Early-onset motor polyneuropathy associated with a novel dominant NAGLU mutation.

INTRODUCTION: NAGLU encodes N-acetyl-alpha-glucosaminidase, an enzyme that degrades heparan sulfate. Biallelic NAGLU mutations cause mucopolysaccharidosis IIIB, a severe childhood-onset neurodegenerative disease, while monoallelic mutations are associated to late-onset, dominantly inherited painful sensory neuropathy. However, to date, only one family with a dominant NAGLU-related neuropathy has been described. CASE REPORT: Here we describe a patient with early-onset motor polyneuropathy harboring a novel monoallelic NAGLU mutation. We found reduced NAGLU enzymatic activity thus corroborating the pathogenic role of the new variant. DISCUSSION: Our report represents the second ever described case with dominant NAGLU-related neuropathy and the first case with early-onset motor symptoms. We underlie the importance of a thorough clinical description of this probably underestimated new clinical entity.

FOLR1 Gene Variation With Adult-Onset Cerebral Folate Deficiency and Stable Clinical and MRI Features up to 2 Years.

Objectives: The objective of this case report was to describe the first report of FOLR1 variants associated with adult-onset paucisymptomatic leukoencephalopathy associated with cerebral folate deficiency (CFD). Methods: Considering the patient's symptoms, a nonprogressive leukoencephalopathy was suspected. CSF 5-methyltetrahydrofolate levels were low (10 nmol/L, normal range 41-117). With no other identifiable causes, a genetic analysis was conducted, revealing a compound heterozygous FOLR1 variation (c.45G>T and c. 493+2T>C). Results: A 47-year-old man with a history of drug and alcohol abuse was admitted to the hospital for double vision and postural instability. MRI of the brain was performed, which showed bilateral leukoencephalopathy. Diffusion tensor imaging revealed a diffuse reduction in fractional anisotropy, suggesting microstructural changes. MRI of the brain and overall clinical picture were stable on subsequent serial examinations. Discussion: Scientific evidence supports the deleterious effect of c.45G>T and c.493+2T>C variations on the folate receptor-α (FRα) protein structure and function. The weakness of the expression and function of FRα without elimination of its function caused by specific compound heterozygous variations may explain the atypical features observed in our patient. Although rare, CFD should be considered in paucisymptomatic adult patients with stable diffuse MRI white matter changes.

Diagnosis, treatment, and follow-up of patients with cerebral amyloid angiopathy-related inflammation.

PURPOSE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare potentially reversible encephalopathy associated with an autoimmune process against proteins deposited in the walls of cortical and leptomeningeal brain vessels. Definite diagnosis requires histopathological features of vascular inflammation and amyloid deposition from brain biopsy. Clinical-neuroradiological criteria have been recently introduced and validated to reduce the need for biopsy. The purpose of this paper is to report a historical retrospective review of clinical-neuroradiological follow-up of two patients with probable CAA-ri and five patients with a reasonably probable suspect of CAA-ri (4 females, 3 males, patient's age at admission: 66-79 years) seen at our institution between 2007 and 2021, focusing on clinical and neuroradiological awareness to this entity and variable response to immunotherapy. MATERIALS AND METHODS: Clinical features at presentation included subacute to acute confusion (6/7), seizures (4/7), cognitive impairment (5/7), and focal neurological signs (3/7). Neuroradiology included braincomputed tomography followed by magnetic resonance imaging. Infectious diseases and autoimmune workups were then performed. RESULTS: CSF analysis was performed in two patients. Cerebral angiography was performed in two patients, to rule out vascular malformations. Hemorrhagic posterior reversible encephalopathy syndrome has been suspected in two patients. Four patients underwent immunotherapy with corticosteroids followed by reduction of brain dysfunctions. Three patients did not undergo immunotherapy but underwent clinical and/or neuroradiological remission. CONCLUSIONS: Patients with CAA-ri present a rare steroid-responsive acute to subacute brain dysfunction. Thus, it has to be known and recognized both clinically and neuroradiologically. Spontaneous clinical and/or neuroradiological improvement is possible in patients with mild symptoms.

Clinical Features and Outcome of the Guillain-Barre Syndrome: A Single-Center 11-Year Experience.

Background: Clinical presentation, electrophysiological subtype, and outcome of the Guillain-Barre' Syndrome (GBS) may differ between patients from different geographical regions. This study aims to assess clinical-neurophysiological features of an adult, Italian GBS cohort over 11 years. Methods: Retrospective (from 1 January 2011 to 31 December 2021) analysis was carried out on patients admitted to the Siena University Hospital who fulfilled the GBS diagnostic criteria. Demographic data, clinical characteristics, treatment, need of mechanical ventilation (MV), laboratory and electrophysiological tests, preceding infections/vaccination/other conditions, and comorbidities were collected for each patient. Results: A total of 84 patients (51 men, median age of 61 years), were identified. GBS subtype was classified as acute inflammatory demyelinating polyneuropathy (AIDP) in the 66.6% of patients, acute motor/sensory axonal neuropathy (AMAN/AMSAN) in 20.2%, and the Miller Fisher syndrome in 5 (5.9%). Flu syndrome and gastrointestinal infection were the most common preceding conditions. In total, five (5.9%) subjects had concomitant cytomegalovirus (CMV) infection. Cranial nerve involvement occurred in 34.5% of subjects. Differences between the axonal and AIDP forms of GBS concerned the presence of anti-ganglioside antibodies. In total, seven (8.33%) patients required MV. Discussion: The epidemiological and clinical characteristics of GBS in different countries are constantly evolving, especially in relation to environmental changes. This study provides updated clinical-epidemiological information in an Italian cohort.

A case of spastic paraplegia type 11 mimicking a GM2-gangliosidosis.

INTRODUCTION: Spastic paraplegia type 11 (SPG11) is the most frequent autosomal recessive HSP. Studies on SPG11 patients' fibroblasts, post-mortem brains, and mouse models revealed endolysosomal system dysfunction and lipid accumulation, especially gangliosides. We report a patient with early clinical findings mimicking a GM2-gangliosidosis. METHODS: A clinical, biochemical, and metabolic characterization was performed. Electron microscopy analysis was completed on rectal mucosa and skin biopsy specimens. A NGS panel of genes associated to neuronal ceroid lipofuscinosis and HSP was analyzed. RESULTS: The patient presented with worsening walking difficulty and psychomotor slowdown since childhood; to exclude a neurometabolic storage disease, skin and rectal biopsies were performed: enteric neurons showed lipofuscin-like intracellular inclusions, thus suggesting a possible GM2-gangliosidosis. However, further analysis did not allow to confirm such hypothesis. In adulthood we detected flaccid paraplegia, nystagmus, axonal motor neuropathy, carpus callosum atrophy, and colon atony. Surprisingly, the NGS panel detected two already reported SPG11 mutations in compound heterozygosity. CONCLUSIONS: We describe for the first time pathological hallmarks of SPG11 in enteric neuron from a rectal mucosa biopsy. The report illustrates the possible overlap between SPG11 and GM2-gangliosidosis, especially in the first disease phases and helps to improve our knowledge about SPG11 physiopathology.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Changes in corticomotor pathway excitability after exercise training in Parkinson's disease.

BACKGROUND: Altered corticospinal excitability in Parkinson's disease (PD) is related to many of the motor signs. OBJECTIVE: We examined whether the recruitment properties of the corticospinal pathway to hand muscles are changed after 8 weeks of specialized upper limbs exercise in PD. METHODS: Seven PD subjects were enrolled. Upper limb exercise was achieved by using a specially designed device. The input-output (I-O) curves were obtained by transcranial magnetic stimulation (TMS). The conduction of peripheral axons and H reflex was also recorded. UPDRS scale, part-III motor examination was used to assess the motor symptom. Clinical and neurophysiological data were obtained before and after 2-month exercise training. RESULTS: After 2-month exercise training, the UPDRS score was significantly improved. Threshold, slope, and V50 (i.e., the stimulus intensity required to obtain a response 50% of the maximum) of the I-O curve were unchanged, whereas the plateau value was significantly higher. CONCLUSIONS: Exercise training affects the larger motoneurons, that is those activated at higher TMS stimulation intensity. These motoneurones are related to the large, type II motor units. Clinical improvement after exercise may depend upon restoration of the recruitment of the large motor unit, i.e., those necessary to perform rapid and strong movements, known to be deficient in PD.

Prevalence and impact of COVID-19 in Parkinson's disease: evidence from a multi-center survey in Tuscany region.

BACKGROUND: If Parkinson's Disease (PD) may represent a risk factor for Coronavirus disease 2019 (COVID-19) is debated and there are few data on the direct and indirect effects of this pandemic in PD patients. OBJECTIVE: In the current study we evaluated the prevalence, mortality and case-fatality of COVID-19 in a PD cohort, also exploring possible risk factors. We also aimed to investigate the effect of lockdown on motor/non-motor symptoms in PD patients as well as their acceptability/accessibility to telemedicine. METHOD: A case-controlled survey about COVID-19 and other clinical features in PD patients living in Tuscany was conducted. In non-COVID-19 PD patients motor/non-motor symptoms subjective worsening during the lockdown as well as feasibility of telemedicine were explored. RESULTS: Out of 740 PD patients interviewed, 7 (0.9%) were affected by COVID-19, with 0.13% mortality and 14% case-fatality. COVID-19 PD patients presented a higher presence of hypertension (p < 0.001) and diabetes (p = 0.049) compared to non-COVID-19. In non-COVID-19 PD population (n = 733) about 70% did not experience a subjective worsening of motor symptoms or mood, anxiety or insomnia. In our population 75.2% of patients was favorable to use technology to perform scheduled visits, however facilities for telemedicine were available only for 51.2% of cases. CONCLUSION: A higher prevalence of COVID-19 respect to prevalence in Tuscany and Italy was found in the PD population. Hypertension and diabetes, as for general population, were identified as risk factors for COVID-19 in PD. PD patients did not experience a subjective worsening of symptoms during lockdown period and they were also favorable to telemedicine, albeit we reported a reduced availability to perform it.

Neurophthalmologic and Orthoptic Ambulatory Assessments Reveal Ocular and Visual Changes in Patients With Early Alzheimer and Parkinson's Disease.

Patients with Alzheimer's disease (AD) and Parkinson's disease (PD) develop a progressive decline of visual function. This condition aggravates overall cognitive and motor abilities, is a risk factor for developing hallucinations, and can have a significant influence on general quality of life. Visual problems are common complaints of patients with PD and AD in the early stages of the disease, but they also occur during normal aging, making it difficult to differentiate between normal and pathological conditions. In this respect, their real incidence has remained largely underestimated, and no rehabilitative approaches have been standardized. With the aim to increase awareness for ocular and visual disorders, we collected the main neurophthalmologic and orthoptic parameters, including optical coherence tomography (OCT), in six patients with a diagnosis of PD, six patients with a diagnosis of early AD, and eight control subjects in an easily assessable outpatient setting. We also evaluated the patient's ability to recognize changes in facial expression. Our study demonstrates that visual problems, including blurred vision, diplopia, reading discomfort, photophobia, and glare, are commonly reported in patients with PD and AD. Moreover, abnormal eye alignment and vergence insufficiency were documented in all patients during examination. Despite the small size of the sample, we demonstrated greater ganglion cell and retinal nerve fibers layer (RNFL) damage and a defect of facial emotion recognition in AD/PD patients with respect to a comparable group of normal elderly persons, with peculiarities depending upon the disease. Ocular defects or visual discomfort could be correctly evaluated in these patients and possibly corrected by means of lens, orthoptic exercises, and visual rehabilitation. Such a practical approach may help to ameliorate motor autonomy, reading ability, and may also reduce the risk of falls, with a positive impact in daily living activities.

Eye movement changes in autosomal dominant spinocerebellar ataxias.

Oculomotor abnormalities are common findings in spinocerebellar ataxias (SCAs), a clinically heterogeneous group of neurodegenerative disorders with an autosomal dominant pattern of inheritance. Usually, cerebellar impairment accounts for most of the eye movement changes encountered; as the disease progresses, the involvement of extracerebellar structures typically seen in later stages may modify the oculomotor progression. However, ocular movement changes are rarely specific. In this regard, some important exceptions include the prominent slowing of horizontal eye movements in SCA2 and, to a lesser extent, in SCA3, SCA4, and SCA28, or the executive deficit in SCA2 and SCA17. Here, we report the eye movement abnormalities and neurological pictures of SCAs through a review of the literature. Genetic and neuropathological/neuroimaging aspects are also briefly discussed. Overall, the findings reported indicate that oculomotor analysis could be of help in differential diagnosis among SCAs and contribute to clarify the role of brain structures, particularly the cerebellum, in oculomotor control.

HTRA1 expression profile and activity on TGF-ß signaling in HTRA1 mutation carriers.

High temperature requirement A1 (HTRA1) is a serine protease playing a modulatory role in various cell processes, particularly in the regulation of transforming growth factor-ß (TGF-ß) signaling. A deleterious role in late-onset cerebral small vessel diseases (CSVDs) of heterozygous HTRA1 mutations, otherwise causative in homozygosity of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, was recently suggested. However, the pathomechanism of these heterozygous mutations is still undefined. Our aim is to evaluate the expression profile and activity of HTRA1 on TGF-ß signaling in fibroblasts from four subjects carrying the HTRA1 heterozygous mutations-p.E42Dfs*173, p.A321T, p.G295R, and p.Q151K. We found a 50% reduction of HTRA1 expression in HTRA1 mutation carriers compared to the control. Moreover, we showed no changes in TGF-ß signaling pathway downstream intermediate, Phospho Smad2/3. However, we found overexpression of genes involved in the extracellular matrix formation in two heterozygous HTRA1 carriers. Our results suggest that each heterozygous HTRA1 missense mutation displays a different and peculiar HTRA1 expression pattern and that CSVD phenotype may also result from 50% of HTRA1 expression.

Functional and Brain Activation Changes Following Specialized Upper-Limb Exercise in Parkinson's Disease.

For the management of Parkinson's disease (PD), the concept of forced exercise (FE) has drawn interest. In PD subjects, the FE executed with lower limbs has been shown to lessen symptoms and to promote brain adaptive changes. Our study is aimed to investigate the effect of an upper-limb exercise, conceptually comparable with the FE, in PD. Upper-limb exercise was achieved in a sitting position by using a specially designed device (Angel's Wings®). Clinical data, computerized dynamic posturography, magnetic resonance imaging (MRI) (resting-state MRI and arterial spin labeling), and neuropsychological tests were used before and after 2 months' exercise training. We found a significant long-lasting improvement in Unified Parkinson Disease Rating Scale (UPDRS)-III and cognitive scales, along with improvement in balance and postural control (better alignment of the gravity center and improvement in weight symmetry and in anticipatory motor strategies). Computerized dynamic posturography pointed out an enhanced central ability to integrate the vestibular signals with afferents from other sensory systems. Neuroimaging analyses after 2 months' exercise training showed, with respect to pretraining condition, many changes. An increase of the cerebral blood flow was evident in the left primary motor cortex (M1), left supplementary motor cortical area, and left cerebellar cortex. The bilateral globus pallidus showed an increased functional connectivity to the right central operculum, right posterior cingulate gyrus, and left sensorimotor cortex. Seed-to-voxel analysis demonstrated a functional connectivity between M1 and the left superior frontal gyrus. Left crus II showed strengthened connections with the left pre-rolandic area, left post-rolandic area, and left supramarginal area. These findings likely reflect compensatory mechanisms to the neuropathological hallmark of PD. Overall, our results show that this upper-limb exercise model, conceptually comparable with the FE already tested in the lower limbs, leads to a global improvement (involving non-exercised limbs) likely consistent with the functional changes observed in the central nervous system.

Next-generation sequencing approach to hyperCKemia: A 2-year cohort study.

OBJECTIVE: Next-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition. METHODS: Sixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies. RESULTS: A molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up. CONCLUSIONS: This study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.

Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study.

BACKGROUND: Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes. We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions. RESULTS: We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants. CONCLUSION: This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders.