Non-Motor Symptoms in PLA2G6-Associated Dystonia-Parkinsonism: A Case Report and Literature Review.

PLA2G6-dystonia-parkinsonism (PLAN-DP) is characterized by levodopa responsive parkinsonism and dystonia. While neuropsychiatric symptoms and early cognitive decline are also common in this entity there is little information regarding other non-motor symptoms (NMS). Here, we describe a 26-year-old patient with PLAN-DP whose motor symptoms were preceded by mild cognitive impairment and anxiety, and who developed many other NMS as the disease evolved. Furthermore, we reviewed the NMS described in all the PLAN-DP patients published to date. A total of 50 patients with PLAN-DP were identified, 42 of whom developed NMS and in 23 of these cases, NMS preceded the motor symptoms of the disease. Neuropsychiatric symptoms dominated the premotor phase of this condition and cognitive impairment/dementia was the most prevalent NMS. Other NMS were reported infrequently like sleep disorders, autonomic symptoms, pain and hyposmia, and mostly as the disease evolved. NMS are very frequent in PLAN-DP and they may appear before diagnosis or during the course of the disease. Neuropsychiatric symptoms and cognitive decline are the most frequent NMS. The appearance of neuropsychiatric symptoms like depression, anxiety or personality changes prior to a diagnosis of parkinsonism in younger individuals might suggest the presence of PLA2G6 gene mutations.

Translational Diagnostics: An In-House Pipeline to Validate Genetic Variants in Children with Undiagnosed and Rare Diseases.

Diagnosis is essential for the management and treatment of patients with rare diseases. In a group of patients, the genetic study identifies variants of uncertain significance or inconsistent with the phenotype; therefore, it is urgent to develop novel strategies to reach the definitive diagnosis. Herein, we develop the in-house Translational Diagnostics Program (TDP) to validate genetic variants as part of the diagnostic process with the close collaboration of physicians, clinical scientists, and research scientists. The first 7 of 33 consecutive patients for whom exome-based tests were not diagnostic were investigated. The TDP pipeline includes four steps: (i) phenotype assessment, (ii) literature review and prediction of in silico pathogenicity, (iii) experimental functional studies, and (iv) diagnostic decision-making. Re-evaluation of the phenotype and re-analysis of the exome allowed the diagnosis in one patient. In the remaining patients, the studies included either cDNA cloning or PCR-amplified genomic DNA, or the use of patients' fibroblasts. A comparative computational analysis of confocal microscopy images and studies related to the protein function was performed. In five of these six patients, evidence of pathogenicity of the genetic variant was found, which was validated by physicians. The current research demonstrates the feasibility of the TDP to support and resolve intramural medical problems when the clinical significance of the patient variant is unknown or inconsistent with the phenotype.