Objective
Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) ...or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium‐dependent phospholipid‐binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11).
Methods
We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls.
Results
Clinico‐radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb‐girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP‐43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions).
Interpretation
These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021;90:239–252
Autonomic function in sporadic and familial ALS type 8 Pazian Martins, Melina; González-Salazar, Carelis; de Lima, Fabricio Diniz ...
Clinical neurophysiology,
November 2023, 2023-11-00, 20231101, Letnik:
155
Journal Article
Recenzirano
•Autonomic function is impaired in fALS8 and involves parasympathetic and sympathetic divisions.•sALS and fALS8 present similar neurophysiological abnormalities but different autonomic ...complaints.•Sudomotor compromise in sALS and fALS8 is mediated by a small fiber, possibly length-dependent, autonomic neuropathy.
To characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8).
We selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant.
SCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs.
Dysautonomia – cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group.
Patients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.
During the 2013 to 2016 outbreak in the Pacific and Americas, Zika virus infection resulted not only in febrile and cutaneous manifestations but also in (severe) neurologic complications. These ...included both central and peripheral nervous system disorders. The most frequent was Guillain-Barré syndrome that typically developed 1 to 2 weeks after the acute infection. Later, other peripheral nervous system syndromes were recognized in association with the viral infection, broadening the spectrum of Zika virus-related peripheral nervous system syndromes. In the current article, the authors review all available clinical neurophysiology data on Guillain-Barré syndrome and other peripheral nervous system syndromes in an attempt to characterize the major patterns of involvement related to Zika virus. The authors also highlight the clinical usefulness of nerve conduction studies and needle EMG in the investigation of suspected Zika virus-related Guillain-Barré syndrome.
•Autonomic dysfunction involves multiple domains in RFC1-related disorder.•This condition is characterized by a small fiber autonomic axonopathy.•Sympathetic and parasympathetic divisions are ...affected in RFC1-related disorder.
To characterize and quantify autonomic involvement in patients with RFC1-related disorder of adult-onset cerebellar ataxia and idiopathic sensory neuropathy.
We enrolled 16 subjects with biallelic RFC1 (AAGGG)n expansions and 16 age and sex-matched healthy controls that underwent comprehensive clinical and neurophysiological evaluation. Scales for Outcomes in Parkinson’s Disease Autonomic Dysfunction (SCOPA-AUT) score was used to assess autonomic symptoms. Electrophysiological testing included assessment of heart rate variability and quantitative sudomotor axon reflex test (QSART). Between-group comparisons were assessed using non-parametric tests.
In the patient group, there were 9 men/7 women and the median age was 60.5 years. SCOPA-AUT scores were significantly higher in the RFC1 group compared to controls (22 vs 10, p < 0.001). Half of patients had cardiac autonomic neuropathy. In neurophysiology, there was resting tachycardia combined with abnormal responses during Valsalva maneuver and deep breathing among patients. QSART responses were also significantly reduced in the RFC1 group, especially in the lower limbs.
Autonomic dysfunction is frequent, clinically relevant and involves multiple domains in RFC1-related disorder. Patients have both sympathetic and parasympathetic involvement. From a topographical perspective, this condition is characterized by a small fiber autonomic axonopathy.
Dysautonomia is frequent, severe and related to peripheral damage in RFC1-related disorder.
• Prevalence of dysarthria in SPG4 is greater than previously considered.• The dysarthria in SPG4 is mild or moderate.• The subsystems of speech more affected are articulatory and phonation.
To ...describe the speech pattern of patients with hereditary Spastic Paraplegia type 4 (SPG4) and correlated it with their clinical data.
Cross-sectional study was carried out in two university hospitals in Brazil. Two groups participated in the study: the case group (n = 28) with a confirmed genetic diagnosis for SPG4 and a control group (n = 17) matched for sex and age. The speech assessment of both groups included: speech task recording, acoustic analysis, and auditory-perceptual analysis. In addition, disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS).
In the auditory-perceptual analysis, 53.5% (n = 15) of individuals with SPG4 were dysarthric, with mild to moderate changes in the subsystems of phonation and articulation. On acoustic analysis, SPG4 subjects’ performances were worse in measurements related to breathing (maximum phonation time) and articulation (speech rate, articulation rate). The articulation variables (speech rate, articulation rate) are related to the age of onset of the first motor symptom.
Dysarthria in SPG4 is frequent and mild, and it did not evolve in conjunction with more advanced motor diseases. This data suggest that diagnosed patients should be screened and referred for speech therapy evaluation and those pathophysiological mechanisms of speech involvement may differ from the length-dependent degeneration of the corticospinal tract.
Little is known about the cognitive profile of Hereditary Spastic Paraplegias (HSP), where most scientific attention has been given to motor features related to corticospinal tract degeneration.
We ...aimed to perform a broad characterization of the cognitive functions of patients with pure and complicated HSP as well as to determine the frequency of abnormal cognitive performances in the studied subtypes.
A two-center cross-sectional case-control study was performed. All individuals underwent cognitive assessment through screening tests (Mini Mental State Examination-MEEM and Montreal Cognitive Assessment-MOCA) and tests to assess specific cognitive functions (Verbal fluency with phonological restriction-FAS; Verbal categorical fluency-FAS-cat and Rey's Verbal Auditory Learning Test -RAVLT).
Fifty four patients with genetically confirmed HSP diagnosis, 36 with spastic paraplegia type 4 (SPG4), 5 SPG11, 4 SPG5, 4 cerebrotendinous xanthomatosis (CTX), 3 SPG7 and 2 SPG3A, and 10 healthy, unrelated control subjects, with similar age, sex, and education participated in the study. SPG4 patients had worse performances in MOCA, FAS, FAS-cat, and RAVLT when compared to controls. Most SPG4 patients presented cognitive changes not compatible with dementia, performing poorly in memory, attention and executive functions. SPG5 patients scored lower in executive functions and memory, and SPG7 patients performed poorly on memory tasks. All evaluated cognitive functions were markedly altered in CTX and SPG11 patients.
Cognitive abnormalities are frequent in HSP, being more severe in complicated forms. However, cognitive impairments of pure HSPs might impact patients' lives, decreasing families' socioeconomic status and contributing to the overall disease burden.
Hereditary spastic paraplegia is a heterogeneous group of genetic disorders characterized by degeneration of the corticospinal tracts, coursing with progressive weakness and spasticity of the lower ...limbs. To date, there are no effective treatments for progressive deficits or disease-modifying therapy for those patients. We report encouraging results for spastic paraparesis after spinal cord stimulation.
A 51-year-old woman suffering from progressive weakness and spasticity in lower limbs related to hereditary spastic paraplegia type 4 underwent spinal cord stimulation (SCS) and experienced also significant improvement in motor function. Maximum ballistic voluntary isometric contraction test, continuous passive motion test and gait analysis using a motion-capture system were performed in ON and OFF SCS conditions. Neurophysiologic assessment consisted of obtaining motor evoked potentials in both conditions.
Presurgical Spastic Paraplegia Rating Scale (SPRS) score was 26. One month after effective SCS was initiated, SPRS went down to 15. At 12 months follow up, she experienced substantial improvement in motor function and in gait performance, with SPRS scores 23 (OFF) and down to 20 (ON). There was an increased isometric muscle strength (knee extension, OFF: 41 N m; ON: 71 N m), lower knee extension and flexion torque values in continuous passive motion test (decrease in spastic tone) and improvement in gait (for example, step length increase).
Despite being a case study, our findings suggest innovative lines of research for the treatment of spastic paraplegia.
•There aren't effective treatments for progressive deficits at SPG4.•In a case report, we report encouraging results for SPG4 after SCS.•The patient had 42% and 23% improvement in SPRS at 1 and 12 months after SCS, respectively.•SCS improve isometric muscle strength and gait and decrease spasticity.
Hereditary spastic paraplegias (HSP) are a group of genetic diseases characterized by lower limb spasticity with or without additional neurological features. Swallowing dysfunction is poorly studied ...in HSP and its presence can lead to significant respiratory and nutritional complications. The aim of this study was to evaluate the frequency and clinical characteristics of dysphagia in different types of HSP.
A two-center cross-sectional prevalence study was performed. Genetically confirmed HSP patients were evaluated using the Northwestern Dysphagia Patient Check Sheet and the Functional Oral Intake Scale. In addition, self-perception of dysphagia was assessed by the Eat Assessment Tool-10 and the Swallowing Disturbance Questionnaire.
Thirty-six patients with spastic paraplegia type 4 (SPG4), five with SPG11, four with SPG5, four with cerebrotendinous xanthomatosis (CTX), three with SPG7, and two with SPG3A were evaluated. Mild to moderate oropharyngeal dysphagia was present in 3/5 (60%) of SPG11 and 2/4 (50%) of CTX patients. A single SPG4 (2%) and a single SPG7 (33%) patient had mild oropharyngeal dysphagia. All other evaluated patients presented with normal or functional swallowing.
Clinically significant oropharyngeal dysphagia was only present in complicated forms of HSP Patients with SPG11 and CTX had the highest risks for dysphagia, suggesting that surveillance of swallowing function should be part of the management of patients with these disorders.
Sensory neuronopathies (SN) are characterized by asymmetric non-length dependent sensory deficits and sensory ataxia. Autonomic dysfunction in SN was not yet evaluated regarding its frequency, ...characteristics and relationship to sensory deficits. To address these issues, we performed a comprehensive clinical and neurophysiological evaluation of a large cohort of patients with non-paraneoplastic SN (np-SN).
We enrolled 50 consecutive patients with npSN and 32 age/sex-matched healthy controls. They were clinically evaluated (SCOPA-Aut scale) and underwent neurophysiological autonomic assessment (quantitative sudomotor axon reflex test, heart rate variability and sympathetic skin response).
Mean age of patients was 50.9 ± 10.3 years and there were 18 men. npSN patients had higher SCOPA-Aut scores than controls (26.63 ± 12.72 vs. 12.66 ± 9.11, p < .001). QSART was abnormal in 92% of the patients - sweat volumes in all examined sites were smaller among patients (p < .001). Cardiovascular autonomic neuropathy was more frequent in these patients as well (p < .001).
Altogether our results suggest that autonomic dysfunction in distinct domains is frequent in npSN patients. These findings suggest that the clinical picture of npSN is related to a double neuronopathy: sensory and autonomic.
•Autonomic dysfunction complaints are frequent in sensory neuronopathy patients.•Sensory neuronopathy patients have significantly decreased sweat volumes in QSART.•Abnormal cardiovagal tests and cardiac autonomic neuropathy are present in sensory neuronopathy.
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.
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