Progressive supranuclear palsy (PSP) is typically characterized by vertical supranuclear gaze palsy and early falls, referred to as Richardson's syndrome (PSP-RS). Other presentations include postural instability (PSP-PI), Parkinsonism (PSP-P), speech/language disorder (PSP-SL), frontal presentation (PSP-F), ocular motor dysfunction (PSP-OM), and corticobasal syndrome (PSP-CBS). However, differences across the early presentations and their subsequent clinical courses remain to be elucidated. This study aimed to characterize early PSP subtypes and their subsequent progressions using a large postmortem dataset. An automated pipeline incorporating fine-tuned Chat Generative Pretrained Transformer (ChatGPT) was developed. The pipeline collected 195 clinical features with onset information from autopsy-confirmed PSP cases without significant neurodegenerative co-pathologies. A structured clinicopathologic dataset from 588 patients was analyzed. The results from unsupervised clustering were distilled into a decision tree model. The mutually exclusive algorithm identified seven subtypes: PSP-PF (postural and frontal dysfunction), PSP-RS, PSP-PI, PSP-P, PSP-SL, PSP-F, and PSP-OM, based on five clinical manifestations: frontal presentation, postural instability, ocular motor dysfunction, speech/language disorder, and Parkinsonism. PSP-PF showed rapid progression, the shortest median disease duration (six years), and high tau burden in cortical and subcortical regions. In PSP-F, frontal presentation preceded other symptoms by four years, with a nine-year disease duration-second longest after PSP-P (10 years). PSP-CBS was not identified as an independent subtype. This data-driven study identified a novel, aggressive PSP phenotype characterized by early postural and frontal dysfunction. Early subtyping using the decision tree model would help clinicians estimate progression and facilitate early patient recruitment for clinical trials.

Progressive supranuclear palsy (PSP) is typically characterized by vertical supranuclear gaze palsy and early falls, referred to as Richardson's syndrome (PSP-RS). Other presentations include postural instability (PSP-PI), parkinsonism (PSP-P), speech/language disorder (PSP-SL), frontal presentation (PSP-F), ocular motor dysfunction (PSP-OM), and corticobasal syndrome (PSP-CBS). Differences across the early presentations and in their subsequent progression have yet to be elucidated. This study aimed to characterize early PSP subtypes and their subsequent progressions using a large postmortem dataset. An automated pipeline incorporating fine-tuned Chat Generative Pre-trained Transformer (ChatGPT) was developed. The pipeline collected 195 clinical features with onset information from autopsy-confirmed PSP cases without significant neurodegenerative co-pathologies. A structured clinicopathologic dataset from 588 patients was analyzed. After distilling results with unsupervised clustering, a decision tree model was developed. With five clinical manifestations: frontal presentation, postural instability, ocular motor dysfunction, speech/language disorder, and parkinsonism, this mutually exclusive algorithm identified seven subtypes: PSP-PF (postural and frontal dysfunction), PSP-RS, PSP-PI, PSP-P, PSP-SL, PSP-F, and PSP-OM. PSP-PF showed rapid progression, the shortest median disease duration (six years), and high tau burden in cortical and subcortical regions. In PSP-F, frontal presentation preceded other symptoms by four years, with a nine-year disease duration-second longest after PSP-P (10 years). PSP-CBS was not identified as an independent subtype. This data-driven study identified a novel, aggressive PSP phenotype characterized by early postural and frontal dysfunction. Early subtyping utilizing the decision tree model would help clinicians estimate progression and facilitate early patient recruitment for clinical trials.

To describe an atypical presentation of a rare disease in a young middle eastern woman with a relatively adult-onset type 1 diabetes mellitus, bilateral optic atrophy and progressive decreased vision diagnosed as the Wolfram disease. A 38-year-old female patient presented with progressive bilateral loss of vision and dyschromatopsia during a 4-year follow-up. On examination at the neuro-ophthalmology clinic the visual acuity was 20/100 in the right eye and 20/80 in the left eye. Color vision evaluated with Ishihara color plates was 0/12 in each eye, optic discs were pale, while visual field testing revealed bilaterally constriction. Optical coherence tomography (OCT) scans showed gross thinning of optic nerve and macular layers. The medical history revealed diabetes mellitus type 1 at the age of 33 years-old. On follow-up visits further progressive vision loss was observed with additional complaints of mild hearing loss. The patient was referred for genetic testing. Wolfram syndrome (WFS) is an autosomal recessive rare neurodegenerative disorder characterized by early onset diabetes mellitus and progressive optic atrophy in the first decade of life, hence known as 'DIDMOAD' syndrome, standing for diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA) and deafness (D)(1). Early onset DM and OA are usually the first manifestations of the syndrome, presenting classically in childhood. In contrast, the present patient presented later with type 1 diabetes mellitus and optic atrophy demonstrating a variability inherent to this syndrome. This is a case of Wolfram Syndrome in an individual of Middle Eastern ancestry. A high index of suspicion is crucial when evaluating patients who present with both diabetes mellitus and optic atrophy, as this combination may indicate atypical manifestations of rare genetic disorders such as Wolfram Syndrome DM and OA. Genetic testing of family members and offspring of patients is required to confirm the diagnosis. There is no definite treatment to date for this disease (2).

The amount of time that a person with a cochlear implant experiences severe-to-profound hearing loss before implantation is thought to impact the underlying neural survival, health, and function of the auditory system, thus likely being closely related to post-implantation performance in auditory tasks. The reporting of this number in the research literature is ubiquitous. Although it is most commonly called "duration of deafness," our point of view is that the term is imprecise and the calculation of this number can be nontrivial, particularly for cases of adult onset of hearing loss. We provide suggestions on changing the terminology to "duration of severe-to-profound hearing loss." We also propose a method of determining this number through a series of questions that leads a participant/patient through their progression of hearing loss. We encourage research methodology that requires researchers to explicitly report the process used to determine the duration of severe-to-profound hearing loss with the overall goals of (1) improving rigor and reproducibility in cochlear-implant research and (2) improving the translation between research findings and clinical recommendations.

Pathogenic variants in B-cell receptor-associated protein (BCAP31) are associated with X-linked, deafness, dystonia and cerebral hypomyelination (DDCH) syndrome. DDCH is congenital and non-progressive, featuring severe intellectual disability (ID), variable dysmorphism, and sometimes associated with shortened survival. BCAP31 encodes one of the most abundant chaperones, with several functions including acting as a negative regulator of endoplasmic reticulum (ER) calcium ion (Ca2+) concentration. Here, we characterize an X-linked syndrome, its underlying genotype, and a functional evaluation of the identified candidate genetic variant. Evaluation of motor features, neuroimaging studies, neurophysiological, and cognitive tests. Whole exome sequencing (WES) was applied, a plasmid encoding BCAP31 with and without a candidate variant was transfected into SH-SY5Y cells to assess subcellular location and to measure Ca2+ levels in the cytoplasm. Adult-onset ataxia, cognitive impairment, and hearing loss leading to deafness are the predominant features. Reduced penetrance, slow progression with preserved ability to walk in advance age, and universal cerebellar atrophy are other features for this syndrome. This condition is associated with the new variant c.22G>A (V8I) in BCAP31 at Xq28. The subcellular location of the V8I BCAP31 protein was not altered but caused significant elevation of cytosolic Ca2+. Our findings expand the spectrum of variants in BCAP31 from neurodevelopmental syndromes to include a progressive neurodegenerative disease with variable expressivity. This is the first time ataxia is described in association with a BCAP31 variant and functional evidence of pathogenicity is provided. Additional BCAP31 cases featuring ataxia are needed to establish an association. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.