Genotype-phenotype relations for episodic ataxia genes: MDSGene systematic review.

BACKGROUND: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms. METHODS: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/). RESULTS: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'. CONCLUSION: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

The definition of precision medicine in neurodegenerative disorders and the one disease-many diseases tension.

Precision medicine is a patient-centered approach that aims to translate new knowledge to optimize the type and timing of interventions for the greatest benefit to individual patients. There is considerable interest in applying this approach to treatments designed to slow or halt the progression of neurodegenerative diseases. Indeed, effective disease-modifying treatment (DMT) remains the greatest unmet therapeutic need in this field. In contrast to the enormous progress in oncology, precision medicine in the field of neurodegeneration faces multiple challenges. These are related to major limitations in our understanding of many aspects of the diseases. A critical barrier to advances in this field is the question of whether the common sporadic neurodegenerative diseases (of the elderly) are single uniform disorders (particularly related to their pathogenesis) or whether they represent a collection of related but still very distinct disease states. In this chapter, we briefly touch on lessons from other fields of medicine that might be applied to the development of precision medicine for DMT in neurodegenerative diseases. We discuss why DMT trials may have failed to date, and particularly the importance of appreciating the multifaceted nature of disease heterogeneity and how this has and will impact on these efforts. We conclude with comments on how we can move from this complex disease heterogeneity to the successful application of precision medicine principles in DMT for neurodegenerative diseases.

Initiating dopamine agonists rather than levodopa in early Parkinson's disease does not delay the need for deep brain stimulation.

BACKGROUND AND PURPOSE: While levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), its use is associated with an increased risk of motor complications (MCs) in the first 5 years of treatment compared to dopamine agonist (DA) first therapy. It is not known whether this translates into true benefit later in the disease. We aimed to determine whether there is a difference in the time between initial levodopa versus DA treatment and the development of disabling MCs prompting deep brain stimulation (DBS) consideration. METHODS: This was a retrospective cohort study of patients with PD attending the DBS Clinic at Toronto Western Hospital, Canada between March 2004 and February 2022, who underwent globus pallidus interna (GPI) or subthalamic nucleus (STN) DBS in 2005 or later for disabling MCs. RESULTS: Of the 438 patients included in the study, 352 underwent STN DBS and 86 underwent GPi DBS. The median (range) disease duration was 9 (2-30) years. The majority of patients (n = 312) received levodopa first and 126 received a DA. There was no significant difference in disease duration or amantadine use between the two groups. The duration from the first treatment to assesment for DBS (levodopa: median 8 years, interquartile range [IQ] 4 years; DA: median 9, IQR 4 years) or DBS surgery (levodopa: median 10 years, IIQR 5 years; DA: median 10 years, IQR 5 years) did not differ. CONCLUSION: To our knowledge, this is the only study to date to evaluate the duration between levodopa/DA-first treatment and the development of MCs of sufficient severity to warrant consideration of DBS. No association was found. The results suggest that the development of disabling MCs warranting DBS is independent of the type of first dopaminergic treatment.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Periodic Limb Movements while Awake (PLMA) as a Manifestation of Wearing-Off in Parkinson's Disease: A Case Series and Review of the Literature.

Background: Periodic limb movements while awake (PLMA) are similar to Periodic limb movements in sleep (PLMS) but occurring during wakefulness and seen in association with restless leg syndrome (RLS). Objectives: To describe PLMA as a wearing-off phenomenon in Parkinson's Disease (PD). Methods: We describe four individuals with PD and PLMS, who had associated similar periodic and stereotypic lower extremity movements during wakefulness, thought to be secondary to PLMA, and were highly responsive to dopaminergic treatment. Results: Despite the prevalence of RLS and PLMS in individuals with PD, the presence of similar movements during wakefulness has not been well characterized. The lack of a specific diagnostic criteria poses a significant diagnostic challenge. Conclusions: We describe, for the first time to our knowledge, PLMA as a wearing-off phenomenon in PD. This entity could be classified in the spectrum of "low-dose dyskinesia," as we found that it was highly responsive to dopaminergic treatment.

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 1: Genetic Disorders.

We selected several "imaging pearls" presented during the Movement Disorder Society (MDS) Video Challenge for this review. While the event, as implicated by its name, was video-centered, we would like to emphasize the important role of imaging in making the correct diagnosis. We divided this anthology into two parts: genetic and acquired disorders. Genetic cases described herein were organized by the inheritance pattern and the focus was put on the imaging findings and differential diagnoses. Despite the overlapping phenotypes, certain described disorders have pathognomonic MRI brain findings that would provide either the "spot" diagnosis or result in further investigations leading to the diagnosis. Despite this, the diagnosis is often challenging with a broad differential diagnosis, and hallmark findings may be present for only a limited time.

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 2: Acquired Disorders.

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these "imaging pearls" into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.

PARKIN, PINK1, and DJ1 analysis in early-onset Parkinson's disease in Ireland.

BACKGROUND: Variants in PARKIN, PINK1, and DJ1 are associated with early-onset Parkinson' disease (EOPD, age-at-onset < 45). We previously reported a single PINK1 and a single DJ1 heterozygous variant carrier. PURPOSE: We aimed to expand upon our previous EOPD studies and investigate for any genotype-phenotype correlations in Irish PD. METHODS: Three hundred fourteen PD patients were recruited from Dublin Neurological Institute, Ireland. Genetic analysis was performed at the Mayo Clinic, Jacksonville, USA. We screened 81 patients with young-onset PD (age-at-onset < 50), of which 58 had EOPD. RESULTS: We identified 4 patients with homozygous/compound heterozygous variants and 3 heterozygote carriers (pathogenic PINK1/DJ1 variants were not found). Expansion of one of the pedigrees showed a novel variant in exon 9, in a symptomatic patient. We identified 6.89% PARKIN variant carriers associated with EOPD. CONCLUSION: These findings suggest that PINK1 and DJ1 are rarely associated with Irish YOPD, while PARKIN variant frequency is similar to that reported worldwide.

Ondine's Curse in Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 Caused by MAPT Variants.

BACKGROUND: "Ondine's curse" or central hypoventilation, induces an apparently spontaneous failure of automatic respiratory drive, henceforth necessitating a conscious effort to breathe and sleep induced hypoventilation. It is typically seen in congenital central hypoventilation syndrome, but may be acquired. OBJECTIVES: To highlight Ondine's curse as part of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) secondary to microtubule associated protein tau (MAPT) variants. METHODS: We describe the clinical and neuropathological findings in two patients with fatal Ondine's curse associated with FTDP-17 and secondary to MAPT variants (FTDP-17t). We discuss neuroanatomical correlates. We review two prior reports of central hypoventilation associated with MAPT variants suggesting that Ondine's curse occurs uncommonly in FTDP-17t. RESULTS: Despite variants affecting different regions of MAPT and a degree of heterogeneity in pathological findings, the patients reviewed all experienced central hypoventilation during their disease course. CONCLUSION: Tauopathy should be considered in patients with adult-onset Ondine's curse.

A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene.

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.

Severe amnestic syndrome due to theophylline toxicity.

We report a case of severe amnestic syndrome following theophylline overdose. A woman in her early 30s was admitted to hospital where she developed status epilepticus following an intentional overdose of theophylline and lansoprazole. She developed a profound acidosis and required intubation in the intensive care unit. Following extubation the patient was noted to have a severe amnestic syndrome with poor short-term memory. A work-up to exclude infectious, autoimmune and paraneoplastic causes for encephalitis was undertaken. Cerebrospinal fluid analysis was normal and autoimmune encephalitis titres were negative. Initial MRI brain imaging demonstrated hyperintensities of the mesial temporal lobes bilaterally. Follow-up imaging at 4 months identified further interval reduction but persistent hippocampal hyperintensities. Theophylline toxicity with corresponding amnestic syndrome and hippocampal hyperintensities has been rarely reported. We believe this case with persistent abnormal Montreal Cognitive Assessment Score at 12 months correlates with persistent hippocampal abnormalities seen on imaging.