| Autor: |
Theunissen TE; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands; Department of Genetics and Cell Biology, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands., Szklarczyk R; Department of Clinical Genetics, Maastricht University Medical Centre , Maastricht , Netherlands., Gerards M; Maastricht Centre for Systems Biology (MaCSBio) , Maastricht , Netherlands., Hellebrekers DM; Department of Clinical Genetics, Maastricht University Medical Centre , Maastricht , Netherlands., Mulder-Den Hartog EN; Department of Neurology , Erasmus MC, Rotterdam , Netherlands., Vanoevelen J; Department of Clinical Genetics, Maastricht University Medical Centre , Maastricht , Netherlands., Kamps R; Department of Clinical Genetics, Maastricht University Medical Centre , Maastricht , Netherlands., de Koning B; Department of Clinical Genetics, Maastricht University Medical Centre , Maastricht , Netherlands., Rutledge SL; Department of Neurology and Genetics, University of Alabama at Birmingham , Birmingham, AL , USA., Schmitt-Mechelke T; Department of Neuropediatrics, Luzerner Kantonsspital , Kinderspital, Luzern , Switzerland., van Berkel CG; Department of Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Center , Amsterdam , Netherlands., van der Knaap MS; Department of Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Center , Amsterdam , Netherlands., de Coo IF; Department of Neurology , Erasmus MC, Rotterdam , Netherlands., Smeets HJ; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands; Department of Genetics and Cell Biology, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands; Maastricht Centre for Systems Biology (MaCSBio), Maastricht, Netherlands. |
| Abstrakt: |
In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient's brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced. |
