Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.

OBJECTIVE: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders. METHODS: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. RESULTS: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients. INTERPRETATION: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.

The minimal clinically important change in the motor section of the Burke-Fahn-Marsden Dystonia Rating Scale for generalized dystonia: Results from deep brain stimulation.

BACKGROUND: The minimal clinically important difference (MCID) describes the smallest change in an outcome that is considered clinically meaningful. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) is the most frequently rating scale assessing the efficacy of deep brain stimulation therapy (DBS) for dystonia. To expand our understanding, we evaluated the MCID thresholds for the BFMDRS motor subscale (MS) using physician-reported outcomes. METHODS: We assessed the MCID thresholds for the BFMDRS using movement disorder specialist ratings of videotapes from patients with genetically determined dystonia (Tor1A and THAP1) who underwent bilateral globus pallidum internum (GPi) DBS. We calculated the effect size of the BFMDRS-MS change and determined the MCID thresholds using the Clinical Global Impression of Change (CGIC). RESULTS: Twelve participants with a median age at DBS of 44.5 (range:27-68) had baseline and follow-up BFMDRS-MS with a median post-DBS follow-up of 5.5 years. Based on descriptive analysis, patients with good improvement after DBS according to the CGIC [8/12 (67%)] had a median BFMDRS-MS score reduction of 77% [Interquartile range (IQR):66.2;91.0) with an effect size of 0.39, and those with non-improvement [4/12 (33%)], had a median BFMDRS-MS score reduction of 62% (IQR:36.6;83.6). CONCLUSIONS: Our MCID estimates can be utilized in clinical practice in judging clinical relevance. However, further larger, powered studies are needed to simultaneously determine and compare MCID using patient and physician-reported outcomes in segmental and generalized dystonia in genetic and non-genetic populations.

Treatment of Acute Delirium in a Patient with Parkinson's Disease by Transfer to the Intensive Care Unit and Administration of Dexmedetomidine.

The treatment of delirium or psychosis in patients with Parkinson's disease (PD) can be complicated by the limited number of pharmacological agents that can be used in this population. Typical and atypical antipsychotics are contraindicated, as they can worsen motor symptoms. The treatment of acute delirium is even more complicated in the hospital setting, as many medications deemed safer in this population are only available in oral form. We present a case of acute delirium in a patient with PD, likely precipitated by a polypharmacy interaction of new medications, that was successfully managed by transferring the patient to the intensive care unit and administering dexmedetomidine for 72 hours.

TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model.

Genetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in all three affected patients, but exercise-induced dystonia persisted into adulthood in two. Furthermore, we identified three additional sporadic paediatric patients with a remarkably similar phenotype, two of whom had compound heterozygous mutations consisting of an in-frame deletion I81_K84 and an A500V mutation, and the third carried T182M and G511R missense mutations, overall revealing that all six patients harbour a missense mutation in the subdomain of TLDc between residues 500 and 511. We solved the crystal structure of the conserved Drosophila TLDc domain. This allowed us to predict destabilizing effects of the G501R and G511R mutations and, to a lesser degree, of R360H and potentially A500V. Next, we characterized the functional consequences of a strong and a weak TLDc mutation (TBC1D24G501R and TBC1D24R360H) using Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign. The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity, which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or α-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity. Our data thus show that mutations in the TLDc domain of TBC1D24 cause Rolandic-type focal motor epilepsy and exercise-induced dystonia. The humanized TBC1D24G501R fly model exhibits sustained activity and vesicle transport defects. We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies. The TLDc and TBC domain mutations' response to antioxidant treatment we observed in the animal model suggests a potential for combining antioxidant-based therapeutic approaches to TBC1D24-associated disorders with previously described lipid-altering strategies for TBC domain mutations.

DYT1 dystonia increases risk taking in humans.

It has been difficult to link synaptic modification to overt behavioral changes. Rodent models of DYT1 dystonia, a motor disorder caused by a single gene mutation, demonstrate increased long-term potentiation and decreased long-term depression in corticostriatal synapses. Computationally, such asymmetric learning predicts risk taking in probabilistic tasks. Here we demonstrate abnormal risk taking in DYT1 dystonia patients, which is correlated with disease severity, thereby supporting striatal plasticity in shaping choice behavior in humans.

Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Milestones in dystonia.

The last 25 years have seen remarkable advances in our understanding of the genetic etiologies of dystonia, new approaches into dissecting underlying pathophysiology, and independent progress in identifying effective treatments. In this review we highlight some of these advances, especially the genetic findings that have taken us from phenomenological to molecular-based diagnoses. Twenty DYT loci have been designated and 10 genes identified, all based on linkage analyses in families. Hand in hand with these genetic findings, neurophysiological and imaging techniques have been employed that have helped illuminate the similarities and differences among the various etiological dystonia subtypes. This knowledge is just beginning to yield new approaches to treatment including those based on DYT1 animal models. Despite the lag in identifying genetically based therapies, effective treatments, including impressive benefits from deep brain stimulation and botulinum toxin chemodenervation, have marked the last 25 years. The challenge ahead includes continued advancement into understanding dystonia's many underlying causes and associated pathology and using this knowledge to advance treatment including preventing genetic disease expression.

Treatment of generalized dystonia.

OPINION STATEMENT: The armamentarium for clinicians treating patients with generalized dystonia, previously restricted to only a few oral medications that often caused intolerable side effects, has been radically expanded in the past decade with the widespread application of deep brain stimulation (DBS). With DBS, patients who in the past would have been restricted to a life of severe motor disability from a young age can now lead lives with only minimal symptoms. Although DBS should therefore be considered as a treatment option for any patient with severe, medically refractory dystonia, important questions remain about patient selection, including what factors predict which patients will benefit from DBS, and when in the course of disease DBS should be performed. Reports show that patients with primary dystonia respond better than those with secondary dystonia, and limb and axial muscles may improve more than cranial dystonia. Some studies also suggest that shorter duration of disease may be associated with better outcomes. However, it is important to note that even among those thought to respond best to DBS, i.e. patients with primary generalized dystonia, there is a subset that will have significant and sustained clinical benefit with oral medications. It is therefore important that adequate trials of oral medications be attempted prior to referral for surgery. On the other hand, once it is clear that medical therapies are not providing significant benefit or are not well tolerated, children with disabling generalized primary dystonia should be referred quickly for DBS. The dramatic clinical improvement that can be seen with DBS can restore normal or near-normal functioning and avoid the physical and emotional costs of an extended period of decreased physical and social functioning. In general, a levodopa trial should always be considered as the first treatment at the time of presentation of any patient with childhood-onset limb dystonia, in order to exclude dopa-responsive dystonia. Once a diagnosis of primary generalized dystonia is established, we typically initiate treatment with trihexyphenidyl, titrating slowly up to a high dose. We then frequently add baclofen as a second agent. If clinical improvement at that point is inadequate and the dystonia is causing significant functional impairment, we then consider referral for DBS.