Camilla Jøsok Nybø1, Emil K Gustavsson2, Matthew J Farrer3, Jan O Aasly4. 1. Department of Pathology, Ålesund Hospital, Ålesund, Norway. 2. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Department of Neurology, St. Olavs University Hospital, Trondheim, Norway. Electronic address: egustavsson@can.ubc.ca. 3. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. 4. Department of Neurology, St. Olavs University Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
Abstract
INTRODUCTION: Biallelic mutations in PTEN-induced putative kinase 1 (PINK1) is a relatively common cause of autosomal recessive early-onset Parkinson's disease (PD). However, only three PINK1 patients with brain autopsy have been reported in the literature. METHODS: We describe the clinical and pathological characteristics of a patient with early-onset PD. We screened for copy number variants SNCA, PRKN, PINK1, DJ-1, ATP13A2, LPA and TNFRSF9 by multiplex ligation-dependent probe amplification (MLPA), and subsequently we performed whole-exome sequencing. RESULTS: Clinically the patient presented with typical parkinsonism that responded well to levodopa. After 23 years of disease she had a bilateral GPi deep brain stimulation (DBS) surgery. Genetic analyses revealed a heterozygous exon 4-5 deletion and a homozygous exon 1 [c. 230T > C (p.Leu77Pro)] mutation in PINK1. Post-mortem neuropathological examination after more than 30 years of disease revealed gliosis and a large loss of melanin-containing neurons in the substantia nigra. Lewy body pathology was evident in substantia nigra, temporal cortex, locus coeruleus and the parahippocampal region. CONCLUSION: We describe the first clinical and pathological characterization of a PINK1 patient with a typical disease presentation and long disease duration. Previous reports describe two patients with Lewy-related pathologies, albeit with differential distribution, and one patient with no Lewy-related pathology. Hence, it seems that only two patients with parkinsonism due to mutations in PINK1 are consistent with α-synucleinopathy distribution like that seen in the majority of cases with sporadic PD. Our data further extend the clinicopathological characterization of PINK1-associated PD.
INTRODUCTION: Biallelic mutations in PTEN-induced putative kinase 1 (PINK1) is a relatively common cause of autosomal recessive early-onset Parkinson's disease (PD). However, only three PINK1patients with brain autopsy have been reported in the literature. METHODS: We describe the clinical and pathological characteristics of a patient with early-onset PD. We screened for copy number variants SNCA, PRKN, PINK1, DJ-1, ATP13A2, LPA and TNFRSF9 by multiplex ligation-dependent probe amplification (MLPA), and subsequently we performed whole-exome sequencing. RESULTS: Clinically the patient presented with typical parkinsonism that responded well to levodopa. After 23 years of disease she had a bilateral GPi deep brain stimulation (DBS) surgery. Genetic analyses revealed a heterozygous exon 4-5 deletion and a homozygous exon 1 [c. 230T > C (p.Leu77Pro)] mutation in PINK1. Post-mortem neuropathological examination after more than 30 years of disease revealed gliosis and a large loss of melanin-containing neurons in the substantia nigra. Lewy body pathology was evident in substantia nigra, temporal cortex, locus coeruleus and the parahippocampal region. CONCLUSION: We describe the first clinical and pathological characterization of a PINK1patient with a typical disease presentation and long disease duration. Previous reports describe two patients with Lewy-related pathologies, albeit with differential distribution, and one patient with no Lewy-related pathology. Hence, it seems that only two patients with parkinsonism due to mutations in PINK1 are consistent with α-synucleinopathy distribution like that seen in the majority of cases with sporadic PD. Our data further extend the clinicopathological characterization of PINK1-associated PD.
Authors: Javier Jarazo; Kyriaki Barmpa; Jennifer Modamio; Cláudia Saraiva; Sònia Sabaté-Soler; Isabel Rosety; Anne Griesbeck; Florian Skwirblies; Gaia Zaffaroni; Lisa M Smits; Jihui Su; Jonathan Arias-Fuenzalida; Jonas Walter; Gemma Gomez-Giro; Anna S Monzel; Xiaobing Qing; Armelle Vitali; Gerald Cruciani; Ibrahim Boussaad; Francesco Brunelli; Christian Jäger; Aleksandar Rakovic; Wen Li; Lin Yuan; Emanuel Berger; Giuseppe Arena; Silvia Bolognin; Ronny Schmidt; Christoph Schröder; Paul M A Antony; Christine Klein; Rejko Krüger; Philip Seibler; Jens C Schwamborn Journal: Mov Disord Date: 2021-10-12 Impact factor: 9.698