JIMD Reports, Volume 35

Sema Kalkan Ucar, Johannes A. Mayr, René G. Feichtinger, Ebru Canda, Mahmut Çoker, Saskia B. Wortmann, Ucar, Sema Kalkan, Mayr, Johannes A., Feichtinger, René G., Canda, Ebru, Çoker, Mahmut, Wortmann, Saskia B.

Dilated cardiomyopathy (DCM), non-progressive cerebellar ataxia (A), testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria are the hallmarks of DNAJC19 defect (or DCMA syndrome) due to biallelic mutations in DNAJC19. To date DCMA syndrome has been reported in 19 patients from Canada and in two Finnish siblings. The underlying pathomechanism is unknown; however, DNAJC19 is presumed to be involved in mitochondrial membrane related processes (e.g., protein import and cardiolipin remodeling). Here, we report an additional patient with progressive cerebellar atrophy and white matter changes. A Turkish boy presented at age 2 months with dilated cardiomyopathy (initially worsening then stabilizing in the second year of life), growth failure, bilateral cryptorchidism, and facial dysmorphism. Mental and motor developmental were, respectively, moderately and severely delayed. Profound intentional tremor and dyskinesia, spasticity (particularly at the lower extremities), and dystonia were observed. Sensorineural hearing loss was also diagnosed. MRI showed bilateral basal ganglia signal alterations. Plasma lactate levels were increased, as was urinary excretion of 3-methylglutaconic acid. He deceased aged 3 years. Sanger Sequencing of DNAJC19 confirmed the clinical diagnosis of DNAJC19 defect by revealing the previously unreported homozygous stop mutation c.63delC (p.Tyr21*). Investigation of enzymes of mitochondrial energy metabolism revealed decreased activity of cytochrome c oxidase in muscle tissue. Sensorineural hearing loss and bilateral basal ganglia lesions are common symptoms of mitochondrial disorders. This is the first report of an association with DNAJC19 defect.