Clinical, Neurophysiological and Genetic Observations in Kufor-Rakeb Syndrome: Report of a New Kindred with Compound Heterozygous Mutations in the ATP13A2 Gene

  • Dr Victor Fung, Movement Disorder Unit, Department of Neurology, Westmead Hospital, Sydney, Australia
  • Ms Prachi Mehta, Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, Sydney, Australia
  • Dr Neil Manwaring, Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, Sydney, Australia
  • A/Prof Carolyn Sue, Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, Sydney, Australia
  • Prof Christian Kubisch, Institute of Human Genetics, University Hospital, Cologne, Germany

    • Objective: Kufor-Rakeb syndrome (KRS) is a form of autosomal recessive juvenile onset Parkinsonism first reported in 1994. Linkage to chromosome 1p36 was shown in 2001 and the locus designated PARK9. Mutations in ATP13A2 were first reported in 2006. We report a new kindred with KRS.
    Case Histories: A Chinese male was seen in 2003 and his sister in 2007. The proband had normal motor milestones but mild developmental delay. He presented at age 17 with social anxiety requiring treatment with SSRIs. He developed bilateral Parkinsonism from age 19 with akinesia, rigidity, upper limb action tremor without rest tremor and postural instability. There were atypical Parkinsonian features of upward supranuclear gaze palsy, facial action tremor, mild upper limb dystonia, lower limb hyperreflexia and cognitive dysfunction. He had a good response to levodopa/benserazide 200/500 tds. His sister had an identical presentation from age 18, except that she also had mild cervical dystonia.
    Results: Surface EMG recordings showed a 10Hz action tremor of the face and upper limbs. NCS and median SEPs were normal and C reflexes absent. Cerebral MRI showed no definite abnormalities. Genetic analysis in both siblings showed compound heterozygosity with novel c.3176T>G/c.3253delC mutations that were not present in over 150 Asian and 95 German controls.
    Conclusion: Our findings extend the clinical spectrum of KRS with a later age of onset, prominent anxiety as the presenting symptom and relatively slower progression. This is the first report of neurophysiological findings in this syndrome. Two novel pathogenic mutations are described.