A 16-year-old left-handed male patient of Caucasian British ancestry presented with a mild, non-progressive upper limb postural tremor but no other symptoms for several years until, without clear precipitant, he experienced two unprovoked generalised tonic-clonic seizures, both occurring in sleep. His antecedent history was unremarkable except for a viral respiratory infection at birth requiring 2 days of mechanical ventilation on the neonatal intensive care unit. He attained his cognitive and motor milestones appropriately, attended mainstream school and completed 14 GCSEs. He was otherwise well, except for ichthyosis. There is no history of parental consanguinity. There is a family history of neurofibromatosis type 1 in a nephew and Perthes disease in a brother, and a history of diabetes and hypertension in his father and mother, respectively. His father also had ichthyosis.
Following the nocturnal seizures, he underwent a number of investigations. His initial MRI and EEG were normal. Anticonvulsant medication, specifically sodium valproate, was commenced following a further convulsive seizure fourteen months later.
He continued to experience convulsive seizures every 3 to 6 months; these were initially nocturnal, but later arose from wakefulness. Some of the seizures were preceded by a visual aura, consisting of superimposition of peripheral vision into the central field (polyopia). There was also gradual worsening of his upper limb tremor, manifesting as an irregular jerky tremor at rest which worsened on action, especially in the right hand. It improved significantly on distraction. He also noticed lower limb tremor with associated unsteadiness, especially when descending stairs or slopes, with his left leg being more affected than the right. He described his legs as feeling 'like jelly' with occasional falls. He also noticed general cognitive slowing, fatigue and effortfulness when engaging in conversations with people less well known to him. The motor symptoms were initially attributed to valproate therapy and he was switched to levetiracetam with no clear improvement.
He underwent further investigations at 20 years of age. An MRI at this time showed some prominence of the cerebellar folia suggestive of mild generalised cerebellar parenchymal volume loss. White cell enzyme analysis was normal. Cerebrospinal fluid analysis revealed normal cell counts and protein values, with no evidence of unmatched oligoclonal bands. No mutations were identified in SLC2A1 or DYT-1a. Total cholesterol was elevated at 6.5 and he tested positive for pANCA but negative for serine proteinase 3 (PR3) antibodies. He was diagnosed with functional movement disorder and referred for specialist physiotherapy with some improvement in his symptoms.
However, his symptoms progressed and by the age of 22 years, he was wheelchair-bound. Fine motor skills had deteriorated such that he was unable to cut up food and his handwriting was illegible. He had prominent and widespread spontaneous and action myoclonus, to the extent that even dreaming about movement would precipitate myoclonus. His voice had developed a stuttering stammer. He had also developed 'twitching' and 'rippling' of muscles in his shoulders, upper limbs and torso. There were no sensory changes or sphincter disturbance. His convulsive seizures had also become more frequent, occurring on average once per week.
Clinical examination at this time revealed occasional facial myoclonus (resembling myokymia) and hypermetric saccades with nystagmus on horizontal gaze. Ophthalmic review revealed normal appearances of the discs and retina. Limb tone and power were normal. Deep tendon reflexes were present and symmetrical in the upper limbs, brisk in the lower limbs with flexor plantar responses. There was a postural tremor markedly exacerbated by action with some action myoclonus. Marked orthostatic tremor was noted on standing. There was subtle dysmetria and dysdiadokokinesia on the right. There was no evidence of telangiectasia or oculomotor apraxia. Systemic examination revealed marked ichthyoses but no organomegaly. Neuropsychometry, including screens of intellect (WAIS-IV), memory (BMIPB), language (graded naming test) and executive function (Wiegl and verbal fluency tests), showed him to be functioning within the normal range without any specific cognitive deficits.
He was admitted for further investigations including prolonged EEG monitoring with video telemetry. There were independent runs of fast activity seen equally in both centroparietal regions. One seizure was captured with head turning to right and posturing of the left arm without a clear focus of onset (Fig. 1). There was no photosensitivity. EMG showed frequent interruptions of muscle tone intermixed with brief muscle jerks whilst holding his limbs against gravity. Short duration (20-30 ms) jerks, a rostrocaudal pattern of muscle activation, negative myoclonus and giant cortical somatosensory evoked potentials (SEPs) suggested a cortical origin of jerks, and a syndrome of progressive myoclonic epilepsy was suspected (Fig. 2).
Genetic analysis was undertaken. There were no pathogenic mutations or large-scale rearrangements of mtDNA detected and no CSTB expansion suggestive of Unverricht-Lundborg disease. His muscle biopsy was unremarkable and a skin biopsy could not be processed due to technical issues.
Whole genome sequencing was performed as part of the 100,000 Genomes Project. This showed one pathogenic variant in CLN6 and two other variants of unknown significance in CLN6. Subsequent targeted sequence analysis of CLN6 showed compound heterozygosity for CLN6 c.13C > T p.(Arg5Trp) & c.150C > G p.(Tyr50*). His mother was heterozygous for the c.13C > T sequence variant and his father heterozygous for the c.150C > G sequence variant, providing evidence that these variants were on opposite alleles and therefore together likely to be pathogenic. The results fully explained the clinical phenotype and confirmed the diagnosis of Kufs disease/cerebral neuronal lipofuscinosis.
A repeat MRI brain scan showed no change in the degree of cerebellar volume loss. However, there were new T2 FLAIR hyperintensities in the right cerebral hemispheric white matter with minor neuroparenchymal volume loss in the right cerebral hemisphere, consistent with either a vascular or infective/inflammatory process. Imaging of the cord was normal (Fig. 3).
Vascular imaging revealed stenoses of the terminal and para-ophthalmic internal carotid arteries (ICAs) and proximal middle cerebral arteries (MCAs) (right worse than left), with collateral vessels. Extracranial vasculature was unremarkable. The features were in keeping with intradural arterial occlusive vasculopathy/Moyamoya disease. He was commenced on a statin and amlodipine for blood pressure management, and bilateral superficial temporal artery to middle cerebral artery (extracranial-intracranial) vascular anastomoses were undertaken to reduce the risk of further ischaemic injury, without post-operative neurological sequelae. Additional genetic sequencing has identified no pathogenic variants in the RNF213 gene on the long arm of chromosome 17 (17q25), the most common genetic mutation associated with Moyamoya disease, and no significant variants in Cerebrovascular disorders (version 1.34) or Cerebral vascular malformations (version 1.36) 100,000 Genomes Project gene panels.