Two more families supporting the existence of monogenic spinocerebellar ataxia 48.

The reduced penetrance of TBP intermediate alleles and the recently proposed possible digenic TBP/STUB1 inheritance raised questions on the possible mechanism involved opening a debate on the existence of SCA48 as a monogenic disorder. We here report clinical and genetic results of two apparently unrelated patients carrying the same STUB1 variant(c.244G > T;p.Asp82Tyr) with normal TBP alleles and a clinical picture fully resembling SCA48, including cerebellar ataxia, dysarthria and mild cognitive impairment. This report provides supportive evidence that this specific ataxia can also occur as a monogenic disease, considering classical TBP allelic ranges.

Sulcal Morphometry Predicts Mild Cognitive Impairment Conversion to Alzheimer's Disease.

Background: Being able to differentiate mild cognitive impairment (MCI) patients who would eventually convert (MCIc) to Alzheimer's disease (AD) from those who would not (MCInc) is a key challenge for prognosis. Objective: This study aimed to investigate the ability of sulcal morphometry to predict MCI progression to AD, dedicating special attention to an accurate identification of sulci. Methods: Twenty-five AD patients, thirty-seven MCI and twenty-five healthy controls (HC) underwent a brain-MR protocol (1.5T scanner) including a high-resolution T1-weighted sequence. MCI patients underwent a neuropsychological assessment at baseline and were clinically re-evaluated after a mean of 2.3 years. At follow-up, 12 MCI were classified as MCInc and 25 as MCIc. Sulcal morphometry was investigated using the BrainVISA framework. Consistency of sulci across subjects was ensured by visual inspection and manual correction of the automatic labelling in each subject. Sulcal surface, depth, length, and width were retrieved from 106 sulci. Features were compared across groups and their classification accuracy in predicting MCI conversion was tested. Potential relationships between sulcal features and cognitive scores were explored using Spearman's correlation. Results: The width of sulci in the temporo-occipital region strongly differentiated between each pair of groups. Comparing MCIc and MCInc, the width of several sulci in the bilateral temporo-occipital and left frontal areas was significantly altered. Higher width of frontal sulci was associated with worse performances in short-term verbal memory and phonemic fluency. Conclusions: Sulcal morphometry emerged as a strong tool for differentiating HC, MCI, and AD, demonstrating its potential prognostic value for the MCI population.

Fabry disease in W162C mutation: a case report of two patients and a review of literature.

BACKGROUND: Fabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or cardiovascular system. As disease-modifying therapies are now available, early diagnosis is paramount to improving life quality and clinical outcomes. Despite the widespread use of non-invasive techniques for assessing organ damage, such as cardiac magnetic resonance imaging (MRI) for patients with cardiac disease, organ biopsy remains the gold standard to assess organ involvement. CASE PRESENTATION: The cases of two patients, father and daughter with a W162C mutation, are described. The father presented with late-onset, cardiac Fabry disease, subsequently developing systolic dysfunction and heart failure. His daughter, while asymptomatic and with normal cardiac assessment (except for slightly reduced native T1 values by cardiac MRI), had already initial myocyte Gb3 deposits on the endomyocardial biopsy, allowing her to start therapy precociously and potentially modifying the course of her disease. A review of the literature concerning the W162C mutation is then provided, showing that it is usually associated to classic, multisystemic Fabry disease rather than the cardiac-restricted form as in these two cases. CONCLUSIONS: Three main points can be concluded from this report. First, the W162C mutation can present with a more variegate phenotype than that predicted on a molecular basis. Second, endomyocardial biopsy was shown in this case to precede non-invasive investigation in determining organ involvement, justifying further studies on this potentially reliable technique, Third, difficulties can arise in the management of asymptomatic female carriers.

Motor unit number estimation via MScanFit MUNE in spinal muscular atrophy.

INTRODUCTION/AIMS: MScanFit MUNE (MScanFit) is a novel tool to derive motor unit number estimates (MUNEs) from compound muscle action potential (CMAP) scans. Few studies have explored its utility in 5q spinal muscular atrophy (SMA5q) patients, assessing only the abductor pollicis brevis (APB) muscle. We aimed to assess different distal muscles in pediatric and adult SMA5q patients, further evaluating clinical-electrophysiological correlations. METHODS: We analyzed MScanFit parameters reflecting the extent of denervation (MUNE; N50) and parameters of collateral reinnervation in APB, abductor digiti minimi (ADM), and tibialis anterior (TA) muscles. SMA patients were clinically evaluated using standardized motor function clinical scales, including the Hammersmith Functional Motor Scale - Expanded and the Revised Upper Limb Module. RESULTS: A total of 23 SMA5q (9 SMA type 2 and 14 SMA type 3) and 12 age-matched healthy controls (HCs) were enrolled. SMA patients showed lower MUNE and N50 values and higher parameters of collateral sprouting in all muscles compared to HC (p < .001). SMA type 2 patients demonstrated lower MUNE and higher collateral reinnervation values in APB and TA compared to SMA type 3 (p < .05). Walker patients showed higher values of MUNE and N50, and lower parameters of reinnervation in all muscles compared to sitters (p < .05). MScanFit parameters showed strong correlations (Rho-values ranging from .72 to .83) with clinical measurements. MUNE values were abnormal in muscles that were not clinically affected. DISCUSSION: MScanFit parameters showed promise as an outcome measure. Further studies, particularly longitudinal ones, are needed to evaluate MScanFit in measuring response to treatments.

Seeding Activity of Skin Misfolded Tau as a Biomarker for Tauopathies.

Background: Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically phosphorylated tau protein in the brain, leading to prion-like propagation and aggregation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking. Methods: We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls. Results: We found that the skin prion-SAA demonstrated a significantly higher sensitivity (75-80%) and specificity (95-100%) for detecting tauopathy, depending on the tau substrates used. Moreover, increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used. Conclusions: Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Skin nerve phosphorylated α-synuclein in the elderly.

To determine the incidence of phosphorylated α-synuclein (p-syn) in skin nerves in very old subjects who are prone to developing incidental Lewy bodies, we prospectively performed skin biopsies on 33 elderly subjects, including 13 (>85 years old) and 20 patients (>70 years) suspected of having an acquired small fiber neuropathy. All subjects underwent neurological examination prior to the biopsy. Two screened female subjects (ages 102 and 98 years) were excluded from the study because they showed evidence of a slight bradykinetic-rigid extrapyramidal disorder on neurological examination and were not considered healthy; both showed p-syn in skin nerves. We did not identify p-syn in skin nerves in the remaining 31 subjects. A PubMed analysis of publications from 2013 to 2023 disclosed 490 healthy subjects tested for skin p-syn; one study reported p-syn in 4 healthy subjects, but the remaining subjects tested negative. Our data underscore the virtual absence of p-syn in skin nerves of healthy controls, including those who are very elderly. These data support skin biopsy as a highly specific tool for identifying an underlying synucleinopathy in patients in vivo.

Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. METHODS: The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. RESULTS: Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. CONCLUSIONS: Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

Primary Lateral Sclerosis: An Overview.

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.

Progressive Ataxia and Palatal Tremor Is Not Associated with IgLON5 Antibodies: Results From Two Cases.

Progressive ataxia and palatal tremor (PAPT) and anti-IgLON5 disease share possible clinical presentations. Furthermore, both have been associated to a tauopathy mainly affecting the brainstem. Nonetheless, anti-IgLON5 antibodies have never been tested in PAPT. We report on two PAPT cases without evidence of anti-IgLON5 antibodies in both CSF and serum. Despite common clinical and pathological characteristics, PAPT and IgLON5 disease are two distinct entities.

Proposal of a new clinical protocol for evaluating fatigability in adult SMA patients.

Objective: Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disease affecting the lower motor neuron, carrying a significant burden on patients' general motor skills and quality of life, characterized by a great variability in phenotypic expression. As new therapeutic options make their appearance on the scene, sensitive clinical tools and outcome measures are needed, especially in adult patients undergoing treatment, in which the expected clinical response is a mild improvement or stabilization of disease progression. Methods: Here, we describe a new functional motor scale specifically designed for evaluating the endurance dimension for the upper and lower limbs in adult SMA patients. Results: The scale was first tested in eight control healthy subjects and then validated in ten adult SMA patients, proving intra- and inter-observer reliability. We also set up an evaluation protocol by using wearable devices including surface EMG and accelerometer. Conclusions: The endurance evaluation should integrate the standard clinical monitoring in the management and follow-up of SMA adult patients.

The genetic puzzle of a SOD1-patient with ocular ptosis and a motor neuron disease: a case report.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex genetic architecture, showing monogenic, oligogenic, and polygenic inheritance. In this study, we describe the case of a 71 years-old man diagnosed with ALS with atypical clinical features consisting in progressive ocular ptosis and sensorineural deafness. Genetic analyses revealed two heterozygous variants, in the SOD1 (OMIM*147450) and the TBK1 (OMIM*604834) genes respectively, and furthermore mitochondrial DNA (mtDNA) sequencing identified the homoplasmic m.14484T>C variant usually associated with Leber's Hereditary Optic Neuropathy (LHON). We discuss how all these variants may synergically impinge on mitochondrial function, possibly contributing to the pathogenic mechanisms which might ultimately lead to the neurodegenerative process, shaping the clinical ALS phenotype enriched by adjunctive clinical features.

Bibrachial amyotrophy as a rare manifestation of intraspinal fluid collection: a case report and systematic review.

INTRODUCTION: Intraspinal cerebrospinal fluid (CSF) collection has been reported as a rare cause of lower motor neuron (LMN) disorder. We report a case of bibrachial diplegia associated with intraspinal CSF collection and perform a systematic literature review. PATIENT AND METHODS: A 52-year-old man developed a bibrachial amyotrophy over 6 years, confirmed by the presence of cervical subacute neurogenic changes at electromyography (EMG). Brain magnetic resonance imaging (MRI) revealed cerebral siderosis, while spine MRI showed a ventral longitudinal intraspinal fluid collection (VLISFC) from C2 to L2. No CSF leakage was localized at myelography; a conservative treatment was chosen. We searched for all published cases until 30th April 2023 and extrapolated data of 44 patients reported in 27 publications. RESULTS: We observed a male predominance, a younger disease onset compared to amyotrophic lateral sclerosis, and a quite long disease duration, highlighting a slow disease progression. LMN signs were more frequently bilateral, mostly involving C5-C6 myotomes. Around 61% of patients presented additional symptoms, but only three referred to a history of headache. Accordingly, CSF opening pressure was mostly normal. Spinal MRI revealed the presence of VLISFC and in some cases myelomalacia. EMG patterns displayed both chronic and subacute neurogenic change in the cervical region. The disease course mainly depended on the treatment choice, which was mostly represented by a surgical approach when a specific dural defect was detected by imaging. CONCLUSION: Bibrachial diplegia due to VLISFC can be a treatable cause of focal amyotrophy and presents some clinical and radiological "red flags" which cannot be missed by a clinical neurologist.

Respiratory function in a large cohort of treatment-naïve adult spinal muscular atrophy patients: a cross-sectional study.

Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72). Fifty-six (37 %) and 41 (31 %) patients had abnormal (<80 %) values of FVC and FEV1, respectively. Fourteen (14 %) patients needed NIV, started at median age of 21 (range 4-68). Motor function, measured by Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module as well as SMA2, loss of walking ability, surgery for scoliosis, use of NIV, and cough assisting device (CAD) were all significantly associated to lower FVC and FEV1 values, while no association with age at baseline, disease duration, gender or 6 min walking test was observed, except for a correlation between FVC and age in SMA3 walkers (p < 0.05). In conclusion, respiratory function in adult SMA patients is relatively frequently impaired, substantially stable, and significantly correlated with motor function and disease severity.

Amyloid-Beta Co-Pathology Is a Major Determinant of the Elevated Plasma GFAP Values in Amyotrophic Lateral Sclerosis.

Recent studies reported increased plasma glial acidic fibrillary protein (GFAP) levels in amyotrophic lateral sclerosis (ALS) patients compared to controls. We expanded these findings in a larger cohort, including 156 ALS patients and 48 controls, and investigated the associations of plasma GFAP with clinical variables and other biofluid biomarkers. Plasma GFAP and Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers were assessed by the single molecule array and the Lumipulse platforms, respectively. In ALS patients, plasma GFAP was higher than in controls (p < 0.001) and associated with measures of cognitive decline. Twenty ALS patients (12.8%) showed a positive amyloid status (A+), of which nine also exhibited tau pathology (A+T+, namely ALS-AD). ALS-AD patients showed higher plasma GFAP than A- ALS participants (p < 0.001) and controls (p < 0.001), whereas the comparison between A- ALS and controls missed statistical significance (p = 0.07). Plasma GFAP distinguished ALS-AD subjects more accurately (area under the curve (AUC) 0.932 ± 0.027) than plasma p-tau181 (AUC 0.692 ± 0.058, p < 0.0001) and plasma neurofilament light chain protein (AUC, 0.548 ± 0.088, p < 0.0001). Cognitive measures differed between ALS-AD and other ALS patients. AD co-pathology deeply affects plasma GFAP values in ALS patients. Plasma GFAP is an accurate biomarker for identifying AD co-pathology in ALS, which can influence the cognitive phenotype.

Clinical and pathology characterization of small nerve fiber neuro(no)pathy in cerebellar ataxia with neuropathy and vestibular areflexia syndrome.

BACKGROUND AND PURPOSE: Biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages. METHODS: RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs). RESULTS: Forty patients, median age at onset 54 years (interquartile range [IQR] 49-61) and disease duration 10 years (IQR 6-16), were enrolled. Mild-to-moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5-22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7-44.3) were frequently reported and showed scarce correlation with disease duration. A non-length-dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5, p < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1, p < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. CONCLUSIONS: RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.

Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance.

RATIONALE & OBJECTIVE: Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex. STUDY DESIGN: Single-center, case series. SETTING & PARTICIPANTS: Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System. OBSERVATIONS: Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age. LIMITATIONS: Retrospective design and inclusion of outpatients partially based on family pedigree. CONCLUSIONS: In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management.

Italian good practice recommendations on management of persons with Long-COVID.

A significant number of people, following acute SARS-CoV-2 infection, report persistent symptoms or new symptoms that are sustained over time, often affecting different body systems. This condition, commonly referred to as Long-COVID, requires a complex clinical management. In Italy new health facilities specifically dedicated to the diagnosis and care of Long-COVID were implemented. However, the activity of these clinical centers is highly heterogeneous, with wide variation in the type of services provided, specialistic expertise and, ultimately, in the clinical care provided. Recommendations for a uniform management of Long-COVID were therefore needed. Professionals from different disciplines (including general practitioners, specialists in respiratory diseases, infectious diseases, internal medicine, geriatrics, cardiology, neurology, pediatrics, and odontostomatology) were invited to participate, together with a patient representative, in a multidisciplinary Panel appointed to draft Good Practices on clinical management of Long-COVID. The Panel, after extensive literature review, issued recommendations on 3 thematic areas: access to Long-COVID services, clinical evaluation, and organization of the services. The Panel highlighted the importance of providing integrated multidisciplinary care in the management of patients after SARS-CoV-2 infection, and agreed that a multidisciplinary service, one-stop clinic approach could avoid multiple referrals and reduce the number of appointments. In areas where multidisciplinary services are not available, services may be provided through integrated and coordinated primary, community, rehabilitation and mental health services. Management should be adapted according to the patient's needs and should promptly address possible life-threatening complications. The present recommendations could provide guidance and support in standardizing the care provided to Long-COVID patients.