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Molecular Syndromology Mar 2024gene variants that decrease or eliminate protein activity have been associated with phenotypes characterized by speech apraxia and intellectual disabilities. This...
INTRODUCTION
gene variants that decrease or eliminate protein activity have been associated with phenotypes characterized by speech apraxia and intellectual disabilities. This condition, distinctly separated from Schinzel-Giedion syndrome, is referred to as autosomal dominant mental retardation 29 (ADR29).
CASE PRESENTATION
In this report, we present the case of a 6-year-old male patient exhibiting fine and global motor skill impairments along with expressive language delay. The patient carried a novel germline, heterozygous, de novo nonsense variant in the gene, specifically the c.532C>T variant, which prematurely terminates protein translation at amino acid 178, p.(Gln178*), and removes more than 10% of the reference protein isoform consisting of 1,596 amino acids. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant has been classified as pathogenic.
CONCLUSION
Given the limited number of ADR29 cases reported to date, it is critical to focus attention on the phenotypic features of each new individual and seek out previously undocumented defects. The clinical findings found in our patient align with current knowledge on the correlation between the genotypes characterized by loss-of-function variants in gene and a particular neurological phenotype. Furthermore, the presence of a severely delayed bone age in this patient, which we report for the first time, could indicate a possible indirect but significant contribution of the SETBP1 protein in bone development and maturation processes. This finding highlights the need for further investigation into the potential effects of gene variants on bone health and the possible involvement of the SETBP1 protein in skeletal growth and development.
PubMed: 38585550
DOI: 10.1159/000535057 -
Journal of Neurology Apr 2024Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on...
BACKGROUND AND OBJECTIVES
Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on their progression remain unclear. We aimed to examine the clinical and neuroimaging evolution of nfvPPA and PPAOS into CBS.
METHODS
We conducted a retrospective longitudinal study in 140 nfvPPA or PPAOS patients and applied the consensus criteria for possible and probable CBS for every visit, evaluating limb rigidity, akinesia, limb dystonia, myoclonus, ideomotor apraxia, alien limb phenomenon, and nonverbal oral apraxia (NVOA). Given the association of NVOA with AOS, we also modified the CBS criteria by excluding NVOA and assigned every patient to either a progressors or non-progressors group. We evaluated the frequency of every CBS feature by year from disease onset, and assessed gray and white matter volume loss using SPM12.
RESULTS
Asymmetric akinesia, NVOA, and limb apraxia were the most common CBS features that developed; while limb dystonia, myoclonus, and alien limb were rare. Eighty-two patients progressed to possible CBS; only four to probable CBS. nfvPPA and PPAOS had a similar proportion of progressors, although nfvPPA progressed to CBS earlier (p-value = 0.046), driven by an early appearance of limb apraxia (p-value = 0.0041). The non-progressors and progressors both showed premotor/motor cortex involvement at baseline, with spread into prefrontal cortex over time.
DISCUSSION
An important proportion of patients with nfvPPA and PPAOS progress to possible CBS, while they rarely develop features of probable CBS even after long follow-up.
PubMed: 38583104
DOI: 10.1007/s00415-024-12344-x -
Geriatrie Et Psychologie... Mar 2024Cortico-basal degeneration is a relatively uncommon cause of degenerative parkinsonism in the elderly. From a clinical point of view, it manifests as a cortico-basal...
Cortico-basal degeneration is a relatively uncommon cause of degenerative parkinsonism in the elderly. From a clinical point of view, it manifests as a cortico-basal syndrome (CBS), featuring a highly asymmetrical akinetic-rigid syndrome, dystonia, myoclonus and cognitive-behavioral impairment with predominant apraxia. Other clinical phenotypes are possible, including variants with mainly language or behavioral impairment, or with axial, symmetrical parkinsonism resembling progressive supranuclear palsy (PSP). Current diagnostic criteria take into account the heterogeneity of clinical presentations. However, a diagnosis of certainty can only be reached by a pathological study, with the evidence of TAU-positive intraneuronal inclusions. Indeed SCB may be underpinned by other lesional substrates, ranging from frontotemporal degeneration to Alzheimer's disease. Symptom management must be early, multidisciplinary and adapted to the progression of the disorder. The identification of the pathological substrate is an essential prerequisite for pathophysiological therapeutic trials.
Topics: Aged; Humans; Corticobasal Degeneration; Syndrome; Alzheimer Disease; Atrophy; Parkinsonian Disorders
PubMed: 38573149
DOI: 10.1684/pnv.2024.1145 -
Parkinsonism & Related Disorders Jun 2024We describe here a 73-year-old patient presenting with atypical MSA-P-like phenotype carrying a monoallelic p. W279X mutation in the APTX gene, which causes ataxia with...
We describe here a 73-year-old patient presenting with atypical MSA-P-like phenotype carrying a monoallelic p. W279X mutation in the APTX gene, which causes ataxia with oculomotor apraxia type 1 (AOA1) when in homozygous state. We hypothesize that rare monoallelic APTX variants could modulate MSA risk and phenotype.
Topics: Aged; Humans; Male; Apraxias; Cogan Syndrome; DNA-Binding Proteins; Heterozygote; Multiple System Atrophy; Mutation; Phenotype
PubMed: 38555792
DOI: 10.1016/j.parkreldis.2024.106943 -
The Lancet. Haematology May 2024Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events.
METHODS
This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sβ-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed.
FINDINGS
Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001).
INTERPRETATION
Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials.
FUNDING
Bayer Pharmaceuticals.
Topics: Humans; Anemia, Sickle Cell; Male; Female; Double-Blind Method; Pyrazoles; Adult; Pyrimidines; Hypertension; Proteinuria; Middle Aged; Treatment Outcome
PubMed: 38554715
DOI: 10.1016/S2352-3026(24)00045-0 -
Medicina (Kaunas, Lithuania) Mar 2024: Despite the increasing use of biomarkers, differentiation between Alzheimer's disease (AD), behavioral variant Frontotemporal Dementia (bvFTD), and Primary Progressive...
: Despite the increasing use of biomarkers, differentiation between Alzheimer's disease (AD), behavioral variant Frontotemporal Dementia (bvFTD), and Primary Progressive Aphasia (PPA) remains a challenge. Apraxia is a supportive feature for diagnosing AD but is underrepresented in other dementia types. Herein, we investigated the presence and characteristic profiles of limb, verbal, and non-verbal apraxia in three major dementia types. : Test for Upper Limb Apraxia (TULIA) and Apraxia Battery for Adults-2 (ABA-2) were administered in patients with AD (n = 22), bvFTD (n = 41), and PPA (n = 22), with 20 individuals serving as healthy controls (HC). Composite and subdomain scores were compared between each patient group and the HC. Praxis profiles indicative of each dementia type and a possible predictive value were sought. : Apraxia provided high diagnostic accuracy for detecting dementia compared with HC (sensitivity: 63.6-100%, specificity: 79.2-100%). Patients with AD performed worse when imitating intransitive gestures as well as pantomiming transitive gestures (mean differences: 2.10 and 3.12, respectively), compared with bvFTD. PPA patients, compared with bvFTD, had comparable results in limb, verbal, and non-verbal praxis assessments, despite the greater deterioration in the outcome. Compared with patients with AD, PPA had increased pathological outcomes in verbal (86.4% vs. 40.9%) and non-verbal apraxia (31.8% vs. 0%), while bvFTD had increased pathological outcomes in verbal apraxia (85.4% vs. 44.5%). Finally, apraxia is correlated with cognitive decline. : Apraxia profile evaluation could contribute to the differentiation between AD and Frontotemporal Dementia (FTD). Both TULIA and ABA-2 are reliable tools that can be performed as bed-side tests in clinical practice.
Topics: Adult; Humans; Alzheimer Disease; Frontotemporal Dementia; Apraxias; Cognitive Dysfunction; Neuropsychological Tests
PubMed: 38541161
DOI: 10.3390/medicina60030435 -
Journal of Speech, Language, and... Mar 2024Neurogenic speech and language disorders-such as acquired apraxia of speech (AOS) and aphasia with phonemic paraphasia (APP)-are often misdiagnosed due to similarities...
PURPOSE
Neurogenic speech and language disorders-such as acquired apraxia of speech (AOS) and aphasia with phonemic paraphasia (APP)-are often misdiagnosed due to similarities in clinical presentation. Word syllable duration (WSD)-a measure of average syllable length in multisyllabic words-serves as a proxy for speech rate, which is an important and arguably more objective clinical characteristic of AOS and APP. This study reports stability of WSD over time for speakers with AOS (and aphasia).
METHOD
Twenty-nine participants with AOS and aphasia (11 women and 18 men, = 53.5 years, = 13.3) repeated 30 multisyllabic words (of three-, four-, and five-syllable lengths) on three occasions across 4 weeks. WSDs were calculated for each word and then averaged across each list (i.e., word length), as well as across combined lists (i.e., all 30 words) to yield four WSDs for each participant at each time point. Stability over time was calculated using Friedman's test for the group and using Spearman's rho for the individual level. Effects of time and word length were examined using robust mixed-effects linear regression.
RESULTS
Friedman's tests and correlations indicated no significant difference in WSDs across sampling occasions for each word length separately or combined. WSD correlated positively with AOS severity and negatively with intelligibility but was not correlated with aphasia severity. Regression analyses confirmed WSD to be stable over time, while WSD calculated from only five tokens (i.e., WSD-5) was less stable over time.
CONCLUSIONS
Results indicate that WSD can be a stable measure over time, at the individual and group level, providing support for its use in diagnosis and/or as an outcome measure, both clinically and for research. In general, WSD outperformed WSD-5, suggesting that it may be better to calculate WSD from more than five tokens. Stability of WSD in other populations and suitability for differential diagnosis need to be determined. Currently, differentiating disorders by speaking rate, alone, is not recommended.
SUPPLEMENTAL MATERIAL
https://doi.org/10.23641/asha.25438735.
PubMed: 38527280
DOI: 10.1044/2024_JSLHR-23-00007 -
Neurology. Genetics Apr 2024To introduce the first case in which primary progressive apraxia of speech (PPAOS) is associated with TAR DNA-binding protein 43 (TDP-43) instead of 4-repeat tau.
OBJECTIVES
To introduce the first case in which primary progressive apraxia of speech (PPAOS) is associated with TAR DNA-binding protein 43 (TDP-43) instead of 4-repeat tau.
METHODS
This patient was identified through a postmortem autopsy. Following an initial diagnostic evaluation, he participated in 3 annual research visits during which speech, language, cognitive, and neurologic assessments were administered. Neuroimaging was also acquired.
RESULTS
Apraxia of speech was diagnosed at his initial visit with a comprehensive neurologic examination further revealing subtle motor findings in the right hand. At subsequent visits, agrammatic aphasia and motor symptoms consistent with corticobasal syndrome were evident. Cognition and behavior remained relatively intact until advanced stages. FDG-PET revealed hypometabolism in the right temporoparietal cortex and left premotor and motor cortices. There was also low-level signal in the right temporoparietal cortex on tau-PET. A sequence variation in the progranulin gene was identified (GRN c.1A>C, p.Met1). Pathologic diagnosis was TDP-43 Type A with an atypical distribution of inclusions in premotor and motor cortices.
DISCUSSION
This case report demonstrates that TDP-43 Type A inclusions in an atypical distribution can present clinically as PPAOS. The sequence variation in the progranulin gene and asymmetric temporoparietal cortex involvement were the strongest indications of the unusual neuropathophysiology prior to autopsy.
PubMed: 38515991
DOI: 10.1212/NXG.0000000000200134 -
Journal of Neurology, Neurosurgery, and... Mar 2024Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying...
BACKGROUND
Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying pathologies: semantic variant PPA (svPPA) with transactive response DNA-binding protein of 43 kD (TDP-43) proteinopathy, agrammatic variant PPA (agPPA) with tau deposition and logopenic variant PPA (lvPPA) with Alzheimer's disease (AD). Our objectives were to differentiate PPA variants using clinical and neuroimaging features, assess progression and evaluate structural MRI and a novel 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) image decomposition machine learning algorithm for neuropathology prediction.
METHODS
We analysed 82 autopsied patients diagnosed with PPA from 1998 to 2022. Clinical histories, language characteristics, neuropsychological results and brain imaging were reviewed. A machine learning framework using a -nearest neighbours classifier assessed FDG-PET scans from 45 patients compared with a large reference database.
RESULTS
PPA variant distribution: 35 lvPPA (80% AD), 28 agPPA (89% tauopathy) and 18 svPPA (72% frontotemporal lobar degeneration-TAR DNA-binding protein (FTLD-TDP)). Apraxia of speech was associated with 4R-tauopathy in agPPA, while pure agrammatic PPA without apraxia was linked to 3R-tauopathy. Longitudinal data revealed language dysfunction remained the predominant deficit for patients with lvPPA, agPPA evolved to corticobasal or progressive supranuclear palsy syndrome (64%) and svPPA progressed to behavioural variant frontotemporal dementia (44%). agPPA-4R-tauopathy exhibited limited pre-supplementary motor area atrophy, lvPPA-AD displayed temporal atrophy extending to the superior temporal sulcus and svPPA-FTLD-TDP had severe temporal pole atrophy. The FDG-PET-based machine learning algorithm accurately predicted clinical diagnoses and underlying pathologies.
CONCLUSIONS
Distinguishing 3R-taupathy and 4R-tauopathy in agPPA may rely on apraxia of speech presence. Additional linguistic and clinical features can aid neuropathology prediction. Our data-driven brain metabolism decomposition approach effectively predicts underlying neuropathology.
PubMed: 38514176
DOI: 10.1136/jnnp-2023-332862 -
American Journal of Speech-language... May 2024Motor deficits are widely documented among autistic individuals, and speech characteristics consistent with a motor speech disorder have been reported in prior...
PURPOSE
Motor deficits are widely documented among autistic individuals, and speech characteristics consistent with a motor speech disorder have been reported in prior literature. We conducted an auditory-perceptual analysis of speech production skills in low and minimally verbal autistic individuals as a step toward clarifying the nature of speech production impairments in this population and the potential link between oromotor functioning and language development.
METHOD
Fifty-four low or minimally verbal autistic individuals aged 4-18 years were video-recorded performing nonspeech oromotor tasks and producing phonemes, syllables, and words in imitation. Three trained speech-language pathologists provided auditory perceptual ratings of 11 speech features reflecting speech subsystem performance and overall speech production ability. The presence, attributes, and severity of signs of oromotor dysfunction were analyzed, as were relative performance on nonspeech and speech tasks and correlations between perceptual speech features and language skills.
RESULTS AND CONCLUSIONS
Our findings provide evidence of a motor speech disorder in this population, characterized by perceptual speech features including reduced intelligibility, decreased consonant and vowel precision, and impairments of speech coordination and consistency. Speech deficits were more associated with articulation than with other speech subsystems. Speech production was more impaired than nonspeech oromotor abilities in a subgroup of the sample. Oromotor deficits were significantly associated with expressive and receptive language skills. Findings are interpreted in the context of known characteristics of the pediatric motor speech disorders childhood apraxia of speech and childhood dysarthria. These results, if replicated in future studies, have significant potential to improve the early detection of language impairments, inform the development of speech and language interventions, and aid in the identification of neurobiological mechanisms influencing communication development.
Topics: Humans; Child; Child, Preschool; Male; Adolescent; Female; Speech Intelligibility; Speech Perception; Speech Production Measurement; Autistic Disorder; Video Recording; Speech Disorders; Speech-Language Pathology; Articulation Disorders
PubMed: 38512040
DOI: 10.1044/2024_AJSLP-23-00237