Gene-based therapies for neuromuscular disorders Zanoteli, Edmar; França, Jr, Marcondes Cavalcante; Marques, Jr, Wilson
Arquivos de neuro-psiquiatria,
06/2024, Letnik:
82, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Neuromuscular diseases (NMD) include a broad group of medical conditions with both acquired and genetic causes. In recent years, important advances have been made in the treatment of genetically ...caused NMD, and most of these advances are due to the implementation of therapies aimed at gene regulation. Among these therapies, gene replacement, small interfering RNA (siRNA), and antisense antinucleotides are the most promising approaches. More importantly, some of these therapies have already gained regulatory approval or are in the final stages of approval. The review focuses on motor neuron diseases, neuropathies, and Duchenne muscular dystrophy, summarizing the most recent developments in gene-based therapies for these conditions.
Previous studies demonstrated cognitive impairments in spinocerebellar ataxia type 3 (SCA3/MJD); however, there is no consensus about the cognitive domains affected and the correlation with ...structural brain abnormalities. We investigated the neuropsychological profile and 3T-MRI findings, including high-resolution T1-images, diffusion tensor imaging and magnetic resonance spectroscopy of 32 patients with SCA3/MJD and 32 age-, gender- and educational level–matched healthy controls. We reviewed patients’ clinical history and CAG repeat length, and performed assessment and rating of ataxia (SARA)-Brazilian version and the neuropsychiatric inventory. Patients presented worse performance in episodic and working memory and Beck inventories (depression and anxiety). SCA3/MJD patients had a reduction of gray matter volume (GM) in the cerebellum, putamen, cingulum, precentral and parietal lobe. A positive correlation was identified between the cognitive findings and GM of temporal, frontal, parietal, culmen and insula. We observed positive correlation between the brainstem′s fractional anisotropy and digit span-forward. The following cerebellar metabolite groups (measured relative to creatine) were reduced in patients:
N
-acetyl-aspartate (NAA), NAA +
N
-acetyl-aspartate-glutamate and glutamate + glutamine (Glx). We found a positive correlation between Corsi’s block-tapping task forward with Glx; semantic verbal fluency with phosphorylcholine and glycerophosphorylcholine; digits span-forward with NAA. The cognitive impairments in SCA3/MJD are associated not only with cerebellar and brainstem abnormalities, but also with neuroimaging evidence of diffuse neuronal and axonal dysfunction, particularly in temporal, frontal, parietal and insular areas.
Aims
Machado–Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is the most common autosomal dominantly‐inherited ataxia worldwide and is characterised by the accumulation of mutant ...ataxin‐3 (mutATXN3) in different brain regions, leading to neurodegeneration. Currently, there are no available treatments able to block disease progression. In this study, we investigated whether carbamazepine (CBZ) would activate autophagy and mitigate MJD pathology.
Methods
The autophagy‐enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using in vitro and in vivo models of MJD. To investigate the optimal treatment regimen, a daily or intermittent CBZ administration was applied to MJD transgenic mice expressing a truncated human ATXN3 with 69 glutamine repeats. Motor behaviour tests and immunohistology was performed to access the alleviation of MJD‐associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients.
Results
We found that CBZ promoted the activation of autophagy and the degradation of mutATXN3 in MJD models upon short or intermittent, but not daily prolonged, treatment regimens. CBZ up‐regulated autophagy through activation of AMPK, which was dependent on the myo‐inositol levels. In addition, intermittent CBZ treatment improved motor performance, as well as prevented neuropathology in MJD transgenic mice. However, in patients, no evident differences in SARA scale were found, which was not unexpected given the small number of patients included in the study.
Conclusions
Our data support the autophagy‐enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.
This study shows that carbamazepine (CBZ) stimulates autophagy by a mechanism dependent on the myo‐inositol levels and AMPK activation. The autophagy‐enhancing activity of CBZ leads to the degradation of mutant ATXN3 in in vitro and in vitro models of MachadocJoseph disease (MJD). Moreover, an intermittent CBZ treatment regimen improves MJD‐associated motor deficits and prevents cerebellar degeneration in transgenic mice, which suggests that CBZ may be a promising therapeutic approach for MJD.
Spinocerebellar ataxia type 1 is an autosomal dominant disorder caused by a CAG repeat expansion in
ATXN1
, characterized by progressive cerebellar and extracerebellar symptoms. MRI-based studies in ...SCA1 focused in the cerebellum and connections, but there are few data about supratentorial/spinal damage and its clinical relevance. We have thus designed this multimodal MRI study to uncover the structural signature of SCA1. To accomplish that, a group of 33 patients and 33 age-and gender-matched healthy controls underwent MRI on a 3T scanner. All patients underwent a comprehensive neurological and neuropsychological evaluation. We correlated the structural findings with the clinical features of the disease. In addition, we evaluated the disease progression looking at differences in SCA1 subgroups defined by disease duration. Ataxia and pyramidal signs were the main symptoms. Neuropsychological evaluation disclosed cognitive impairment in 53% with predominant frontotemporal dysfunction. Gray matter analysis unfolded cortical thinning of primary and associative motor areas with more restricted impairment of deep structures. Deep gray matter atrophy was associated with motor handicap and poor cognition skills. White matter integrity loss was diffuse in the brainstem but restricted in supratentorial structures. Cerebellar cortical thinning was found in multiple areas and correlated not only with motor disability but also with verbal fluency. Spinal cord atrophy correlated with motor handicap. Comparison of MRI findings in disease duration-defined subgroups identified a peculiar pattern of progressive degeneration.
The present study aimed to characterize clinical and molecular data of a large cohort of subjects with childhood-onset hereditary spastic paraplegias (HSPs). A multicenter historical cohort was ...performed at five centers in Brazil, in which probands and affected relatives' data from consecutive families with childhood-onset HSP (onset < 12 years-old) were reviewed from 2011 to 2020. One hundred and six individuals (83 families) with suspicion of childhood-onset HSP were evaluated, being 68 (50 families) with solved genetic diagnosis, 6 (5 families) with candidate variants in HSP-related genes and 32 (28 families) with unsolved genetic diagnosis. The most common childhood-onset subtype was SPG4, 11/50 (22%) families with solved genetic diagnosis; followed by SPG3A, 8/50 (16%). Missense pathogenic variants in SPAST were found in 54.5% of probands, favoring the association of this type of variant to childhood-onset SPG4. Survival curves to major handicap and cross-sectional Spastic Paraplegia Rating Scale progressions confirmed the slow neurological deterioration in SPG4 and SPG3A. Most common complicating features and twenty variants not previously described in HSP-related genes were reported. These results are fundamental to understand the molecular and clinical epidemiology of childhood-onset HSP, which might help on differential diagnosis, patient care and guiding future collaborative trials for these rare diseases.
A 4-year-old boy with LAMA2-related congenital muscular dystrophy had two pathogenic variants (NM_000426):c.1255de1A and c.2461A>C. Magnetic resonance imaging (MRI) of the brain showed signal ...abnormalities in supratentorial white matter (WM), which are conspicuous findings in this disease. Interestingly, MRI also depicted malformations of cortical development - symmetric bilateral parieto-occipital bumpy or pebbly cortical surface (cobblestone malformation). This report expands LAMA2-related radiological phenotype to include not only WM abnormalities, but also predominantly posterior cerebral cortex changes.
Background
ATXN2 is the causative gene of spinocerebellar ataxia type 2 (SCA2) and has been implicated in glaucoma pathogenesis. Therefore, studying ocular changes in SCA2 could uncover clinically ...relevant changes.
Objective
The aim was to investigate optic disc and retinal architecture in SCA2.
Methods
We evaluated 14 patients with SCA2 and 26 controls who underwent intraocular pressure measurement, fundoscopy, and macular and peripapillary spectral domain optical coherence tomography (SD‐OCT). We compared SD‐OCT measurements in SCA2 and controls, and the frequency of glaucomatous changes among SCA2, controls, and 76 patients with other SCAs (types 1, 3, 6, and 7).
Results
The macula, peripapillary retinal nerve fiber and inner plexiform layers were thinner in SCA2 than in controls. Increased cup‐to‐disc ratio was more frequent in SCA2 than in controls and other SCAs.
Conclusions
Ocular changes are part of SCA2 phenotype. Future studies should further investigate retinal and optic nerve architecture in this disorder.
Introduction/Aims
Amyotrophic lateral sclerosis (ALS) type 8 (ALS8) is caused by VAPB gene mutations. The differences between neuropsychological and behavioral profiles of patients with sporadic ALS ...(sALS) and those with ALS8 are unclear. We aimed to compare cognitive performance and behavioral aspects between sALS and ALS8 patients.
Methods
Our study included 29 symptomatic ALS8 patients (17 men; median age 49 years), 20 sALS patients (12 men; median age 55 years), and 30 healthy controls (16 men; median age 50 years), matched for sex, age, and education. Participants underwent neuropsychological assessments focused on executive functions, visual memory, and facial emotion recognition. Behavioral and psychiatric symptoms were evaluated using the Hospital Anxiety and Depression Scale and the Cambridge Behavioral Inventory.
Results
Clinical groups (sALS and ALS8) exhibited lower global cognitive efficiency and impaired cognitive flexibility, processing speed, and inhibitory control compared with controls. ALS8 and sALS showed similar performance in most executive tests, except for poorer verbal (lexical) fluency in those with sALS. Apathy, anxiety, and stereotypical behaviors were frequent in both clinical groups.
Discussion
sALS and ALS8 patients demonstrated similar deficits in most cognitive domains and had comparable behavioral profiles. These findings should be considered in the care of patients.
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