Juvenile Onset Niemann-Pick Type C Disease with Refractory Seizures

Sir,

Niemann–Pick disease type C (NP-C) is an autosomal recessively inherited neurovisceral disease. It may manifest itself as progressive cognitive decline (78%), gait and limb ataxia (70%), dysarthria, dystonia, dysphagia, and cataplexy. Vertical supranuclear gaze palsy is a robust clinical indicator of NP-C.[1]

NP-C can be subdivided according to the age of onset into peri-natal (onset before 3 months), early-infantile (3 months to < 2 years), late-infantile (2 to <6 years), juvenile (6–15 years), and adolescent or adult (>15 years) forms. NP-C occurs due to mutations in the NPC1 gene (95%), or NPC2 gene (5%).[2]

Due to the variable age of onset, and heterogeneous clinical manifestations, diagnosis of this disease becomes challenging. Herein, we report a 14-year-old girl, genetically confirmed NP-C, who presented with varied clinical features, including refractory seizures.

A 14-year-old girl, born of non-consanguineous marriage, and full-term normal delivery, achieved normal developmental milestones as per her age. Her mother initially noticed her speech to be slurred and effortful at around 6 years of age. Simultaneously she started having episodes of seizures, semiologically akin to absences. She developed gait and limb ataxia in the next 6 months. In the next year, she developed dystonia of both feet, leading to occasional falls. She also developed dystonic posturing of her both hands, which was observed during walking. She developed behavioural abnormalities at 7 years of age in the form of unprovoked laughing and crying and poor social interaction. Her scholastic performance also declined, leading to drop out of school by 8 years of age. Since the age of 12 years, she is also having generalised tonic-clonic seizures (3-5 episodes per month). For the last 6 months, she has developed focal motor seizures also, in the form of twitching movements of the face. She has dysphagia, both for solids and liquids, and excessive drooling of saliva in the last 2 years. There was no history of cataplexy. Family history was unremarkable. At the time of admission, she was symptomatic for uncontrolled seizures.

On examination, no facial dysmorphism or organomegaly was noted. Speech was dysarthric with scanning character. Horizontal eye movements were normal, whereas vertical saccades, as well as pursuits, were impaired. Vertical vestibulo-ocular reflex showed preserved eye movements. [Video 1] Generalised dystonia was noted involving both hands, both feet and trunk. [Video 2] Bilateral cerebellar signs were present.

Complete hemogram and routine biochemical tests were normal. Serum ceruloplasmin, 24-hour-urinary copper, lactate, and ammonia were normal. Tests for urinary organic acids, plasma amino acids, and plasma acylcarnitine profile were normal. Magnetic resonance imaging (MRI) of the brain had shown diffuse cerebral atrophy. Electroencephalogram (EEG) revealed intermittent paroxysms of 2-3 Hz, 50-100 mV amplitude, slow wave activity, lasting for 2-3 seconds. Ultrasound of the abdomen revealed mild splenomegaly. Bone marrow aspiration could not be done because of negative consent by the parents.

The score on NP-C suspicion index was 123 (immediate testing for NP-C should be done if score is >70).[3] The NPC1 gene sequencing was done by Next Generation Sequencing (NGS) and detected mutations c. 352_353delAG in exon four resulting in a frameshift and premature truncation of the protein eight amino acid downstream to codon 119, and c. 547G > C in exon 5 in the heterozygous state, confirming the diagnosis of NP-C disease. [Supplementary Figure 1 ^{(522.6KB, tif)} ].

The patient was started on supportive management. She was started on tablet levetiracetam 500 mg bid (25 mg/kg), syrup sodium valproate 1000 mg per day (25 mg/kg), and clobazam 10 mg daily. Miglustat could not be procured due to non-affordability. Genetic counselling was done. She was discharged on request of her parents with occasional seizures.

Juvenile onset NP-C usually presents with falls due to gait problems, cataplexy, clumsiness, and organomegaly.[4] In contrast, our patient's initial presentation was of absence seizures, and dysarthria progressing to gait and limb ataxia.

Phenotypic features such as gait ataxia, dysarthria, supranuclear vertical gaze palsy, generalised dystonia, pyramidal signs were observed in our patient. All these features have been documented in the literature.[4,5,6]

NP-C patients can experience any seizure type, including generalised, focal, absence, or myoclonic seizures. Seizures are more frequent in late infantile and juvenile-onset cases (40%–55%). Early infantile and adult-onset cases rarely present with seizures. Development of seizures in NP-C indicates the progression of the disease. Patients may have seizure-like episodes including gelastic cataplexy and cortical myoclonus. Different types of myoclonus, including arrhythmic cortical myoclonus and stimulus-sensitive myoclonus, can occur in NP-C. Patients may even present with refractory epilepsy, and clear predominance of any seizure type is not reported.[7]

Definition of drug-resistant epilepsy as proposed by the International League against Epilepsy (ILAE) task force[8] which defines it as “failure to achieve sustained seizure freedom even after adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination)” is applicable in this setting also. Our patient presented with multiple seizure types, including absence, generalised tonic-clonic, and focal motor seizures, which were uncontrolled despite being on three antiepileptic drugs.

EEG in NP-C may show diffuse background slowing and interictal discharges (focal, multifocal, or generalised spikes or spike and wave activity). EEG is normal in gelastic cataplexy and shows high-frequency oscillations in case of cortical myoclonus.[7,9]

Antiepileptic drugs useful in patients with NP-C include levetiracetam, sodium valproate, benzodiazepines, and lamotrigine. Use of carbamazepine, oxcarbazepine, and vigabatrin should be avoided, as they can precipitate myoclonus.[7,9]

Brain imaging changes pertaining to specific seizure type in NP-C have not been described. Brain imaging may be normal or show diffuse cerebral or cerebellar atrophy, particularly cerebellar vermian atrophy, probably due to overexpression of NPC1 gene in cerebellar neurons.[10] Early infantile onset NP-C patients may have white matter hyperintensities. Thalamus, hippocampus, and striatum are the other areas affected.[2] Our patient had diffuse cerebral atrophy without any cerebellar atrophy.

Miglustat has been approved for the treatment of NP-C patients presenting with progressive and disabling neurological manifestations.[2] Effect of miglustat on seizure frequency is not known. Other than this, treatment is mostly symptomatic and aims at providing rehabilitative therapy.

Our better understanding and knowledge of the clinical profile of NP-C might help in early diagnosis of the disease and secondary prevention of complications. NP-C should be considered as a differential diagnosis in any young patient presenting with gradually progressive neurobehavioural manifestations with eye movement abnormalities, and extrapyramidal features.

Appropriate written consent was taken from patient foe publication of this manuscript.

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Conflicts of interest

There are no conflicts of interest.

SUPPLEMENTARY DATA

Supplementary Figure 1

The NPC 1 gene NGS showing mutations c.352_353delAG in exon 4, and c. 547G > C in exon 5 in heterozygous state