No

4/M

b

1985

Birth

1 ma

Yes

Yes

No

c.3501C > G(p.Phe1167Leu)/c.3501C > G(p.Phe1167Leu)

5/M

b

1985

Birth

2 ma

Yes

Yes

No

c.3501C > G(p.Phe1167Leu)/c.3501C > G(p.Phe1167Leu)

6/F

c

2009

2 m

7 ma

Yes

Yes

No

c.3020C > T(p.Pro1007Leu)/c.3020C > T(p.Pro1007Leu)

aPatient died; ‘–’, no data/not known; C cataplexy, E epilepsy, FA foetal ascites, HS/S hepatosplenomegaly/splenomegaly, LD liver disease, m months, PJ prolonged jaundice, PM post mortem, y years, w weeks

Early-infantile onset patients

All but one of the early-infantile onset patients were female (Table 3). The mean (SD; range) age at onset of neurological manifestations in this subgroup was 1.1 (0.7; 0–2.0) years. Overall, the mean (SD) time between onset of neurological manifestations and diagnosis was 0.26 (1.49) years, with diagnostic testing commenced based on recognition of visceral symptoms in four patients.
Table 3

Patients with early-infantile neurological onset

Patient number/Gender

Sibship

Date of birth

Age at diagnosis

Age at last FU (y, m)/deathb

Neonatal LD

HS/S

Seizures/cataplexy

VSGP

Dev. delay

Ataxia

Swallowing problems

Psychiatric disturbance

Slurred speech

Miglustat?

Age at 1st miglustat start

Miglustat duration

Genetic mutations

7/F

2000

4 m

3y 4 mb

PJ LD

Yes

C 2y 11 m

<18 m

<2y

13 m

<2y

No

c.3578_3591 + 9del/c.3578_3591 + 9del

8/F

2006

19 m

3y 9 mb

PJ

Yes

No

No

Yes

Yes

19 m

Yes

No

9/F

2005

3 m

4y 1 mb

PJ LD, LTx

Yes

Yes

Yes

Yes

Yes

No

c.1526A > C(p.Tyr509Ser/?

10/F

2003

6 m

4y 5 mb

PJ LD

Yes

E 3y 5 m

<18 m

Yes

Yes

3y

No speech

No

c.2801G > A(p.Arg934Gln)/c.2978del(p.Gly993Glu fsX4)

11/M

d

1990

PM

7y 8 mb

No

No

C 2y E 4y

Yes

<2y

<2y

5y

Yes

No

c.2819C > T(p.Ser940Leu/?a

12/F

e twin

1998

11 m

8y 5 mb

PJ

Yes

C 5y E 5y 10 m

3y

Yes

Never mobile

No

<3y

Yes

7y

1w

c.3107C > T(p.Thr1036Met/c.3557G > A(p.Arg 1186His)

13/F

e twin

1998

11 m

7y 1 mb

PJ

Yes

C 5y E 5y 10 m

3y

Yes

Never mobile

No

<3y

Yes

7y

1w

c.3107C > T(p.Thr1036Met/c.3557G > A(p.Arg 1186His)

14/F

1995

4y 5 m

6y 5 mb

No

No

C 4y E 5y

4y

1y 5 m

4y

5y

Yes

c.3503G > A(p.Cys1168Tyr)/c.3503G > A(p.Cys1168Tyr)

aSecond mutant allele not found after full genome sequencing; bPatient died; ‘–’, no data/not known; C cataplexy, E epilepsy, FA foetal ascites, HS/S hepatosplenomegaly/splenomegaly, LD liver disease, LTx liver transplant, m months, PJ prolonged jaundice, PM post mortem, y years, w weeks

The mean (SD) age at death was 5.6 (2.0) years. The most common recorded cause of death (7/8 cases [88 %]) was ‘NP-C’, reflecting a gradual and in some cases rapid deterioration, with eventual loss of all skills and bodily functions with no one apparent causative factor. However, the recorded causes of death could reflect the way death certificates are completed in the UK, where the primary disease is often stated as the causative factor.

A total of 6/8 patients (75 %) exhibited both prolonged neonatal jaundice and hepatosplenomegaly (Fig. 2). One patient (patient 9) underwent liver transplantation due to severe cholestatic liver disease.

Developmental delay, ataxia and dysarthria were the most commonly recorded neurological symptoms, each occurring in all eight patients (Fig. 1). Cataplexy/epileptic seizures and swallowing difficulties were each recorded in 6/8 (75 %) patients. Ophthalmic assessments revealed VSGP in 5/8 (63 %) patients.

Late-infantile onset patients

The mean (SD; range) age at neurological onset in this subgroup was 4.1 (1.2; 0.4–8.0) years, and the overall mean (SD) time period between neurological onset and diagnosis among patients with available data was 0.56 (5.25) years. Again, diagnostic testing was commenced in approximately half of this patient subgroup after initial recognition of visceral symptoms.

Overall, 30/51 (59 %) patients died before data cut-off at the end of 2011 (mean [SD] age at death 13.4 [6.7] years). ‘NP-C’ was listed as the cause of death in 26/30 patients (87 %) with available information. Pneumonia was listed specifically as the cause of death in two cases, but any association with dysphagia or previous food aspiration was not recorded.

Neurological manifestations were more common than visceral symptoms in this subgroup (Table 4). Again, developmental delay was recorded most frequently (in all 51 patients), followed by ataxia (in 45/51 [88 %]) and VSGP (in 42/51 [82 %]). Dysarthria, dysphagia and seizures/cataplexy were observed in 42/51 (82 %), 36/51 (71 %) and 34/51 (67 %) patients, respectively (Fig. 1).
Table 4

Patients with late-infantile neurological onset

Patient number/Gender

Sibship

Date of birth

Age at diagnosis

Age at last FU (y, m)/deathb

Neonatal LD

HS/S

Seizures/cataplexy

VSGP

Dev. delay

Ataxia

Swallowing problems

Psychiatric disturbance

Slurred speech

Miglustat?

Age at 1st miglustat start

Miglustat duration

Genetic mutations

15/M

f

2000

2y

5 y 4 mb

<1y 8 m

E <4y 11 m

<4y 6 m

<4y 6 m

<4y 6 m

<3y

No

c.3020C > T(p.Pro1007Leu)/c.3020C > T(p.Pro1007Leu)

16/F

2004

11 m

7y 2 m

PJ

S

No

5y

5y

4y

No

Mild <4y

Yes

6y

1y

17a/M

2005

1y 2 m

6y 7 m

HS

No

<6y

<5y

No

No

<6y

Yes

5y

1y

c.1526A > C(p.Tyr509Ser)/c.688_693del(p.Ser230_Val231del

18/F

2002

6 m

6y 4 mb

PJ

S

C 3y

Yes

3y

Yes

3y

3y

No

c.2008_2011del(p.Cys670ProfsX17/?d

19a/M

1990

15y

21y 2 m

E 15y

Yes

5y

Yes

Yes

16y

5y

c.2292G > A(p.Gly764Ala)/?

20/F

1987

6y

13y 6 mb

No

4y

7y

5y 5 m

7y

4y

Yes

No

c.2324A > C(p.Gln775Pro)/c.2956G > A(p.Gly986Ser)

21/M

g

2003

2y 11 m

7yb

PJ

HS

C 4y

2y 11 m

3y

<4y

Yes

<4y

No

c.2464_2465insT(p.Lys822IlefsX48)/c.2201G > T(p.ser734Ile)

22a/F

g

2005

4y

6y 10 m

Slight jaundice

No

No

<6y

<5y

<6y

No

<6y

Yes

3y

3y

c.2464_2465insT(p.Lys822IlefsX48)/c.2201G > T(p.ser734Ile)

23/F

d

1997

3y 9 m

12y 9 mb

No

No

C 6y

6y

6y 5 m

4y 7 m

7y

Yes

Yes

c.2819C > T(P.Ser940Leu)/?

24a/F

2001

7y

10y 10 m

No

No

E 9y C 8y

9y

<5y

9y

6y

<6y

Yes

8y

2y

c.3019C > g(p.Pro1007Ala)/?

25a/F

c/twin

2006

At birth

5y 6 m

PJ LD

HS

No

4y

<4y

<4y

No

4y

Yes

4y

1y

c.3020C > T(p.Pro1007Leu)/c.3020C > T(p.Pro1007Leu)

26a/F

c/twin

2006

At birth

5y 6 m

PJ LD

HS

No

4y

<4y

<4y

No

4y

Yes

4y

1y

c.3020C > T(p.Pro1007Leu)/c.3020C > T(p.Pro1007Leu)

27/F

f

2008

At birth

3y

Yes

Yes

No

No

<3y

Mild

No

No

Yes

0.5y

2.5y

c.3020C > T(p.Pro1007Leu)/c.3020C > T(p.Pro1007Leu)

28/M

1994

9 m

9y 3 mb

PJ LD

HS

C 4y E 7y

4y

1y

<5y

5y

5y

No

c.3182 T > C(p.Ile1061Thr)/?d

29/F

1990

9 m

9y 5 mb

PJ LD

No

Yes

<6y

<6y

6y 5 m

No

c.3182 T > C(p.Ile1061Thr)/?

30/F

1975

8y

28yb

PJ LD

HS

E 17y

8y

13y

5y

Yes

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

31/F

2003

3 m

8y 6 m

PJ LD

At birth

E 8y

4y

<4y

<4y

<7y

5y

Yes

c.3182 T > C(p.Ile1061Thr)/?d

32//M

h

1989

2y

11y 2 mb

PJ LD

No

E 6y 5 m

Yes

4y

Yes

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

33/M

h

1988

1y

8y 5 mb

PJ LD

No

C 6y E 6y

No

<5y

8y

No

c.3182 T > C(p.Ile1061Thr)/?

34/F

1990

4y 9 m

14yb

No

4y

C 7y E 8y

7y

6y

4y

8y

7y

No

c.3182 T > C(p.Ile1061Thr)/?

35/F

1989

7y

16yb

No

At birth

C 8y E 10y

5y

4y

4y 5 m

9y

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

36/M

1987

8 m

12y 1 mb

PJ LD

At birth

C 5y 5 m E 7y 8 m

5y

5y

5y

9y

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

37/M

1991

4y 3 m

9yb

PJ LD

HS 3y

C 5y

4y

4y 6 m

2y

5y

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

38/M

16y

22y 11 mb

PJ

No

No

16y

8y

4y

17y

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

39/M

2001

8 m

10y 6 m

PJ

HS

No

Yes

4y 6 m

Yes

No

No

Yes

7y

3y

c.3182 T > C(p.Ile1061Thr)/del10bp962

40/M

1995

10 m

10yb

PJ LD

S

C 4y 9 m

4y

>4y

Yes

Yes

Yes

No

c.3182 T > C(p.Ile1061Thr)/c.1142G > A(p.Trp381X)

41/F

1996

12 m

11y 9 mb

No

HS 9 m

C 5y 6 m

5y

5y

5y 6 m

No

11y

Yes

7y

4y

c.3182 T > C(p.Ile1061Thr)/c.2656G > C(p.Gly886Arg)

42/F

1983

9y 5 m

25y 7 mb

No

S 9y 6 m

E 5y

Yes

Yes

12y

Yes

Yes

No

c.3182 T > C(p.Ile1061Thr)/c.3019C > G(p.Pro1007Ala)

43/F

1993

6y

9y 6 mb

PJ

5y

C 5y E6y

5y

5y

5y

6y

Yes

No

c.3182 T > C(p.Ile1061Thr)/c.3107C > T(p.Thr1036Met)

44a/M

2007

4 m

4y 1 m

NC

Yes

No

No

<3y

<3y

No

<3y

Yes

2y

2y

c.3182 T > C(p.Ile1061Thr)/c.3107C > T(p.Thr1036Met)

45a/M

1998

4 m

13y 9 m

PJ

Yes

C 8y

5y

9y

No

No

No

Yes

5y

8y

c.3182 T > C(p.Ile1061Thr)/c.3175C > T(p.Arg1059X)

46/F

1996

7y 8 m

15y 6 mb

No

No

C 8y

7y 8 m

7y 8 m

5y

8y 5 m

Yes

No

c.3182 T > C(p.Ile1061Thr)/c.3182 T > C(p.Ile1061Thr)

47a/M

2006

At birth

5y

PJ LD

Yes

C <4y

No

3y

Yes

<5y

<4y

Yes

4y

1y

c.3182 T > C(p.Ile1061Thr)/c.3422 T > G(p.Val1141Gly)

48/F

1982

3y

29y 4 m

PJ

HS at birth

No

3y

3y

5y

18y

Yes

Yes

c.3182 T > C(p.Ile1061Thr)/c.3467A > G(p.Asn1156Ser)

49a/F

2001

12 m

10y 7 mb

No

S

C 9y

4y

4y

4y

7y

6y

No

c.3182 T > C(p.Ile1061Thr)/c.3591 + 4delA

50a/M

2004

1y 11 m

7y 5 mb

No

6 m

C 4y

4y

3y 5 m

3y

4y 5 m

Yes

Yes

5y

2y

c.3259 T > C(p.Phe1087Leu)/c.2516 T > G(p.Ile839Arg)

51/F

i

1984

8y 6 m

27y 5 m

No

2y

C 5y

8y

13y

5y

13y

11y

No

c.3467A > G(p.Asn1156Ser)/?d

52/F

i

1978

14y 5 m

33y 5 mb

No

No

E 13y

14y

5y

13y

13y

12y

No

c.3467A > G(p.Asn1156Ser)/?d

53/F

j

1995

8y 4 m

16y 11 m

No

No

E 7y 5 m C 8y

6y 9 m

3y 5 m

4y

8y 6 m

Yes

No

c.3591 + 4delA/?d

54a/M

2006

At birth

5y 5 m

PJ LD

Yes

No

No

Yes

No

Yes

Yes

No

c.58G > T(p.Glu20X)/c.58G > T(p.Glu20X) [NPC2]

55/M

k

2000

10y 5 mb

No

No

C 6y

5y

5y

5y

5y

Yes

No

56/M

2005

3y 10 m

Yes

4y

4y

No

57/F

l

2y

6yb

No

HS 6 m

No

3y

2y 5 m

2y 5 m

5y

No

No

58/M

9y 5 m

15yb

No

No

C + E 5y

6y

6y

4y

10y

Yes

No

59/F

1987

8y

17y 6 mb

No

4y

C 5y E 10y

7y

5y

6y

11y

Yes

No

60/M

b

1983

8y

16yb

PJ

No

E 16y

Yes

8y

5y

12y

Yes

No

c.3501C > G(p.Phe1167Leu)/c.3501C > G(p.Phe1167Leu)

61/M

l

1990

7y 1 m

17y 5 mb

No

S 2y 6 m

C 10y

7y 1 m

4y 5 m

5y 5 m

10y

Yes

No

62/F

1993

5y

9y 5 mb

PJ

HS 5y 5 m

C 5y

No

18 m

4y

No

Yes

No

63/M

k

1998

Yes

Yes

Yes

Yes

Yes

No

64/F

1982

29y

29y 6 m

No

No

No

29y

Yes

Yes

20y

24y

No

c.3022A > C(p.Asn108His)/c.182 T > C(p.Ile 1061Thr)

65/F

2008

2y

3y 9 m

Yes

HS

No

No

Yes

No

No

No

No

[NPC2]c

aPatients included in previously reported NPC Registry baseline characteristics study [19]; bpatient died; cmutation found but information not accessible during observation period; dsecond mutant allele not found after full genome sequencing. ‘–’, no data/not known; C cataplexy, E epilepsy, FA foetal ascites, HM hepatomegaly, HS/S hepatosplenomegaly/splenomegaly, LD liver disease, LTx liver transplant, m months, NC neonatal cholestasis, PJ prolonged jaundice, PM post mortem, y years, w weeks

The only two patients in the UK cohort who had NPC2 mutations were in this age-at-onset subgroup (patients 54 and 65), both of whom displayed neonatal jaundice and hepatosplenomegaly, as was common among other late-infantile onset patients. However, both of these patients displayed relatively few typical neurological manifestations: patient 54 had developmental delay, dysarthria and dysphagia, and only developmental delay was recorded in patient 65.

Overall, hepatosplenomegaly was the most common visceral symptom in this patient subgroup, recorded in 32/51 (63 %) patients. A history of neonatal jaundice was recorded in 29/51 (57 %) (Fig. 2).

Juvenile-onset patients

Among juvenile-onset patients, neurological manifestations were first noted at a mean (SD; range) age of 9.4 (2.6; 5.0–15.0) years. The mean (SD) time between neurological onset and diagnosis was 1.64 (6.09) years. In this subgroup, diagnostic testing was commenced based on the appearance of neurological signs in the majority (approximately three-quarters) of cases.

In total, 19/42 (45 %) patients had died by data cut-off (mean [SD] age at death, 25.9 [8.9] years) (Table 5). As for late-infantile onset patients, most deaths (11/18 evaluable patients [61 %]) in this subgroup were recorded as being due to ‘NP-C’. Four of the 18 (22 %) patients with available information died due to respiratory-related complications but again, no associations with dysphagia or previous aspiration were noted.
Table 5

Patients with juvenile neurological onset

Patient number/Gender

Sibship

Date of birth

Age at diagnosis

Age at last FU (y, m)/deathc

Neonatal LD

HS/S

Seizures/cataplexy

VSGP

Dev. delay/cognitive problems

Ataxia

Swallowing problems

Psychiatric disturbance

Slurred speech

Miglustat?

Age at 1st miglustat start

Miglustat duration

Genetic mutations

66/F

1970

24y 5 m

41y 2 m

No

Yes

C 24y

12y

11y

24y

24y

32y

24y

Yes

32y

c.1211G > A(p.Arg404Gln)/?d

67/F

1995

10y 1 m

16y 3 m

No

No

E 10y 3 m

10y 1 m

8y

10y

13y

No

Yes

Yes

12y

4y

c.1552C > T(p.Arg518Trp)/c.283 T > C(p.Ser95Pro)

68/F

1996

10y 6 m

15y 1 m

<10y

Yes

<10y

<10y

<10y

No

<10y

No

c.2848G > A(p.Val950Met)/?

69/F

1994

14y

17y 10 m

No

No

No

Yes

10y

Yes

Yes

6y

No

c.2974G > T(p.Gly992Trp)/?

70/F

1983

14y

21y 11 mc

No

No

E 12y

Yes

8y

11y

17y

No

Yes

No

c.3019C > G(p.Pro1007Ala)/?

71a/M

1991

17y

20y 4 m

E 12y

Yes

At birth

Yes

Yes

Yes

Yes

Yes

18y

2y

c.3019C > G(p.Pro1007Ala)/c.1553G > A(p.Arg518Gln

72/F

1986

2 m

25y 10 m

FA LD

At birth

E 14y

11y

11y

14y

15y

No

<14y

No

c.3176G > A(p.Arg1059Gln)/?

73/M

1996

14y

15y 5 m

No

No

No

12y

7y

7y

13y

No

12y

Yes

14y

1y

c.3182 T > C(p.Ile1061Thr)/?

74/M

7y 5 m

20yc

PJ

HS

No

7y

6y 5 m

7y

8y

No

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

75/F

1986

10y

19y 2 mc

No

No

C 11y

10y

7y

7y

11y

No

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

76/M

2000

7y

11y 1 mc

E 7y

Yes

Yes

Yes

Yes

No

Yes

No

c.3182 T > C(p.Ile1061Thr)/?

77a/F

1996

4y 5 m

15y 4 m

PJ

HS 4y 5 m

E 12y

7y

7y

6y

No

No

No

Yes

7y

8y

c.3182 T > C(p.Ile1061Thr)/c.2801G > A(p.Arg934Gln)

78a/F

2002

2 m

9y 10 m

PJ

HS

C 6y

Yes

6y

No

No

No

No

Yes

7y

2y

c.3182 T > C(p.Ile1061Thr)/c.2819C > T(p.Ser940Leu)

79/F

1985

4y 1 m

26y 4 m

PJ LD

HS 11y

C 7y E 17y

11y

13y

13y

16y

No

No

Yes

c.3182 T > C(p.Ile1061Thr)/c.2974G > T(p.Gly992Trp)

80/M

m

1978

12y

18y 8 mc

No

S 2–10y

E 11y

10y

8y

10y

18y

No

Yes

No

c.3182 T > C(p.Ile1061Thr)/c.3019C > G(p.Pro1007Ala

81/M

2003

6 m

8y 8 m

PJ LD

HS

No

Yes

7y

1y

c.3182 T > C(p.Ile1061Thr)/ c.3182 T > C(p.Ile1061Thr)

82/M

1970

At birth

32yc

No

No

E 22y

Yes

12y

Yes

27y

No

Yes

No

c.3182 T > C(p.Ile1061Thr)/ c.3182 T > C(p.Ile1061Thr)

83/F

1991

13y

18y 2 mc

No

No

No

Yes

10y

14y

14y 5 m

No

Yes

No

c.3182 T > C(p.Ile1061Thr)/ c.3182 T > C(p.Ile1061Thr)

84b/M

1988

12y

23y 7 m

No

S 7 y

No

11y 9 m

17y

17y

No

No

No

Yes

21y

2y

c.3182 T > C(p.Ile1061Thr)/ c.3182 T > C(p.Ile1061Thr)

85b/F

1991

6y 5 m

20y 1 m

No

S 5y 5 m

No

8y 3 m

11y 1 m

9y

19y

No

No

Yes

12y

8y

c.3182 T > C(p.Ile1061Thr)/c.3493G > A(p.Val1165Met)

86/F

2005

8w

6y 6 m

PJ LD

HS

No

Mild 6y

No

No

No

No

No

Yes

4y

2y

c.3182 T > C(p.Ile1061Thr)/c.350-351delAG

87/F

1986

17y

25y 5 m

No

No

E 16y

Yes

5y (FAS)

<16y

<16y

Yes

No

c.3182 T > C(p.Ile1061Thr)/c.3566A > G(p.Glu1189Gly)

88/M

1985

18y

26y 7 m

No

S 18 y

No

15y

13y

13y

18y

18y 6 m

18y

Yes

c.3182 T > C(p.Ile1061Thr)/c.3566A > G(p.Glu1189Gly)

89a/F

1994

10y 4 m

17y 9 m

No

No

C <4y E <17y

<17y

<10y 4 m

<10y 4 m

<17y

No

<17y

Yes

14y

3y

c.3182 T > C(p.Ile1061Thr)/c.410C > T(p.Thr137Met)

90/F

1983

15y

22y 8 mc

PJ

Birth

E 14y

11y

8y

11y

16y

No

Yes

No

c.3263A > G(p.Tyr1088Cys)/c.1201C > A(p.Pro401Thr)

91/M

1989

17y

23y

No

No

No

Yes

8y

9y

18y

17y

17y

Yes

18y

3 m

c.3493A > G(p.Val1165Met)/c.3493A > G(p.Val1165Met)

92/F

b

1990

3 m

17y 2 mc

PJ

No

E 15y

11y

10y

10y 5 m

15y

No

Yes

Yes

c.3501C > G(p.Phe1167Leu)/c.3501C > G(p.Phe1167Leu)

93/F

j

1998

10y

13y 6 m

No

No

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

10y

3y

c.3591 + 4delAla/?

94/F

1997

10y

14y 8 mc

No

No

C + E 10y

No

<10y

<10y

Yes Gx

No

Yes

No

c.3019C > G(p.Pro1007Ala)/c.2464-2465insT

95/M

1998

12y

13y 6 m

No

No

C 11y

11y

9y

Tremor 11y

No

No

<5y

Yes

13y

6 m

96/F

1996

9y

15y 8 mc

Mild jaundice

S

Yes

Yes

Yes

Yes Gx

No

9y

No

97/F

1991

16y

17y 6 mc

S, C

Yes

<15y

<15y

<17y

No

Yes

No

98/M

1967

PM

25yc

PJ

S 2 y

No

Yes

11y

2y

14y

25y

Yes

No

99/F

1972

16y

39y 11 m

PJ

No

No

16y

11y

28y

30y

30y

Yes

Yes

c.1211G > A(p.Arg404Gln)/c.1133 T > C(P.Val378Ala)

100/M

1971

14y

29y 2 mc

No

13y 5 m

13y

13y 5 m

13y

13y 5 m

13y

No

Yes

No

101/F

1963

18y

40y 3 mc

PJ

No

E 31y

16y

12y

16y

23y

16y

Yes

No

c.1843C > T(p.Arg615Cys)/c.2972-2973del(p.Gln991ArgfsX15)

102/F

n

Teens

23yc

No

No

No

Teens

Teens

Teens

23y

No

c.3182 T > C(p.Ile1061Thr)/?

103/M

1987

20y

24y 5 m

No

No

No

<19y

No

13y

22y

No

13y

Yes

22y

2y

c.2861C > T(p.Ser954Leu)/c.3107C > T(p.Thr1036Met)

104/M

1972

6y

39y 8 m

No

HS 5y

No

No

No

6y

No

No

No

No

c.1844G > T(p.Arg615Leu)/c.1844G > T(p.Arg615Leu)

105/M

1969

Early 20s

37y 8 mc

PJ

S 4y

E 30y

Yes

11y

20s

Yes

No

Yes

No

106a/F

o

1976

27y

35y 10 m

No

No

No

27y

13y

26y

26y

No

27y

Yes

c.1552C > T(p.Arg518Trp)/c.1552C > T(p.Arg518Trp)

107/M

o

1972

30y

37y 2 mc

No

No

Teens

26y

26y

26y

27y

25y

26y

No

c.1552C > T(p.Arg518Trp)/c.1552C > T(p.Arg518Trp)

aPatients included in previously reported NPC Registry baseline characteristics study [19]; bPatients included in previously reported NPC Registry baseline and longitudinal data study [19, 20]; cpatient died; dsecond mutant allele not found after full genome sequencing. ‘–’, no data/not known; C cataplexy, E epilepsy, FA foetal ascites, Gx gastrostomy, HM hepatomegaly, HS/S hepatosplenomegaly/splenomegaly, LD liver disease, LTx liver transplant, m months, NC neonatal cholestasis, PJ prolonged jaundice, PM post mortem, y years, w weeks

Neurological manifestations were substantially more common than visceral symptoms in this subgroup. Ataxia was the most common neurological manifestation (in 39/42 [93 %] patients), followed by VSGP and childhood developmental delay or cognitive problems (both in 38/42 [91 %]), dysphagia (35/42 [83 %]), dysarthria (33/42 [79 %]) and seizures/cataplexy (25/42 [60 %]) (Fig. 1). Unlike younger patient subgroups, psychiatric disturbances were recorded in juvenile-onset patients (8/42 [19 %] cases). The age at onset of psychiatric disturbances ranged from 16 to 32 years.

Neonatal jaundice and/or cholestatic liver disease were recorded in 14/42 (33 %) patients, and organomegaly was seen in 18/42 (43 %) patients (Fig. 2). While no specific neurological signs were recorded in one patient (patient 81), evidence of neurological involvement was documented at the local treatment centre. However, it is not possible to report this patient’s presenting neurological manifestation as he was lost to follow up.

Adolescent/adult-onset patients

Overall, patients with neurological onset during adolescence or adulthood were characterized by insidious onset and slow disease progression (Table 6). Neurological onset in this older age subgroup occurred at a mean (SD; range) age of 24.2 (8.8; 15.0–40.0) years. The mean (SD) period between neurological onset and diagnosis was 6.0 (6.26) years, and all evaluable patients in this subgroup were diagnosed after the appearance of neurological symptoms. By data cut-off, a total of 8/24 (32 %) patients had died (mean [SD] age at death, 33.7 [6.2] years). Among patients with available records, seven were recorded as being due to NP-C.
Table 6

Patients with adolescent-adult neurological onset

Patient number/Gender

Sibship

Date of birth

Age at diagnosis

Age at last FU (y, m)/deathc

Neonatal LD

HS/S

Seizures/cataplexy

VSGP

Dev. delay/cognitive problems

Ataxia

Swallowing problems

Psychiatric disturbance

Slurred speech

Miglustat?

Age at 1st miglustat start

Miglustat duration

Genetic mutations

108b/M

m

1976

23y

39y

PJ

No

No

17y

17y

25y

25y

No

Yes

Yes

32y

3y

c.3182 T > C(p.Ile1061Thr)/c.3019C > G(p.Pro1007Ala)

109/F

1975

18y

30yc

No

No

E 18y 6 m

18y

15y

15y

24y

18y

Yes

No

c.3182 T > C(p.Ile1061Thr)/c.3019C > G(p.Pro1007Ala)

11/M

1978

20y

27y 3 mc

No

No

No

<24y

<20y

No

23y

Yes

No

111/F

1975

25y 6 m

30yc

No

No

C 25y

25y

16y

24y

23y

No

23y

No

112/M

n

1971

24y

40y 2 m

No

No

No

16y

24y

<24y

No

29y

32y

No

c.3182 T > C(p.Ile1061Thr)/?

113/M

p

1968

19y

43y 2 mc

No

S 18y

E 17y

25y

18y

18y

25y

17y

18y

No

c.1843C > T(p.Arg615Cys)/c.3289-3291del(p.Asp1097del)

114a/M

1987

22y

24y 11 m

No

No

No

22y

15y

15y

23y

No

18y

Yes

24y

0.5y

115/M

p

1969

18y

28y 8 mc

No

S 1y 4 m

No

Yes

Yes

Yes

25y

28y

Yes

No

c.1843C > T(p.Arg615Cys)/c.3289-3291del(p.Asp1097del)

116/F

1963

38y

48y 6 m

No

No

No

<34y

37y

34y

39y

No

34y

Yes

39ye

c.1133 T > C(p.Val378Ala)/c.422_423dup(p.Lys142X)

117a/F

o

1978

25y

33y 11 m

No

No

No

No

25y

25y

32y

No

32y

Yes

29y

4y

c.1552C > T(p.Arg518Trp)/c.1552C > T(p.Arg518Trp)

118/M

27y

35y 4 m

Yes

Teens

No

Yes

Yes

Yes

20s

Yes

No

119d/F

1966

32y

42y

No

No

No

Yes

<18y

29y

38y

No

38y

Yes

37y

8

c.3182 T > C(p.Ile1061Thr)/?

120/M

1972

29y

39y 10 mc

Yes

No

121a/M

1982

20y

29y 2 m

No

No

No

Yes

Yes

No

122/M

1964

31y

48y 6 m

No

Yes

No

Yes

46y

No

Yes

No

No

Yes

42y

5y

123a/M

q

1967

40y

44y 5 m

No

Tremor

<40y

<40y

<40y

No

No

No

Yes

43y

1y

c.1408G > C(p .Ala 470 Pro/c.1816G > C (p.Glu608Gln)

124/F

1961

49y

50y 11 m

No

No

No

46y

42y

42y

49y

40y

42y

Yes

49y

1y

c.2000C > G(p.Ser667Trp)/?

125/F

r

1981

29y

30y 3 mc

No

20y

No

20s

20s

20s

20s

Teens

20s

c.2764C > T(p.Gln922X)/c.1133 T > C(p.Val378Ala)

126/M

r

1985

25y

26y 8 m

No

No

No

25y

Mild 25y

No

No

No

No

Yes

25y

1y

c.2764C > T(p.Gln922X)/c.1133 T > C(p.Val378Ala)

127/M

1969

42y

42y 6 m

No

Tremor (20s)

<34y

<34y

Yes

40y

No

Yes

No

43y

c.2903A > G(p.Asn968Ser)/c.3182 T > C(p.Ile1061Thr)

128/F

1954

49y 6 m

57y 6 m

No

No

No

Yes

Yes

20s

No

No

20s

No

c.3182 T > C(p.Ile1061Thr)/?

129/F

PM

40yc

c.3182 T > C(p.Ile1061Thr)/c.2861C > T(p.Ser954Leu)

130/M

q

40y

41y 9 m

40y

Tremor (35y)

Yes

No

Yes

40y

No

No

Yes

39y

c.1408G > C(p .Ala 470 Pro/c.1816G > C (p.Glu608Gln)

131/F

27y

27y 8 m

No

No

No

No

No

25y

No

27y

No

No

c.3022A > C p (Asn 1008 His)/c.3182 T > C p.(Ile 1061Thr)

132a/M

s

1974

Early 30s

20y

Yes

c.2336del (p.Phe779SerfsX2)/c.2621A > T(p.Asp874Val)

aPatients included in previously reported NPC Registry baseline characteristics study [11]; bPatients included in previously reported NPC Registry baseline and longitudinal data study [11, 12]; cpatient died; dpatient 119 F previously subject of case report by Lachmann et al. [10]; etreatment interrupted (first treatment start at 39 y, second treatment start at 46 y); ‘–’, no data/not known; C cataplexy, E epilepsy, FA foetal ascites, HM hepatomegaly, HS/S hepatosplenomegaly/splenomegaly, LD liver disease, LTx liver transplant, m months, NC neonatal cholestasis, PJ prolonged jaundice, PM post mortem, y years, w weeks

A history of developmental delay and/or cognitive deterioration was the most frequently recorded neurological manifestation (in 21/25 [84 %] patients), followed by VSGP and ataxia (both in 18/25 [72 %] patients). Dysarthria, dysphagia and seizures/cataplexy were present in 28–64 % of patients. Among those with available information on time of onset of specific manifestations, the majority of neurological signs seemed to appear during adulthood. In particular, patient 124 had no observable neurological symptoms up until her 4th decade of life, during which a full spectrum of characteristic neurological signs as well as psychiatric problems occurred. Patient 129 had a long history of neurological problems but no data on age at onset or recorded details on specific neurological manifestations. Patient 132 displayed cognitive deterioration since his twenties, but again, no information is available regarding specific neurological manifestations.

As in the juvenile-onset subgroup, psychiatric disturbances and/or cognitive deterioration were prominent in the adolescent/adult-onset subgroups, recorded in a total of nine patients (36 %). The age at onset of psychiatric disturbances ranged between 17 and 40 years.

There was only one historical record of neonatal jaundice in this subgroup, and organomegaly was recorded in a total of 6/25 (24 %) patients. Splenomegaly or hepatosplenomegaly were observed in three patients during adulthood (at age 18–40 years; patients 113, 125 and 130), and splenomegaly was recorded during the neonatal period in one patient (patient 115 at age 16 months).

Patients with no neurological manifestations

There were a total of 14 patients who had not displayed any neurological manifestations by data cut-off (Table 7). Genetic analyses have revealed NPC1 mutations in the majority (n = 10; 71 %) of these patients, confirming NP-C. Diagnoses among those without identified gene mutations were confirmed based on filipin staining. All of these patients had at least one early visceral symptom of NP-C: neonatal liver disease (mostly prolonged jaundice) and organomegaly both occurred in 11/14 (79 %) patients in this subgroup. Two patients (141 and 143) died in their 2nd and 3rd decades of life due to non NP-C related causes, and patient 146 died aged 4 years due to liver cancer. The remainder of non-neurological patients were alive at data cut-off. The mean (SD) age at last follow up prior to data cut off was 2.5 (1.8) years (range 0.5–6.1 years; n = 11). Among the three patients who died, mean age at death was 20.8 (15.9) years (range 4.9–36.7).
Table 7

Patients with no neurological symptoms

Patient number/Gender

Sibship

Date of birth

Age at diagnosis

Age at last FU (y, m)/deatha

Neonatal LD

HS/S

Seizures/cataplexy

VSGP

Dev. delay/cognitive problems

Ataxia

Swallowing problems

Psychiatric disturbance

Slurred speech

Genetic mutations

133/M

2010

4 m

6 m

Yes

No

No

No

No

No

No

No

134/M

2010

8 m

8 m

Yes

c.3182 T > C(p.Ile1061Thr)/?

135/M

2010

1y

1y

Yes (LTx)

Yes

No

No

No

No

No

No

No

136/M

2006

6 m

2y 5 m

PJ LD

<4y

No

No

No

No

No

No

No

c.3182 T > C (p.Ile1061Thr)/c.3182 T > C (p.Ile1061Thr)

137/M

2003

2y6m

6y 1 m

No

Yes

No

No

No

No

No

No

No

c.3182 T > C (p.Ile1061Thr)/c.3467A > G (p.Asn1156Ser)

138/M

2009

4 m

2y 1 m

PJ LD

Yes

No

No

No

No

No

No

No

c.3182 T > C (p.Ile1061Thr)/?

139/M

t

2010

<1y

1y

Yes

Yes

No

No

No

No

No

No

No

c.3182 T > C (p.Ile1061Thr)/c.3289G > A (p.Asp1097Asn)

140/M

t

2006

5y

No

No

No

No

No

No

No

No

No

c.3182 T > C (p.Ile1061Thr)/c.3289G > A (p.Asp1097Asn)

141/F

s

1971

1y5m

36y 8 ma

PJ LD

Birth

No

No

Yes

No

No

No

No

c.2336del (p.Phe779SerfsX2)/c.2621A > T (p.Asp874Val)

142/F

2008

2y5m

3y

Yes

Yes

No

No

No

No

No

No

No

c.3182 T > C (p.Ile1061Thr)/c.3259 T > C (p.Phe1087Leu)

143/M

1987

16y

20y 10 ma

PJ

Birth

No

No

No

No

No

No

No

c.2621A > T (p.Asp874Val)/c.3591 + 4 delA

144/M

2007

1y9m

4y

No

Yes

No

No

No

No

No

No

No

145/M

2009

4 m

2y

Yes

Yes

No

No

No

No

No

No

No

146/F

2004

7 m

4y 11 ma

PJ

Yes

No

No

No

No

No

No

c.3083-3084delP.Gly1028AlafsX22)/c.2201G > T(p.Ser734Ile)

aPatient died; ‘–’, no data/not known; HS/S hepatosplenomegaly/splenomegaly, LD liver disease, LTx liver transplant, m months, PJ prolonged jaundice, y years, w weeks. Note that none of the non-neurological patients had received miglustat by data cut-off end-2011

Genetics

Overall, 116/146 (79 %) patients had at least one identified NP-C gene mutation (Tables 26 ). Two mutations were recorded in 78/146 (53 %) patients and one mutation was recorded in 38/146 (26 %) patients. Most patients (98 %) with recorded mutant alleles had NPC1 mutations, and two patients (2 %) had NPC2 mutations (one with homozygous c.58G > T(p.Glu20X) mutant alleles and one with a single identified mutation for which information was not available). Thirty patients (21 %) had no recorded information regarding identified NP-C gene mutations. This number may be reduced in future with the increasing availability of next-generation sequencing methods.

Amongst a total of 194 identified mutant NP-C gene alleles, 53 have been classified as novel mutations. The common I1061Thr mutation was recorded in a total of 55 (38 %) patients in the whole cohort (heterozygous in 89 % and homozygous in 11 % of cases). Among the age-at-neurological onset subgroups, I1061Thr mutant alleles were mainly observed in patients with the late infantile- (23/51 [45 %]) and juvenile-onset forms (18/42 [43 %]). A lower proportion of patients in the adolescent-adult onset group had this mutation (7/25 [28 %]). However, the prevalence of I1061Thr mutations was particularly high among non-neurological patients (n = 7 [50 %]; six heterozygotes and one homozygote). One patient with a I1061Thr allele (patient 73), also had a c.882-40 T > A mutant allele, and family studies detected this genotype in the child’s father. However, it is not currently known if the c.882-40 T > A allele is a pathogenic mutation.

Eight patients with available genetic information had the p.Pro1007Ala mutation. Cases were fairly evenly distributed between the late-infantile, juvenile and adolescent/adult-onset subgroups.

Full genome sequencing performed in a number of patients with one identified mutation failed to detect any second mutation. These patients (and their listed genotypes) were: 11 (c.2819C > T(p.Ser940Leu/?), 18 (c.2008_2011del(p.Cys670ProfsX17/?), 28 (c.3182 T > C(p.Ile1061 Thr)/?), 31 (c.3182 T > C(p.Ile1061Thr)/?), 51 (c.3467A > G(p.Asn1156Ser)/?), 52 (c.3467A > G(p.Asn1156Ser)/?), 53 (c.3591 + 4delA/?) and 66 (c.1211G > A(p.Arg404Gln)/?).

Miglustat use

The information regarding miglustat use should be regarded in recognition of the year during which miglustat became commercially available in the EU (2009), and of the time of data cut-off. Overall, 51 patients (35 %) received miglustat during the observation period (Tables 26): 2/8 (25 %) early infantile-onset patients and 17/51 (33 %), 20/42 (48 %) and 12/25 (48 %) patients in the late infantile-, juvenile-, and adolescent/adult-onset subgroups, respectively. No patients with the neonatal form of NP-C and no patients in the ‘non-neurological’ subgroup received miglustat.

The mean ages at treatment start ranged from 0.5 to 49.0 years across the age-at-onset subgroups. Among a total of 38 patients with evaluable information on treatment duration, the overall estimated mean (SD) treatment duration was 2.6 (2.3) years: median (range) 2.0 years (1 week to 8 years). Approximate mean (SD) durations per evaluable age-at-onset subgroup were: 2.6 (2.0) years in late infantile-, 2.8 (2.4) years in the juvenile-, and 2.9 (2.6) years in the adolescent/adult-onset subgroups.

Disease course among related patients

A total of 44 patients from 20 families in this cohort were siblings, most of whom (38 [86 %]) had at least one identified NPC1 mutant allele (see Additional file 1: Table S1). No NP-C gene mutations were identified in three sibling pairs: diagnoses were established by other means based on clinical symptoms and/or laboratory biochemical (filipin testing) and histological methods.

In general, ages at neurological onset and clinical phenotypes appeared congruent between siblings with identical mutant genotypes. Exceptions included patient 6, the sister of patients 25 and 26, all of whom were homozygous for the c.3020C > T (p.Pro1007Leu) mutant allele. Patient 6 had the neonatal-onset form of NP-C, neonatal liver disease and hepatosplenomegaly, and died aged 2 months due to failure to thrive and severe chest infection. Her sisters are twins and have late-infantile onset NP-C. Both twins also had neonatal jaundice and hepatosplenomegaly, with a variety of characteristic neurological signs observed from before the age of 4 years, but both were still alive at the time of data cut-off.

Another sibling pair (patients 80 and 108) were both heterozygotes with c.3182 T > C (p.Ile1061Thr) and c.3019C > G (p.Pro1007Ala) mutant alleles. The older sibling (patient 108) has adolescent/adult-onset NP-C, presented with VSGP, developmental delay and psychiatric disturbances in his late-teens, and survives aged 39 years at last follow up: he had received miglustat therapy for 3 years at data cut-off. His brother (patient 80) had juvenile-onset NP-C and presented with developmental delay and VSGP before 10 years of age. He also had severe seizures that are considered likely to have contributed to his death ‘due to NP-C’ at the age of 18 years.

Finally, patients 139 and 140 both have no neurological manifestations. While patient 139 was diagnosed at an early age following investigations of neonatal liver disease and organomegaly, his older brother has no record of systemic manifestations, and was diagnosed (based on genetic testing) due to mainly to his sibling disease history.

Discussion

It is important to continue gathering knowledge on the natural history of NP-C in order to aid in the clinical management and targeted therapy of affected patients, and to aid in providing counselling and support for their families and caregivers. This summary of data from 146 historical and current UK-based NP-C patients analysed between 1999 and end-2011 provides findings from the largest national NP-C cohort reported to date. Although some patients have minimal data available, they are still included in this report to indicate the full extent of the UK NP-C cohort and provide as full a clinical picture of diagnosed patients as possible.

Based on recent estimates of the total UK population (64.1 million) and national birth rate (12.27/1000) the current birth prevalence of NP-C in the UK is 0.78 cases per 100,000 births, which seems roughly in line with previous estimates of birth prevalence of NP-C in Western Europe (France, Germany and the UK) over the period 1988–2002 [21, 22]. Based on records of all known UK cases diagnosed since 1985, the rate of diagnoses per decade (i.e., the mean number across all years within each decade) has risen steadily over the last three decades, from 3.5 new cases/year during 1985–1994 to 5.1 new cases per year during 1995–2004, and 6.0 new cases per year during 2005–2011. In addition, a total of 21 new cases have been diagnosed between 2012 and 2015, although these most recent cases are not included in this cohort analysis due to non-availability of access to full clinical information after data cut-off. This trend possibly reflects increased awareness of the disease over the last two decades and, in particular, improvements in genetic analysis methods for confirmation of disease-causing mutations.

Data on visceral symptoms in this cohort were in line with baseline data from 163 patients included in the International NP-C Registry [19]. Neonatal liver disease and/or prolonged jaundice, or a history of just neonatal jaundice, was a feature in all age subgroups in this cohort. As could be expected, neonatal jaundice was recorded in many patients (50–100 %) in the infantile-onset subgroups, and in far lower proportions of patients (0–33 %) in the juvenile- and adolescent/adult-onset subgroups. There was a clear trend for decreased occurrence of organomegaly with increasing age at neurological onset, although organomegaly was not as common in the neonatal-onset subgroup as it was among early-infantile onset patients due to its incremental nature. Nevertheless, splenomegaly is generally considered a consistent indicator of possible NP-C in neonates, and has often served as a signal leading to early diagnosis.

NP-C has been reported as the second most common genetic cause of liver disease during infancy in the UK, after alpha-1-antitrypsin deficiency [23, 24], and investigations to exclude NP-C are common practice in liver disease/neonatal units. A large proportion of early-onset patients in this cohort underwent extensive liver investigations during the neonatal period, but in many cases NP-C was subsequently diagnosed years later, after the appearance of neurological signs. This seems typical of the NP-C population as a whole, as reflected by substantial delays to diagnosis in many cases, globally, and reflects the need for clinicians in all specialities to take a full clinical history when seeing new patients.

Based on previous clinical observations, neonatal jaundice without other overt signs of liver disease can herald a more aggressive clinical course of NP-C, particularly if neurological abnormalities appear during the first 4 years of life [15, 24]. However, the degree of neonatal liver disease does not appear to be a reliable indicator of future disease progression, as illustrated by cases where neurological manifestations became apparent during adulthood despite a history of neonatal liver disease. It is important to consider that early visceral symptoms lack prognostic value in NP-C during family counselling for NP-C cases diagnosed during the neonatal period, providing advice for planning ahead for the emotional and financial burdens of the disease [25]. Of particular note are the sibling patients 132 and 141, who share identical novel heterozygous NPC1 mutations. Both had very severe neonatal liver disease necessitating intensive care, and were followed up over a course of years by their hepatologist. Patient 141 had non-neurological NP-C and died at the age of 36 due to a severe infection in late pregnancy: post-mortem examination showed no storage or neurological problems. Her brother (patient 132) was still alive and self-caring at data cut off, and displayed mild cognitive impairment at last follow up.

The profile of neurological manifestations recorded in this cohort was consistent with other large-cohort NP-C studies [2, 4, 16, 19, 26], with over half of patients displaying one or more of: ataxia; VSGP; dysarthria; dysphagia; and seizures/cataplexy. In terms of age at neurological onset, two-thirds of patients fell into the late infantile-onset and juvenile-onset subgroups. Given the frequency of childhood-onset forms of NP-C in this UK cohort up to the end of 2011, it is not surprising that developmental delay or cognitive deterioration were the most frequently recorded neurological manifestations. Similarly, the frequency of seizures and/or cataplexy was reflective of the overall young age at onset among UK patients, as seizure activity has generally been reported most frequently among patients with late-infantile and juvenile-onset disease [1].

It is notable that ataxia, which is a central component of the recently developed NP-C suspicion index (SI) for the detection of NP-C among patients with suggestive clinical symptoms [9], was the second-most common neurological manifestation in this cohort. VSGP is recognised as one of the earliest signs of neurological deterioration in NP-C [1, 9, 27, 28], so it is unsurprising that this neurological sign was also common. Excluding neonatal cases, VSGP was observed in over half of all UK patients, and was most frequent in those with the juvenile-onset (classical) form of NP-C.

Psychiatric manifestations were only recorded in patients in the juvenile and adolescent/adult-onset subgroups, which is in agreement with previous screening data [29] and numerous other published findings [1, 2, 3034]. While little information was available on the precise types of psychiatric disorders for this analysis, patients with juvenile-onset NP-C tend to manifest behavioural problems, impaired learning, and expressive language disorder, which often culminate in failure at school [1]. Patients with adolescent/adult-onset NP-C and psychiatric disorders often exhibit schizophrenia-like psychosis (in up to 25 % of cases), but can also be diagnosed with bipolar disorder, depression and obsessive-compulsive disorder [1, 34].

While the severe neonatal and early-infantile onset forms of NP-C resulted in rapid deterioration and early mortality in the current cohort, total mortality decreased with increasing age at neurological onset among the late-infantile (59 %), juvenile (45 %) and adolescent/adult-onset (32 %) subgroups. Mean age at death values reflected this trend. Some adolescent/adult-onset patients have survived into their fifth and sixth decade of life, which confirms the more insidious, mild course of neurological deterioration that has been reported before among adults with NP-C [1, 26]. Indeed, a recent case has been reported of a 66 year-old female who remains free of any neurological or psychiatric manifestations 18 years after initial presentation [35].

Wide genetic variability coupled with a high degree of phenotypic heterogeneity make genotype–phenotype correlations difficult in NP-C. Variable clinical phenotypes have even been observed in monozygotic twins with the same genetic mutation [36]. Overall, 53/194 (27 %) mutations identified in this cohort were classified as novel. The exon 21 (p.I1061Thr) mutant allele of NPC1 has previously been associated with the common juvenile-onset form of the disease, and is associated with a relatively well characterised cellular function and biochemical phenotype [3739]. The overall prevalence of this allele has been quoted as approximately 15 % [21], although more recently it has been reported as particularly frequent (in 20–25 % of diagnosed cases) in France and the UK [2]. Based on this cohort update, the p.I1061Thr mutant allele was present in 38 % of patients overall, occurring in approximately equal proportions of patients in the late-infantile and juvenile-onset subgroups. The incidence of the second most frequent known NPC1 mutation – p.1007Ala – appeared relatively much lower, occurring in the heterozygous state in only eight patients overall. The prevalence range for p.1007Ala alleles among the late-infantile, juvenile and adolescent/adult-onset subgroups was 4–10 %.

Interestingly, the prevalence of p.I1061Thr mutations was particularly high in the non-neurological subgroup, where it occurred in 50 % of patients. This begs the question of whether some patients currently in the non-neurological group might progress to develop neurological manifestations in the future. For instance, ‘non-neurological’ patient 136 had no neurological symptoms at last documented follow up aged 2.5 years. However, other patients with homozygous p.I1061Thr mutations (patients 46 and 81–84) all had late-infantile or juvenile onset neurological symptoms. In the same way, many patients with heterozygous p.I1061Thr mutations developed neurological symptoms during the late-infantile period (up to 6 years of age, n = 21), the juvenile period (n = 14), or during adolescence/adulthood (n = 7). Further follow-up might therefore result in re-categorisation of some or all of the ‘non-neurological’ p.I1061Thr patients as having symptomatic neurological disease. Nevertheless, the same cannot be said for eight patients in the non-neurological group in whom p.I1061Thr mutations have been excluded, and/or in whom no known NPC1 mutant alleles have been detected.

Substrate reduction therapy (SRT) using miglustat has been shown to be effective in treating adult patients with Gaucher disease [4044], and subsequently in the treatment of progressive neurological manifestations in children and adults with NP-C [1, 28, 4548]. In total 34 % of UK patients have received miglustat therapy for any period of time. Longitudinal analyses of serial clinical status assessments are required to determine the impact of miglustat on neurological disease progression in this cohort.

Conclusions

In summary, the prevalence of NP-C in the UK is in line with previous observational data from other European cohorts, and it is notable that the annual rate of diagnosis of the condition has increased over the past 30 years, possibly due to increasing awareness and improvements in molecular diagnostic methods. The wide phenotypic variability and the overall profile of genotypes detected among UK patients are also consistent with data from other Western populations. In particular, age at onset of neurological manifestations once more appeared associated with more rapid disease progression and a lower age at death. Further analyses are required to assess the impact of miglustat therapy on neurological disease progression.

Abbreviations

LDL: 

low-density lipoprotein

NP-C: 

Niemann-Pick disease type C

NPC1/NPC2

genes affected in NP-C

SD: 

standard deviation

SRT: 

substrate reduction therapy

VSGP: 

vertical supranuclear gaze palsy

Declarations

Acknowledgements

We extend thanks to specialist nurses Alison Cousins, Victoria Crook, Liz Morris, Louise Simmons and Collette Stainforth for their help in updating data on the NP-C patients under their care. We are also indebted to the late Professor Ed Wraith for his expert guidance during the development of the UK NP-C database. Matthew Reilly PhD at InTouch Medical Ltd provided medical writing support in the preparation of this manuscript, paid for by Actelion Pharmaceuticals Ltd.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
NPUK, Vermont House, Concord, Washington
(2)
Department of Genetic Medicine, University of Manchester
(3)
The Care Forum

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