Faculty Bibliography

Background/UNASSIGNED:gene have recently been linked to a spectrum of phenotypes including epilepsy, cerebellar ataxia, cortical myoclonus and intellectual disability (ID), and primary congenital defects of glycosylation. Case Report/UNASSIGNED:-associated clinical phenotypes. Discussion/UNASSIGNED:should be included in the genetic screening of undiagnosed forms of myoclonus, myoclonus-ataxia, and progressive myoclonus epilepsies.

BACKGROUND:Late-Onset Tay-Sachs (LOTS) disease is a rare, progressive neurological condition that can dramatically affect the life of these patients. The diagnosis of LOTS is easily missed because of the multifaced presentation of these patients, who can initially be assessed by neuromuscular or movement disorder specialists, or psychiatrists. Clinical trials are now becoming available for LOTS. Therefore, early diagnosis can be detrimental for these patients and for insuring informative research outcomes. METHODS:We characterized a cohort of nine patients with LOTS through a detailed clinical and video description. We then reviewed the available literature regarding the clinical description of patients with LOTS. Our findings were summarized based on the predominant phenotype of presentation to highlight diagnostic clues to guide the diagnosis of LOTS for different neurology specialists (neuromuscular, movement disorders) and psychiatrist. RESULTS:We described a cohort of 9 new patients with LOTS seen at our clinic. Our literature review identified 76 patients mainly presenting with a neuromuscular, cerebellar, psychiatric, stuttering, or movement disorder phenotype. Diagnostic tips, such as the triceps sign, distinct speech patterns, early psychiatric presentation and impulsivity, as well as neurological symptoms (cerebellar or neuromuscular) in patients with a prominent psychiatric presentation, are described. DISCUSSION:Specific diagnostics clues can help neurologists and psychiatrists in the early diagnosis of LOTS disease. Our work also represent the first video presentation of a cohort of patients with LOTS that can help different specialists to familiarize with these features and improve diagnostic outcomes. HIGHLIGHTS:Late-Onset Tay-Sachs (LOTS) disease, a severe progressive neurological condition, has multifaced presentations causing diagnostic delays that can significantly affect research outcomes now that clinical trials are available. We highlight useful diagnostic clues from our cohort (including the first video representation of a LOTS cohort) and comprehensive literature review.

An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.

SMN is a ubiquitously expressed protein and is essential for life. SMN deficiency causes the neurodegenerative disease spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. SMN interacts with itself and other proteins to form a complex that functions in the assembly of ribonucleoproteins. SMN is modified by SUMO (Small Ubiquitin-like Modifier), but whether sumoylation is required for the functions of SMN that are relevant to SMA pathogenesis is not known. Here, we show that inactivation of a SUMO-interacting motif (SIM) alters SMN sub-cellular distribution, the integrity of its complex, and its function in small nuclear ribonucleoproteins biogenesis. Expression of a SIM-inactivated mutant of SMN in a mouse model of SMA slightly extends survival rate with limited and transient correction of motor deficits. Remarkably, although SIM-inactivated SMN attenuates motor neuron loss and improves neuromuscular junction synapses, it fails to prevent the loss of sensory-motor synapses. These findings suggest that sumoylation is important for proper assembly and function of the SMN complex and that loss of this post-translational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of SMA mice.

Sialidosis type 1 is a rare lysosomal storage disorder caused by mutations of the neuraminidase gene. Specific features suggesting this condition include myoclonus, ataxia and macular cherry-red spots. However, phenotypic variability exists. Here, we present detailed clinical and video description of three patients with this rare condition. We also provide an in-depth characterization of eye movement abnormalities, as an additional tool to investigate pathophysiological mechanisms and to facilitate diagnosis. In our patients, despite phenotypic differences, eye movement deficits largely localized to the cerebellum.

Patients with essential tremor, vocal tremor, torticollis, myoclonus-dystonia and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from ingestion of a modest amount of alcohol (ethanol). Despite considerable investigation, the mechanism of ethanol's ability to produce this effect remains a mystery. In this paper, we review the pharmacology of ethanol and its analogue GHB (or sodium oxybate), summarize the published literature of alcohol-responsive hyperkinetic movement disorders, and demonstrate videos of patients we have treated over the last fifteen years with either an ethanol challenge or with chronic sodium oxybate therapy. We then propose a novel explanation for this phenomenon-namely, that ingestion of