Hearing rehabilitation of adults with auditory processing disorder: a systematic review and meta-analysis of current evidence-based interventions.

Background: For adults with auditory processing disorder (APD), listening and communicating can be difficult, potentially leading to social isolation, depression, employment difficulties and certainly reducing the quality of life. Despite existing practice guidelines suggesting treatments, the efficacy of these interventions remains uncertain due to a lack of comprehensive reviews. This systematic review and meta-analysis aim to establish current evidence on the effectiveness of interventions for APD in adults, addressing the urgent need for clarity in the field. Methods: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic search across MEDLINE (Ovid), Embase (Ovid), Web of Science and Scopus, focusing on intervention studies involving adults with APD. Studies that met the inclusion criteria were grouped according to intervention with a meta-analysis only conducted where intervention, study design and outcome measure were comparable. Results: Out of 1,618 screened records, 13 studies were included, covering auditory training (AT), low-gain hearing aids (LGHA), and personal remote microphone systems (PRMS). Our analysis revealed: AT, Mixed results with some improvements in speech intelligibility and listening ability, indicating potential benefits but highlighting the need for standardized protocols; LGHA, The included studies demonstrated significant improvements in monaural low redundancy speech testing (p < 0.05), suggesting LGHA could enhance speech perception in noisy environments. However, limitations include small sample sizes and potential biases in study design. PRMS, Demonstrated the most consistent evidence of benefit, significantly improving speech testing results, with no additional benefit from combining PRMS with other interventions. Discussion: PRMS presents the most evidence-supported intervention for adults with APD, although further high-quality research is crucial for all intervention types. The establishment and implementation of standardized intervention protocols alongside rigorously validated outcome measures will enable a more evidence-based approach to managing APD in adults.

De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.

Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis (fALS) and fronto-temporal dementia (FTD), based on identification of likely pathogenic variants in patients from distinct ALS and FTD cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in-silico tools. In addition, gene burden analyses in the 100,000 genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls (OR: 57.0847 [10.2- 576.7]; p = 4.02 x10-07). Altogether, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harboring a predicted pathogenic TUBA4A missense mutation, including 5 confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from 3 patients harboring distinct TUBA4A missense showed significant alterations in microtubule organisation and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.

Cognitive Decline and Other Late-Stage Neurologic Complications in Cockayne Syndrome.

Background and Objectives: Cockayne syndrome (CS) is an ultra-rare, autosomal recessive, premature aging disorder characterized by impaired growth, neurodevelopmental delays, neurodegeneration, polyneuropathy, and other multiorgan system complications. The anatomic aspects of CS neurodegeneration have long been known from postmortem examinations and MRI studies, but the clinical features of this neurodegeneration are not well characterized, especially at later stages of the disease. Methods: This was a retrospective observational study in which individuals with CS who survived beyond 18 years were ascertained at 3 centers in the United States, France, and the United Kingdom. Medical records were examined to determine the frequencies and features of the following neurologic complications: neurocognitive/neuropsychiatric decline (8 symptoms), tremors, neuropathy, seizures, and strokes. Results: Among 18 individuals who met inclusion criteria, all but one (94.4%) experienced at least one symptom of neurocognitive/neuropsychiatric decline, with most individuals experiencing at least half of those symptoms. Most participants experienced tremors and peripheral neuropathy, with a few experiencing seizures and strokes. For individuals with available data, 100.0% were reported to have gait ataxia and neuroimaging showed that 85.7% had generalized cerebral atrophy on MRI while 78.6% had white matter changes. Discussion: Symptoms of neurocognitive/neuropsychiatric decline are nearly universal in our cohort of adults with CS, suggesting that these individuals are at risk of developing neurocognitive/neuropsychiatric decline, with symptoms related to but not specific to dementia. Considering the prominent role of DNA repair defects in CS disease mechanisms and emerging evidence for increased DNA damage in neurodegenerative disease, impaired genome maintenance may be a shared pathway underlying multiple forms of neurocognitive/neuropsychiatric decline. Components of the DNA damage response mechanism may bear further study as potential therapeutic targets that could alleviate neurocognitive/neuropsychiatric symptoms in CS and other neurodegenerative disorders.

Elevated Bile Acid 3ß,5α,6ß-Trihydroxycholanoyl Glycine in a Subset of Adult Ataxias Including Niemann-Pick Type C.

Ataxia is a common neurological feature of Niemann-Pick disease type C (NPC). In this disease, unesterified cholesterol accumulates in lysosomes of the central nervous system and hepatic cells. Oxidation by reactive oxygen species produces oxysterols that can be metabolised to specific bile acids. These bile acids have been suggested as useful biomarkers to detect NPC. Concentrations of 3ß,5α,6ß-trihydroxycholanyl glycine (3ß,5α,6ß-triOH-Gly) and 3ß,7ß-dihydroxy-5-cholenyl glycine (3ß,7ß-diOH-Δ5-Gly) were measured in plasma of 184 adults with idiopathic ataxia. All patients were tested with whole genome sequencing containing hereditary ataxia panels, which include NPC1 and NPC2 mutations and other genetic causes of ataxia. Plasma 3ß,5α,6ß-triOH-Gly above normal (>90 nM) was found in 8 out of 184 patients. One patient was homozygous for the p.(Val1165Met) mutation in the NPC1 gene. The remaining seven included one patient with Friedreich's ataxia and three patients with autoimmune diseases. Oxidative stress is known to be increased in Friedreich's ataxia and in autoimmune diseases. Therefore, this subset of patients possibly shares a common mechanism that determines the increase of this bile acid. In a large cohort of adults with ataxia, plasma 3ß,5α,6ß-triOH-Gly was able to detect the one patient in the cohort with NPC1 disease, but also detected oxidation of cholesterol by ROS in other disorders. Plasma 3ß,7ß-diOH-Δ5-Gly is not a potential biomarker for NPC1.

Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease.

Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls. The reference transcript (ATXN3-251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3-208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3-251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3-214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies.

The COVID-19 pandemic impact on continuity of care provision on rare brain diseases and on ataxias, dystonia and PKU. A scoping review.

One of the most relevant challenges for healthcare providers during the COVID- 19 pandemic has been assuring the continuity of care to patients with complex health needs such as people living with rare diseases (RDs). The COVID-19 pandemic accelerated the healthcare sector's digital transformation agenda. The delivery of telemedicine services instead of many face-to-face procedures has been expanded and, many healthcare services not directly related to COVID-19 treatments shifted online remotely. Many hospitals, specialist centres, patients and families started to use telemedicine because they were forced to. This trend could directly represent a good practice on how care services could be organized and continuity of care could be ensured for patients. If done properly, it could boast improved patient outcomes and become a post COVID-19 major shift in the care paradigm. There is a fragmented stakeholders spectrum, as many questions arise on: how is e-health interacting with 'traditional' healthcare providers; about the role of the European Reference Networks (ERNs); if remote care can retain a human touch and stay patient centric. The manuscript is one of the results of the European Brain Council (EBC) Value of Treatment research project on rare brain disorders focusing on progressive ataxias, dystonia and phenylketonuria with the support of Academic Partners and in collaboration with European Reference Networks (ERNs) experts, applying empirical evidence from different European countries. The main purpose of this work is to investigate the impact of the COVID-19 pandemic on the continuity of care for ataxias, dystonia and phenylketonuria (PKU) in Europe. The analysis carried out makes it possible to highlight the critical points encountered and to learn from the best experiences. Here, we propose a scoping review that investigates this topic, focusing on continuity of care and novel methods (e.g., digital approaches) used to reduce the care disruption. This scoping review was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) standards. This work showed that the implementation of telemedicine services was the main measure that healthcare providers (HCPs) put in place and adopted for mitigating the effects of disruption or discontinuity of the healthcare services of people with rare neurological diseases and with neurometabolic disorders in Europe.

Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease.

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V ß = -1.06, P < 0.001; lobules VI-VII ß = -0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion.

Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study.

BACKGROUND: Friedreich's ataxia (FA) is a rare multisystemic disorder which can cause premature death. OBJECTIVES: To investigate predictors of survival in FA. METHODS: Within a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.gov identifier NCT02069509) we enrolled genetically confirmed FA patients at 11 tertiary centers and followed them in yearly intervals. We investigated overall survival applying the Kaplan-Meier method, life tables, and log-rank test. We explored prognostic factors applying Cox proportional hazards regression and subsequently built a risk score which was assessed for discrimination and calibration performance. RESULTS: Between September 2010 and March 2017, we enrolled 631 FA patients. Median age at inclusion was 31 (range, 6-76) years. Until December 2022, 44 patients died and 119 terminated the study for other reasons. The 10-year cumulative survival rate was 87%. In a multivariable analysis, the disability stage (hazard ratio [HR] 1.51, 95% CI 1.08-2.12, P = 0.02), history of arrhythmic disorder (HR 2.93, 95% CI 1.34-6.39, P = 0.007), and diabetes mellitus (HR 2.31, 95% CI 1.05-5.10, P = 0.04) were independent predictors of survival. GAA repeat lengths did not improve the survival model. A risk score built on the previously described factors plus the presence of left ventricular systolic dysfunction at echocardiography enabled identification of four trajectories to prognosticate up to 10-year survival (log-rank test P < 0.001). CONCLUSIONS: Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.