C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.

BACKGROUND: C9orf72 gene repeat expansion (C9RE) is the most frequent gene variant associated with amyotrophic lateral sclerosis (ALS). We aimed to study the phenotype of motor neurone disease (MND) patients with C9RE in a Portuguese cohort. METHODS: Demographical and clinical data of MND patients with (C9RE+) and without C9RE were compared. ALS al Rating Scale-Revised (ALSFRS-R) and Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were used to evaluate functional and cognitive performance, respectively. Survival analysis was performed using Kaplan Meier log-rank test and Cox proportional hazards model. RESULTS: We included 761 patients of whom 61 (8.0 %) were C9RE+. C9RE+ patients had a higher frequency of ALS (95.1 vs 78.4 %, p = 0.002), and lower frequency of progressive muscular atrophy (3.3 vs 16.7 %, p = 0.006). C9RE+ was associated with earlier age of onset (58.1 vs 62.6 years, p = 0.003) and more frequent MND family history (65.5 vs 11.4 %, p < 0.001). Gender, ethnicity, onset site, diagnostic delay, disease progression rate until diagnosis (ΔF), ALSFRS-R and time until non-invasive ventilation did not differ between groups. Cognitive/behavioural symptoms and ECAS did not differ between groups, except a worse visuospatial score in C9RE+ group (p = 0.035). Death rate was 1.8 and 1.6 times higher in C9RE+ patients with MND and ALS, respectively. Significant survival prognostic factors in C9RE+ group were diagnosis delay (HR = 0.96, 95 %CI 0.92-0.99, p = 0.008) and ΔF (HR = 1.93, 95 %CI 1.26-2.96, p = 0.002). CONCLUSION: Our study corroborates most previous cohorts' findings, but harbours some singularities regarding onset site, phenotype, and cognitive profile, that contribute to a better understanding of C9RE epidemiology.

Physiological Biomarkers of Upper Motor Neuron Dysfunction in ALS.

Upper motor neuron (UMN) dysfunction is an important feature of amyotrophic lateral sclerosis (ALS) for the diagnosis and understanding of pathogenesis. The identification of UMN signs forms the basis of ALS diagnosis, although may be difficult to discern, especially in the setting of severe muscle weakness. Transcranial magnetic stimulation (TMS) techniques have yielded objective physiological biomarkers of UMN dysfunction in ALS, enabling the interrogation of cortical and subcortical neuronal networks with diagnostic, pathophysiological, and prognostic implications. Transcranial magnetic stimulation techniques have provided pertinent pathogenic insights and yielded novel diagnostic and prognostic biomarkers. Cortical hyperexcitability, as heralded by a reduction in short interval intracortical inhibition (SICI) and an increase in short interval intracortical facilitation (SICF), has been associated with lower motor neuron degeneration, patterns of disease evolution, as well as the development of specific ALS clinical features including the split hand phenomenon. Reduction in SICI has also emerged as a potential diagnostic aid in ALS. More recently, physiological distinct inhibitory and facilitatory cortical interneuronal circuits have been identified, which have been shown to contribute to ALS pathogenesis. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction. Resting-state EEG is a novel neurophysiological technique developed for directly interrogating cortical neuronal networks in ALS, that have yielded potentially useful physiological biomarkers of UMN dysfunction. The present review discusses physiological biomarkers of UMN dysfunction in ALS, encompassing conventional and novel TMS techniques developed to interrogate the functional integrity of the corticomotoneuronal system, focusing on pathogenic, diagnostic, and prognostic utility.

Upper motor neuron signs in primary lateral sclerosis and hereditary spastic paraplegia.

INTRODUCTION/AIMS: The frequency and distribution of upper motor neuron (UMN) signs in primary lateral sclerosis (PLS) are unknown. We aimed to study the spectrum of UMN signs in PLS and compare it with hereditary spastic paraplegia (HSP). METHODS: We retrospectively analyzed the frequency of different UMN signs, including hyperreflexia (limbs and jaw), limb and tongue spasticity, Babinski, and Hoffman signs, in PLS patients at first observation and compared this respect to onset region and symptom duration. We also compared PLS versus HSP patients. RESULTS: We included 34 PLS and 20 HSP patients, with a median symptom duration at first visit of 3.0 (interquartile range, IQR = 4.0) and 19.0 (IQR = 22.0) years, respectively. In PLS patients, hyperreflexia of upper (UL) (88.2%) and lower (LL) (91.2%) limbs, and LL spasticity (79.4%) were the most common findings. Spasticity of LL was significantly (p = .012) more frequent in LL-spinal onset subgroup, tongue spasticity in bulbar-onset subgroup (p = .021), and Hoffman sign in UL-spinal onset subgroup (p = .024). The PLS subgroup with shorter disease duration had a higher frequency of abnormal jaw jerk reflex (p = .037). Compared with HSP, PLS patients had a higher frequency of UL hyperreflexia (88.2% vs. 42.1%, p < .001) and UL spasticity (44.1% vs. 0.0%, p < .001). Asymmetric distribution of UMN signs was present in PLS and not in HSP. DISCUSSION: In PLS, UL UMN signs are nearly always present and UMN sign distribution appears to be associated with onset region. At first observation, bulbar involvement, asymmetrical distribution of UMN signs and UL spasticity may indicate PLS versus HSP.

Multisystemic RFC1-Related Disorder: Expanding the Phenotype Beyond Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome.

Background and Objectives: The RFC1 spectrum has become considerably expanded as multisystemic features beyond the triad of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) have started to be unveiled, although many still require clinical replication. Here, we aimed to clinically characterize a cohort of RFC1-positive patients by addressing both classic and multisystemic features. In a second part of this study, we prospectively assessed small nerve fibers (SNF) and autonomic function in a subset of these RFC1-related patients. Methods: We retrospectively enrolled 67 RFC1-positive patients from multiple neurologic centers in Portugal. All patients underwent full neurologic and vestibular evaluation, as well as neuroimaging and neurophysiologic studies. For SNF and autonomic testing (n = 15), we performed skin biopsies, quantitative sensory testing, sudoscan, sympathetic skin response, heart rate deep breathing, and tilt test. Results: Multisystemic features beyond CANVAS were present in 82% of the patients, mainly chronic cough (66%) and dysautonomia (43%). Other features included motor neuron (MN) affection and motor neuropathy (18%), hyperkinetic movement disorders (16%), sleep apnea (6%), REM and non-REM sleep disorders (5%), and cranial neuropathy (5%). Ten patients reported an inverse association between cough and ataxia severity. A very severe epidermal denervation was found in skin biopsies of all patients. Autonomic dysfunction comprised cardiovascular (67%), cardiovagal (54%), and/or sudomotor (50%) systems. Discussion: The presence of MN involvement, motor neuropathy, small fiber neuropathy, or extrapyramidal signs should not preclude RFC1 testing in cases of sensory neuronopathy. Indeed, the RFC1 spectrum can overlap not only with multiple system atrophy but also with hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, and feeding dystonia phenotypes. Some clinical-paraclinical dissociations can pose diagnostic challenges, namely large and small fiber neuropathy and sudomotor dysfunction which are usually subclinical.

Exploring the split hand phenomenon with the neurophysiological index.

In 164 subjects of different age groups, we studied the neurophysiological index (NI) ([CMAP amplitude/Distal motor latency] *[F-wave frequency]; CMAP=compound muscle action potential) for three hand muscles (APB= abductor pollicis brevis; FDI= first dorsal interosseous; ADM= abductor digiti minimi). A split hand index based on CMAP amplitude (SHI_CMAP) and NI (SHI_NI) were calculated ([APB CMAP amplitude or NI * FDI CMAP amplitude or NI]/[ADM CMAP amplitude or NI]). All these neurophysiological measurements differed between age groups (p<0.001). Hand muscle NIs, as well as SHI_NI and SHI_CMAP were age dependent. This may be relevant for diagnostic purposes in motor neuron diseases.

Thyroid dysfunction in Portuguese amyotrophic lateral sclerosis patients.

INTRODUCTION: Thyroid hormones influence neuromuscular function, and it has been thought that this might contribute to degeneration of motor neurons. METHODS: We used case-control methods to investigate the prevalence of thyroid dysfunction (hyperthyroidism and hypothyroidism) in ALS patients followed in our centre, between 2015 and 2020. Data from patients with neuromuscular disorders not derived from thyroid dysfunction, followed within the same time frame, were used as controls. Thyroid dysfunction was defined by previous thyroid replacement medication managed by an endocrinologist. We used odds ratios (OR) with a 95% confidence interval (CI) to compare 579 ALS patients and 415 age-gender-matched disease controls. Additionally, we provide a summarized review of the literature. RESULTS: Hypothyroidism (prevalence of 5.0 versus 8.6%; OR = 0.56, 95% CI 0.34-0.92, p = 0.023), hyperthyroidism (prevalence of 0.3 versus 1.2%; OR = 0.28, 95% CI 0.06-1.47, p = 0.134) and overall thyroid dysfunction (prevalence of 5.4 versus 9.9%; OR = 0.52, 95% CI 0.32-0.84, p = 0.015) were less prevalent in ALS patients than in controls, but similar to the national epidemiological data for thyroid disease. Our data are in line with the findings of most previous studies. CONCLUSIONS: We conclude that thyroid dysfunction is not associated with ALS.

Motor neuron disease in three asymptomatic pVal50Met TTR gene carriers.

We describe three unrelated patients with sporadic motor neuron disease (MND) and hereditary amyloid transthyretin (ATTRv) amyloidosis family history, who were asymptomatic carriers of the pVal50Met mutation of transthyretin (TTR) gene. Patients 1 and 2 were a 43-year-old man with a spinal-onset of ALS and a 37-year-old woman with a bulbar-onset of ALS, who died due to respiratory complications five and two years after disease onset, respectively. Patient 3 is a 52-year-old woman, with a two-year history of a probable primary lateral sclerosis, and a frontotemporal dysfunction. Imaging, cerebrospinal fluid (CSF) and nerve conduction and small fiber tests were normal in all. Genetic testing for ALS was negative in the two patients tested. Previous studies in MND patients have identified reduced TTR levels in CSF and neuronal gene overexpression, suggesting a neuroprotective role of TTR. The association of MND in patients with TTR gene mutations has not yet been described.