Article

Clinical spectrum of Kufor‐Rakeb syndrome in the Chilean kindred with ATP13A2 mutations

Centro de Estudios del Movimiento, Santiago, Chile
Movement Disorders (Impact Factor: 5.63). 09/2010; 25(12):1929 - 1937. DOI: 10.1002/mds.22996
Source: PubMed

ABSTRACT We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages ∼10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 ± 5.5 (mean ± SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation. © 2010 Movement Disorder Society.

1 Bookmark
 · 
112 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in ATP13A2 (PARK9), encoding a lysosomal P-type ATPase, are associated with both Kufor-Rakeb syndrome (KRS) and neuronal ceroid lipofuscinosis (NCL). KRS has recently been classified as a rare genetic form of Parkinson's disease (PD) while NCL is a lysosomal storage disorder. Although the transport activity of ATP13A2 has not been defined, in vitro studies show that its loss compromises lysosomal function, which in turn is thought to cause neuronal degeneration. To understand the role of ATP13A2 dysfunction in disease, we disrupted its gene in mice. Atp13a2(-/-) and Atp13a2(+/+) mice were tested behaviorally to assess sensorimotor and cognitive function at multiple ages. In the brain, lipofuscin accumulation, α-synuclein aggregation, and dopaminergic pathology were measured. Behaviorally, Atp13a2(-/-) mice displayed late-onset sensorimotor deficits. Accelerated deposition of autofluorescent storage material (lipofuscin) was observed in the cerebellum and in neurons of the hippocampus and cortex of Atp13a2(-/-) mice. Immunoblot analysis showed increased insoluble α-synuclein in the hippocampus, but not in cortex or cerebellum. There was no change in the number of dopaminergic neurons in the substantia nigra or in striatal dopamine levels in aged Atp13a2(-/-) mice. These results show that loss of Atp13a2 causes sensorimotor impairments, α-synuclein accumulation as occurs in PD and related synucleinopathies, and accumulation of lipofuscin deposits characteristic of NCL, thus providing the first direct demonstration that null mutations in Atp13a2 can cause pathological features of both diseases in the same organism.
    Human Molecular Genetics 02/2013; · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Syndromes of neurodegeneration with brain iron accumulation (NBIA) are characterized by increased iron deposition in the basal ganglia leading to complex progressive neurological symptoms. Several genetically distinct subforms have been recognized. In addition to pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), further genetic causes continue to be identified. Most of these present in childhood and are inherited following an autosomal recessive trait. However, the clinical and pathological spectrum has broadened and new age-dependent presentations have been described and there is overlap between the different NBIA disorders and with other diseases (such as spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis). Thus, additional clinical information (e.g., radiological findings such as precise patters of deposition of iron or co-occurrence of white matter lesions) may be useful when prioritizing genetic screening. Neuropathological work-up demonstrated variable involvement of iron deposition, but also Lewy bodies, neurofibrillary tangles and spheroid bodies. Treatment remains symptomatic. Here we review characteristic features of NBIA syndromes with a focus on pediatric cases.
    Current Treatment Options in Neurology 07/2013; · 1.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recently, a number of genetic parkinsonian conditions have been recognized that share some features with the clinical syndromes of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA), the classic phenotypic templates of atypical parkinsonism. For example, patients with progranulin, dynactin, or ATP13A gene mutations may have vertical supranuclear gaze palsy. This has made differential diagnosis difficult for practitioners. In this review, our goal is to make clinicians aware of these genetic disorders and provide clinical clues and syndromic associations, as well as investigative features, that may help in diagnosing these disorders. The correct identification of these patients has important clinical, therapeutic, and research implications. © 2013 Movement Disorder Society.
    Movement Disorders 05/2013; · 5.63 Impact Factor

Full-text (2 Sources)

View
46 Downloads
Available from
May 31, 2014