Upper Motor Neuron Research Articles

Upper motor neuron assessment in amyotrophic lateral sclerosis using the patellar tendon reflex and motor-evoked potentials to the lower limbs

Amyotrophic lateral sclerosis (ALS) diagnosis relies on signs of progressive damage to both lower motoneuron (LMN), given by clinical examination and electromyography (EMG), and upper motoneuron (UMN), given by clinical examination only. Recognition of UMN involvement, however, is still difficult, so that diagnostic delay often remains too long. Shortening the time to clinical and genetic diagnosis is essential in order to provide accurate information to patients and families, avoid time-consuming investigations and for appropriate care management. This study investigates whether combined patellar tendon reflex recording with motor-evoked potentials to the lower limbs (T-MEP-LL) is relevant to assess corticospinal function in ALS, so that it might serve as a tool improving diagnosis. T-MEP-LL were recorded in 135 patients with suspected motor neuron disease (MND) from February 2010 to March 2021. The sensitivity, specificity, and ability to improve diagnosis when added to Awaji and Gold Coast criteria were determined. The main finding of the study is that T-MEP-LL can detect UMN dysfunction with a 70% sensitivity and 63% specificity when UMN clinical signs are lacking. The sensitivity reaches 82% when considering all MND patients. Moreover, at first evaluation, using T-MEP-LL to quantify reflex briskness and to measure central conduction time, can improve the diagnostic accuracy. T-MEP-LL is easy to perform and does not need any electrical stimulation, making the test rapid, and painless. By the simultaneous quantification of both UMN and LMN system, it could also help to identify different phenotype with more accuracy than clinical examination in this broad-spectrum pathology. The question whether T-MEP-LL could further be a real biomarker need further prospective studies.

Are tactile function and body awareness of the foot related to motor outcomes in children with upper motor neuron lesions?

Somatosensory function can be reduced in children with Upper Motor Neuron (UMN) lesions. Therefore, we investigated relationships between somatosensory functions of the foot and motor outcomes in children with UMN lesions. In this cross-sectional study, we assessed the Tactile Threshold (TT) with monofilaments and body awareness with Tactile Localisation Tasks for spatial-related action (TLTaction) and structural-related perception (TLTperception) body representation at the foot sole. Furthermore, we assessed four motor outcomes: the Selective Control Assessment of the Lower Extremity (SCALE), the modified Timed Up and Go test (mTUG), the Gillette Functional Assessment Questionnaire (FAQ), and the Functional Mobility Scale (FMS). Spearman's correlations (ρ) were applied to assess relationships between the somatosensory function of the foot sole and the applied motor outcomes. Thirty-five children with UMN lesions, on average 11.7 ± 3.4 years old, participated. TLTperception correlated significantly with all lower limb motor outcomes (|ρ|=0.36-0.57; p < 0.05), but TLTaction (|ρ|=0.00-0.27; p = 0.15-0.97, and TT did not (|ρ|=0.01-0.83; p = 0.73-0.94). TLTperception correlated strongly with the Gross Motor Function Classification System (|ρ|=0.62; p = 0.001) in children with cerebral palsy (n = 24). Assessing structural body representation of the foot sole should be considered when addressing lower limb motor impairments, including gait, in children with upper motor neuron lesions. Our results suggest that the assessment of tactile function and spatial body representation may be less related to lower limb motor function.

Differing patterns of cortical grey matter pathology identified by multifractal analysis in UMN-predominant ALS patients with and without corticospinal tract hyperintensity

The pathological hallmarks of amyotrophic lateral sclerosis (ALS) are degeneration of the primary motor cortex grey matter (GM) and corticospinal tract (CST) resulting in upper motor neuron (UMN) dysfunction. Conventional brain magnetic resonance imaging (MRI) shows abnormal CST hyperintensity in some UMN-predominant ALS patients (ALS-CST+) but not in others (ALS-CST–). In addition to the CST differences, we aimed to determine whether GM degeneration differs between ALS-CST+ and ALS-CST– patients by cortical thickness (CT), voxel-based morphometry (VBM) and fractal dimension analyses. We hypothesized that MRI multifractal (MF) measures could differentiate between neurologic controls (n = 14) and UMN-predominant ALS patients as well as between patient subgroups (ALS-CST+, n = 21 vs ALS-CST–, n = 27). No significant differences were observed in CT or GM VBM in any brain regions between patients and controls or between ALS subgroups. MF analyses were performed separately on GM of the whole brain, of frontal, parietal, occipital, and temporal lobes as well as of cerebellum. Estimating MF measures D (Q = 0), D (Q = 1), D (Q = 2), Δf, Δα of frontal lobe GM classified neurologic controls, ALS-CST+ and ALS-CST– groups with 98% accuracy and > 95% in F1, recall, precision and specificity scores. Classification accuracy was only 74% when using whole brain MF measures and < 70% for other brain lobes. We demonstrate that MF analysis can distinguish UMN-predominant ALS subgroups based on GM changes, which the more commonly used quantitative approaches of CT and VBM cannot.

A scoping review on muscle cramps and spasms in upper motor neuron disorder-two sides of the same coin?

Muscle cramps are typically regarded as benign muscle overactivity in healthy individuals, whereas spasms are linked to spasticity resulting from central motor lesions. However, their striking similarities made us hypothesize that cramping is an under-recognized and potentially misidentified aspect of spasticity. A systematic search on spasms and cramps in patients with Upper Motor Neuron Disorder (spinal cord injury, cerebral palsy, traumatic brain injury, and stroke) was carried out in Embase/Medline, aiming to describe the definitions, characteristics, and measures of spasms and cramps that are used in the scientific literature. The search identified 4,202 studies, of which 253 were reviewed: 217 studies documented only muscle spasms, 7 studies reported only cramps, and 29 encompassed both. Most studies (n = 216) lacked explicit definitions for either term. One-half omitted any description and when present, the clinical resemblance was significant. Various methods quantified cramp/spasm frequency, with self-reports being the most common approach. Muscle cramps and spasms probably represent related symptoms with a shared pathophysiological component. When considering future treatment strategies, it is important to recognize that part of the patient's spasms may be attributed to cramps.

Боковой амиотрофический склероз: клинико-эпидемиологические особенности: клинический случай

ABSTRACT INTRODUCTION. Amyotrophic lateral sclerosis is a disease of the central nervous system, characterized by a steadily progressive course with selective damage to the upper and lower motor neurons. AIM. Conduct an analysis of literary sources of domestic and foreign authors describing the modern understanding of methods of diagnosis and treatment of amyotrophic lateral sclerosis. Present a clinical case of a patient with amyotrophic lateral sclerosis. MATERIAL AND METHODS. An analysis of the literature was carried out for the period from 2013–2023. Sources from the Russian scientific electronic library eLIBRARY, RSCI databases, and PubMed were used. A clinical case is presented. RESULTS AND DISCUSSION. The article presents clinical and epidemiological features, diagnostic methods, modern achievements and promising directions in the treatment of the disease. CASE PRESENTATION. Patient N., 60 years old, was admitted to the neurological department of a multidisciplinary hospital with complaints of weakness in the upper extremities, more in the distal parts, impaired fine motor skills, impaired articulation, general weakness, and fatigue. Considers himself sick for a year, when complaints of blurred speech and weakness in the hands first appeared. Needle electromyography — signs of morphofunctional reorganization of motor units associated with damage to motor neurons. Based on clinical data and the results of additional examination methods, a clinical diagnosis was established — motor neuron disease, amyotrophic lateral sclerosis, bulbospinal form, bulbar disorder syndrome, upper paraparesis with impaired selfcare. The features of the presented clinical example are the rapid rate of progression of the disease, as well as the importance of risk factors in the development of the disease. As is known from the family history, the patient served in the missile forces for a long time. The problem of environmental safety still remains relevant. Falling separated parts of launch vehicles have a detrimental effect not only on the environment, but also on the human body. CONCLUSION. Identification of risk factors is an important task necessary for the early detection of electromyography, as well as the possibility of taking preventive measures that can lead to a significant reduction in morbidity and mortality. KEYWORDS: amyotrophic lateral sclerosis, motor neuron disease, diagnosis, therapy, SOD1 gene

IMU-Based Approach to Detect Spastic Cerebral Palsy in Infants at Early Stages

INTRODUCTION: Cerebral Palsy (CP) is a non-progressive neurological disorder affecting muscle control in early childhood, leading to permanent alterations in body posture and movement. Early identification is crucial for accurate diagnosis and therapy-based interventions. In recent years, an automated monitoring system has been developed to facilitate the health assessment of infants, enabling early recognition of neurological dysfunctions in high-risk infants. However, the interpretation of these assessments lacks standardization and is subject to examiner bias.&#x0D; OBJECTIVES: Many infants with CP exhibit increased tonic stretch reflexes due to Upper Motor Neuron Syndrome (UMNS), resulting from motor neuron damage that disrupts muscle signalling.&#x0D; METHOD: To detect abnormal muscle reactions, our team employed an Inertial Measurement Unit (IMU) sensor, comprising three tri-axial sensors (accelerometer, gyroscope, magnetometer) that capture movement data continuously and unobtrusively. IMU sensors are compact, cost-effective, and have low processing requirements, requiring attachment to the infant's body to measure inter-body part angles. Our team analyzed muscle activity and posture using IMU sensors, collecting tri-axial data from 43 infants in real-time. Additional factors like age, stride length, and leg length were incorporated into the dataset.&#x0D; RESULTS: Our team has applied various supervised machine learning approaches to predict CP in infants due to the limited dataset size, validating models through k-fold cross-validation. Among the models, Naive Bayes (NB) outperformed Logistic Regression (LR), Decision Tree (DT), Linear Discriminant Analysis (LDA), k-Nearest Neighbors (kNN), and Support Vector Machine (SVM), achieving an accuracy of 88%. CONCLUSION: This research contributes to the early detection and intervention of CP in infants, potentially improving their long-term outcomes.

Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants in a series of Italian patients, shedding light upon genetic and phenotypic variability

IntroductionHereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype. This speculation suggests that a wider range of HSP genes could be linked to various inheritance patterns.Purpose and backgroundWith documented cases of HSP loci exhibiting both dominant and recessive patterns, this study emphasizes that the concept of zygosity is no longer a limiting factor in the establishment of molecular diagnoses for HSP. Recent cases have demonstrated phenoconversion in SPG18, from HSP to an amyotrophic lateral sclerosis (ALS)-like syndrome.Methods and resultsThis report highlights two cases out of five exhibiting HSP-ALS phenoconversion, discussing an observed prevalence in autosomal dominant SPG18. Additionally, the study emphasizes the relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases. This mutation appears to be particularly common in cases of HSPALS phenoconversion, indicating its potential role as a hotspot for a distinctive SPG18 phenotype with an ALS-like syndrome.ConclusionsClinicians need to be aware that patients with HSP may show ALS signs and symptoms. On the other hand, HSP panels must be included in genetic testing methods for instances of familial ALS.

Combined Hyperselective Neurectomy and Fractional Lengthening Technique for Triceps Spasticity.

Triceps spasticity can occur in patients with upper motor neuron syndrome. It is often undetected when there is predominant elbow flexion spasticity and/or contracture. This condition can become apparent after surgery for elbow flexor spasticity, leading to impaired active elbow. Although triceps muscle-tendon lengthening procedures can be performed, these techniques do not directly address the issue of spasticity which is neurally mediated. This article presents a surgical technique for addressing triceps spasticity with a combined approach of hyperselective neurectomy of the medial head of the triceps and muscle-tendon lengthening of the long and lateral heads.

Tactile stimulation of the perigenital region during manual bladder expression improved the urine stream in cats affected by upper motor neuron injury.

The aim of the study was to evaluate whether the tactile stimulation of the perigenital region together with manual bladder expression (MBE) facilitated the urine stream in cats with acute or chronic upper motor neuron injury (UMNI). 34 cats with UMNI having urinary retention. All the cats had a complete neurologic examination, which determined the localization of the UMNI between T3 and L3. They were classified as chronic UMNI if the injury had occurred more than 3 days previously. The cats were divided equally into 2 groups: the M group (n = 17) managed with only MBE, and the MT group (17) managed with MBE and tactile stimulation. In both groups, all the cats affected by chronic UMNI resumed urination. The time required to obtain a urine stream in the chronic UMNI was 9.3 seconds in the M group and 3.1 seconds in the MT group (P < .05). In the cats affected by acute UMNI, a urine stream was achieved in 54% of the M group and 100% of the MT group (P < .05). The time to obtain a urine stream in the acute UMNI cats was 7.8 seconds in the M group and 3.75 seconds in the MT group (P < .05). Adding tactile stimulation of the perigenital region to the MBE improved the urine stream in cats affected by UMNI.

The usage and advantages of several common amyotrophic lateral sclerosis animal models.

Amyotrophic lateral sclerosis is a fatal, multigenic, multifactorial neurodegenerative disease characterized by upper and lower motor neuron loss. Animal models are essential for investigating pathogenesis and reflecting clinical manifestations, particularly in developing reasonable prevention and therapeutic methods for human diseases. Over the decades, researchers have established a host of different animal models in order to dissect amyotrophic lateral sclerosis (ALS), such as yeast, worms, flies, zebrafish, mice, rats, pigs, dogs, and more recently, non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms of motor neuron degeneration in ALS, contributing to the development of new promising therapeutics. In this review, we describe several common animal models in ALS, classified by the naturally occurring and experimentally induced, pointing out their features in modeling, the onset and progression of the pathology, and their specific pathological hallmarks. Moreover, we highlight the pros and cons aimed at helping the researcher select the most appropriate among those common experimental animal models when designing a preclinical ALS study.

How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that, at present, has no effective cure. Evidence of increased circulating glutamate and hyperexcitability of the motor cortex in patients with amyotrophic lateral sclerosis have provided an empirical support base for the 'dying forward' excitotoxicity hypothesis. The hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. Many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not all are effective. As such, there is a growing tension between the rising tide of evidence for the 'dying forward' excitotoxicity hypothesis and the failure of therapies that target neuronal activation. One possible solution to these contradictory outcomes is that our interpretation of the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays we use to study it. In this review we provide an evaluation of evidence relevant to the 'dying forward' excitotoxicity hypothesis and by doing so, identify key gaps in our knowledge that need to be addressed. We hope to provide a road map from hyperexcitability to excitotoxicity so that we can better develop therapies for patients suffering from amyotrophic lateral sclerosis. We conclude that studies of upper motor neuron activity and their synaptic output will play a decisive role in the future of amyotrophic lateral sclerosis therapy.

Current potential pathogenic mechanisms of copper-zinc superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which damages upper and lower motor neurons (UMN and LMN) innervating the muscles of the trunk, extremities, head, neck and face in cerebrum, brain stem and spinal cord, which results in the progressive weakness, atrophy and fasciculation of muscle innervated by the related UMN and LMN, accompanying with the pathological signs leaded by the cortical spinal lateral tract lesion. The pathogenesis about ALS is not fully understood, and no specific drugs are available to cure and prevent the progression of this disease at present. In this review, we reviewed the structure and associated functions of copper-zinc superoxide dismutase 1 (SOD1), discuss why SOD1 is crucial to the pathogenesis of ALS, and outline the pathogenic mechanisms of SOD1 in ALS that have been identified at recent years, including glutamate-related excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, axonal transport disruption, prion-like propagation, and the non-cytologic toxicity of glial cells. This review will help us to deeply understand the current progression in this field of SOD1 pathogenic mechanisms in ALS.

Case Report: Comprehensive management of Bulbar Motor Neuron disease in an elderly male: A Multidisciplinary case report approaching the treatment

Abstract* Bulbar Motor Neuron Disease (MND), a specific form of amyotrophic lateral sclerosis (ALS) primarily affecting the upper and lower motor neurons in the brainstem’s bulbar region, presents a significant challenge in clinical management. This case report delves into the clinical presentation and management of an 85-year-old male patient with typical symptoms, such as left-sided weakness, dysphagia, and dysarthria, along with a history of aphasia and hypertension, underlining the complexities associated with diagnosing and managing this condition. Methods: The patient underwent a thorough clinical examination, diagnostic investigations, and imaging, leading to a confirmed diagnosis of bulbar MND. Multidisciplinary interventions were employed to addressed the diverse symptoms, including compensation therapy, swallowing function training, physiotherapy, bolus modification, behavioral adjustments, oromotor exercises, postural corrections, and sensory and neurophysiologic stimulation to enhance swallowing safety and comfort. Additionally, interventions for dysarthria and left-sided weakness encompassed speech rate control, strength training, and the use of augmentative communication aids. Results: Over a 30-day follow-up period, the patient showed improvements in dysphagia, dysarthria, and activities of daily living. The treatment strategies effectively addressed the specific challenges associated with bulbar MND, focusing on enhancing the patient’s quality of life and functional abilities. Conclusions: This case report underscores the need for a comprehensive, multidisciplinary approach to manage bulbar MND. It highlights the complexities of diagnosing and addressing the diverse symptoms and difficulties that patients with this condition encounter, emphasizing the importance of a holistic and individualized therapeutic strategy.

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as “TDP-43 proteinopathies”. Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.

MILLER FISHER SYNDROME: A RARE BENIGN VARIANT OF GUILLAIN- BARRE SYNDROME

Abstract&#x0D; Introduction : Guillain-Barré Syndrome (GBS) is a broad category of syndromes that includes several types of acute immune-mediated polyneuropathy. Miller Fisher Syndrome (MFS) is a scarce variant of GBS (1-2:1,000,000) that presents at least 2 of ataxia, areflexia, and ophthalmoplegia.&#x0D; Case Illustration : A 32 years-old-man came to JEC-Candi with ophthalmic discomfort and exhibited a week onset of total ophthalmoplegia, ptosis, diplopia, and lagophthalmos. Two weeks backward, the patient had a respiratory infection then emerged symmetrical sensory abnormalities (glove-and-stocking-type pinprick sensations in distal extremities). Neurological examinations were performed, and the patient got multiple cranial nerve weaknesses (oculomotor, trochlear, abducens, trigeminal, and facial) both in motoric and sensory, ataxia (positive Romberg sign, stepping test, gait, shallow-knee- bend), and negative pathologic reflexes. Hematology showed leukocytosis, MRI and CT-Scan were normal. Pulse therapy was given (Methylprednisolone 1g/day) for three days, neuroprotector and artificial tears added. Ataxia and diplopia improved, then the patient was referred to Kariadi Hospital for five-times plasmapheresis that involved neurologist and internist. Ophthalmoplegia improved slowly, and lagophthalmos disappeared one month after hospital admission.&#x0D; Discussion : GBS subvariant could overlap; this case presents bifacial weakness with paresthesia and MFS. Viral infection precedes neurological symptoms in most cases, with an average of 10 days of the incubation period. Ataxia, diplopia, and ophthalmoplegia may confuse the physician and presume an upper motor neuron sign or central cause. Steroid and plasmapheresis evince meaningful upturn.&#x0D; Conclusion : This rare disease requires a multidisciplinary approach to cure and diagnose. Nonetheless, MFS has a good prognosis. Appropriate treatment selection will enhance patients' quality of life.

Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature.

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations. About thirty families have been described worldwide, with different phenotypes like complicated HSP, recessive cerebellar ataxia or Marinesco-Sjögren Syndrome. Herein, we report five SPG46 patients harbouring five novel GBA2 mutations, the largest series described in Italy so far. Probands were enrolled in five different centres and underwent neurological examination, clinical cognitive assessment, column imaging for scoliosis assessment, ophthalmologic examination, brain imaging, GBA2 activity in peripheral blood cells and genetic testing. Their phenotype was consistent with HSP, with notable features like upper gaze palsy and movement disorders. We review demographic, genetic, biochemical and clinical information from all documented cases in the existing literature, focusing on the global distribution of cases, the features of the syndrome, its variable presentation, new potential identifying features and the significance of measuring GBA2 enzyme activity.

Electromyographic findings directing the diagnosis of an upper motor neuron lesion of the hypoglossal nerve

A 45-year-old woman presented with a subacute, intermittent deviation of the tongue to the right side, and dysarthria. Symptoms worsen and become more evident when the patient attempts to speak for a prolonged period of time. Neurological examination

Clinical features and molecular genetic investigation of infantile-onset ascending hereditary spastic paralysis (IAHSP) in two Chinese siblings caused by a novel splice site ALS2 variation

ObjectiveALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts, among which autosomal recessive Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare phenotype. In this study, we gathered clinical data from two Chinese siblings who were affected by IAHSP. Our aim was to assess the potential pathogenicity of the identified variants and analyze their clinical and genetic characteristics.MethodHere, Whole-exome sequencing (WES) was performed on proband to identify the candidate variants. Subsequently, Sanger sequencing was used to verify identified candidate variants and to assess co-segregation among available family members. Utilizing both silico prediction and 3D protein modeling, an analysis was conducted to evaluate the potential functional implications of the variants on the encoded protein, and minigene assays were performed to unravel the effect of the variants on the cleavage of pre-mRNA.ResultsBoth patients were characterized by slurred speech, astasia, inability to walk, scoliosis, lower limb hypertonia, ankle clonus, contracture of joint, foot pronation and no psychomotor retardation was found. Genetic analysis revealed a novel homozygous variant of ALS2, c.1815G > T(p.Lys605Asn) in two Chinese siblings. To our knowledge, it is the first confirmed case of a likely pathogenic variant leading to IAHSP in a Chinese patient.ConclusionThis study broadens the range of ALS2 variants and has practical implications for prenatal and postnatal screening of IAHSR. Symptom-based diagnosis of IAHSP is frequently difficult for medical practitioners. WES can be a beneficial resource to identify a particular disorder when the diagnosis cannot be determined from the symptoms alone.

Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.

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.