Recurrent major depression, ataxia, and cardiomyopathy: association with a novel POLG mutation?

Willem MA Verhoeven^1,2, Jos IM Egger^1,3,4, Berry PH Kremer⁵, Boudewijn JHB de Pont¹, Carlo LM Marcelis^6
1Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, The Netherlands; ²Erasmus University Medical Centre, Department of Psychiatry, Rotterdam, The Netherlands; ³Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; ⁴Donders Institute for Brain, Cognition and Behaviour, Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands; ⁵Department of Neurology, University Medical Centre Groningen, The Netherlands; ⁶Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Abstract: At present, more than 100 disease mutations in mitochondrial DNA polymerase γ (POLG) have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being associated with Parkinsonism and depressive or psychotic syndromes. In this report, a middle-aged female patient with recurrent major depression with melancholic features, slowly progressive gait instability, and dilated cardiomyopathy is described. Detailed diagnostic evaluation was performed to elucidate the supposed relationship between ataxia, cardiomyopathy, and major depression with melancholia. After extensive genetic and metabolic investigation, a nucleotide substitution c.2207 A→G in the POLG gene resulting in amino acid change Asn 736Ser in exon 13 was demonstrated. This mutation was considered to be compatible with a mitochondrial disorder and implicated in the pathophysiology of the neuropsychiatric syndrome. It is concluded that this novel POLG mutation forms the most parsimonious etiological explanation for the here-described combination of ataxia, major depression, and cardiomyopathy. Therefore, in patients with a complex neuropsychiatric presentation, extensive diagnostic analysis is warranted, including the search for mitochondriopathies, in order to avoid unnecessary delay of adequate treatment.

Keywords: DNA polymerase γ, mitochondrial disease, cerebellar ataxia, major depression