Ataxia and Action Myoclonus Related to Novel Mutations in ATP13A2 Gene
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).1-3 The ATP13A2 gene encodes a lysosomal 5P-type ATPase responsible for the selective transport of cations, its mutations causing lysosomal and mitochondrial dysfunction.4 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.5 Tremor, dystonia, bulbar dysfunction, slow saccades and facial minimyoclonus were also described, as well as psychiatric manifestations.6 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.7-9 More recently, a phenotype with late-onset ataxia and action myoclonus without parkinsonism has been reported.10
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 non-consanguineous 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, anti-thyroid, 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]). Both identified variants are novel, not previously reported in reference databases and are predicted to generate a premature stop codon that results in a protein truncation. The LoFtool predictor algorithm predicted both variants as probably damaging. The Tyr1045 amino acid resides in a transmembrane helix domain located at the lysosomal lumen, while the Leu1157 residue lies at the protein cytosolic side. Both residues are evolutionary conserved; the Tyr1045 residue is conserved from amphibians to humans; whereas the Leu1157 residue is conserved from fishes to humans. To further determine these variants' pathogenicity, segregation study was performed and confirmed that patient's mother and sibling were heterozygous for one variant (Fig. 1A). However, the unavailability to test the father or the offspring does not allow us to completely rule out the remote hypothesis that both variants could be in “cis” configuration. On the other hand, this case shows how stop variants do not always determine a more severe phenotype.
The patient's phenotype was mainly characterized by action myoclonus and ataxia, in the absence of parkinsonism, however other manifestations reported in Kufor-Rakeb syndrome such as pyramidalism, neuropathy and mild cognitive impairment were also part of the phenotype.
In summary, this case illustrates a new rarely reported phenotype of late-onset myoclonic ataxia associated with two novel genetic variants in the ATP13A2 gene. According to published cases, this phenotype does not seem to be related to a specific type of mutation.7-10
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique.
L.M.: 1B, 1C, 3A, 3B
A.S.R.: 1C, 3B
A.L.P.N.: 1B, 1C, 3B
M.C.J.: 1C, 3B (genetic diagnosis)
A.M.D.: 1C, 3B (genetic diagnosis)
J.I.: 1A, 1B, 1C, 3C
Disclosures
Ethical Compliance Statement
Informed consent for video recording was obtained from the patient. The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest
No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months
LMA, ASR, ALPN, MCJ, AMD report no conflict of interests. JI receives research support from the Fondo de Investigación Sanitaria-ISCIII (PI17/00936) and from Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), has also received speaker honoraria from Abbvie and Zambon.
