OBJECTIVE:We tested the hypothesis that resuming dietary control in early-treated phenylketonuria (PKU) is associated with improvements in white matter integrity, using data from the ReDAPT study, which previously demonstrated cognitive and psychiatric improvements with reduced phenylalanine (Phe) levels. METHODS:We re-initiated dietary control for early-treated patients with PKU and assessed the T1w/T2w ratio from standard T1-and T2-weighted magnetic resonance images, a marker of myelination and microstructural integrity. General linear mixed-effects model (GLMM) analyses were performed to assess change in the T1w/T2w ratio from baseline over twelve months after resumption of dietary control. RESULTS:Seven participants (mean age 31 years; five female) with neuroimaging were included, with a mean of 16 years off diet and baseline Phe levels of 1157 µmol/L. GLMM analyses showed significant increases in T1w/T2w ratio over time for the whole brain (β = 0.47 [95%CI = 0.28, 0.66]), left hemisphere (β = 0.36 [95%CI = 0.19, 0.54]) and right hemisphere regions of interest (β = 0.52 [95%CI = 0.30, 0.72]). Longer time off diet was also positively associated with greater T1w/T2w changes. There was no evidence for the effects of gender or age at baseline. CONCLUSIONS:This study demonstrated significant increases in the T1w/T2w ratio in PKU patients as they resumed dietary control over a 12-month period. Raw Phe levels were not strongly associated with neuroimaging measures. These findings support the importance of lifelong treatment for PKU and also demonstrate the potential reversibility of white matter changes in the disease.

In 2018, the International Niemann-Pick Disease Alliance (INPDA) and the International Niemann-Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann-Pick disease type C (NPC)-an ultra-rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease-modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high-quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re-evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up-to-date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital-based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Niemann-Pick type C (NP-C) disease is a fatal, neurodegenerative disorder caused by lysosomal lipid accumulation with variable symptomatic penetrance at the primary disease locus encoded by the NPC1 gene. We identified genetic modifiers of disease progression by integrating genetic, genomic, and lipidomic analyses across yeast, mice, and human patients. A yeast screen identified 45 candidate modifiers of disease severity, including phosphatidic acid hydrolase (PAH1), a key enzyme in triacylglycerol (TAG) synthesis. Lipidomic profiling of liver, cerebral cortex, and cerebellum from Npc1-/- mice at multiple ages demonstrated that dysregulation of TAG metabolism strongly correlates with disease progression. Deletion of the murine PAH1 orthologues Lpin1 or Lpin2 in Npc1-/- mice reduced lifespan, accelerated Purkinje cell loss, and increased hepatic lipid accumulation. In NP-C patients, two LPIN3 variants were associated with early childhood onset. These findings identify lipins as modifiers of NP-C disease and expand our understanding of lipid metabolism in neurodegeneration.

OBJECTIVE:The Neuropsychiatry Unit Cognitive Assessment is a valid and reliable screening tool used in detecting cognitive deficits in a range of neurological and psychiatric conditions. We aimed to develop abbreviated versions of the Neuropsychiatry Unit Cognitive Assessment tool using retrospective data, and to assess their psychometric performance in distinguishing between healthy cognition and dementia. METHODS:Healthy controls (n = 132, 41%) and those with dementia (n = 191, 59%) were randomised into a 'training' cohort (n = 226, 70%) for the development and a 'testing' cohort (n = 97, 30%) for validation of the short-form versions. Receiver-operating characteristic curves were first computed for each of the 24 original Neuropsychiatry Unit Cognitive Assessment items. Items were ranked according to area under the curve values to create five-, 10- and 15-item short-form versions, which were subsequently validated. RESULTS:The psychometric properties of the Neuropsychiatry Unit Cognitive Assessment short-form versions were comparable with the original, with all maintaining high convergent validity and reliability. Of the three versions, the 10-item version strikes the ideal balance of breadth and brevity. With a cut-off score of 42/54, the 10-item version generated similar sensitivity, specificity and predictive values for dementia as the original Neuropsychiatry Unit Cognitive Assessment, with a sensitivity of 0.98, specificity of 0.95, and positive and negative predictive values of 0.97. CONCLUSIONS:The 10-item Neuropsychiatry Unit Cognitive Assessment has strengths in its shorter administration time, of approximately 10 minutes, high reliability and validity, and retention of items from each cognitive domain from the original Neuropsychiatry Unit Cognitive Assessment. Future research may involve testing these short forms in non-tertiary settings, across dementia subtypes and in non-dementia groups.

Background Niemann-Pick disease type C (NP-C) is the fifth most prevalent lysosomal disorder in Australia. Diagnostic delay is common, impacted by disease heterogeneity, limited awareness within clinical gateway services and exclusion from state-based newborn screening programmes. A formal diagnosis, once established, places a substantial burden on the whole family, the negative impact of which is far-reaching. A clear understanding of diagnostic pathways and management objectives in NP-C is critical for optimal care.Aims To develop an Australian standard of care for individuals diagnosed with NP-C and their families, reflecting international best practice and tailored to the Australian healthcare system.Methods The Australian NPC Disease Foundation Inc. convened a national, multidisciplinary collaboration including NP-C treating clinicians, allied health professionals and a community advisory group. Using an iterative consensus approach, published international guidance statements were reviewed, ratified, excluded or modified to align with the Australian context.Results Consensus outputs included a diagnostic algorithm, a multidisciplinary care framework and management-centred management statements. The collaborative process resulted in a unified Australian standard of care for NP-C. This framework incorporates the carer perspective, emphasises shared decision-making and situates NP-C within the broader context of 'childhood dementias.' Consensus statements provide practical, evidence-aligned guidance on early recognition, diagnostic referral pathways and multidisciplinary management throughout disease progression.Conclusions This initiative represents the first Australia-specific standard of care for NP-C. It is hoped that adoption of the framework will lead to improved experiences for Australians living with NP-C and their carers as they navigate the healthcare setting.

Niemann-Pick disease type C (NPC) is a rare genetic lysosomal storage disorder with a clinically heterogeneous phenotype that primarily affects the brain, liver and spleen. Most cases of NPC are diagnosed in childhood, but a subset of patients who are diagnosed in adulthood present with psychiatric symptoms and are initially diagnosed as schizophrenia or a mood disorder. Neuroimaging studies in NPC show a predilection for neurodegeneration in the subcortical nuclei, the cerebellum and subcortical white matter. We aimed to explore how adult NPC affects the connectivity of networks and hypothesized a state of widespread disconnectivity, particularly in subcortical areas. This cross-sectional neuroimaging study used diffusion-weighted magnetic resonance imaging to perform whole-brain tractography in 9 adult patients with NPC and 70 matched healthy controls. Connections between 84 unique brain regions were modelled with streamlines and weighted according to fibre bundle capacity. Statistical testing by each connection allowed the identification of significantly affected networks and regions in NPC. We observed diffusive disconnectivity in NPC primarily affecting left frontotemporal and subcortical networks. Globally and regionally, NPC showed reductions in the strength and number of affected connections, particularly in the thalamus and dorsal striatum. We show that left frontotemporal and subcortical networks are markedly affected in NPC. These findings may facilitate early diagnostic differentiation, monitoring and prognostication and may represent the neural correlates of neuropsychiatric symptoms in NPC.

Young-onset dementia (YOD) refers to the occurrence of dementia symptoms in people under the age of 65. Neuropsychiatric symptoms (NPS) are increasingly considered as the preclinical manifestations of YOD, posing a challenge to differentiate from psychiatric conditions with overlapping symptoms. The aim of this study is to investigate the AT(N), neuronal and glial pathologies underlying NPS and cognition in YOD. This study used clinical data from the Neuropsychiatry Centre, the Royal Melbourne Hospital, Melbourne, Australia. Sixty-nine people with YOD were identified and assessed for biomarkers, NPS and cognition (mean age [SD] = 57.6 [7.3], female N = 23 [33%]). Their cerebrospinal fluid and plasma levels of amyloid-beta, total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) were measured. Common NPS such as depressive and behavioural symptoms were also measured. Cognitive functions were measured by a comprehensive battery of neuropsychological assessments. General linear regressions were used to investigate the associations between biomarkers, NPS and cognition. Memory recall was correlated with levels of amyloid-beta (r = .52, 95% conference interval [CI] = [.32, .75]), t-tau (r = -.4, 95% CI = [-.65, -.16]) and p-tau (r = -.34, 95% CI = [-.58, -.11]). Executive function was correlated with levels of NfL (r = -.4, 95% CI = [-.78, -.03]). Levels of NfL were further correlated with the severity of stress (r = -.41, 95% CI = [-.73, -.11]). No evidence of associations between levels of GFAP and NPS or cognition was observed. Visuoconstruction was correlated with levels of amyloid-beta (r = .45, 95% CI = [.24, .67]), in which this relationship was moderated by the severity of self-care problems (F [6, 28] = 5.48, p < .05). The results suggest that the changes in memory recall are associated with an intricate interplay between AT(N) pathologies in people with YOD. Executive function in YOD may be related to neuronal alterations rather than glial alternations in the brain. Combining biomarker results, the real challenge of self-care problems in people with YOD observed by their caregivers may serve as a surrogate estimate to predict outcomes in visuoconstruction.

Younger-onset neurocognitive symptoms result from a heterogenous group of neurological and psychiatric disorders which present a diagnostic challenge. To identify such factors, we analysed the BeYOND (Biomarkers in Younger-Onset Neurocognitive Disorders) cohort, a study of individuals less than 65 years old presenting with neurocognitive symptoms for a clinical diagnosis and who have undergone cognitive and biomarker analyses. 65 participants were recruited during their index presentation to the Royal Melbourne Hospital Neuropsychiatry Centre, a tertiary specialist service in Melbourne, Australia. Specific diagnoses were clinically determined and categorised as either early-onset Alzheimer’s disease (AD, n=18), non-AD neurodegeneration (nAD-ND, n=23) or primary psychiatric disorders (PPD, n=24). Using Simoa technology, blood levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated-tau at threonine 181 (p-tau181), amyloid-β 1-40 (Aβ 40 ), Aβ 42 and Aβ 42/40 ratio were measured. Apolipoprotein E (APOE) genotypes and polygenic risk scores (PRSs), based on genome-wide association studies for late-onset AD, were determined. Generalized linear and multinomial models, as well as information-theoretic model selection, were used to identify discriminatory factors, adjusted for age and sex. NfL, GFAP and p-tau181 levels were up to 3-fold higher in individuals with AD compared to nAD-ND and PPD (Dunn-adjusted p<0.05). Aβ-species levels were not significantly different between the groups. While the PRS was not associated with diagnostic categories (p=0.25), a higher PRS was associated with increased NfL and GFAP levels (OR=1.08, p<0.05). Multi-omic model selection identified various combinations of NfL and p-tau181 levels, APOE genotype and global cognitive function as parsimonious models that discriminated between AD and PPD with AUC≥0.975 (95% CI: 0.925–1.000). A model containing only p-tau181 significantly discriminated between AD and nAD-ND causes (AUC=0.950, 95% CI: 0.877–1.000). Multinomial regression models identified NfL, GFAP and p-tau181 as significant variables for discriminating between the three diagnostic categories (p<0.0005). Discriminating between AD, nAD-ND and PPD causes of younger-onset neurocognitive symptoms is possible using a combination of cognitive profiling with protein and genetic biomarkers. These results support utilising blood biomarkers for work-up of younger-onset neurocognitive symptoms as well as highlight the need for the development of a younger-onset AD-specific PRS.

BackgroundNiemann-Pick disease type C (NPC) is a pan-ethnic, progressive, recessively inherited lysosomal disorder that affects 1:100,000 live births. Emerging biochemical, genetic, and clinical evidence challenges the traditional view that disease-associated variants in the genes associated with the typical phenotype NPC manifest as an exclusively autosomal recessive disorder. While biallelic pathogenic variants cause the NPC disease phenotype, heterozygous carriers may exhibit phenotypic traits attributable to a partial loss of NPC1 or NPC2 function.MethodsWe conducted a literature search of articles relevant to heterozygosity in NPC genes and genes associated with other lysosomal diseases. A narrative mini-review format was employed with the intention of providing a brief overview of the frequency of NPC carriers, as well as the biochemical, genetic, non-clinical, and clinical evidence available for readers seeking to understand the scientific basis for why NPC heterozygosity should be discussed and considered as a potential risk factor for the development of neurological phenotype or neurodegenerative diseases.ConclusionHeterozygosity for many genes, including NPC1 variants, (“carriers” of a single variant in an NPC gene) can be clinically consequential. Recognizing the effects of NPC1 heterozygosity has profound implications for diagnosis, clinical monitoring, and potential early intervention. By broadening our understanding of the genetic and phenotypic spectrum of NPC, we can improve detection (which is straightforward in obligate heterozygotes, i.e., parents of NPC patients), reduce long-term health risks, and utilize targeted treatments that address the needs of carriers as well as affected individuals.

OBJECTIVE:Young-onset dementia (YOD), defined by symptom onset before age 65, encompasses diverse aetiologies and presents with prominent neuropsychiatric symptoms (NPS) that often accompany or exacerbate cognitive decline. However, the pathological mechanisms linking NPS, cognition, and biomarkers remain unclear. It was hypothesised that relationships between NPS and cognition would be mediated or moderated by cerebrospinal fluid (CSF) biomarker levels in individuals with YOD. METHODS:This retrospective, cross-sectional study included 46 participants with YOD (24 with Alzheimer's disease [AD], 22 with non-AD dementias) diagnosed at the Neuropsychiatry Centre, Royal Melbourne Hospital. NPS were measured using the Depression Anxiety and Stress Scale and Cambridge Behavioural Inventory-Revised. Cognition was assessed using standardised neuropsychological assessments. CSF amyloid-β (Aβ42), phosphorylated tau 181 (P-tau181), total tau (T-tau), and neurofilament light chain protein (NfL) were analysed. General linear models (GLMs) examined associations between biomarkers, cognition, and NPS. RESULTS:Higher P-tau181 (unstandardised beta [B] = -0.10, 95% confidence interval = [-0.20, -0.01]) and T-tau (B = -0.06 [-0.13, -0.01]) levels were associated with poorer memory recall in participants with YOD. In non-AD dementias, higher T-tau levels predicted greater NPS severity (B = 0.76 [0.06, 3.52]). NfL showed no significant associations with NPS or cognition. CONCLUSION:Tau-related neurodegeneration (P-tau181 and T-tau) appears more closely linked to memory impairment in YOD than axonal injury markers such as NfL. In non-AD dementias, T-tau was additionally associated with behavioural symptom severity, suggesting tau-related mechanisms across subtypes. These associations require validation in larger, longitudinal, and multimodal studies to clarify temporal and mechanistic pathways.

BACKGROUND AND OBJECTIVES:N-acetyl-l-leucine (NALL) has been established to improve the neurologic manifestations of Niemann-Pick disease type C (NPC) after 12 weeks in a placebo-controlled trial. In the open-label extension phase (EP) follow-up, data were obtained after 12 and 18 months to evaluate the long-term effects of NALL for NPC. METHODS:This is an ongoing, multinational, multicenter EP. Patients with a genetic diagnosis of NPC aged 4 years or older who completed the placebo-controlled trial were eligible to continue in the EP and receive orally administered NALL 2-3 times per day in 3 tiers of weight-based dosing. The primary end point is the modified 5-domain NPC Clinical Severity Scale (NPC-CSS) (range 0-25 points; lower score representing better neurologic status); data from the EP cohort are compared with the expected annual trajectory of decline (i.e., disease progression) established in natural history studies. Analyses are also performed on exploratory end points, including the 15-domain and 4-domain NPC-CSSs and the Scale for Assessment and Rating of Ataxia (SARA). RESULTS:Fifty-three patients aged 5-67 years (45.3% female, 54.7% male) were enrolled in the EP. After 12 months, the mean (±SD) change from baseline on the 5-domain NPC-CSS was -0.27 (±2.42) with NALL vs +1.5 (±3.16) in the historical cohort (95% CI -3.05 to -0.48; p = 0.009), corresponding to a 118% reduction in annual disease progression. After 18 months, the mean (±SD) change was +0.05 (±2.95) with NALL vs +2.25 (±4.74) in the historical cohort (95% CI -4.06 to -0.35; p = 0.023). The 15-domain and 4-domain NPC-CSSs were consistent with the 5-domain NPC-CSS. The improvements in neurologic manifestations demonstrated in the placebo-controlled trial on the primary SARA end point were sustained over the long-term follow-up. NALL was well tolerated, and no treatment-related adverse events or serious reactions occurred. DISCUSSION:Treatment with NALL was associated with a significant reduction in NPC disease progression after 12 and 18 months, demonstrating a disease-modifying, neuroprotective effect. TRIAL REGISTRATION INFORMATION:The trial is registered with ClinicalTrials.gov (NCT05163288; registered December 6, 2021), EudraCT (2021-005356-10). The first patient was enrolled into the EP on March 8, 2023. The trial was funded by IntraBio Inc. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that NALL reduces disease progression in NPC.

INTRODUCTION:Young-onset neurocognitive symptoms result from a heterogeneous group of neurological and psychiatric disorders which present a diagnostic challenge. To identify such factors, we analysed the Biomarkers in Younger-Onset Neurocognitive Disorders cohort, a study of individuals <65 years old presenting with neurocognitive symptoms for a diagnosis and who have undergone cognitive and biomarker analyses. METHODS:Sixty-five participants (median age at assessment of 56 years, 45% female) were recruited during their index presentation to the Royal Melbourne Hospital Neuropsychiatry Centre, a tertiary specialist service in Melbourne, Australia, and categorized as either early-onset Alzheimer's disease (n = 18), non-Alzheimer's disease neurodegeneration (n = 23) or primary psychiatric disorders (n = 24). Levels of neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181, apolipoprotein E genotype and late-onset Alzheimer's disease polygenic risk scores were determined. Information-theoretic model selection identified discriminatory factors. RESULTS:Neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181 levels were elevated in early-onset Alzheimer's disease compared with other diagnostic categories. A multi-omic model selection identified that a combination of cognitive and blood biomarkers, but not the polygenic risk score, discriminated between early-onset Alzheimer's disease and primary psychiatric disorders (area under the curve ⩾ 0.975, 95% confidence interval: 0.825-1.000). Phosphorylated-tau 181 alone significantly discriminated between early-onset Alzheimer's disease and non-Alzheimer's disease neurodegeneration causes (area under the curve = 0.950, 95% confidence interval: 0.877-1.00). DISCUSSION:Discriminating between early-onset Alzheimer's disease, non-Alzheimer's disease neurodegeneration and primary psychiatric disorders causes of young-onset neurocognitive symptoms is possible by combining cognitive profiles with blood biomarkers. These results support utilizing blood biomarkers for the work-up of young-onset neurocognitive symptoms and highlight the need for the development of a young-onset Alzheimer's disease-specific polygenic risk score.

Objectives: This study examined whether currently existing clinical structural magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (18FDG-PET) capabilities and board-certified radiologists' reports and interpretations can assist with traumatic encephalopathy syndrome (TES) diagnosis. Design: retrospective case series. Setting: this study assessed six patients with TES criteria recruited from the Sydney area, Australia Main outcomes: patients' clinical history and clinical presentation along TES diagnostic criteria, board-certified radiologist reports of structural MRI and 18FDG-PET. Results: one patient was classified as possible CTE, and the others were classified as probable CTE with significant RHI exposure history and a spectrum of cognitive deficits and other neuropsychiatric disturbances consistent with TES diagnostic criteria. Most common radiological features included atrophy of posterior superior parietal region and Evans Index > 0.25. FDG-PET's pattern of common regions of hypometabolism and differing hypometabolism across participants suggested that FDG-PET and structural MRI have the potential for stratifying different TES stages. Conclusions: this study highlights the potential of a combined clinical and radiological approach using solely current capabilities to improve TES diagnosis and suggests a larger study. Such expanded investigation is crucial for advancing the ante-mortem diagnosis and management of CTE.

Objective Given the rapid shift to in-home teleneuropsychology models, more research is needed to investigate the equivalence of non-facilitator models of teleneuropsychology delivery for people with younger onset dementia (YOD). This study aimed to determine whether equivalent performances were observed on neuropsychological measures administered in-person and via teleneuropsychology in a sample of people being investigated for YOD. Method Using a randomized counterbalanced cross-over design, 43 participants (Mage = 60.26, SDage = 7.19) with a possible or probable YOD diagnosis completed 14 neuropsychological tests in-person and via teleneuropsychology, with a 2-week interval. Repeated measures t-tests, intraclass correlation coefficients (ICC), and Bland Altman analyses were used to investigate equivalence across the administration conditions. Results No statistical differences were found between in-person and teleneuropsychology conditions, except for the Hospital Anxiety and Depression Scale Anxiety subtest. Small to negligible effect sizes were observed (ranging from .01 to .20). ICC estimates ranged from .71 to .97 across the neuropsychological measures. Bland Altman analyses revealed that the Wechsler Adult Intelligence Scale—Fourth Edition Block Design subtest had slightly better overall performance in the in-person condition and participants reported higher levels of anxiety symptoms during the teleneuropsychology condition; however, average anxiety symptoms remained within the clinically normal range. Participants reported a high level of acceptability for teleneuropsychology assessments. Conclusions These results suggest that performances are comparable between in-person and teleneuropsychology assessment modalities. Our findings support teleneuropsychology as a feasible alternative to in-person neuropsychological services for people under investigation of YOD, who face significant barriers in accessing timely diagnoses and treatment options.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

We conducted a Phase 3 trial to confirm the safety and efficacy of the active L-enantiomer, N-acetyl-L-leucine (NALL) for pediatric (≥ 4 years) and adult patients with NPC.