Atypical Clinical Phenotypes Research Articles

Default mode network tau predicts future clinical decline in atypical early Alzheimer's disease.

Identifying individuals with early-stage Alzheimer's disease (AD) at greater risk of steeper clinical decline would enable better-informed medical, support, and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau positron emission tomography (PET) in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. Across heterogeneous clinical phenotypes, patients with atypical AD consistently exhibit abnormal tau accumulation in the posterior nodes of the default mode network of the cerebral cortex. This evidence suggests that tau burden in this functional network could be a common imaging biomarker for prognostication across the syndromic spectrum of AD. Here, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes: Posterior Cortical Atrophy (n = 16), logopenic variant Primary Progressive Aphasia (n = 15), and amnestic syndrome with multi-domain impairment and young age of onset < 65 years (n = 17). All patients underwent magnetic resonance imaging (MRI), tau PET, and amyloid PET scans at baseline. Each patient's longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Atypical early AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, p < .001, Cohen's d = 0.95. Across clinical phenotypes, baseline tau in the default mode network was the strongest predictor of clinical decline (R2 = .30), outperforming a simpler model with baseline clinical impairment and demographic variables (R2 = .10), tau in other functional networks (R2 = .11-.26), and the magnitude of cortical atrophy (R2 = .20) and amyloid burden (R2 = .09) in the default mode network. Overall, these findings point to the contribution of default mode network tau to predicting the magnitude of clinical decline in atypical early AD patients one year later. This simple measure could aid the development of a personalized prognostic, monitoring, and treatment plan, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient's tau burden while still early in the disease course.

Phenotypic/Genotypic Profile of Children with Neuronal Ceroid Lipofuscinosis in Southern Brazil

Abstract Introduction Neuronal ceroid lipofuscinoses (CLNs) are a group of lysosomal storage disorders of genetic origin, characterized by progressive neurodegeneration and intracellular accumulation of autofluorescent lipopigment. Thirteen genes related to CLNs are currently described, showing genetic and allelic heterogeneity, most of them with an autosomal recessive pattern. Due to the few descriptions of cases related to CLNs in Brazil, it is necessary to describe the phenotypic and genotypic characteristics of these patients. This study aims to evaluate the genotypic profile and correlate it with the phenotypic characteristics of patients with CLN in a children's hospital. Methods This study was performed as a descriptive cross-sectional study with analysis of medical records, imaging, and laboratory tests of patients who had a confirmed molecular diagnosis of CLN. Results The sample consisted of 11 patients from nine families with different subtypes of CLNs (CLN2, 5, 6, 7, and 8), with CLN2 being the most prevalent in the study. A total of 16 mutation variants were identified in genes associated with the five CLNs described in this study, with typical and atypical clinical phenotypes depending on the subtype and its variants. Conclusion Novel mutations identified in the patients in this study showed phenotypes of rapid and severe progression in the CLN2 patient and similar characteristics in CLN6 and CLN7 patients, as previously described in the literature.

Biomarkers for Alzheimer's Disease – An Overview

AbstractAlzheimer's disease (AD) is a complex neurodegenerative disorder with a significant global impact on public health. The emergence of atypical clinical phenotypes challenges traditional diagnostic approaches, necessitating a deeper exploration of biomarkers for accurate identification. The US Food and Drug Administration (FDA) classification of biomarkers and their integration into different stages of AD provide a structured framework for their application in research and clinical settings. Within the context of AD drug development, biomarkers are essential for participant selection, target engagement evaluation, and assessment of pathological hallmarks, including Aβ and tau protein abnormalities. The incorporation of nanoparticles with a biodegradable approach introduces innovative strategies to address the complexities of AD. This paper extensively discusses biomarkers associated with synaptic dysfunction, neuroinflammation, and glial activation, recognizing their significance in elucidating disease mechanisms. Common pathologies such as synuclein and TDP‐43 further underscore the multifaceted nature of AD. Current biomarkers for AD diagnosis, encompassing cerebral spinal fluid (CSF) biomarkers and various imaging modalities, reflect the ongoing efforts to enhance early detection and monitoring. Intriguingly, novel biomarkers continue to emerge, offering promising avenues for improved understanding and intervention. Current review provides a comprehensive survey of biomarkers for AD, elucidating their diverse roles across different aspects of the disease. By highlighting their contributions to diagnosis, drug development, and mechanistic insights, this overview underscores the importance of biomarker research in the pursuit of effective AD management and treatment strategies.

Genetic Drivers of Atypical Alzheimer’s Disease Neuropathologic Change

AbstractBackgroundQuantitative differences in neurofibrillary tangle density are not well captured by more global measures such as Braak staging. Indeed, amongst cases with high Alzheimer’s disease neuropathologic change (ADNC), quantitative differences in the distribution of neurofibrillary tangle density is associated with atypical, non‐amnestic clinical presentations. We sought here to study the effect of TREM2 and APOE risk genotypes on neuropathologically and clinically defined atypical Alzheimer’s disease.MethodsTREM2 variant versus wild‐type autopsy cases with an intermediate to high level of ADNC were identified from the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Archived clinical records were used to classify cases into typical versus atypical AD. Neuropathologic classification of cases into typical versus atypical AD was based on quantification of neurofibrillary tangle density using PHF1 stained sections from neocortical and hippocampal regions. Morphology from Iba1 stained sections was used to quantify microglial reactivity.Results31 AD cases with TREM2 risk genotypes were compared to wild‐type TREM2 AD cases (n = 119). TREM2 variants were associated with a significantly higher proportion of atypical AD clinical phenotypes including behavioral/dysexecutive variants, primary progressive aphasias, posterior cortical atrophy, and others (19.33% versus 48.39%, Fisher’s exact test p = 0.002). These clinical phenotypes were associated with a significantly higher proportion of TREM2 variant cases with neuropathologically defined atypical AD, namely hippocampal sparing AD (8.7% versus 28.57%, Fisher’s exact test p = 0.046). Moreover, the proportion of microglia with a dystrophic morphology correlated with neurofibrillary tangle density and not amyloid burden. Finally, to get a sense of the magnitude of this TREM2 association relative to other genetic risk factors, we observed a non‐significant trend towards the absence of the APOE E4 risk genotype being associated with hippocampal sparing AD.ConclusionsThis clinicopathologic correlation study suggests that TREM2 risk variants are associated with clinically and neuropathologically defined atypical AD. Given that both TREM2 and APOE affect microglial reactivity to amyloid, the observed tendency towards TREM2 variant cases exhibiting hippocampal sparing AD suggests that altered microglial reactivity to amyloid may change downstream tauopathy patterns leading to atypical AD clinical phenotypes.

Biomarkers of Alzheimer’s disease pathology in atypical non‐amnestic clinical phenotypes

AbstractBackgroundAlzheimer’s disease (AD) is most commonly presented with memory loss features. However, there are atypical clinical phenotypes including predominant visual, language, executive, behavioural, or motor dysfunction. The goal of our study was to estimate the prevalence of Alzheimer’s pathology in non‐amnestic clinical variants.MethodWe examined 40 patients (17 males, 23 females, 66.1±8.3 yrs) with atypical phenotypes of AD (Table 1). Seven patients had the phenotype of logopenic variant of primary progressive aphasia (lvPPA), 3 patients had the diagnosis of posterior cortical atrophy (PCA), 19 had corticobasal syndrome (CBS), and 11 cases met research criteria of clinical behavioral variant of AD (bvAD). All patients underwent lumbar puncture. CSF biomarkers Abeta‐42 (cutoff 150 pg/mL) and p‐tau181 (cutoff 600 pg/mL) were analyzed. According to the recommendations of International Working Group (2021) we defined probable and possible AD based on clinical phenotype and studied CSF biomarkers.ResultThe overall prevalence of AD pathology in the studied groups was 42.5% (20% for probable diagnosis and 22.5% for possible). All results are presented in Table 1. The highest prevalence of AD pathology in atypical clinical phenotypes was found in the group of PCA (66.7%), the lowest ‐ in the group of bvAD (36.4%). Almost a half of patients in both lvPPA and CBS groups had AD pathology based on biomarkers – 42.9% and 42.2%, respectively.ConclusionThe results showed the importance of verifying AD pathology biomarkers in common (PCA, lvPPA) and uncommon (CBS) phenotypes. Behavioral variant, considered as a rare AD phenotype, in our studied cohort was characterized by relatively high occurrence of positive AD biomarkers. Increasing the use of AD biomarkers in clinical practice and greater recognition of atypical phenotypes can ensure early diagnosis, treatment and care for these patients.

A case of long QT syndrome with atypical clinical phenotype caused by KCNQ1-R555C missense mutation

A case of long QT syndrome with atypical clinical phenotype caused by KCNQ1-R555C missense mutation

A rare case of Cushing syndrome ectopic-ACTH: A case report

Malignant tumors, nevertheless, have been associated with extremely high circulating ACTH and cortisol levels, and short duration of symptoms of Cushing syndrome (CS) besides atypical clinical phenotype, when compared with pituitary-dependent Cushing. A 33-year-old woman with a history of insulin-induced diabetes admitted to our department for suspicion of ACTH-dependent Cushing's syndrome held in front of : a Cushing's syndrome clinic, biological Cushing's syndrome, CLU : 2894ug/24h, minute braking : negative, cortisolemia 32.1ug/dl, ACTH : 232ng/l, CT scan of the adrenal glands in favor of moderate adrenal hyperplasia. MRI Pituitary without anomaly, strong negative braking. An Octreoscan objectified the presence of two thyroid nodules of hypodense generation moderately fixing the radiotracer, measuring respectively 1.9*1.2cm on the right and 1.5*1.1cm on the left. The focus intensely fixes the retrotracheal radiotracer and the right paravertebral retrotracer. Tumor markers are negative. The patient was operated on for anopathy : thyroid nodular dystrophy, reactive lymphadenitis, a review of the anopathy with iminohistochemistry is requested results in progress. The patient comes to our training 1 month post-operative, the patient reports a regular cycle return, the clinical examination shows a disappearance of purple stretch marks and bruises. Control octreoscan shows the absence of signs in favor of a neuroendocrine tumor at the pleuro-pulmonary, digestive or thyroid level. The nodule resected to objective the presence of anti-ACTH antibodies in immunohistochemistry. . Identification of the source of ACTH can be challenging, as sometimes the primary lesion is not identified even after prolonged and repeated follow-up.

Early markers of neurodevelopmental disorders based on general movements for very preterm infants: study protocol for a multicentre prospective cohort study in a clinical setting in China

IntroductionVery preterm (VPT) infants may experience varying degrees of neurodevelopmental challenges. Lack of early markers for neurodevelopmental disorders may delay referral to early interventions. The detailed General Movements Assessment (GMA)...

A diagnostic conundrum in the time of a pandemic: a subtle, isolated myelopathy. (P10-5.028)

<h3>Objective:</h3> NA <h3>Background:</h3> Anti-CV2/collapsin response-mediator protein 5 (CRMP5) antibodies are considered “high-risk” markers, frequently associating with paraneoplastic syndromes (PNS). <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 44-year-old woman was recovering from a mild case of COVID-19 when she presented with a single episode of urinary retention and a subacute paraparesis with prominent sensory disturbances and girdle-like pain. Since a spinal cord MRI did not show any lesions and EMG did not detect any conduction defects, she refused further examinations and underwent empiric antimicrobial and steroid therapy, along with physical treatment. However, almost two months later she was still suffering from dysesthesia, dysuria, dyschezia and gait disturbance. A second MRI revealed multiple, asymmetric, short-segment lesions in the spinal cord, with persistent contrast-enhancement (despite the previous steroid treatment), but no brain involvement. Cerebrospinal fluid (CSF) analysis and infectious workup were unremarkable, detecting only a slight increase in CSF proteins and a mirror pattern. An extensive screening for autoimmune and paraneoplastic diseases disclosed anti-CV2/CRMP5 antibodies in the serum; however, antibody titer and confirmatory tests were not available at that time and there was no corresponding reactivity in her CSF. After 3 months the antibodies were still present, arguing for a PET scan, which was uneventful. In the meanwhile the woman was treated with IV steroids, followed by a slow oral tapering with gradual but significant improvement. Indeed, after 6 months the MRI showed a diffuse reduction of the spinal cord swelling and T2 signal change, with no contrast enhancement; her neurological exam still remains strikingly normal. <h3>Conclusions:</h3> This remarkable response to immunotherapy, along with the atypical clinical phenotype and radiographic findings (when compared to reported anti-CV2/CRMP-5 myelopathies), argues for an alternative diagnosis, contemplating a post-infectious etiology rather than a PNS. The case also underlines how commercial line blots should always be confirmed by alternative and more reliable techniques. <b>Disclosure:</b> Federica Boso has nothing to disclose. Dr. Giometto has nothing to disclose.

Fulminant Idiopathic Intracranial Hypertension Refractory to Treatment Associated to SARS-CoV-2: A Case Report (P14-4.004)

<h3>Objective:</h3> NA <h3>Background:</h3> Idiopathic Intracranial Hypertension (IIH) is characterized by increased intracranial pressure, which most frequently occurs in childbearing-age obese women. Scarce reports of COVID-19 infection associated IIH exist and have only described this in women and children. “Fulminant IIH” is defined as intracranial hypertension without secondary cause, with severe vision loss within 4 weeks of onset, and progressive vision loss over days. A 36-year-old man with obesity came to the Ophthalmology clinic for evaluation of vision loss and headache, the patient tested positive for SARS-CoV-2 one month before this. He was identified to have bilateral grade V papilledema, confirmed with optical coherence tomography (OCT), and admitted to Neurology for IIH management. The patient was started intravenous therapy with high-dose steroids and acetazolamide without relief of headache or vision improvement (20/100). Lumbar puncture was performed, revealing an opening pressure of ≥55 cm H20. The MRI only showed findings of increased intracranial hypertension, and the MRV ruled out thrombosis. The lack of improvement in his headaches and vision loss ultimately required ventriculoperitoneal shunt placement. The patient had immediate subjective visual improvement after this, with unchanged visual acuity. On follow-up 4 weeks later, the patient continued to have headaches and the opening pressure was 30 cm H20. Lumboperitoneal shunt was placed. Both optic nerves became completely atrophic. Despite finally reaching an opening pressure of 15 cm H20, headaches did not resolve, and the patient currently only perceives light. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> This case represents, to our best knowledge, the first description of fulminant IIH associated with SARS-CoV-2. The previous reports described mild to moderate cases in women and children with response to treatment. This occurred to an adult male who despite receiving promptly treatment, had a poor response. Further studies are needed to determine if atypical clinical phenotypes are associated with refractory forms. <b>Disclosure:</b> Dr. Murguia Fuentes has nothing to disclose. Mr. Murguia Fuentes has nothing to disclose. Dr. Adamu has nothing to disclose. Dr. Carvajal- Gonzalez has nothing to disclose. Dr. Arvas has nothing to disclose.

Anti-Yo autoimmunity in patients with post-immune checkpoint inhibitors neurological syndromes (P4-5.027)

<h3>Objective:</h3> We report for the first time the occurrence of Yo-antibodies (Abs) in the setting of post-immune checkpoint inhibitors (ICI) neurological syndromes. <h3>Background:</h3> Among Abs carrying a high risk for paraneoplastic neurological syndromes (PNS), anti-Yo-Abs are mostly detected in women with gynecological malignancies who develop a paraneoplastic cerebellar degeneration (PCD). <h3>Design/Methods:</h3> Yo-Abs were initially detected in serum and cerebrospinal fluid (CSF) samples by commercial line dots (RAVO diagnostika and Euroimmun) and further confirmed with in-house techniques: immunohistochemistry on rat brain sections, cell-based assay and Western blot for cerebellar degeneration-related 2 (CDR2) and CDR2-like (CDR2L) proteins. <h3>Results:</h3> Three patients were referred to the French national reference center for PNS: 59-year-old woman and 60-year-old man with lung adenocarcinoma, and 63-year-old woman with ovarian adenocarcinoma, all developing the first neurological symptoms within 3 months of ICI (pembrolizumab) first dose. The woman with ovarian cancer and the man with lung adenocarcinoma had a PCD, while the woman with lung cancer had a myelitis. In all patients, CSF analysis disclosed pleocytosis and brain magnetic resonance imaging was normal. Yo-Abs were retrospectively detected in pre-ICI serum samples in the patient with ovarian cancer. Management consisted of permanent ICI discontinuation (3/3) and immunomodulation, including corticosteroids (3/3), immunoglobulins (2/3), rituximab (1/3), or cyclophosphamide (1/3). No patient substantially improved (modified Rankin Score pre- and post-treatment 4). In all cases, cancer progressed after ICI discontinuation and at last follow-up (4–16 months after neurological onset) the two patients with PCD were dead and the one with myelitis was in palliative care. <h3>Conclusions:</h3> While the pre-ICI Yo-Abs positivity in the patient with ovarian cancer suggests that ICI might have triggered a latent PNS, both the unusual cancer type association (lung) in the other two patients and the atypical clinical phenotype in one of them (myelitis) poses a challenge to the classic understanding of Yo-Abs associated PNS. <b>Disclosure:</b> Dr. Farina has nothing to disclose. Veronique Rogemond has nothing to disclose. Mrs. Peter has nothing to disclose. Dr. Wucher has nothing to disclose. Dr. Villagran Garcia has nothing to disclose. Dr. DO has received research support from Agence Nationale de la Recherche (ANR) ANR-18-RHUS-0012. Géraldine Picard has nothing to disclose. Bastien Joubert, MD has nothing to disclose. The institution of Jerome Honnorat, MD, PhD has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for journal of neurology. Prof. Desestret has nothing to disclose.

Hospital admissions and need for mechanical ventilation in children with respiratory syncytial virus before and during the COVID-19 pandemic: a Danish nationwide cohort study

The incidence of respiratory syncytial virus (RSV) increased in several countries after the relaxation of COVID-19 restrictions. We aimed to investigate the age-related risk of RSV-associated hospital admissions and need for mechanical ventilation during the RSV resurgence in summer and autumn 2021 compared with the four RSV seasons preceding the COVID-19 pandemic. We also aimed to describe the clinical complications necessitating mechanical ventilation. This population-based cohort study included patients aged 0-17 years admitted to hospital with RSV in Denmark during the RSV resurgence in summer and autumn 2021, and the four pre-COVID-19 RSV seasons (2016-17, 2017-18, 2018-19, and 2019-20). We retrieved data on RSV-associated hospital admissions from the Danish National Patient Registry and demographic and clinical details of children who received mechanical ventilation through prospective real-time data collection in 2021-22 and retrospective data collection for the 2016-17 to 2019-20 RSV seasons from all eight paediatric and neonatal intensive care units in Denmark. Risk factors for severe RSV disease were as defined as age younger than 3 months or severe comorbidities. We calculated the risk of RSV-associated hospital admissions per 100 000 population in each RSV season from week 21 to week 20 of the following year. We also calculated the risk rate of receiving mechanical ventilation per 100 000 population and 1000 RSV-associated hospital admissions during each RSV season from week 21 to week 20 of the following year. We calculated risk ratios (RRs) for hospital admission and mechanical ventilation by dividing the risk rate of hospital admission and mechanical ventilation in 2021-22 by annual mean risk rates in the four pre-COVID-19 RSV epidemics (2016-17 to 2019-20). We compared RRs using Fisher's exact test. We compared complications leading to intubation between children with and without risk factors for severe RSV disease. The study is registered at ClinicalTrials.gov, NCT05186597. Among 310 423 Danish children aged younger than 5 years, the mean number of RSV-associated hospital admissions increased from 1477 (SD 226) in the 2016-17 to 2019-20 RSV seasons to 3000 in the 2021-22 RSV season (RR 2·0 [95% CI 1·9-2·1]). 54 children with RSV received mechanical ventilation in 2021-22 compared with 15-28 annually in the 2016-17 to 2019-20 RSV seasons (2·3 [1·6-3·3]). The highest increase in hospital admissions and need for mechanical ventilation occurred among children aged 24-59 months (4·1 [3·6-4·7] for hospital admission; 4·6 [1·7-12·6] for mechanical ventilation). Among children admitted to hospital, the risk of mechanical ventilation was similar in 2021-22 and the four pre-COVID-19 seasons (risk rate 14·3 per 1000 RSV-associated hospital admissions [95% CI 10·4-19·3] vs 12·9 [10·1-16·1]; RR 1·1 [95% CI 0·8-1·6]). Across all RSV seasons studied, among children younger than 3 months or those with severe comorbidities, respiratory failure due to bronchiolitis led to mechanical ventilation in 69 (79%) of 87 children. Of 46 children with no risk factors for severe RSV, 40 (87%) received mechanical ventilation due to additional complications, including neurological (n=16; 35%), cardiac (n=1; 2%), and pulmonary complications (n=23; 50%; eg, wheeze responsive to bronchodilator therapy, severe bacterial co-infections, and pneumothorax). In Denmark, RSV disease did not seem to be more severe for the individual child during the RSV resurgence in 2021 following relaxation of COVID-19 restrictions. However, hospital admissions were higher among older children, possibly due to a postponed first RSV infection or no recent reinfection. Older children without risk factors for severe RSV disease had atypical complications that led to intubation. If new RSV-preventive interventions for healthy infants delay first RSV infection, a higher number of older children might be admitted to hospital due to atypical clinical phenotypes, rather than classical bronchiolitis. National Ministry of Higher Education and Science and the Innovation Fund Denmark.

Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations

Fas ligand (FasL) is expressed by activated T cells and induces death in target cells upon binding to Fas. Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers. While most ALPS patients carry heterozygous FAS mutations, FASLG mutations are rare and usually biallelic. Only 2 heterozygous variants were reported, associated with an atypical clinical phenotype. We revisited the significance of heterozygous FASLG mutations as a cause of ALPS. Clinical features and biomarkers were analyzed in 24 individuals with homozygous or heterozygous FASLG variants predicted to be deleterious. Cytotoxicity assays were performed with patient T cells and biochemical assays with recombinant FasL. Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised vitamin B12, and usually no soluble FasL. In contrast, heterozygous variants affected FasL function by reducing expression, impairing trimerization, or preventing Fas binding. However, they were not associated with elevated DNT and vitamin B12, and they did not affect FasL-mediated cytotoxicity. The dominant-negative effects of previously published variants could not be confirmed. Even Y166C, causing loss of Fas binding with a dominant-negative effect in biochemical assays, did not impair cellular cytotoxicity or cause vitamin B12 and DNT elevation. Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG.

A novel TP63 variant in a patient with ankyloblepharon-ectodermal defect–cleft lip/palate syndrome and Rapp–Hodgkin syndrome-like ectodermal dysplasia

Ankyloblepharon-ectodermal defect–cleft lip/palate syndrome and Rapp–Hodgkin syndrome are well-known TP63-related autosomal-dominant genetic disorders with various similar ectodermal dysplasias. In this study, whole-exome sequencing revealed a novel, potentially pathogenic TP63 nonsense variant (NM_001114980.2:c.25 C > T: p.Gln9Ter) in a patient with an atypical clinical phenotype. This variant was detected near translation initiation sites and has an effect only on ΔNp63α, the short isoform protein product of the TP63 gene.

The Clinical Phenotypes of Cutaneous Leishmaniasis in Central and Southwest Regions of Yemen.

Cutaneous leishmaniasis (CL) is endemic in Yemen. CL displays a spectrum of typical and atypical morphologies yet understudied in the central and southwest regions of Yemen. To identify the typical and atypical clinical phenotypes of CL in the central and southwest regions of Yemen. A survey of 145 patients who visited Prof. Al-Qubati Clinic in Taiz between 2010 and 2015, was conducted. Children and residents of the rural areas were at high risk of exposure to the insect vector. The typical phenotype was single (67%), facial (58%) and ulcerated nodule (35%). Other usual phenotypes were small ulcers (21.4%) and non-ulcerative papules and nodules (21%). Unusual phenotypes constituted 12% of the cohort and included psoriasiform, eczematous, erysipeloid, lupoid, verrucous, large ulcerative, leishmania recidivens, satellite, granulomatous infiltrative and hyperkeratotic plaques. Mucous membrane involvement was evident in 10.6% and was also polymorphic. CL has many morphologic patterns in central and southwest regions of Yemen, some are clinically deceptive.

Survey outcomes on neuropsychological testing in posterior cortical atrophy

AbstractBackgroundPosterior cortical atrophy (PCA) is a clinico‐radiological syndrome mostly commonly underpinned by Alzheimer’s disease (AD) pathology and has been referred to as the most common atypical AD clinical phenotype. PCA consensus classification criteria emphasize core clinical and cognitive features comprising visual and other posterior features in contrast to relatively spared episodic memory, language, executive functions and behavior (Crutch et al., Alzheimers Dement., 2017). However, posterior features are less commonly evaluated in standard neuropsychological batteries compared to other domains, possibly contributing towards common diagnostic delays, and memory and executive function tests that have visual or numerical demands are particularly challenging in the evaluation of relatively spared functions. Standardization of the neuropsychological assessment of PCA is vital for multi‐center research collaborations, the development of outcome measures for future clinical trials, and better characterization of the extent of overlap with related neurodegenerative syndromes. Experts were surveyed regarding their practice preferences in the assessment of the PCA syndrome.MethodThe membership of the ISTAART Atypical Alzheimer’s Disease Professional Interest Area was invited to participate in a survey examining preferences for measures employed in the assessment of the visual and core cognitive features of PCA, as defined by the 2017 PCA consensus criteria.ResultAtypical AD PIA members included those with backgrounds in neurology, neuropsychology, psychiatry, geriatric medicine and clinical research (respondents N=55). Most commonly assessed features were space perception deficits, simultanagnosia and constructional apraxia, followed by dominant parietal features and alexia. Object perception deficits and early visual functions were less frequently assessed. A subset of respondents included preferred tests to evaluate global functioning and relatively spared features, including example measures less susceptible to visual dysfunction.ConclusionVariations in assessing PCA features are considered with implications for characterizing the extent of AD phenotypic heterogeneity, including proposed ventral and caudal PCA presentations. Results will inform future work to develop consensus recommendations for a short clinical PCA battery and an extended, formal PCA battery, in order to promote capacity for multi‐center studies and advance the development of appropriate outcome measures in trials enrolling patients with PCA and/or prominent posterior dysfunction.

89 CSF BIOMARKER UTILITY IN SUPPORTING ALZHEIMER’S DISEASE DIAGNOSIS: CLINICAL PERSPECTIVES FROM AN IRISH REGIONAL SPECIALIST MEMORY SERVICE

Abstract Background CSF (cerebrospinal fluid) biomarkers [amyloid- beta-42 (AB-42), phosphorylated tau (p-tau)] are increasingly used in supporting clinical diagnosis of Alzheimer’s Disease (AD). Both elevated CSF p-tau and reduced AB-42 are necessary for pathological diagnosis of AD. The aim of this study is to apply recent international recommendations to patients attending a regional specialist memory service, evaluating consistency with detailed clinical, neuroimaging, and neuropsychological ad-phenotype profiling. Methods All patients age &amp;lt; 80, with mild/subjective cognitive and/or atypical neurobehavioral symptoms, non-significant vascular burden on neuroimaging, and without contraindication to lumbar puncture are offered CSF analysis. Clinical diagnosis was ascribed on the basis of specialist multi-disciplinary consensus review. We undertook a case-note and database retrospective review of those who had ad-biomarker CSF analysis, collecting demographic, clinical phenotype diagnosis, and neuropsychological performance. Data was extracted and analysed using SPSS v.25. Results One-hundred-sixteen patients underwent CSF biomarker testing. Forty-nine patients (42%) had positive AD-CSF biomarkers, 41/49 (84%) of whom presented with common ad phenotypes (Amnestic/Logopenic PPA/PCA). Twenty patients (17%) had negative ad-CSF (elevated AB-42, and low p-tau) studies, and half of those (10/20, 50%) had a consistent atypical non-AD clinical phenotype. Patients with negative ad-CSF were younger and tended to have non-amnestic neuropsychological profile. Therefore there was a mismatch in 18/69 (26%) people in these groups with definitive +/− ad biomarker results and ad/Non-ad clinical phenotype. A further forty seven (40%) patients had indeterminate CSF studies with one or other changes in AB-42 or p-tau, but not both as is necessary for definitive diagnosis. Conclusion Incorporation of CSF biomarker analysis is quickly being established as a key component of the neurocognitive/dementia diagnostic pathway. However, there are challenges and limitations arising as they are applied in clinical settings, and further research is warranted to explore variations between pathological results and clinical phenotype presentation.

Myelin oligodendrocyte glycoprotein (MOG) antibodies in a patient with glioblastoma: Red flags for false positivity

We present a patient with positive medium titer MOG-IgG and progressive neurological decline whose clinical and radiological phenotype were not consistent with a MOG-IgG associated disorder and ultimately received a diagnosis of glioblastoma after brain biopsy and died 4 weeks later. This represents an important topic with a high frequency of MOG-IgG testing in clinical practice. Due to this there are increasing reports of MOG-IgG positivity in atypical clinical phenotypes, raising the possibility of false positives, which can have important implications. It is important to highlight that judicious clinical evaluation is needed when interpreting MOG-IgG results in atypical settings.

Detailed clinical features and genotype\u2013phenotype correlation in an OTOF-related hearing loss cohort in Japan

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype–phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype–phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a “typical” phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85–90% of the patients showed a hearing level of 20–39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed “true” auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype–phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype–phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

Atypical presentation of Charcot-Marie-Tooth disease type 1C with a new mutation: a case report

BackgroundCharcot-Marie-Tooth 1C (CMT1C) is a rare form of dominantly inherited CMT1 neuropathy caused by a mutated gene encoding lipopolysaccharide-induced tumour necrosis alpha factor (LITAF).Case presentationWe report a 56-year-old patient with an atypical clinical phenotype of CMT1C, which started as progressive weakness of a single upper limb resembling acquired inflammatory neuropathy. Nerve conduction studies (NCS) and temporarily limited and partial effects of immunotherapy supported the diagnosis of inflammatory neuropathy. Significant progression of polyneuropathy, despite intensive long-lasting immunotherapy, together with repeatedly negative auxiliary investigations (CSF, MRI and antibodies) and genetic testing results finally led to the diagnosis of CMT1C neuropathy.ConclusionsCMT1C should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy.