Adult-onset Niemann–Pick disease type C: A diagnostic and therapeutic odyssey of a rare condition

INTRODUCTION

Niemann–Pick disease type C (NPTC) is a rare, progressive, and fatal lysosomal lipid storage disorder. It belongs to the class of sphingolipidoses and is caused by mutations in the NPC1 and NPC2 genes, leading to autosomal recessive inheritance. This disease is characterized by disrupted endosome-lysosome lipid transport and abnormal lipid accumulation in lysosomes. The estimated incidence of all types of the disease is 1/100.000, with 95% linked to mutations in the NPC1 gene.^[1] The spleen, liver, lungs, bone marrow, and brain are the organs where lipids accumulate the most.

While traditionally diagnosed in infancy or childhood, NPTC can also manifest in adults, presenting a diagnostic challenge due to its subtle and varied neurological symptoms. Adult-onset NPTC often mimics common neuropsychiatric conditions, leading to misdiagnosis and delayed therapeutic interventions. Neurological complications in adults may include cognitive impairment, ataxia, dysarthria, and psychiatric symptoms, which progressively worsen, emphasizing the need for early recognition and management.^[1,2]

Adult-onset NPTC is a critical consideration in differential diagnosis for unexplained neurological and psychiatric symptoms in adults. The condition underscores the importance of comprehensive genetic screening and awareness among clinicians to facilitate early diagnosis and treatment. Miglustat, the only approved disease-modifying therapy, has shown potential in altering the course of the disease, making early diagnosis pivotal for improving patient outcomes.^[1,2] As research advances, it is hoped that better diagnostic tools and treatments will emerge, offering hope to those affected by this challenging condition.

CASE REPORT

A 34-year-old male patient presented to the neurology clinic with inattention and forgetfulness. His complaints had been present for 2 years and were progressively worsening. He had previously consulted a psychiatry clinic and was being followed up with diagnoses of attention deficit and depression, treated with sertraline 100 mg/day and olanzapine 2.5 mg/day. Upon further investigation, it was found that he had been experiencing clumsiness and attention deficits for approximately 8 years. The patient, who did not benefit from treatment and whose complaints increased, began to forget his own phone number. His routine neurological examination was normal with no evidence of motor weakness, sensory deficits, or cerebellar signs. Cranial magnetic resonance imaging (MRI) revealed mild global atrophy without any focal lesions or white matter abnormality. Electroencephalography was normal and did not demonstrate epileptogenic activity or generalized slowing. An extensive biochemistry was requested. Routine blood biochemistry, thyroid function tests, Vitamin B12 and folate levels, and liver and renal function tests were all within normal ranges.

The neuropsychiatric test battery suggested organic factors that could lead to impairment in attention, visual– verbal memory, visual-motor functions, and frontal lobe functions. Cerebrospinal fluid analysis was normal. The paraneoplastic antibody panel, autoimmune encephalitis markers, and infectious workup were all negative. In light of all these negative findings and complaints, genetic testing was pursued, and it was confirmed with Niemann–Pick disease type C. The patient was started on miglustat at a dosage of 200 mg 3 times daily. Multidisciplinary follow-up, including neuropsychological support and physiotherapy, was arranged.

DISCUSSION

Adult-onset Niemann–Pick disease type C is a rare presentation of a disease more commonly diagnosed in infancy or childhood. Its ability to mimic many neuropsychiatric diseases, presenting with a wide clinical variety including cognitive decline, learning difficulties, vertical supranuclear gaze palsy, dysarthria, dysphagia, tremor, ataxia, epilepsy, psychosis, and depression, makes the disease difficult to recognize and easy to overlook.^[2,3] For instance, vertical supranuclear gaze palsy, a hallmark sign of NPC, may not be recognized at symptom onset, contributing to diagnostic delays.^[4] Differential diagnoses to consider include Huntington’s Disease, Wilson’s Disease, Cerebrotendinous Xanthomatosis, Gangliosidosis, and Friedreich’s Ataxia. The absence of peripheral neuropathy and brain MRI findings other than atrophy are significant in Niemann–Pick disease type C. Our patient’s presentation with attention deficits and clumsiness, initially managed as psychiatric conditions, highlights the diagnostic challenges faced in neurology clinics due to the broad spectrum of symptoms that can be mistaken for more common disorders.

The rarity of adult-onset NPTC and the variability of its clinical presentation pose significant challenges for neurologists. Patients may present to neurology clinics with symptoms that are atypical for their age, such as cognitive impairment or unexplained neurological symptoms, which could be indicative of NPTC.^[5] The absence of peripheral neuropathy and non-specific findings on brain MRI further complicate the diagnosis, as seen in our case.

Our case also underscores the importance of considering NPTC in the differential diagnosis of early-onset dementia, particularly when patients present with a combination of neuropsychiatric symptoms and a lack of clear etiology.^[6-8] The identification of NPTC in such patients is crucial, as it opens the door to targeted therapies such as miglustat, which may slow disease progression and improve quality of life.^[8]

A multidisciplinary approach is important in treatment. Miglustat, a competitive inhibitor of glucosylceramide synthase, is currently the only licensed disease-modifying treatment. It is thought to have a positive effect over 5 years of use. Miglustat has been shown to prevent irreversible neurological damage and slow/stop disease progression in some patients. Hydroxypropyl-beta-cyclodextrin is a potential treatment option for Niemann–Pick disease type C.^[9] In addition, a healthy, low-cholesterol diet and cholesterol-lowering medications can be beneficial in managing the disease. Nutrition, medication, physical therapy, occupational therapy, and specialist follow-up can help alleviate many symptoms.^[1,2,9]

CONCLUSION

The unique aspect of the case presented here is the detailed account of the patient’s neuropsychiatric symptoms that were initially misdiagnosed as psychiatric conditions. This highlights the importance of considering NPTC in the differential diagnoses of early-onset dementia and psychiatric disorders, especially when the symptoms are atypical for the patient’s age and do not respond to standard psychiatric treatments. Our case also emphasizes the potential for misdiagnosis due to the absence of peripheral neuropathy and nonspecific findings on brain MRI, which are often relied upon in the diagnostic process. The comprehensive neuropsychiatric evaluation and the subsequent genetic confirmation of NPTC in this patient underscore the need for a multidisciplinary approach to diagnosis and the importance of genetic testing.