A 30-year-old male with unremarkable birth history had poor coordination since childhood and below-average school performance. He developed delusions at the age of 21, for which he was treated with bupropion and aripiprazole. At the age of 23, he developed memory difficulty, hand tremor, loss of hand dexterity, and imbalance with occasional falls. He also developed slurred speech at the age of 28. His neurological examination showed impaired smooth pursuit, saccades, and optokinetic nystagmus in the vertical direction with relatively preserved horizontal eye movements (Video 1). The impaired eye movements were even more prominent in the downward direction than the upward direction. He also had cognitive impairment (Montreal Cognitive Assessment score of 19: he lost 2 points in visuospatial/executive, 2 points in attention, 5 points in delayed recall, and 2 points in orientation), mild dysarthria, and features of cerebellar ataxia.
Routine laboratory testing revealed a reduced platelet count of 122,000 per µL, and an ultrasound showed splenomegaly. A brain magnetic resonance imaging (MRI) scan showed cerebellar atrophy with pontine and medullary atrophy. Targeted genetic testing showed bi-allelic mutations in the NPC1 gene: c.3265 G>A, (E1089K) and c.2903 A>G, (N968S); both mutations have been reported in patients with a classical biochemical phenotype of Niemann–Pick type C (NPC).1,2 No mutations were detected in the NPC2 gene. Subsequently, his brother, who also reportedly exhibited cognitive symptoms and lack of coordination, was also found to carry these two mutations in NPC1.
Impaired vertical eye movements, in combination with cerebellar ataxia, cognitive impairment, and/or psychiatric symptoms, are pathognomonic for NPC.3 Other considerations for vertical eye movements include progressive supranuclear palsy and Whipple’s disease. NPC is a rare lysosomal storage disorder caused by mutations in either NPC1 (∼95% of cases) or NPC2 (∼5% of cases), which lead to abnormal intracellular lipid trafficking and accumulation. NPC most commonly manifests in middle to late childhood after normal development; however, neonatal and adult onset may also occur. In addition to the above-mentioned symptoms, NPC patients may exhibit dystonia, myoclonus, parkinsonism, and gelastic cataplexia, which are not present in our patient.
Although no curative therapies are currently available for treatment of NPC, early detection is important as patients can be offered treatments with potential disease-modifying agents. These include miglustat,4 which reduces the synthesis of glycolipids by inhibiting glucosylceramide synthase and possibly slows disease progression, and arimoclomol,5 which is a co-inducer of heat shock protein and was recently granted rare pediatric disease designation by the US Food and Drug Administration for the treatment of NPC.
1 Funding: Dr. Kuo has received funding from the National Institutes of Health: NINDS #K08 NS083738 (principal investigator), and the Louis V. Gerstner Jr. Scholar Award, Parkinson’s Disease Foundation, and International Essential Tremor Foundation. Dr. Gupta is supported by a Parkinson’s Foundation fellowship grant.
2 Financial Disclosures: None.
3 Conflicts of Interest: The authors report no conflicts of interest.
4 Ethics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.
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