Parkinsonism, cognitive deficit and behavioural disturbance caused by a novel mutation in the polymerase gamma gene.
Polymerase γ (POLG) is the enzyme responsible for the replication and maintenance of mitochondrial DNA (mtDNA). Mutations in the POLG1 gene can lead to mitochondrial dysfunction, producing a wide range of neurological and non-neurological phenotypes. Neurological manifestations include ataxia, muscular weakness, epilepsy, progressive external ophthalmoplegia (PEO), ptosis, neuropathy, psychiatric disorders and, more rarely, parkinsonism. We present the case of an 80-year old female patient with a history of PEO, ptosis, childish behaviour, obsessive disorder, cognitive decline, and parkinsonism. A comprehensive study showed striatal dopamine deficiency on DaT Scan and ragged red fibres as evidenced by Gomori staining in a biopsy of the biceps brachii. Multiple deletions of mtDNA were detected, and sequencing of the POLG1 gene identified a novel substitution, 2834A>T, in exon 18, changing the p.His945Leu amino acid. In silico analysis using PolyPhen-2 (http://genetics.bwh.hardvard.edu/pph2/) predicted that this change is probably damaging, with a score of 1.0 (0-1).
Neuroscience Area, Biodonostia Research Institute, San Sebastián, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Manuel
M
Delgado-Alvarado
University Hospital Donostia, San Sebastián, Spain.
Patricia
P
de la Riva
Neuroscience Area, Biodonostia Research Institute, San Sebastián, Spain.
Haritz
H
Jiménez-Urbieta
Neuroscience Area, Biodonostia Research Institute, San Sebastián, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Belén
B
Gago
University Hospital Donostia, San Sebastián, Spain.
Alazne
A
Gabilondo
Servicio de Bioquímica, Hospital Universitario Puerta de Hierro and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Belén
B
Bornstein
Neuroscience Area, Biodonostia Research Institute, San Sebastián, Spain; University Hospital Donostia, San Sebastián, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. Electronic address: maria.rodriguezoroz@biodonostia.org.
María Cruz
MC
Rodríguez-Oroz
D000369:Aged, 80 and over; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D006801:Humans; D001523:Mental Disorders / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics*
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
Cognitive impairment; Obsessive disorder; POLG; Parkinsonism; Progressive external ophthalmoplegia; Ptosis