Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations.

Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.

Primary lateral sclerosis: a distinct entity or part of the ALS spectrum?

Primary lateral sclerosis (PLS) has been traditionally viewed as a distinct upper motor neuron condition (UMN) but is increasingly regarded as a sub-phenotype within the amyotrophic lateral sclerosis (ALS) spectrum. Despite established diagnostic criteria, formal diagnosis can be challenging and the protracted diagnostic journey and uncertainty about longer-term prognosis cause considerable distress to patients and caregivers. PLS patients are invariably excluded from ALS clinical trials, while PLS pharmacological trials are lacking. There remains an unmet need for diagnostic biomarkers for upper motor neuron predominant conditions and prognostic indicators regarding prognosis, survival, and risk of conversion to ALS. Validated biomarkers will not only have implications for individualized patient care but also serve as outcome measures in pharmaceutical trials. Given the paucity of post-mortem studies in PLS, novel pathological insights are generally inferred from state-of-the-art imaging studies. Computational neuroimaging has already contributed significantly to the characterization of PLS-associated pathology in vivo and has underscored the role of neuro-inflammation, the presence of extra-motor changes, and confirmed pathological patterns similar to ALS. This systematic review assesses the current state of PLS research across clinical, neuroimaging and neuropathological domains from a combined clinical and academic perspective. We discuss patterns of pathological overlap with other ALS phenotypes, examine if the biological processes of PLS warrant therapeutic strategies distinct from ALS, and evaluate the evidence that classes PLS as a distinct clinico-pathological entity.

Electrophysiological Assessment and Classification of Motor Pathway Function in Patients With Spinal Dural Arteriovenous Fistula.

PURPOSE: The diagnosis of spinal dural arteriovenous fistula (SDAVF) is difficult and often delayed because clinical features are often nonspecific. We assessed the motor function electrophysiologically in patients with SDAVF. METHODS: Motor-evoked potentials after transcranial magnetic stimulation and compound muscle action potentials and F-waves after electrical stimulation in the ulnar and tibial nerves were measured from the abductor hallucis (AH) muscles in 14 patients with SDAVF (SDAVF group), 12 patients with compressive thoracic myelopathy (CTM group), and 16 normal subjects (control group). The peripheral conduction time determined from abductor hallucis muscles (PCT-AH) and the central motor conduction time determined from abductor hallucis muscles (CMCT-AH) were calculated. According to the neurological findings, patients in the SDAVF group were classified to upper motor neuron (UMN) sign and lower motor neuron (LMN) sign categories. RESULTS: CMCT-AH in the SDAVF and CMT groups were significantly longer than those in the control group. PCT-AH in the SDAVF group was significantly longer than that in the control and CMT groups. Twelve patients in the SDAVF group showed abnormal CMCT-AH and/or PCT-AH. Abnormal CMCT-AH and PCT-AH were detected in five cases that exhibited UMN sign and/or LMN sign. Three cases with abnormal CMCT-AH and normal PCT-AH exhibited UMN sign. LMN sign without UMN sign was observed in four cases with abnormal PCT-AH and normal CMCT-AH. CONCLUSIONS: Our study revealed abnormalities in the corticospinal tract and/or lower motor neurons, and classified the patients with SDAVF into three types: the UMN type, LMN type, and mixed type.

O'Sullivan-McLeod syndrome: Unmasking a rare atypical motor neuron disease.

Atypical motor neuron disease represents a rare heterogeneous group of neurodegenerative disorders with clinical, genetic and neuroimaging features distinct from those of the classic spinal or bulbar-onset amyotrophic lateral sclerosis (ALS). O'Sullivan-McLeod syndrome represents an extremely rare lower motor neuronopathy with early adult-onset distal amyotrophy and weakness in the upper limbs with asymmetrical involvement. To add to the few case series and epidemiological and genetic studies describing this variant syndrome, our team here presents a series of seven unrelated Brazilian patients with O'Sullivan-McLeod syndrome in a detailed review of their clinical, neuroimaging, laboratory and neurophysiological findings. A male-to-female ratio of 2.5 to 1 and a mean age at onset of 34.3years was observed, with a mean time delay of 6.6years between symptom-onset and a definitive diagnosis. A positive family history was observed in one case, yet whole-exome sequencing results were negative. Neuroimaging studies were unremarkable. All cases presented with chronic denervation restricted to cervical myotomes and normal sensory nerve conduction studies. This case series, one of the largest groups of patients with O'Sullivan-McLeod syndrome reported in the literature, confirms the sporadic nature of the condition and the difficulties faced in arriving at a definite diagnosis, and also expands the age limit in late adult-onset cases.

Primary lateral sclerosis and the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.

AIM: To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum of diseases. METHODS: Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS-FTD (n = 12). Clinical features, Addenbrooke's Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS). RESULTS: Global cognition was impaired in PLS (mean total ACE score 82.5 ± 13.6), similar to ALS-FTD (mean total ACE score 76.3 ± 7.7, p > 0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5 ± 6.2) compared ALS-FTD (50.1 ± 7.2, p < 0.001) and ALS (62.3 ± 12.6, p = 0.046). Average short-interval intracortical inhibition (SICI) was similar in all three patient groups. The mean survival time was longest in PLS (217.4 ± 22.4 months) and shortest in ALS-FTD (38.5 ± 4.5 months, p = 0.002). Bulbar onset disease (ß = - 0.45, p = 0.007) and RMT (ß = 0.54, p = 0.001) were independent predictors of global cognition while motor scores (ß = 0.47, p = 0.036) and SICI (ß = 0.58, p = 0.006) were significantly associated with ALSFRS. CONCLUSION: The cognitive profile in PLS resembles ALS-FTD, without prominent behavioural disturbances. A higher RMT in PLS than ALS and ALS-FTD is consistent with differential cortical motor neuronal abnormalities and more severe involvement of corticospinal axons while SICI, indicative of inhibitory interneuronal dysfunction was comparable with ALS and ALS-FTD. Overall, while these findings support the notion that PLS lies on the ALS-FTD spectrum, the mechanisms underlying slow disease progression are likely to be distinct in PLS.

Demographics and clinical characteristics of primary lateral sclerosis: case series and a review of literature.

AIM: Primary lateral sclerosis (PLS) is a form of motor neuron disease involving only upper motor neurons. In some patients presenting as PLS, the disease progresses to involve lower motor neurons and thereby converting to amyotrophic lateral sclerosis (ALS). However, pure forms of PLS do exist. Our aim was to study epidemiological and clinical characteristics of pure PLS patients treated at our neuromuscular clinic. METHODS: We retrospectively reviewed 15 patients from July 2011 to October 2014 with PLS treated at the neuromuscular disorder clinic at our hospital. Data collection included patient demographics, age and site of onset, duration of symptoms and duration of follow-up. We also studied clinical features such as bulbar involvement; pseudobulbar affect; depression; spasms/pain; bladder involvement; diagnostic work up, in other words, MRI; brain/electromyography findings; clinical course, namely years to wheelchair; and need for gastrostomy tube requirement baclofen pump placement. We also tried to find a correlation between PLS and environmental factors such as urban/suburban/rural living, consumption of well water, socioeconomic status/occupation and history of trauma. RESULTS: Male-to-female ratio was 1:2, mean age at onset of symptoms was 58.6 years, with the oldest patient being an 84-year-old female at the time of onset of symptoms. Mean duration of follow-up was 51 months. Mean duration of symptoms was 77.4 months. About eight (53%) patients presented with bulbar symptoms in the form of spastic speech and dysphagia, pseudobulbar affect, developed depression and had bladder involvement. Seven (47%) patients presented with symmetric spasticity in the extremities. A third of the patients required baclofen for spasticity and a third required gastrostomy tube placement for dysphagia. None of them had abnormal neuroimaging or electrodiagnostic testing. Only one patient had history of trauma. About half of the patients were from lower socioeconomic status as well as middle class. One of the patients had consumed well water during younger years and three (20%) patients lived in the rural area. CONCLUSION: Though on review of literature there is no clear consensus about the existence of PLS as a distinct disease entity, we believe that there are rare cases of motor neuron disease with progressive upper motor neuron symptoms that throughout their course never convert to ALS. Our series highlights the demographic and clinical features of these patients and underscores the longer survival of these patients when compared with ALS.

A case series of PLS patients with frontotemporal dementia and overview of the literature.

OBJECTIVE: Primary lateral sclerosis (PLS) is a rare form of motor neuron disease characterised by UMN degeneration leading to slowly progressive spasticity. Whether it is a separate disease or a subtype of ALS has been debated. In ALS comorbid frontotemporal dementia (FTD) is frequently seen (±15%). However, cognitive and behavioural changes are generally not considered to be a part of PLS. METHODS: To report the clinical findings and frequency of PLS patients that developed FTD in a referral-based cohort and provide an overview of the literature. RESULTS: In our cohort six out of 181 (3.3%) PLS patients developed FTD. In the literature a few cases of PLS with FTD have been reported and only a limited number of small studies have investigated cognition in PLS. However, when these studies are summarised a pattern emerges with FTD diagnoses in ±2% and frontotemporal impairment in 22% of patients. CONCLUSIONS: These findings suggest that PLS is part of the FTD-MND continuum and would favour viewing it as a subtype of ALS. It is, however, not a restricted (isolated UMN involvement) phenotype.

Analysis of terms used for the diagnosis and classification of amyotrophic lateral sclerosis and motor neuron disease.

There is no test for amyotrophic lateral sclerosis (ALS) and so attempts have been made to produce standardized diagnostic criteria based on clinical and electrophysiological findings, e.g. El Escorial. However, the phenotypic classification of the subtypes of ALS is also based on clinical features leading to conflation of diagnosis and phenotype. We used a five-question online survey with ALS specialists to explore the range of descriptors and how they are used. Of 101 specialists approached, 72 completed the survey. The most frequently used labels were 'ALS', 'PLS' and 'familial'. Labels other than the El Escorial categories were mainly used as clinical descriptors (83%). Approximately 50% of respondents recorded that the El Escorial criteria had no useful role in patient discussion or in the diagnostic process. Only 31% of respondents rated their current classification system above the median for being logical. A more rational system explicitly distinguishing diagnostic and phenotypic criteria is essential.

Utility of Paraneoplastic Antibody Testing in the Diagnosis of Motor Neuron Disease.

OBJECTIVE: To evaluate the role of paraneoplastic autoantibody testing in the diagnosis of motor neuron disease (MND). BACKGROUND: There have been rare case reports of paraneoplastic MND that have prompted many physicians to test for paraneoplastic autoantibodies in patients with MND. Our study is the first to determine the utility of such testing. METHODS: Retrospective chart review of patients with MND from a tertiary referral center from 2007 to 2014. RESULTS: Of 316 patients with MND reviewed, 44% (n = 138) were evaluated by a Mayo Clinic paraneoplastic autoantibody panel. Of note, 73% of these patients (n = 101) were diagnosed with amyotrophic lateral sclerosis, fulfilling possible, probable, or definite revised El Escorial criteria. Of note, 9% of patients (13/138) of those who had paraneoplastic antibody testing performed were positive for at least 1 paraneoplastic antibody. Three patients had negative testing for malignancy. None had a different disease course than expected. CONCLUSIONS: Testing for paraneoplastic antibodies does not seem to change the diagnosis, management, or outcome in the setting of MND and is therefore of limited value.

Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS.

Progressive Muscular Atrophy.

Progressive muscular atrophy (PMA) is a rare, sporadic, adult-onset motor neuron disease, clinically characterized by isolated lower motor neuron features; however, clinically evident upper motor neuron signs may emerge in some patients. Subclinical upper motor neuron involvement is identified pathologically, radiologically, and neurophysiologically in a substantial number of patients with PMA. Patients with subclinical upper motor neuron involvement do not fulfill the revised El Escorial criteria to participate in amyotrophic lateral sclerosis clinical trials. Intravenous immunoglobulin therapy is only marginally beneficial in a small subgroup of patients with lower motor neuron syndrome without conduction block.

The classification of motor neuron defects in the zebrafish embryo toxicity test (ZFET) as an animal alternative approach to assess developmental neurotoxicity.

Rodents are widely used to test the developmental neurotoxicity potential of chemical substances. The regulatory test procedures are elaborate and the requirement of numerous animals is ethically disputable. Therefore, non-animal alternatives are highly desirable, but appropriate test systems that meet regulatory demands are not yet available. Hence, we have developed a new developmental neurotoxicity assay based on specific whole-mount immunostainings of primary and secondary motor neurons (using the monoclonal antibodies znp1 and zn8) in zebrafish embryos. By classifying the motor neuron defects, we evaluated the severity of the neurotoxic damage to individual primary and secondary motor neurons caused by chemical exposure and determined the corresponding effect concentration values (EC50). In a proof-of-principle study, we investigated the effects of three model compounds thiocyclam, cartap and disulfiram, which show some neurotoxicity-indicating effects in vertebrates, and the positive controls ethanol and nicotine and the negative controls 3,4-dichloroaniline (3,4-DCA) and triclosan. As a quantitative measure of the neurotoxic potential of the test compounds, we calculated the ratios of the EC50 values for motor neuron defects and the cumulative malformations, as determined in a zebrafish embryo toxicity test (zFET). Based on this index, disulfiram was classified as the most potent and thiocyclam as the least potent developmental neurotoxin. The index also confirmed the control compounds as positive and negative neurotoxicants. Our findings demonstrate that this index can be used to reliably distinguish between neurotoxic and non-neurotoxic chemicals and provide a sound estimate for the neurodevelopmental hazard potential of a chemical. The demonstrated method can be a feasible approach to reduce the number of animals used in developmental neurotoxicity evaluation procedures.

Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins.

Motor neuron diseases (MNDs) are neurodegenerative disorders that specifically affect the survival and function of upper and/or lower motor neurons. Since motor neurons are responsible for the control of voluntary muscular movement, MNDs are characterized by muscle spasticity, weakness and atrophy. Different susceptibility genes associated with an increased risk to develop MNDs have been reported and several mutated genes have been linked to hereditary forms of MNDs. However, most cases of MNDs occur in sporadic forms and very little is known on their causes. Interestingly, several molecular mechanisms seem to participate in the progression of both the inherited and sporadic forms of MNDs. These include cytoskeleton organization, mitochondrial functions, DNA repair and RNA synthesis/processing, vesicle trafficking, endolysosomal trafficking and fusion, as well as protein folding and protein degradation. In particular, accumulation of aggregate-prone proteins is a hallmark of MNDs, suggesting that the protein quality control system (molecular chaperones and the degradative systems: ubiquitin-proteasome-system and autophagy) are saturated or not sufficient to allow the clearance of these altered proteins. In this review we mainly focus on the MNDs associated with disturbances in protein folding and protein degradation and on the potential implication of a specific class of molecular chaperones, the small heat shock proteins (sHSPs/HSPBs), in motor neuron function and survival. How boosting of specific HSPBs may be a potential useful therapeutic approach in MNDs and how mutations in specific HSPBs can directly cause motor neuron degeneration is discussed.

Use of the international classification of functioning, disability and health to describe patient-reported disability: a comparison of motor neurone disease, Guillain-Barré syndrome and multiple sclerosis in an Australian cohort.

PURPOSE: To compare patient-reported disability across three long-term neurological conditions [motor neurone disease (MND), Guillain-Barré syndrome (GBS) and multiple sclerosis (MS)] using the International Classification of Functioning, Disability and Health (ICF). METHODS: A prospective cross-sectional survey of Australian community-based persons with MND (n = 44). Their MND-related problems were linked with ICF categories (second level) using open-ended questionnaires and 'linkage rules' and compared to similar data collected for GBS (n = 77) and MS (n = 101) participants. RESULTS: MND participants were older (mean age 61 years, GBS 55, MS 49) with more males (66%, GBS 59%, MS 29%). Seventy ICF categories in MND were identified (GBS 41, MS 63): "body function" 15 (GBS 7; MS 18); "body structure" 5 (GBS 3, MS 5); "activities and participation" 40 (GBS 25, MS 30); "environmental factors" 10 (GBS 6, MS 10). The main areas linked in "activities and participation" were mobility, self care, general tasks and demands, domestic life, interpersonal interactions and relationships, major life areas and community, social and civic life; environmental factors included products and technology, natural environment, support and relationships, services, systems and policies. CONCLUSIONS: Comparison of three long-term neurological conditions will assist with development of a core set of categories to optimise consensus of care and communication amongst treating clinicians.

Motor neuron, nerve, and neuromuscular junction disease.

PURPOSE OF REVIEW: The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders. RECENT FINDINGS: Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis. SUMMARY: Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies.

Spasticity or reversible muscle hypertonia?

BACKGROUND AND OBJECTIVE: The increase in resistance to passive muscle stretch in a paretic limb due to an upper motor neurone lesion is often referred to as muscle spasticity. However, this terminology is inaccurate and does not take into account the complex pathogenesis of the condition or describe the factors that contribute to the clinically observed changes in muscle tone. In this report we propose an alternative terminology and explain the reasons for doing so.

Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy.

Motor neuron disease (MND) may present as an isolated lower motor neuron (LMN) disorder. Although the significance of pathological 43 kDa transactive responsive sequence DNA binding protein (TDP-43) for amyotrophic lateral sclerosis (ALS) was appreciated only recently, the topographical distribution of TDP-43 pathology in MND clinically isolated to the LMN versus normal controls (COs) is only incompletely described. Therefore, we performed longitudinal clinical evaluation and retrospective chart review of autopsied patients diagnosed with isolated LMN disease. Cases with a disease duration over 4 years were designated as progressive muscular atrophy (PMA), and those with a more rapid course as MND/LMN. Immunohistochemistry was employed to identify neuronal and glial TDP-43 pathology in the central nervous system (CNS) in patients and COs. We examined 19 subjects including six patients (i.e., four with MND/LMN and two with PMA) and 13 COs. All patients showed significant TDP-43 linked degeneration of LMNs, and five cases showed a lesser degree of motor cortex degeneration. Additional brain areas were affected in varying degrees, ranging from predominantly brainstem pathology to significant involvement of the whole CNS including neocortical and limbic areas. Pathological TDP-43 was present only rarely in the CO group. We conclude that MND limited to the LMN and PMA is part of a disease continuum that includes ALS and FTLD-TDP, all of which are characterized by widespread TDP-43 pathology. Hence, we suggest that the next revision of the El Escorial criteria for the diagnosis of ALS include MND patients with disease clinically limited to the LMN and PMA as variants of ALS, which like classical ALS, are TDP-43 proteinopathies.