Neuropsychiatric presentation of genetically confirmed juvenile Niemann–Pick type C in two siblings

Niemann–Pick type C (NPC) is an autosomal recessive lysosomal storage disorder caused by impaired intracellular cholesterol trafficking, resulting in lipid accumulation and neurodegeneration. NPC1 and NPC2 mutations disrupt endosomal cholesterol transport and membrane homeostasis [1]. Clinical presentation of NPC is heterogeneous and age-dependent; juvenile and adolescent forms often manifest with cognitive decline, seizures and psychiatric symptoms mimicking neurodevelopmental or psychotic disorders [2,3]. Diagnosis is frequently delayed; however, early initiation of miglustat may stabilise neurological progression [4].

This study aimed to characterise neuropsychiatric presentation, genetic findings and clinical course in two siblings with juvenile-onset NPC presenting with epilepsy and attentional deficits.

Two siblings with genetically confirmed juvenile-onset NPC were evaluated. Assessments included seizure monitoring, mental status examination and neuropsychological testing (WAIS-R, WISC-R). Brain MRI and abdominal ultrasound were carried out. Given the atypical and progressive course, clinical exome sequencing using a targeted hereditary panel was performed, identifying compound heterozygous pathogenic variants in NPC1. Following confirmation, miglustat was initiated and the patients were followed up. Descriptive analysis of longitudinal clinical changes was performed.

Patient 1, evaluated at age 23, had a history consistent with juvenile-onset disease. Early development was unremarkable; cognitive difficulties emerged at age 7, requiring special education, and epilepsy was diagnosed at age 14. The patient subsequently developed progressive deterioration with persistent generalised seizures reaching two to three episodes daily, despite receiving levetiracetam 2000 mg/day. WAIS-R confirmed mild intellectual disability. Psychiatric evaluation revealed disorganised thought processes, behavioural dysregulation and intermittent persecutory overvalued ideas with agitation, for which risperidone 1 mg/day was initiated. Brain MRI was unremarkable, whereas abdominal ultrasound revealed splenomegaly (13.5 cm). Following initiation of miglustat (titrated to 600 mg/day), seizure frequency decreased from daily episodes (mean 2–3/day) to rare breakthrough events over 6 months, indicating clinically meaningful reduction.

Patient 2 was a 15-year-old male initially diagnosed with attention-deficit and specific learning difficulties. WISC-R carried out at age 7 demonstrated a full-scale IQ of 77. Progressive deterioration at age 15, along with a similar presentation in his sibling, prompted clinical exome sequencing, which confirmed NPC. Repeat WISC-R showed a decline to ≤40, reflecting marked longitudinal cognitive deterioration. Neurological examination demonstrated pyramidal signs (positive Hoffmann reflex and vestibulospinal abnormalities), while brain MRI was unremarkable. Oral miglustat was initiated at 400 mg/day; however, dose titration was not feasible due to incomplete adherence to a lactose-free diet, and clinical follow-up is currently ongoing.

These cases illustrate the diagnostic complexity of juvenile-onset NPC presenting predominantly with neuropsychiatric and epileptic features in the absence of early systemic signs. The occurrence of compound heterozygous pathogenic variants in two siblings born to non-consanguineous parents emphasises that autosomal recessive neurogenetic disorders should be considered even without consanguinity. The substantial reduction in seizure frequency observed in one sibling following substrate reduction therapy suggests potential therapeutic benefit, although variability in response highlights the need for cautious interpretation. Early genetic evaluation and longitudinal neuropsychiatric monitoring may contribute to improved diagnostic accuracy and optimised clinical management.

References

1. Pentchev, P.G., 2004. Niemann–Pick C research from mouse to gene. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1685 (1–3), 3–7.
2. Saini, P., Kumawat, B., Sharma, C.B., Sharma, M., Manu, L.S., 2019. Juvenile-onset Niemann–Pick type C disease with refractory seizures. Ann. Indian Acad. Neurol. 22, 539–540.
3. Walterfang, M., Fietz, M.J., Fahey, M.C., 2006. The neuropsychiatry of Niemann–Pick type C disease in adulthood. J. Neuropsychiatry Clin. Neurosci. 18 (2), 158–170.
4. Vanier, M.T., 2010. Niemann–Pick disease type C. Orphanet J. Rare Dis. 5 (1), 16. https://doi.org/10.1186/1750-1172-5-16