Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing.

Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient's genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole-exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies.

Status Epilepticus After Subthalamic Deep Brain Stimulation Surgery in a Patient with Parkinson's Disease.

BACKGROUND: Subthalamic deep brain stimulation (DBS) is a well-established treatment for patients with Parkinson's disease who suffer from severe motor fluctuations. The most common surgery-related complications are temporary confusion, bleedings, infections, and seizures. Seizures have been described to occur mainly around the time of the implantation of electrodes and, at present, the best established risk factors for seizures in association with DBS surgery are bleedings. A postoperative status epilepticus as complication of DBS surgery has never been described before. CASE DESCRIPTION: We report on a patient with Parkinson's disease who developed focal seizures of the right hand and an increasing somnolence, which led to a comatose state 3 days after DBS surgery. Repeated electroencephalograms indicated a status epilepticus, which continued for 2 months until the patient regained consciousness. The patient's state improved slowly. Although basically a good effect of DBS on her parkinsonian symptoms was observed, severe neuropsychologic deficits persisted. Unfortunately, she died 8 months after surgery as a consequence of a fall with a complicated pelvic fracture. CONCLUSIONS: This is a first report on a status epilepticus after DBS surgery, implicating that this complication has to be considered as differential diagnosis in somnolent patients after this operation.

Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation.

BACKGROUND: Recently, mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as a novel genetic factor in neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein-associated neurodegeneration with brain iron accumulation (MPAN). METHODS/RESULTS: We describe the clinical phenotype and MRI of 3 newly identified individuals with MPAN due to either previously reported or novel homozygous or compound heterozygous genetic alterations in C19orf12. CONCLUSIONS: MPAN is characterized by a juvenile-onset, slowly progressive phenotype with predominant lower limb spasticity, generalized dystonia, and cognitive impairment. Typical additional features include axonal motor neuropathy and atrophy of the optic nerve. MRI showed iron deposition in the globus pallidus and substantia nigra without the eye-of-the-tiger sign, which is typical for PKAN, the most frequent form of NBIA.