Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.

BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18. AIM: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes. METHODS: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects. RESULTS: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal. DISCUSSION: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.

Oromandibular dystonia: from onset to spread a multicenter italian study.

BACKGROUND: Detailed information about the epidemiological and phenomenological differences among the aetiological subtypes of oromandibular dystonia (OMD) is lacking. Moreover, the OMD tendency to spread to other body sites has never been investigated. AIM: To compare the main demographic and clinical features of OMD in different aetiological groups and assess the risk of spread. MATERIALS AND METHODS: We retrospectively analysed data from patients contained in the Italian Dystonia Registry. The risk of spread was assessed by Kaplan Meyer curves and Cox regression analysis. RESULTS: The study included 273 patients (175 women) aged 55.7 years (SD 12.7) at OMD onset. Female predominance was observed. Idiopathic dystonia was diagnosed in 241 patients, acquired dystonia in 22. In 50/273 patients, dystonia started in the oromandibular region (focal OMD onset); in 96/273 patients the onset involved the oromandibular region and a neighbouring body site (segmental/multifocal OMD onset); and in 127/273 patients OMD was a site of spread from another body region. Sensory trick (ST) and positive family history predominated in the idiopathic group. No dystonia spread was detected in the acquired group, whereas spread mostly occurred within the first five years of history in 34% of the focal OMD onset idiopathic patients. Cox regression analysis revealed ST as a significant predictor of spread (HR, 12.1; 95% CI, 2.5 - 18.8; P = 0.002). CONCLUSION: This large study provides novel information about the clinical phenomenology of idiopathic and acquired OMD. We pointed out a possible role of oestrogens in favouring dystonia development. Moreover, we described for the first time the association between ST and dystonia spread, revealing possible common pathophysiological mechanisms. Our findings may be suggested as a referral point for future pathophysiological and therapeutic studies on OMD.

Does sex influence the natural history of idiopathic adult-onset dystonia?

BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

A case of hemichorea associated with nonketotic hyperglycaemia: A new magnetic resonance spectroscopy (MRS) finding and possible future implications.

BACKGROUND: Diabetic Striatopathy (DS) is a rare complication of a poor-controlled Diabetes Mellitus consisting of sudden onset of movement disorders. To date, there is still poor knowledge about the pathogenesis. CASE: We describe a 79 year old men affected by sudden onset hemichoreic movements whose cause was a non-ketotic hyperglycaemia diagnosed despite the normal blood glucose levels thanks to brain CT and magnetic resonance imaging. Then, we introduce a new magnetic resonance spectroscopy (MRS) finding never described until today which allowed us to produce a new pathogenetic theory of a phenomenon still without definitive explanations. LITERATURE REVIEW: We performed a review of DS cases using the Medline database and we extracted main data regarding imaging findings. CONCLUSIONS: Thanks to our MRS we show new imaging findings never described until today, with a new pathogenetic explanation, since all the causative hypotheses produced during the past years have never found evidence.

The long-term response to botulinum toxin injections in patients with blepharospasm undergoing upper eyelid surgery.

BACKGROUND: Upper eyelid surgery (UES) is a therapeutical strategy used for those patients affected by blepharospasm (BSP) who either do not respond or experience a gradual decrease in responsiveness to botulinum toxin (BoNT) injections. Nevertheless, most of them need to restart with BoNT despite the intervention. AIM: To evaluate the long-term post-surgical response to BoNT in patients with BSP and to identify predictive factors associated to treatment outcome. METHODS: We collected data of 60 BS patients, divided into two groups - blepharoplasty YES (8) and NO (52), collecting demographic - age, sex - and clinical data -disease duration, duration of the treatment with BoNT. Respective responses to injections - evaluated through the differences of both Jancovic Rating Scale and the Blepharospasm Disability Index pre and post BoNT (delta JRS and delta BSDI) just before their periodic three-month injection and after 1 month from it - were compared. Finally, clinical and demographics variables were included in multivariate regression and correlation analyses to assess their impact on the long-term response to injections. RESULTS: Patients who underwent UES had significantly lower delta at both scales, showing a poorer outcome after BoNT treatment. No variable was found to be associated with the response. DISCUSSION: Our data seem to suggest that surgery does not improve response to BoNT injections on the long run. As such, UES could be considered as an efficacious treatment in BSP just if evaluated soon after its performing. Long-term BSP management seems still difficult to be performed adequately and new therapeutical approaches are still needed.

Do cerebrovascular risk factors impact the clinical expression of idiopathic isolated adult-onset dystonia?

BACKGROUND: Although acquired dystonia may develop following ischaemic/haemorrhagic stroke, the relationship between cerebrovascular disease and idiopathic dystonia has been poorly investigated. This cross sectional study aimed at evaluating the impact of cerebrovascular risk factors on the clinical expression of idiopathic adult onset dystonia (IAOD), with reference to dystonia localization and dystonia-associated features. METHODS: Data were obtained from the Italian Dystonia Registry. Patients with IAOD were stratified into two groups according to the presence of diabetes mellitus and/or arterial hypertension and/or dyslipidemia and/or heart disease. The two groups were compared for demographic features, dystonia phenotype, and dystonia-associated features (sensory trick, tremor, eye symptoms in blepharospasm, and neck pain in cervical dystonia). RESULTS: A total of 1108 patients participated into the study. Patients who reported one cerebrovascular factor or more (n = 555) had higher age and longer disease duration than patients who did not. On multivariable logistic regression analysis, blepharospasm was the only localization, and sensory trick was the only dystonia-associated feature that was significantly associated with cerebrovascular risk factors. Linear regression analysis showed that the strength of the association between cerebrovascular factors and blepharospasm/sensory trick increased with increasing the number of cerebrovascular factors per patient. CONCLUSIONS: Results of the present study showed that cerebrovascular risk factors may be associated with specific features of IAOD that is development of blepharospasm and sensory trick. Further studies are needed to better understand the meaning and the mechanisms underlying this association.

Phenotypic Variability in Acquired and Idiopathic Dystonia.

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias. Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias. Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia. Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor. Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories.

Clinimetrics of the Italian version of the Montreal Cognitive Assessment (MoCA) in adult-onset idiopathic focal dystonia.

This study aimed at assessing the clinimetrics of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of patients with adult-onset idiopathic focal dystonia (AOIFD). N = 86 AOIFD patients and N = 92 healthy controls (HCs) were administered the MoCA. Patients further underwent the Trail-Making Test (TMT) and Babcock Memory Test (BMT), being also screened via the Beck Depression Inventory-II (BDI-II) and the Dimensional Apathy Scale (DAS). Factorial structure and internal consistency were assessed. Construct validity was tested against TMT, BMT, BDI-II and DAS scores, whilst diagnostics against the co-occurrence of a defective performance on at least one TMT measure and on the BMT. Case-control discrimination was examined. The association between MoCA scores and motor-functional measures was explored. The MoCA was underpinned by a mono-component structure and acceptably reliable at an internal level. It converged towards TMT and BMT scores, as well as with the DAS, whilst diverging from the BDI-II. Its adjusted scores accurately detected cognitive impairment (AUC = .86) at a cut-off of < 17.212. The MoCA discriminated patients from HCs (p < .001). Finally, it was unrelated to disease duration and severity, as well as to motor phenotypes. The Italian MoCA is a valid, diagnostically sound and feasible cognitive screener in AOIFD patients.

A novel ANO3 variant in two siblings with different phenotypes.

INTRODUCTION: Dystonia type 24 is due to the mutation of the ANO3 gene. It generally consists of craniocervical dystonia associated with tremor; however, other neurological manifestations may also occur. Scientific literature has been expanding on its phenotype over the past few years. CASE: Here we present two siblings affected by dystonia 24 associated to a novel missense mutation of the ANO3 gene. Description of their phenotype, with regard to motor and non-motor features, may improve the knowledge on DYT 24. Consistent with previous reports, our patients presented with cranio-cervical involvement, and they also exhibited different severity and phenotypes. However non-motor symptoms were present too. CONCLUSION: Dystonia 24 spectrum is continuously expanding. This case suggests that the ANO3 missense mutation should be sought in all cases of dystonia and isolated tremor and that non-motor symptoms are an integral part of dystonic syndromes. It also shows that clinical and treatment features may vary from patient to patient, even if they may present the same mutation.

Concomitant diagnosis of multiple sclerosis and human immunodeficiency virus (HIV) infection: case report and the review of literature.

BACKGROUND: To date, few cases of multiple sclerosis (MS) patients with concomitant Human Immunodeficiency Virus (HIV) infection have been described. However, none of the previously described cases has been treated with Natalizumab, probably due to the increasing risk of progressive multifocal leukoencephalopathy (PML). CASE: We report the case of a patient concomitantly diagnosed for HIV infection and MS treated with combined antiretroviral therapy (cART) and Natalizumab for 19 months, without clinical or radiological MS activity. CONCLUSIONS: Our case might suggest considering Natalizumab in patients with concomitant HIV infection, especially for those with significant disease activity requiring a high efficacy disease modifying treatment.

The C-Terminal Cross-linked Telopeptide of Type I Collagen (CTX-I) as a Potential Cardiomyopathy Biomarker in Friedreich Ataxia Patients.

Friedreich's ataxia (FRDA) is the most common inherited recessive ataxia. Cardiomyopathy (CM) with myocardial hypertrophy is the predominant cause of death. The presence of CM is variable and the risk factors for cardiac involvement are not entirely clear. Markers of collagen degradation, such as C-terminal cross-linked telopeptide of type I collagen (CTX-I), seem to be associated with unfavorable cardiovascular outcomes. The aim of our study was to measure serum CTX-I as a marker of cardiac fibrosis in FRDA patients. We measured serum CTX value in twenty-five FRDA patients (mean age, 31.3 ± 14.7 years) and nineteen healthy controls (mean age, 34.0 ± 13.5 years). Patients underwent echocardiography and SARA scale evaluation. CTX values were significantly higher in the patients than in the control group (31.82 ± 2.27 vs 16.44 ± 1.6 µg/L; p = 0.006). CTX-I was inversely correlated with age (R = - 0,535; n = 44; p < 0.001). The regression model identified disease duration and TT3 levels to be independent predictors of CTX-I (model R2 = 0.938; intercept - 64.0, p = 0.071; disease duration coefficient = - 2.34, p = 0.005; TT3 coefficient = 127.17, p = 0.011). CTX-I, a biomarkers of collagen turnover, is elevated in FRDA and should provide complementary information to identify patients with high cardiological risk even if longitudinal studies are needed to define the role of this serologic marker of collagen metabolism in the natural history of cardiomyopathy in FRDA patients.

Effects of three-months folate supplementation on early vascular abnormalities in hyperhomocysteinemic patients with epilepsy.

BACKGROUND: Epilepsy has been associated with an increased risk of cardiovascular events. Anti-seizure medication (ASM) may contribute to vascular risk by several mechanisms, including increased homocysteine levels. This study aims to assess the global vascular burden in hyperhomocysteinemic people with epilepsy (PWE) on long-term ASM before and after folic acid supplementation and in subgroups of PWE treated with single enzyme-inducing or single non-enzyme inducing ASM. METHODS: One hundred and seventy-four hyperhomocysteinemic (HHcy) PWE who met the inclusion criteria were enrolled. Carotid Doppler ultrasonography, FMD and ultrasound assessment of the brachial artery properties at the baseline and after 90 days of folic acid supplementation were performed. The vascular biomarkers MMP-9 and TIMP-1 were also detected. RESULTS: After folic acid supplementation, in HHcy patients homocysteine levels reduced from 26.8 ± 10.5 to 20.2 ± 5.3 µmol/L, carotid Intima-Media-Thickness reduced from 0.83+0.06 mm to 0.79±0.05 mm, and FMD, distensibility coefficient and ß-stiffness improved (p < 0.05). Moreover, MMP-9 and TIMP-1 reduced after supplementation (p < 0.05). PWE treated with a single enzyme-inducing ASM showed an impairment of vascular parameters compared to patients treated with non-enzyme inducing ASM. CONCLUSIONS: The results highlight the importance of assessing homocysteine levels and estimating the cardiovascular risk of PWE, preferring non-enzyme inducing ASM in high cardiovascular-risk patients. An adequate correction of homocysteine levels with folate supplementation should be considered to improve the cardiovascular profile.

The impact of the reclusion on patients with blepharospasm during the COVID19 pandemic.

BACKGROUND: Blepharospasm (BS) is a focal dystonia that can be treated successfully with Botulinum toxin (BoNT). During the reclusion due to the Covid 19 pandemic many patients missed the scheduled treatment. OBJECTIVES: Aim of the study is to evaluate Level of Disability (LoD) related to BS during the lockdown period. METHODS: LoD was assessed by an adapted version of Blepharospasm Disability Index (4iBSDI) during reclusion (T1), and three months after the first injection following the lock down phase (T2). 4iBSDI scores were compared between T1 and T2, a correlation between the change of LoD in the two periods (t-delta) and patients' clinical data was analyzed. RESULTS: LoD was not modified between the two periods in most of the patients and it was reduced at T1 in almost one third of the participants. No correlation between t-delta and clinical data was found. CONCLUSIONS: LoD did not increase during the lock down period in most of BS patients although BoNT treatment was suspended. Environmental and psychosocial factors may contribute to determine the LoD due to BS.

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.

Essential tremor and cognitive impairment: who, how, and why.

BACKGROUND AND AIMS: Recent years have witnessed the switch from considering essential tremor (ET) a monosymptomatic disorder to consider it as part of a spectrum, including other neurological signs, such as mild cognitive impairment and dementia, thus defining it as "ET plus." There are few data on cognitive impairment in ET patients. The aim of this review is to analyze the clinical characteristics of ET patients developing cognitive impairment, their neuropsychological profile, the underpinning mechanisms, and the possible biomarkers. METHODS: The authors performed a narrative review on cognitive decline in essential tremor, including articles written in English since the year 2000. DISCUSSION: The most recent pathogenetic theories of cognitive impairment in ET rely on the cerebellar dysfunction, being part of the Cerebellar Cognitive Affective Syndrome spectrum. Cognitive impairment in ET patients could be assessed through many tests that demonstrate the involvement of different domains, such as attention, executive functions, and language. There are some clinical characteristics of ET that may indicate a greater risk of developing cognitive impairment, namely, cerebellar symptoms, falls, age at onset, and family history. However, there are no established clinical, neurophysiological, neuropathological, and fluid biomarkers of cognitive impairment in ET. CONCLUSIONS: Increasing data are showing in ET the presence of cerebellar symptoms and cognitive impairment. Further studies are needed to better understand cognition in ET patients, and to define the boundary between ET and ET plus, since deeper phenotyping might have important clinical and therapeutic implications.