Clinical, genotypic, and neuropsychological profile in a series of cases of patients with Niemann-Pick type C disease

doi:10.21203/rs.3.rs-4177612/v1

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Clinical, genotypic, and neuropsychological profile in a series of cases of patients with Niemann-Pick type C disease

https://doi.org/10.21203/rs.3.rs-4177612/v1

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Background

Niemann-Pick type C (NPC) disease is a rare neurodegenerative disorder with a wide spectrum of clinical manifestations and genetic variability. This cross-sectional study aimed to comprehensively describe the neuropsychological impact of NPC and investigate its correlation with specific genotypes.

Results

Eight patients from six unrelated families were included in this study. The age at symptom onset ranged from 2–16 years, with all patients presenting with ataxia, dysarthria, and cognitive impairment. Following the initiation of miglustat treatment, five patients showed a decrease in the Scale for the Assessment and Rating of Ataxia (SARA) score, whereas two demonstrated subsequent increases. Brain magnetic resonance imaging scans were performed in five patients, revealing white matter abnormalities and/or brain volumetric reduction in three cases. Despite the small sample size, the overall cognitive performance of the cohort was significantly below average. The Family Environmental Scale highlighted positive structural patterns, particularly regarding Personal Growth and System Maintenance. Genetic analysis identified five mutations in the NPC1 gene, correlating with the severity of impairments and clinical outcomes.

Conclusions

This study highlighted a consistent association between cognitive and behavioral impairments, with severity correlating with age and specific genetic variants. Notably, a subgroup showed a higher prevalence of psychotic and behavioral symptoms, suggesting a potential link with specific genetic variants.

Niemann-Pick Disease

Type C

Neuropsychological Assessment

Mental Disorders

Cognition

Genetic Association Studies

Familial Impact

Niemann-Pick type C (NPC) is a rare hereditary disorder caused by mutations in NPC1 or NPC2 genes. The clinical manifestations of NPC vary significantly, making early diagnosis challenging [1]. This disease is characterized by defects in lipid metabolism and lysosomal storage, leading to the accumulation of cholesterol and sphingolipids in the lysosomes [2]. Clinical heterogeneity in NPC is evident through differences in age at onset, presenting signs, and patterns of organ system involvement [3].

Genotype-phenotype relationships for NPC1 variants are increasingly being identified, enabling greater predictability of symptom severity and disease progression [3]. Additionally, the broader utilization of whole-exome sequencing allows the identification of non-classical phenotypes of NPC, ranging from more severe to milder forms [4].

Cognitive impairment is a primary symptom of NPC, with some studies suggesting its presence in nearly all patients with NPC [5]. Nevertheless, limited data are available concerning the neuropsychological profiles of patients with NPC, particularly in adults, and their correlation with specific genotypes [6, 7]. Conducting further assessments of cognitive impairments and functioning of the families are crucial for gaining a comprehensive understanding of the challenges faced by patients. Such assessments can help tailor cognitive remediation strategies and facilitate the provision of appropriate support in educational and occupational settings [7].

This study aimed to provide a comprehensive analysis of the clinical, genetic, and psychological data to contribute to a deeper understanding of the disease.

This cross-sectional, observational, descriptive study was conducted at Pequeno Príncipe Children’s Hospital and approved by our Ethics Committee (Approval #CAAE 31880620.9.0000.0097). All experiments were performed in accordance with the guidelines and regulations of the Brazilian National Commission of Health (Commission of Ethics in Human Research-CEP/CONEP). The participants and/or their parents provided formal written consent for the use of all data in the publication of this study.

We included participants with a pathogenic or likely pathogenic variant in homozygosity or compound heterozygosity in NPC1 or NPC2 gene. Genetic testing was conducted for the new generation sequence of genes NPC1 and NPC2. Buccal swab samples were collected, and deoxyribonucleic acid (DNA) was extracted from the samples for genetic analysis using probes for the target regions. Next-generation sequencing was performed using Illumina technology, and alignment and variant identification were performed based on bioinformatics protocols using the GRCh38 human genome as a reference. Potential pathogenic variants and regions with inadequate sequencing depth were confirmed using automated Sanger sequencing, which was conducted using a genetic analyzer. Variants were described according to the nomenclature recommended by the Human Genomic Variation Society.

Novel variants were classified according to the guidelines of the American College of Medical Genetics and Genomics [8], based on very low allele frequency, compound heterozygosity with a pathogenic variant, residue evolutionary conservation, and biochemical results. New variants were checked using the Human Gene Variant Database and ClinVar database. Mutations were grouped according to their type (missense or non-missense). The pathogenicity of novel missense mutations was predicted using in silico analysis.

For the clinical severity assessment of patients, the 5‑domain NPC Clinical Severity Scale (NPCCSS) score [9] and the Scale for the Assessment and Rating of Ataxia (SARA) were used [10].

The estimated full-scale intelligence quotient (FISQ) was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI) [11]. The WASI comprised four subtests, two verbal and two performance scales: Vocabulary, Similarities, Block Design, and Matrix Reasoning. The raw scores obtained using the four subtests were converted into scaled scores.

We utilized the Portuguese-validated version of the Family Environment Scale (FES), a self-reported scale consisting of 90 items designed to assess family functioning across 10 different domains: (1) cohesion, (2) expressiveness, (3) conflict, (4) independence, (5) achievement orientation, (6) intellectual cultural orientation, (7) active recreational orientation, (8) moral-religious emphasis, (9) organization, and (10) control. The presence of problems is typically indicated by high scores on the conflict and control scales or low scores on other scales [13, 14].

The Adult Self-Report (ASR) and the Child Behavior Check List (CBCL) are part of a set of scales used to monitor behavioral and emotional problems in individuals aged 18–80 years, and 1 1/2–18 years, respectively. The raw score is converted into T-scores using the Assessment Data Manager (ADM) software and quantified across dimensions, such as anxiety/depression, withdrawal, somatic complaints, social problems, thinking problems, attention problems, rule-breaking behavior, aggressive behavior, depressive problems, anxiety problems, somatic problems, attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, and conduct disorder. Additionally, the ASR also provides a total problem score and scores for internalizing and externalizing problems [15].

Eight patients with NPC were identified from six unrelated families, including four (50%) females and four (50%) males, aged between 5 and 36 years. Table 1 summarizes the clinical, genetic, and neuropsychological findings of all the patients.

Table 1

Clinical, genetic, and neuropsychological data of the patients with NPC
		P1	P2	P3	P4	P5	P6	P7	P8
Sex		F	F	M	M	M	F	F	M
Age		36	23	22	19	23	24	5	17
Family		1	1	1	2	3	4	5	6
Gene		NPC1	NPC1	NPC1	NPC1	NPC1	NPC1	NPC1	NPC1
Variant 1	Variation	c.3019C > G	c.3019C > G	c.3019C > G	c.3104C > T	c.3104C > T	IVS24 + 2T > G	c.3104C > T	c.2972_2973delAG
	Consequence	P1007A	P1007A	P1007A	A1035V	A1035V	-	A1035V	Q991fs
	Type	Missense	Missense	Missense	Missense	Missense	Splicing	Missense	Frameshift
Variant 2	Variation	c.3019C > G	c.3019C > G	c.3019C > G	c.3019C > G	c.3019C > G	c.3019C > G	c.3689del	c.3019C > G
	Consequence	P1007A	P1007A	P1007A	P1007A	P1007A	P1007A	L1230fs	P1007A
	Type	Missense	Missense	Missense	Missense	Missense	Missense	Frameshift	Missense
Age of first neurological symptoms		16	14	12	6	8	5	2	2
Age of onset of ataxia		16	14	12	10	12	6	2	2
Epilepsy		-	-	-	+	+	+	+	+
NPCCSS		9	8	3	7	4	18	25	25
SARA		NA	19	7	33	NA	NA	40	40
WASI		40	55	60	55	NA	46	44	NA
Internalizing problems		48	44	40	44	73	51	53	NA
Externalizing problems		59	39	45	29	93	57	37	NA
Total problems		54	40	41	40	86	58	49	NA
NA: Testing could not be performed; P8 was too compromised and hospitalized in a psychiatric clinic. M, male; F, female; NPCCSS, Niemann-Pick type C disease Clinical Severity Scale; SARA, Scale for the Assessment and Rating of Ataxia; WASI, Wechsler Abbreviated Scale of Intelligence.

The age at the onset of neurological symptoms ranged from 2–16 years, and all patients exhibited ataxia, dysarthria, and cognitive impairment. Comorbidities included epilepsy and psychiatric disorders, with six patients using psychotropic drugs (such as antipsychotics and antidepressants) and five taking anticonvulsant drugs.

The SARA scores were comparatively assessed for some patients across consultations in 2013, 2016, and 2023. Some patients exhibited a ceiling effect during the initial assessment (P7 and P8). Following the commencement of miglustat treatment, five patients (P1, P2, P3, P4, and P5) showed a decrease in the SARA score, whereas one (P6) exhibited an increase in score despite treatment initiation. Follow-up evaluation of three of these patients (P2, P3, and P4) revealed that one patient (P3) had a slight increase in the score, whereas the other two (P2 and P4) demonstrated substantial increases, with scores surpassing their values before treatment. These findings are illustrated in Fig. 1.

Brain magnetic resonance imaging (MRI) scans were performed on five patients (P2, P3, P4, P5, and P7). Among them, two (P2 and P3) displayed normal results, whereas the remaining three (P4, P5, and P7) showed abnormalities. Notably, two patients (P4 and P5) exhibited diffuse brain volumetric reduction, particularly in the cerebellar region. White matter changes were observed in three patients (P4, P5, and P7), with one showing peritrigonal hyperintensities (P4), another presenting scattered oval foci (P5), and the third (P7) displaying symmetrical bilateral involvement of both cerebral hemispheres with frontoparietal subcortical predominance.

Five mutations were identified in the NPC1 gene: two missense (P1007A and A1035V), two frameshift (L1230fs and Q991fs), and one splice-site mutation (IVS24 + 2T > G). All newly described mutations have been predicted to be disease-causing according to the guidelines of the American College of Medical Genetics and Genomics [8].

Figure 2 summarizes the family dynamics using the FES, revealing the family’s emphasis on ethical and religious values, with clear organization and structure in planning family activities and responsibilities.

Table 2 summarizes the behavioral and emotional problems evaluated in all patients. Patient (P5) presented attention problems and ADHD symptoms, P6 exhibited depressive problems, and P7 showed several psychopathological symptoms, including withdrawal, attention problems, thought disturbances, aggressiveness, rule-breaking behavior, and intrusiveness. In the DSM-oriented scale, P7 showed symptoms of depression, avoidant personality, ADHD, and antisocial personality.

Table 2

Behavioral and emotional problems evaluation of patients with NPC
		P1	P2	P3	P4	P5	P7			P6
ASR Syndrome Scale Scores (score T)	Anxious/depressed	52	51	51	50	50	61	CBCL Syndrome Scale Scores (score T)	Emotionally reactive	50
	Withdrawal	51	50	50	50	61	70		Anxious/depressed	56
	Somatic complaints	51	51	50	52	52	79		Somatic complaints	53
	Thought problems	55	50	50	56	50	90		Withdrawal	56
	Attention problems	59	52	50	50	73	73		Sleep problems	56
	Aggressive behavior	59	50	50	50	53	100		Attention problems	51
	Rule-breaking behavior	51	50	50	50	61	76		Aggressive behavior	50
	Intrusive	63	50	53	62	57	80
ASR DSM-Oriented Scales (score T)	Depressive problems	50	57	50	50	59	65	CBCL DSM-Oriented Scales (score T)	Depressive problems	70
	Anxiety problems	51	50	59	50	50	60		Anxiety problems	54
	Somatic problems	51	50	50	56	50	75		Autism spectrum problems	58
	Avoidant personality	50	50	51	50	50	65		AD/H problems	50
	AD/H problems	54	50	50	50	70	85		Oppositional defiant problems	50
	Antisocial personality	56	50	50	50	53	86
ASR	Internalizing problems	48	44	44	40	51	73	CBCL	Internalizing problems	53
	Externalizing problems	59	29	39	45	57	93		Externalizing problems	37
	Total problems	54	40	40	41	58	86		Total problems	49
NPC, Niemann-Pick type C; AD/H, attention-deficit/hyperactivity; CBCL, Child Behavior Checklist; DSM, Diagnostic and Statistical Manual of Mental Disorders; ASR, Adult Self-Report.

Here, we present a series of eight patients who were followed up since the onset of their first symptoms at the largest pediatric hospital in Brazil. We analyzed the clinical, neuropsychological, and land genetic profiles of these patients, as well as their familial characteristics.

Ataxia is a cardinal and frequent symptom of NPC [16]. Previous studies have reported improvements in ataxic symptoms following the initiation of miglustat treatment [17]. However, in our study, only one patient showed sustained stabilization of their condition. The other two initially stabilized and then exhibited sequential progressive worsening. Given the small sample size, attributing this medication stabilization solely to transience is challenging and may represent an individual characteristic of this sample.

Neuroimaging in patients with NPC reveals a variable pattern, with some individuals showing normal results, whereas others exhibit the most common changes, such as cortical and cerebellar atrophy [18]. The accumulation of lipid substrates within neurons leads to structural changes, including the formation of meganeurites, axonal distension, spheroid formation in axons, and ectopic dendritogenesis. Certain brain regions, such as the cerebellum, brain stem, hippocampus, and basal ganglia, are notably more affected in NPC, resulting in neuroaxonal dystrophy due to ganglioside accumulation [19]. These neuronal changes become evident during neuroimaging examinations as the disease progresses, manifesting as alterations in white matter integrity, myelination, and axonal integrity. Macroscopically, atrophy occurs in the cerebellum, thalamus, hippocampus, caudate, and cortical nucleus, which aligns with the MRI findings in the individuals in this study [20]. Consistent with previous studies, imaging changes are correlated with increased phenotypic severity, particularly ataxia and ocular motor function [18, 21]. These abnormalities may also be influenced by the patient’s genotype.

The Family Environment was evidenced as a structured and supportive family function, with better agreement between family members. This data is consistent with previous findings demonstrating a relationship between patient functioning and family agreement, which can influence the family's emotional state and prevent internal conflicts, especially during stressful events [22].

Cognitive and/or behavioral impairments were identified at different severities in all patients analyzed. Cognitive impairment is consistently observed in patients with NPC, and its extent is directly proportional to the patient's age and severity of clinical symptoms [5, 7]. The pathogenicity of the variant correlated with both greater clinical severity and cognitive impairment. Interestingly, even in milder variants, the cognitive impact increased with advancing age.

Psychotic symptoms are reported in approximately 25% of patients with NPC, although some studies have observed rates as high as 55% [23–25]. Notably, these patients often show resistance to antipsychotic medications, which may not be effective in managing these symptoms [26]. Moreover, behavioral symptoms commonly associated with frontal dysfunction, such as hyperactivity, social cognitive impairment, disinhibition, and impulsive behaviors, are most prevalent in patients with NPC [25]. Unlike cognitive impairment, the frequency of behavioral disorders did not increase in older patients despite signs of worsening as the disease progressed. Conversely, behavioral problems, especially those related to aggression, were predominantly reported in patients with the A1035V variant, indicating a potential relationship between the type of mutation and the observed behavioral disorders. Behavioral deterioration tends to occur in patients susceptible to this variant.

NPC exhibits a broad phenotypic spectrum, encompassing variations in the age of symptom onset, disease progression rate, severity, affected organs, impact on the central nervous system, and response to pharmacological treatments [27]. Moreover, the phenotypic expression of NPC can be influenced by factors such as the level of residual function of the defective protein and specific genetic variants involved. Cardinal symptoms primarily manifest as motor-related, behavioral, and psychiatric abnormalities that have a significant impact on the lives of patients and their families. Neurobehavioral and psychiatric manifestations, like phenotypic severity and neuroimaging abnormalities, correlate with the patient's genotype.

P1007A was initially described in Canadian patients [28] and represents one of the most common "variant" alleles [18, 29]. The P1007A mutation presents cellular changes typical of the so-called "variant biochemical phenotype," characterized by normal low-density‐lipoprotein (LDL)-induced cholesterol ester formation rate and minimal accumulation of non-esterified cholesterol in the vesicles [30]. A single P1007A allele is adequate for maintaining some degree of cholesterol trafficking, resulting in a variant phenotype typically diagnosed at a later age with lower biomarker levels [3, 30]. Despite the observed intrafamilial phenotypic variability in patients with homozygous P1007A variants, all patients had NPCCSS scores below 9, with the highest score recorded in a patient aged over 35 years.

A1035V appears as a relatively frequent allele in Portugal and Brazil [3, 30, 31]. A1035V is a conserved mutation that partially affects the level of mature mutant proteins, leading to a severe phenotype [32]. Typically, it manifests with a classical phenotype [3, 30].

Patients with compound heterozygosity for the A1035V and P1007A variants scored lower than 10; however, both patients experienced significant psychiatric and behavioral problems that were not identified in the other patients in this study. Psychotic symptoms and impulsivity are common manifestations of NPC [33]. Although these findings were primarily observed in patients with the A1035V variant, this may not necessarily indicate a direct correlation between psychiatric or behavioral symptoms and the A1035V variant. Instead, the milder clinical severity in patients with homozygous P1007A mutations or greater clinical severity in patients with loss-of-function or intronic variants could explain these findings.

Truncating mutations include nonsense, frameshift, and splice-site mutations [34], with one patient displaying a variant in the splice donor site in compound heterozygosity. Other variants of the splice donor site in intron 24 have been described in patients with NPC [29, 35]. All truncating mutations are severe [34]. In the case of patient (P5), who possessed both a mild and a severe variant, a moderate phenotype was observed.

Other truncating mutations, specifically L1230fs and Q991fs, were identified, both being uncommon variants resulting in loss of function. As presented in this study, patients with loss-of-function variants had more severe forms (neonatal and early childhood) [36], with an earlier age of onset and a higher NPCCSS score. Although the classical definition of a severe phenotype typically implies the presence of severe mutations in both alleles [34], the reported patients exhibited only one severe variant. This suggests that the presence of a single severe variant may be adequate for the development of an early and severe form of the disease.

Regarding family functioning, most analyzed families exhibited a typology characterized by a strong moral and religious structure, emphasizing ethical and religious values and issues within the family. This profile results from the condition of patients with NPC and can also be attributed to the cultural context in which these families are situated. Hispanics often rely significantly on religion as a vital support system for their families [37].

Despite its rarity, this study was constrained by a small sample size and the analysis conducted at a single site. Nevertheless, a comprehensive approach involving clinical, genetic, and psychological data contributes to a better understanding of this population.

NPC exhibits diverse clinical presentations and consistently shows associations with cognitive and behavioral impairments. The severity of these impairments correlates with age and specific genetic variants. Family functioning within this population displays a common characteristic influenced by cultural and religious values, potentially attributed to the Latin culture in which they are embedded rather than solely to the patients' condition. Despite the small sample size, a subgroup showed a higher prevalence of psychotic and behavioral symptoms, suggesting a potential link with specific genetic variants. These insights highlight the multifaceted nature of NPC, where cognitive and behavioral challenges are influenced by genetics, age, and cultural factors.

ADHD

Attention-deficit/hyperactivity disorder

ADM

Assessment Data Manager

ASR

Adult Self-Report

CBCL

Child Behavior Checklist

DNA

Deoxyribonucleic acid

DSM

Diagnostic and statistical manual of mental disorders

FES

Family Environment Scale

GRCh38

Genome reference consortium human build 38 patch release

LDL

low-density‐lipoprotein

MRI

magnetic resonance imaging

NPC

Niemann-Pick disease type C

NPCCSS

NPC Clinical Severity Scale

SARA

Scale for the Assessment and Rating of Ataxia

SDQ

Strengths and Difficulties Questionnaire

WASI

Wechsler Abbreviated Scale of Intelligence

Ethics approval and consent to participate: All research aspects were approved by the Ethics Committee on Research Involving Human Subjects at our institution (approval number 31880620.9.0000.0097). The participants and/or their parents provided formal written consent for the use of all data in the publication of this study.

Consent for publication: Consent for publication was obtained from all patients.

Availability of data and materials: The deidentified data supporting this study's findings can be requested from the corresponding author, Dr. Cordeiro, upon reasonable request based on Data Transfer Agreement. Genetic data has been deposited at ClinVar.

Competing interests: The authors declare that they have no conflicts of interest.

Funding: This study was funded in part by Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES, grant #001 to RS, DAV, MZ and TSB).

Authors’ contributions:

RM, DAV and MLC wrote this article.

RM, MLFSS, DAV and MZ conducted the clinical evaluations, physical examinations, and treatment administration.

TB and VL did the cognitive and behavioral testing.

TB was responsible for the statistical analysis.

MLC the principal investigator, revised the manuscript, and conducted critical reviews of the manuscript for key intellectual content.

All authors contributed to the drafting of the manuscript, approved the final version, and agreed to be accountable for all aspects of the work.

Acknowledgments: We would like to thank the families of all participants in this study. The Associação Hospitalar de Proteção A Infância Dr. Raul Carneiro for their support.

Authors' information:

Authors and Affiliations:

Faculdades Pequeno Principe, Curitiba, PR, Brazil.

R.Mendes, D.A. do Valle, T.S. Bara, M.L. Cordeiro.

Instituto de Pesquisa Pelé Pequeno Principe, Curitiba, PR, Brazil.

T.S. Bara, V. Furlin, M.L. Cordeiro

Hospital Pequeno Príncipe

R. Mendes, D.A. do Valle, M.S. Zeny, M.L.F. Santos

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.

M.L.Cordeiro

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Editorial decision: Major revision
30 Jul, 2024
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29 Apr, 2024
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Clinical, genotypic, and neuropsychological profile in a series of cases of patients with Niemann-Pick type C disease

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