First Report of Kufor‐Rakeb Syndrome ( <scp>PARK</scp> 9) from India, and a Novel Nonsense Mutation in <i> <scp>ATP</scp> 13A2 </i> Gene

Abstract

Kufor-Rakeb syndrome (KRS; PARK 9) is a rare autosomal-recessive form of juvenile-onset Parkinson's disease (PD) caused by ATP13A2 gene mutations. The classical description of KRS is that of rapidly progressive symptoms in the form of parkinsonism, spasticity, supranuclear upgaze paresis, facial-faucial-finger minimyoclonus, visual hallucinations, oculogyric dystonic spasms, and dementia, usually noted between 12 and 16 years of age, resulting in early severe motor handicap.1 World-wide prevalence of KRS is unknown, with only case reports/series being published.2, 3 We report on the first case of KRS from India, with previously unreported nonsense mutation in exon 22 of ATP13A2 gene (chr1: 17316187; G>A). An 18-year-old adolescent male born of consanguineous parentage presented with history of reduced interactions, withdrawn behavior, which was noted at the age of 16. Over a period of time, he started to have flexed posturing of the upper limb with small and illegible handwriting along with keeping his mouth open constantly. During the last 6 to 8 months, he started to notice mild tremors of the right upper limb with dragging of the right foot while walking. He was initially evaluated with a diagnosis of depression/behavior disorder by various doctors. Subsequently, he was considered to have PD and was started on levodopa (50 mg, twice a day) with which he developed dyskinetic movements of the tongue and foot, at which time he was referred to us for further evaluation. On evaluation, he was noted to have masked facies, rigidity, bradykinesia (right > left), and slow saccades (horizontally and vertically). Range of eye movements, power, sensory examination, reflexes, and coordination were normal (see Video 1). There was no family history of parkinsonism. The only nonmotor symptom noted was of anxiety. All his blood and metabolic workup for early-onset parkinsonism, including brain MRI, was normal (Supporting Fig. 1). He was started on dopamine agonist (pramipexole), with which significant clinical improvement has been noticed and is currently attending his college, albeit mild difficulty of writing still persists (slowness). Genomic DNA from the proband was used to perform exome sequencing using the Agilent SureSelectXT capture kit (Agilent Technologies, Santa Clara, CA). The sample was sequenced with mean coverage of 80 to 100× on an Illumina HiSeq 2500 sequencing platform (Illumina, San Diego, CA). Sequenced data were aligned to the human reference genome (GRCh37/hg19) using the BWA program.4, 5 Subsequent to this, the GATK-Lite pipeline was used for realignment, base recalibration, variant calling, and variant filtering.6, 7 Filtered variants were annotated using the VariMAT pipeline (internal data analysis pipeline of MedGenome), and clinically relevant mutations were identified from published literature and various databases, including ClinVar, OMIM, SwissVar, HGMD, GWAS, ExAC, 1000-Genome, dbSNP, EVS.8-15 Only nonsynonymous and splice-site variants detected in the targeted genes were used for clinical interpretation. Whole-exome sequencing, performed to identify the causative gene variation, did not detect any literature-reported variations for the clinical symptoms. A homozygous nonsense variation in exon 22 of ATP13A2 gene (chr1: 17316187; G>A), which results in a stop codon and premature truncation of the protein at codon 826 (ENST00000341676:c.2476C>T, ENSP00000341115:p.Q826Ter), was detected. This variant was not found in different common variation databases, such as 1000Genome, ExAC, dbSNP, and EVS. The variant was also not detected in 100 normal controls that were screened by us. The Exome Aggregation Consortium does not report this variant in its database.12 After this, analysis of both the parents showed the same mutation in the heterozygous state, indicating that they are the carriers for this likely pathogenic mutation (Fig. 1). Since the initial description of KRS, case reports/series have been published from various parts of the world, including Pakistan and Afghanistan. To date, no documented cases have been published from India. Initial description of KRS was a rapidly progressive disorder with early development of significant motor disabilities. However, newer publications have indicated variable phenotypes, including that of intact cognition, absence of myoclonus/tremors, and slower clinical progression. Most of these patients have good l-dopa response.16 In comparison to published literature, our case had a clear autosomal-recessive inheritance, with both parents being heterozygous carriers, typical onset, and early ocular signs. In contrast to classical descriptions, he did not have any cognitive deficits, has slow clinical progression, and no myoclonus or hallucinations. Our case also had a nonsense mutation, which has not been documented to date. In being the first case reported from India, and also with higher prevalence of consanguinity in Southern India, this may provide the option to screen for juvenile-onset parkinsonism and study clinical heterogeneity. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique. L.K.P.: 1A, 1B, 1C, 2A, 2B S.M.: 1C, 2B V.K.: 1B, 2B R.G.: 1B, 2B R.J.: 1B, 2B S.S.: 1B, 2B V.L.R.: 1A, 1C, 2B Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest. Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report. A video accompanying this article is available in the supporting information here. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.