Supranuclear Gaze Palsy Research Articles

Asymmetry in Atypical Parkinsonian Syndromes—A Review

Background/Objectives: Atypical parkinsonian syndromes (APSs) are a group of neurodegenerative disorders that differ from idiopathic Parkinson’s disease (IPD) in their clinical presentation, underlying pathology, and response to treatment. APSs include conditions such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). These disorders are characterized by a combination of parkinsonian features and additional symptoms, such as autonomic dysfunction, supranuclear gaze palsy, and asymmetric motor symptoms. Many hypotheses attempt to explain the causes of neurodegeneration in APSs, including interactions between environmental toxins, tau or α-synuclein pathology, oxidative stress, microglial activation, and vascular factors. While extensive research has been conducted on APSs, there is a limited understanding of the symmetry in these diseases, particularly in MSA. Neuroimaging studies have revealed metabolic, structural, and functional abnormalities that contribute to the asymmetry in APSs. The asymmetry in CBS is possibly caused by a variable reduction in striatal D2 receptor binding, as demonstrated in single-photon emission computed tomography (SPECT) examinations, which may explain the disease’s asymmetric manifestation and poor response to dopaminergic therapy. In PSP, clinical dysfunction correlates with white matter tract degeneration in the superior cerebellar peduncles and corpus callosum. MSA often involves atrophy in the pons, putamen, and cerebellum, with clinical symmetry potentially depending on the symmetry of the atrophy. The aim of this review is to present the study findings on potential symmetry as a tool for determining potential neuropsychological disturbances and properly diagnosing APSs to lessen the misdiagnosis rate. Methods: A comprehensive review of the academic literature was conducted using the medical literature available in PubMed. Appropriate studies were evaluated and examined based on patient characteristics and clinical and imaging examination outcomes in the context of potential asymmetry. Results: Among over 1000 patients whose data were collected, PSP-RS was symmetrical in approximately 84% ± 3% of cases, with S-CBD showing similar results. PSP-P was symmetrical in about 53–55% of cases, while PSP-CBS was symmetrical in fewer than half of the cases. MSA-C was symmetrical in around 40% of cases. It appears that MSA-P exhibits symmetry in about 15–35% of cases. CBS, according to the criteria, is a disease with an asymmetrical clinical presentation in 90–99% of cases. Similar results were obtained via imaging methods, but transcranial sonography produced different results. Conclusions: Determining neurodegeneration symmetry may help identify functional deficits and improve diagnostic accuracy. Patients with significant asymmetry in neurodegeneration may exhibit different neuropsychological symptoms based on their individual brain lateralization, impacting their cognitive functioning and quality of life.

Metronome-Guided Balance Exercises to Aid in Dynamic Balance and Postural Control in a Novel Genetic Presentation of Niemann–Pick Disease Type C: A Case Report

Abstract Niemann–Pick disease type C is a rare progressive lysosomal lipid storage disorder. The disorder is characterized by a range of neurological consequences and complications at different points of its progression including spasticity, incoordination, ataxia, supranuclear gaze palsy, asthenia, and balance impairment, with a higher risk of falls. Among various approaches to managing such a debilitating condition, the role of physical therapy in managing the symptoms of such patients is often limited or underreported in the literature. A combination of spasticity and ataxia leads to impaired timing of agonist–antagonist control. Therefore, balance loss and falls are the most prevalent symptoms. We advocated a 12-week metronome-guided balance training program. Niemann–Pick type C disease is a rare genetic phenomenon that often presents with multi-system changes at structural and functional levels for the patient. Metronome-guided balance training is beneficial for improving dynamic balance variables, including movement velocity, center of gravity sway velocity, and step width.

A Case of Anti-IgLON5 Disease with Aplastic Anemia and review of the literature

Anti-IgLON5 is a neurological condition with neurodegenerative and autoimmune etiology. A 64-year-old man with a 2-year history of aplastic anemia presented with symmetrical parkinsonism, fluctuating consciousness, supranuclear gaze palsy, mild fasciculation, and muscular atrophy. He had disturbances in his sleep cycle and brain MRI. CSF analysis was positive for the IgLON5 antibody. We initiated immunotherapy with high-dose methylprednisolone, intravenous immunoglobulin, and rituximab. The patient showed a mild to moderate response to treatment. We reviewed 29 published case reports regarding anti-Iglon-5 and examined the clinical manifestation. None of the cases showed aplastic anemia, which was the main presentation in our case. All of the patients experienced sleep disturbances, while other symptoms were heterogeneous. Anti-Iglon-5 is usually diagnosed late, leading to a weak prognosis. This study helped us establish a better understanding of the correlation between antiIglon5 disease and other autoimmune disorders like anemia.

Kufor-Rakeb syndrome-associated psychosis: a novel loss-of-function ATP13A2 variant and response to antipsychotic therapy

Biallelic (autosomal recessive) pathogenic variants in ATP13A2 cause a form of juvenile-onset parkinsonism, termed Kufor-Rakeb syndrome. In addition to motor symptoms, a variety of other neurological and psychiatric symptoms may occur in affected individuals, including supranuclear gaze palsy and cognitive decline. Although psychotic symptoms are often reported, response to antipsychotic therapy is not well described in previous case reports/series. As such, we describe treatment response in an individual with Kufor-Rakeb syndrome-associated psychosis. His disease was caused by a homozygous novel loss-of-function ATP13A2 variant (NM_022089.4, c.1970_1975del) that was characterized in this study. Our patient exhibited a good response to quetiapine monotherapy, which he has so far tolerated well. We also reviewed the literature and summarized all previous descriptions of antipsychotic treatment response. Although its use has infrequently been described in Kufor-Rakeb syndrome, quetiapine is commonly used in other degenerative parkinsonian disorders, given its lower propensity to cause extrapyramidal symptoms. As such, quetiapine should be considered in the treatment of Kufor-Rakeb syndrome-associated psychosis when antipsychotic therapy is deemed necessary.

Patterns of brain volume and metabolism predict clinical features in the progressive supranuclear palsy spectrum.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that presents with highly heterogenous clinical syndromes. We perform cross-sectional data-driven discovery of independent patterns of brain atrophy and hypometabolism across the entire PSP spectrum. We then use these patterns to predict specific clinical features and to assess their relationship to phenotypic heterogeneity. We included 111 patients with PSP (60 with Richardson syndrome and 51 with cortical and subcortical variant subtypes). Ninety-one were used as the training set and 20 as a test set. The presence and severity of granular clinical variables such as postural instability, parkinsonism, apraxia and supranuclear gaze palsy were noted. Domains of akinesia, ocular motor impairment, postural instability and cognitive dysfunction as defined by the Movement Disorders Society criteria for PSP were also recorded. Non-negative matrix factorization was used on cross-sectional MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans. Independent models for each as well as a combined model for MRI and FDG-PET were developed and used to predict the granular clinical variables. Both MRI and FDG-PET were better at predicting presence of a symptom than severity, suggesting identification of disease state may be more robust than disease stage. FDG-PET predicted predominantly cortical abnormalities better than MRI such as ideomotor apraxia, apraxia of speech and frontal dysexecutive syndrome. MRI demonstrated prediction of cortical and more so sub-cortical abnormalities, such as parkinsonism. Distinct neuroanatomical foci were predictive in MRI- and FDG-PET-based models. For example, vertical gaze palsy was predicted by midbrain atrophy on MRI, but frontal eye field hypometabolism on FDG-PET. Findings also differed by scale or instrument used. For example, prediction of ocular motor abnormalities using the PSP Saccadic Impairment Scale was stronger than with the Movement Disorders Society Diagnostic criteria for PSP oculomotor impairment designation. Combination of MRI and FDG-PET demonstrated enhanced detection of parkinsonism and frontal syndrome presence and apraxia, cognitive impairment and bradykinesia severity. Both MRI and FDG-PET patterns were able to predict some measures in the test set; however, prediction of global cognition measured by Montreal Cognitive Assessment was the strongest. MRI predictions generalized more robustly to the test set. PSP leads to neurodegeneration in motor, cognitive and ocular motor networks at cortical and subcortical foci, leading to diverse yet overlapping clinical syndromes. To advance understanding of phenotypic heterogeneity in PSP, it is essential to consider data-driven approaches to clinical neuroimaging analyses.

Artery of Percheron infarct – An ophthalmologist’s perspective

Thalamus is an important relay station in diencephalon which receives its blood supply mostly from the posterior cerebral artery. The Artery of Percheron (AOP) arises from the posterior cerebral artery and bifurcates to supply paramedian thalami. AOP infarction, though rare, presents with a triad of clinical features including altered mental status, memory impairment, and supranuclear vertical gaze palsy. Our patient had concurrent manifestation of vertical gaze palsy (both upward and downward) and third cranial nerve palsy in the left eye, which is an interesting clinical amalgamation. Our case report elucidates the quick recognition of the abnormalities in ocular motility through a simple, yet effective nine gaze ocular motility evaluation and thereby enhancing clinical recognition of this entity among the practicing general Ophthalmologists.

Comparing classic-onset corticobasal syndrome to speech/language-onset corticobasal syndrome

IntroductionPatients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS. MethodsWe conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy. ResultsMedian age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS. ConclusionClassic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course.

Detecting Abnormal Eye Movements in Patients with Neurodegenerative Diseases - Current Insights.

This review delineates the ocular motor disturbances across a spectrum of neurodegenerative disorders, including Alzheimer's Disease (AD) and related disorders (ADRD), Parkinson's Disease (PD), atypical parkinsonism, and others, leveraging advancements in eye-tracking technology for enhanced diagnostic precision. We delve into the different classes of eye movements, their clinical assessment, and specific abnormalities manifesting in these diseases, highlighting the nuanced differences and shared patterns. For instance, AD and ADRD are characterized by increased saccadic latencies and instability in fixation, while PD features saccadic hypometria and mild smooth pursuit impairments. Atypical parkinsonism, notably Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS), presents with distinct ocular motor signatures such as vertical supranuclear gaze palsy and saccadic apraxia, respectively. Our review underscores the diagnostic value of eye movement analysis in differentiating between these disorders and also posits the existence of underlying common pathological mechanisms. We discuss how eye movements have potential as biomarkers for neurodegenerative diseases but also some of the existing limitations.

Challenges to Distinguish Idiopathic Normal Pressure Hydrocephalus from Progressive Supranuclear Palsy

Idiopathic normal pressure hydrocephalus (iNPH) is a clinical condition characterized by symptoms of gait disturbance, cognitive dysfunction, and urinary disturbance. In contrast, progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by supranuclear gaze palsy, akinetic rigidity, gait disturbance, and dementia. PSP manifests various clinical phenotypes that mimic other diseases and occasionally present iNPH-like presentations. Our previous publication showed that PSP develops iNPH-like magnetic resonance imaging (MRI) features more frequently than other neurodegenerative diseases. It is thus sometimes challenging to distinguish iNPH from PSP. Recently, we showed that patients with PSP, particularly those with iNPH-like MRI findings, often demonstrate amelioration of their gait disturbance following a spinal tap or shunt operation. Moreover, our study revealed that both patients with iNPH and PSP often manifest a placebo effect that can be evaluated by implementing a sham spinal tap. Therefore, although a positive response to a spinal tap has been thought of as a distinct feature of iNPH, it may not be useful in differentiating iNPH and PSP. However, in clinical practice, comparing the response to a spinal tap with that of a sham spinal tap may help accurately specify patients with iNPH or PSP who definitively respond to the shunt operation.

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

Kufor-Rakeb syndrome in two Iranian brothers due to different and novel mutations

Kufor-Rakeb Syndrome (KRS) is an uncommon autosomal recessive neurological condition that frequently has clinical symptoms including supranuclear gaze palsy, dementia, and generalized brain atrophy

At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years

Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients’ clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype–phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0–64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C > G, p.(P1007A), c.3104C > T, p.(A1035V), and c.2861C > T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p < 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype–phenotype relationships for “frequent” NPC1 variants.

A Man with Rapid Speech and Handwriting.

Video 1 Video showing abnormal speech, handwriting, partial supranuclear gaze palsy, and impaired postural reflexes. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Whole-Brain Magnetic Resonance Spectroscopy Reveals Distinct Alterations in Neurometabolic Profile in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages. The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopicimaging (wbMRSI). Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment). In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers. In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Imaging Criteria for the Diagnosis of Progressive Supranuclear Palsy: Supportive or Mandatory?

We present the case of a 54-year-old male, without any significant medical history, who insidiously developed speech disturbances and walking difficulties, accompanied by backward falls. The symptoms progressively worsened over time. The patient was initially diagnosed with Parkinson's disease; however, he failed to respond to standard therapy with Levodopa. He came to our attention for worsening postural instability and binocular diplopia. A neurological exam was highly suggestive of a Parkinson-plus disease, most likely progressive supranuclear gaze palsy. Brain MRI was performed and revealed moderate midbrain atrophy with the characteristic "hummingbird" and "Mickey mouse" signs. An increased MR parkinsonism index was also noted. Based on all clinical and paraclinical data, a diagnosis of probable progressive supranuclear palsy was established. We review the main imaging features of this disease and their current role in diagnosis.

Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) has been reported as a disorder mainly characterized by a tendency to fall, vertical supranuclear gaze palsy, and constriction of the body axis, akinesia, and cognitive impairment. Patients presenting with these typical clinical features are diagnosed as having the PSP-Richardson syndrome (PSP-RS). Electronystagmography (ENG) is useful for the detection of ocular motility disorder, which is the main feature of PSP. In cases of PSP, ocular motility disorder in the vertical direction occurs from the initial stage of the disease, and is characterized by prolonged latency and reduced velocity of the saccadic eye movement in the vertical direction. Horizontal saccadic eye movement disorder also occurs after the intermediate stage. Square wave jerks (SWJ) are often recognized from the initial stage of the disease. In terms of nystagmus, the quick phase is impaired due to impaired saccadic eye movements, and impairment of optokinetic nystagmus also starts from the quick phase movements. Pursuit (smooth) eye movement may also be impaired as the disease progresses. On the other hand, the vestibulo-ocular reflex is maintained even after disease progression to a late stage.

Novel Mutation In The APT13A2 Gene Associated With Ataxia, Cerebellar Tremor, Bipolar Disease and Epilepsy (P9-11.010)

<h3>Objective:</h3> To Report a Novel Mutation In The ATP13A2 Gene Causing Cerebellar Ataxia With Bipolar Disorder And Epilepsy Without Parkinsonism. <h3>Background:</h3> ATP13A2 gene mutations are rare and initially were identified in patients with autosomal recessive (AR) juvenile onset of parkinsonism with supranuclear gaze palsy, and dementia, also known as Kufer-Rakeb disease. Subsequently, recognized phenotypic variability of biallelic mutations in this gene widened and include AR hereditary spastic paraplegia or spastic ataxia. Pure cerebellar ataxia is rarely caused by mutations in this gene. <h3>Design/Methods:</h3> Case report and genetic analysis of the ATP13A2 gene in affected proband and both parents. <h3>Results:</h3> The proband is a 40-year-old male of Iranian descent who developed difficulties walking with multiple falls as a teenager. He transitioned from a walker to a wheelchair dependency in his 20s. He was diagnosed with spinocerebellar ataxia with Holmes tremor in both arms. His examination showed vertical ophthalmoplegia without any signs of Parkinsonism or spasticity. The patient had signs of a mild developmental delay and in his 20s he was also diagnosed with bipolar disorder. He developed seizures in his 40s and they were well-controlled on levetiracetam. Brain MRI showed cerebellar atrophy with no iron deposits in basal ganglia. His parents were first cousins. Family history was noticeable for similar problems in two deceased cousins who were also from consanguineous marriages. Genetic testing showed a novel homozygous mutation in exon 26 of ATP13A2, c.2899G&gt;C (p.Asp967His). We did not find this in 100 controls. Both parents were heterozygous at the same codon. We also confirmed the mutation in the CLIA certified laboratory, which is cataloged as rs772870846. In vitro analysis showed this variant being deleterious. <h3>Conclusions:</h3> We report a novel mutation in the ATP13A2 gene with unique constellation of clinical features, further expanding the phenotypic spectrum of movement disorders associated with this genetic condition. <b>Disclosure:</b> Dr. Yousaf has nothing to disclose. Dr. D’Aguiar Rosa has nothing to disclose. Dr. Ghani has nothing to disclose. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Hedera has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for University of Louisville.

Vertical supranuclear gaze palsy in Primary Familial Brain Calcification associated with a novel SLC20A2 mutation (P14-11.003)

<h3>Objective:</h3> We herein describe a patient with Primary Familial Brain Calcification secondary to a novel solute carrier family 20 member 2 (<i>SLC20A2</i>) gene mutation presenting with vertical supranuclear gaze palsy (VSGP). <h3>Background:</h3> The spectrum of clinical features associated with PFBC remains broad. Despite considerable clinical heterogeneity, motor abnormalities including parkinsonism, tremor, and speech disturbances have been frequently described in these cases. VSGP has been rarely documented and is posited to arise from calcification-related disruptions of the basal ganglia pathways, specifically those linking the caudate and midbrain. <h3>Design/Methods:</h3> Not applicable. <h3>Results:</h3> This 74-year-old Chinese woman with a negative relevant family history presented with a six-year history of parkinsonism, frequent falls, speech disturbances and VSGP on examination that failed to respond to levodopa/carbidopa. Non-contrast computed tomography revealed abnormal calcium deposition in the bilateral lentiform nuclei, dentate nuclei, occipital subcortical white matter, and right caudate head. Blood investigations including calcium, magnesium, phosphate, alkaline phosphatase, and thyroid and parathyroid hormone levels were normal. A Parkinson’s disease gene panel revealed a heterozygous missense likely pathogenic <i>SLC20A2</i> variant ((c.625del) p. (Val209Phefs*7)) that creates a shift in the reading frame. <h3>Conclusions:</h3> VSGP has been reported in only eight patients with diffuse brain calcification, four diagnosed with PFBC. The increasing number of reported individuals with PSP-like features raises the possibility of this syndrome being a PFBC-associated phenotype, which may arise from inherent PFBC pathophysiological mechanisms irrespective of the causative gene. Given the recent evidence, it is possible that the downstream effects of PFBC pathology including neurovascular unit compromise and neurotoxic astrocytic responses contribute to disruptions in pathways in or projecting to the midbrain, resulting in this patient’s clinical expression. Further work is needed to fully characterize the gaze abnormalities and clinical spectrum of PFBC. Our work also highlights the importance of having oculomotor assessments well documented in future reports of patients with PFBC. <b>Disclosure:</b> Dr. Reyes has nothing to disclose. Dr. Lang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie, Acorda, AFFiRis, Biogen, Denali, Janssen, Intracellular, Kallyope, Lundbeck, Paladin, Retrophin, Roche, Sun Pharma, Theravance, and Corticobasal Degeneration Solutions, Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion. The institution of Dr. Lang has received research support from AbbVie. Dr. Lang has received publishing royalties from a publication relating to health care.

Dystonia with myoclonus and vertical supranuclear gaze palsy associated with a rare GNB1 variant (P11-11.008)

<h3>Objective:</h3> We report a case of <i>GNB1</i> encephalopathy arising from a <i>de novo</i> mutation in an uncommon locus presenting with a unique phenotype consisting of dystonia with myoclonus and vertical supranuclear gaze palsy (VSGP). <h3>Background:</h3> <i>GNB1</i> encephalopathy (OMIM: 616973), caused by pathogenic variants in the <i>GNB1</i> gene, is a rare neurodevelopmental syndrome variably co-occurring with movement disorders, with dystonia being the most frequently reported. Myoclonus occurring alongside dystonia and VGSP are uncommon findings. Most pathogenic variants occur in exons 6 and 7, which are considered to be mutational hotspots. <h3>Design/Methods:</h3> Not applicable. <h3>Results:</h3> This 27-year-old female presented with hypotonia and global developmental delay, intellectual disability, short stature, low body weight, dysarthria, a wide-based gait, and dystonia. She only had partial improvement with a trial of amantadine, and did not respond to dopaminergic therapy. In the ensuing years, she developed myoclonus, which persisted despite a gradual tapering off of amantadine. At 12 years of age, further examination disclosed a VSGP. Her axial dystonia, posture, and gait significantly improved with botulinum toxin (BoNTA) injections to the paraspinal muscles beginning at 18 years of age. Investigations including blood work, CSF neurotransmitters, imaging, and metabolic parameters were unrevealing. Electrophysiologic testing were consistent for both myoclonus superimposed on dystonia. Initial genetic investigations, which also included a proband whole exome sequencing (WES) were nondiagnostic. Updated trio WES six years after identified a <i>de novo</i>, heterozygous missense, likely pathogenic variant in the <i>GNB1</i> gene (c.1009A&gt;C (p.Lys337Gln); exon 11). <h3>Conclusions:</h3> Our case illustrates the evolving clinical phenotypes of <i>GNB1</i> encephalopathy and highlights its importance as a diagnostic consideration for neurodevelopmental syndromes presenting with movement disorders and gaze abnormalities. In cases where the constellation of clinical findings suggests a genetic syndrome yet ascertainment of diagnosis is challenging, our experience highlights the value of repeating next-generation sequencing tests. <b>Disclosure:</b> Dr. Reyes has nothing to disclose. Dr. Garbin Di Luca has nothing to disclose. Dr. McNiven has nothing to disclose. Dr. Lang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie, Acorda, AFFiRis, Biogen, Denali, Janssen, Intracellular, Kallyope, Lundbeck, Paladin, Retrophin, Roche, Sun Pharma, Theravance, and Corticobasal Degeneration Solutions, Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion. The institution of Dr. Lang has received research support from AbbVie. Dr. Lang has received publishing royalties from a publication relating to health care.

Frequency of anti-IgLON5 disease in patients who meet the clinical diagnostic criteria for progressive supranuclear palsy/corticobasal syndrome (S22.010)

<h3>Objective:</h3> To confirm the prevalence of anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease in patients who fulfill the diagnostic criteria for progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS). <h3>Background:</h3> Anti-IgLON5 disease can present symptoms that mimic PSP and CBS, including vertical supranuclear gaze palsy and parkinsonism. Some patients who are diagnosed with PSP or CBS are expected to have anti-IgLON5 antibodies; however, the frequency of such patients remains unknown. <h3>Design/Methods:</h3> We included 360 subjects enrolled in the Japanese Longitudinal Biomarker Study in PSP and Corticobasal Degeneration (JALPAC). We noted the age and sex of each patient and evaluated their diagnosis using diagnostic criteria for each subtype of PSP (PSP with Richardson’s syndrome [PSP-RS], PSP with parkinsonism [PSP-P], PSP-pure akinesia with gait freezing [PSP-PAGF], and PSP with cerebellar ataxia [PSP-C]), and using the revised Cambridge criteria and Armstrong criteria for CBS. In patients who fulfilled any diagnostic criteria, we then tested serum anti-IgLON5 antibodies via a cell-based assay. <h3>Results:</h3> Of 360 subjects in JALPAC, 223 fulfilled at least one of the diagnostic criteria for possible or probable PSP/CBS. The median age of these 223 patients was 73 (range 51–88) years; 123 (55%) were male. The numbers of patients who met each set of criteria were as follows: PSP-RS, 52; PSP-PAGF, 6; PSP-C, 2; CBS, 117; PSP-RS and CBS, 37; PSP-PAGF and CBS, 4; PSP-RS and PSP-PAGF, 1; PSP-RS and PSP-P, 1; PSP-P and CBS, 1; PSP-RS, PSP-PAGF, and CBS, 1; and PSP-RS, PSP-C, and CBS, 1. All 223 patients were negative for anti-IgLON5 antibodies. <h3>Conclusions:</h3> Anti-IgLON5 disease is likely absent or extremely rare in patients who meet the diagnostic criteria for PSP/CBS and have typical clinical presentations. Atypical symptoms such as sleep disturbance, dysautonomia, and respiratory failure may be crucial clinical features of anti-IgLON5 disease with PSP-/CBS-like presentations. <b>Disclosure:</b> Yoya Ono has nothing to disclose. Akira Takekoshi has nothing to disclose. Dr. Yoshikura has nothing to disclose. Dr. Takigawa has nothing to disclose. Ikuko Aiba has nothing to disclose. Ritsuko Hanajima has nothing to disclose. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for DAIICHI SANKYO COMPANY, LIMITED. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eli Lilly Japan K.K.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen Inc.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda Pharmaceutical Company Limited.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Kyowa Kirin Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Chugai Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for ONO PHARMACEUTICAL CO., LTD.. Dr. Kanazawa has nothing to disclose. Dr. ?? has nothing to disclose. Aya Tokumaru has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Hasegawa has nothing to disclose. Kenji Nakashima has nothing to disclose. Dr. Ikeuchi has nothing to disclose. Dr. Kimura has nothing to disclose. Dr. Shimohata has nothing to disclose.