Movement Disorders Clinical Practice | 2021
Ataxia and Action Myoclonus Related to Novel Mutations in ATP13A2 Gene
Abstract
Mutations in the ATP13A2 gene have been causally associated with Kufor-Rakeb syndrome and later with neuronal ceroid lipofuscinosis and a complicated form of hereditary spastic paraplegia (SPG78). The ATP13A2 gene encodes a lysosomal 5Ptype ATPase responsible for the selective transport of cations, its mutations causing lysosomal and mitochondrial dysfunction. Kufor-Rakeb syndrome was first described in 1994 in a consanguineous family from Kufor-Rakeb (Jordan). All affected members presented with the typical clinical features: juvenile-onset parkinsonism, pyramidal signs, dementia and supranuclear gaze palsy. Tremor, dystonia, bulbar dysfunction, slow saccades and facial minimyoclonus were also described, as well as psychiatric manifestations. Cerebellar signs were very uncommon however action myoclonus, ataxia and seizures have been reported together with parkinsonism in a single Iranian family carrying ATP13A2 mutation. More recently, a phenotype with lateonset ataxia and action myoclonus without parkinsonism has been reported. We report a 47-year-old male presenting with late-onset myoclonic ataxia syndrome related to heterozygous variants in the ATP13A2 gene. The patient was born at term in a nonconsanguineous Caucasian family and his family history was unremarkable. He has an unaffected younger brother. He had normal developmental milestones, however, hyperactivity and poor academic performance were observed. The symptoms started at age 39 with action myoclonus in the upper and lower limbs associated with cerebellar ataxia, which rapidly progressed to wheelchair confinement at the age of 44. Examination at age 47 showed severe action myoclonus involving both upper and lower limbs and moderate dysarthria. No resting myoclonus or tremor was noted, although there were tongue, palpebral and facial perioral myoclonus, which increased with motor activity. Myoclonus was partially tactile stimulous-sensitive. Vertical and horizontal saccades were mildly slowed and broken pursuit was observed. There was no nystagmus. Speech and breathing difficulties were noted due to the presence of diaphragmatic action myoclonus as well as mild dyphagia. Deep tendon reflexes were brisk with sustained ankle clonus and bilateral flexor plantar responses. He also had pes cavus. The patient was unable to walk or even stand upright without strong support due to severe ataxia and axial myoclonus (Video 1). A very modest improvement of action myoclonus was obtained combining levetiracetam, valproate and perampanel. Blood examination, microbiological and serological tests values were all normal. Immunological tests were performed to exclude causes of acquired ataxia including antineuronal, antithyroid, celiac disease and anti-GAD antibodies and were all negative. Cerebrospinal fluid analysis data were normal including the absence of oligoclonal bands. Magnetic resonance imaging of the brain revealed cerebellar and brainstem atrophy with secondary dilatation of the fourth ventricle. T2-weighted images showed focal hyperintense lesions in the inferomedial region of the right cerebellar hemisphere and right parietal region related to residual encephalomalacia due to mild traumatic brain injury in childhood (Fig. 1C). Electroencephalogram showed focal irregular delta waves located in the right temporal lobe without epileptiform discharges. Nerve conduction studies evidenced a chronic axonal motor polyneuropathy. Somatosensory evoked potential showed giant potentials. Long latency reflex responses were identified in both median nerves. Back-average technique was not performed. Electromyography and electroretinography were normal. The neuropsychological assessment demonstrated dyscalculia, executive dysfunction, and visual-perceptual, verbal memory and learning impairment. Genetic testing for Friedreich’s Ataxia and for spinocerebellar ataxia types 1–3, 6, 7, 12, 17 and DRPLA were negative. Analysis of ataxia and hereditary paraplegia genes by NGS showed predicted pathogenic variants in compound heterozygosity, c.3135C>A; p.Tyr1045Ter and c.3469A>T; p.Lys1157Ter, within the ATP13A2 gene [NM_022089.4 (ENST00000326735.13]).