CHCHD10 mutations and motor neuron disease: the distribution in Finnish patients

Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.

Motor neuron diseases encompass a range of phenotypes, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and spinal muscular atrophy (SMA). Related conditions include spinal and bulbar muscular atrophy (SBMA) and hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). Hereditary spastic paraplegia (HSP)-a group of disorders primarily affecting the corticospinal tract-also exhibits diverse clinical manifestations. This review summarizes the genetic basis of these diseases, along with their clinical characteristics, diagnostic approaches, and disease-specific therapies.

Motor neuron disease (MND) is a group of neurological disorders which is characterized by selectively progressive degeneration of motor neurons in the brain and spinal cord. On the basis of the degree of upper or lower neuron involvement, MND is broadly divided into several subtypes: pure upper neuron diseases (primary lateral sclerosis), pure lower motor neuron diseases (progressive spinal muscular atrophy, progressive bulbar palsy, spinal muscular atrophy, X-linked spinal and bulbar muscular atrophy, etc.), and mixed upper and lower motor neuron diseases (amyotrophic lateral sclerosis). Generally, MND can be sporadic, or it can occur as an inherited disorder. To date, a great number of genes have been identified to be responsible for inherited MND. The distinct causative genes usually result in different clinical phenotypes. Therefore, the genetic testing is crucial for inherited MND. In this chapter, we mentioned several cases of inherited motor neuron diseases and described the way how these definitive causative genes were identified. In addition, to make clear definition for MND, several other inherited neurologic diseases, such as hereditary spasticity paraplegia and inherited peripheral neuropathy, were also presented in this chapter.

Motor neuron disease (MND) is a type of chronic progressive neurodegenerative disease involving upper and/or lower motor neurons, including amyotrophic lateral sclerosis, progressive bulbar palsy, primary lateral sclerosis, progressive muscular atrophy, and spinal muscular atrophy. Different types of motor neuron diseases have distinct characteristics. Therefore, the diagnosis mainly depends on clinical manifestations, physical examination and electrophysiological examination, and is made by exclusion of other diseases. Atypical cases are sometimes difficult for clinical physicians to distinguish from other diseases involving upper and/or lower motor neurons. This article is going to introduce various types of MND and their differential diagnosis according to site of lesion of motor neuron disease. Key words: Motor neuron disease; Amyotrophic lateral sclerosis; Upper motor neuron; Lower motor neuron; Differential diagnosis

Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder traditionally characterised by progressive degeneration of upper motor neurons (UMNs), leading to spasticity, weakness, and loss of mobility. Historically, PLS has been regarded as a disease confined to the UMNs. However, accumulating evidence of cognitive and behavioural impairments, parkinsonian features, and subtle lower motor neuron (LMN) involvement challenges this narrow view and suggests a broader clinical spectrum overlapping with other motor neuron diseases (MNDs), particularly amyotrophic lateral sclerosis (ALS). This thesis investigates the diagnostic complexity, clinical heterogeneity, cognitive and behavioural involvement, long-term disease course, and genetic and pathological features of PLS, questioning its classification as a “pure” UMN disorder. Part I addresses the diagnostic criteria of PLS and its differentiation from ALS and PLS mimics. A long-term natural history study demonstrates that PLS remains a diagnosis of exclusion and is frequently difficult to distinguish from ALS and hereditary spastic paraplegia (HSP). Some patients were reclassified during follow-up, underscoring the limitations of relying on clinical criteria alone. Disease progression was heterogeneous: patients with limb-only involvement showed slower progression, whereas bulbar involvement was associated with greater disability and an increased risk of conversion to ALS. The findings support the use of a four-year disease duration threshold to reduce misclassification, while highlighting the urgent need for biomarkers and advanced imaging techniques to improve early diagnostic accuracy. Part II focuses on cognitive and behavioural impairment in PLS and its relationship to ALS and progressive muscular atrophy (PMA). A large case series shows that a small but relevant proportion of PLS patients meet criteria for frontotemporal dementia (FTD), while a substantial subset exhibits milder cognitive and behavioural deficits. Comprehensive neuropsychological and behavioural assessments reveal impairments in executive functioning, fluency, memory, and social cognition, with caregiver reports identifying behavioural changes consistent with behavioural variant FTD in a notable proportion of patients. Comparative analyses across PLS, ALS, and PMA demonstrate that cognitive and behavioural abnormalities are prevalent across the MND spectrum, challenging the concept of PLS and PMA as restricted phenotypes and supporting their inclusion within the FTD–MND continuum. Part III explores neuropathological and genetic aspects of PLS. Neuropathological findings confirm predominant UMN degeneration but also reveal variable LMN involvement and non-motor pathology in some cases, in line with observed cognitive and behavioural features. TDP-43 pathology, a hallmark of ALS and FTD, is inconsistently present, suggesting partial overlap with ALS pathophysiology. Genetic analyses show that PLS is largely sporadic, with limited overlap with known ALS-associated mutations, including rare C9ORF72 repeat expansions, supporting both distinction from and relatedness to ALS within the broader MND spectrum. In conclusion, this thesis demonstrates that PLS is a clinically and biologically heterogeneous disorder that extends beyond isolated UMN degeneration. Improved diagnostic criteria, systematic cognitive and behavioural assessment, and integration of pathological and genetic data are essential to refine disease classification, enhance diagnostic accuracy, and advance understanding of PLS within the MND spectrum.

Defects in the RNA-binding proteins survival motor neuron (SMN) and TAR DNA-binding protein 43 (TDP-43) cause progressive motor neuron degeneration in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. While low levels of SMN protein in motor neurons result in SMA, recent studies implicate abnormal SMN levels and function in ALS pathogenesis. Here, we determine that SMN protein is upregulated early and progressively in spinal and cortical motor neurons of male transgenic mutant TDP-43A315T mice. Cytoplasmic SMN aggregates that contain TDP-43 and HuR were identified in motor neurons of TDP-43A315T mice, consistent with the incorporation of SMN into stress granules. To test the impact of augmenting SMN levels in TDP-43 proteinopathy, we demonstrate that neuronal overexpression of human SMN in TDP-43A315T mice delayed symptom onset and prolonged survival. SMN upregulation also countered motor neuron degeneration, attenuated activation of astrocytes and microglia and restored AMP kinase activation in spinal cords of TDP-43A315T mice. We also reveal that expression of another factor conferring motor neuron vulnerability, androgen receptor (AR), is reduced in spinal cords of male TDP-43A315T mice. These results establish that SMN overexpression in motor neurons slows disease onset and outcome by ameliorating pathological signs in this model of mutant TDP-43-mediated ALS. Further approaches to augment SMN levels using pharmacological or gene therapy agents may therefore be warranted in ALS. Our data also reinforce a novel potential link between ALS and spinal bulbar muscular atrophy (SBMA), another motor neurodegenerative disease mediated by reduced AR function in motor neurons.

ObjectivesCognitive and behavioural changes within the spectrum of frontotemporal dementia (FTD) are observed frequently in patients with amyotrophic lateral sclerosis (ALS). Whether these changes also occur in other forms of...

93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA) – clinical picture (6–8 April 2001, Naarden, The Netherlands)

Motor neurone disease includes a heterogeneous group of disorders with motor neurone involvement, such as amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, and primary lateral sclerosis. Amyotrophic lateral...

BackgroundRare neurological diseases (RNDs) result in severe health burdens worldwide. Data from China are limited. We aimed to investigate the health burden of 20 RNDs in Guangdong Province (GD), which contains two-thirds of the population of South China.MethodsThe hospitalization data of 20 RNDs were described using hospital-based front sheet data from 3,037 hospitals of GD from 2016 to 2022. The 20 RNDs included amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth Disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, congenital myotonia, congenital myasthenic syndrome, Dravet syndrome, Fabry disease, hereditary spastic paraplegia, Huntington disease, Leber hereditary optic neuropathy, mitochondrial encephalopathy (ME), multi-focal motor neuropathy, myotonic dystrophy, primary hereditary dystonia, progressive muscular dystrophy (PMD), spinal and bulbar muscular atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, Wilson disease (WD) and X-linked adrenoleukodystrophy. Age were presented as mean and standard deviation while length of hospital stay as median and interquartile range (25th and 75th percentiles). The other variables were described as number and percentage. The data were analyzed by Joinpoint regression.ResultsThere were 9,351 cases, including 330 ICU and 155 death cases. The average age was 33.7 ± 22.0 y, and 63.8% of patients were male. From 2016 to 2022, the number of RND (and juvenile RND) cases were 1034 (184), 1174 (293), 1443 (374), 1422 (320), 1331 (337), 1432 (409) to 1515 (515). ICU (and juvenile ICU) cases rose from 28 (3), 34 (6), 24 (4), 38 (11), 46 (13), 54 (24) to 106 (56). Joinpoint regression showed significant upward trend in percentages of juvenile and juvenile ICU cases (APC = 8.13, P< 0.05; APC = 28.42, P< 0.05). The fop five RNDs were WD, ASL, PMD, ME, and SMA, which accounted for 79.7% of all, 99.1% of ICU, and 94.8% of death cases.ConclusionsWe demonstrated that the increase in health burden of RNDs was mainly evident in juveniles in South China from 2016 to 2022. The top 5 RNDs accounted for majority of the critical patients.

The degeneration of motor neurons is a pathological hallmark of motor neuron diseases (MNDs), but emerging evidence suggests that neuronal vulnerability extends well beyond this cell subtype. The ability to assess motor function in the clinic is limited to physical examination, electrophysiological measures, and tissue-based or neuroimaging techniques which lack the resolution to accurately assess neuronal dysfunction as the disease progresses. Spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS) are all MNDs with devastating clinical outcomes that contribute significantly to disease burden as patients are no longer able to carry out normal activities of daily living. The critical need to accurately assess the cause and progression of motor neuron dysfunction, especially in the early stages of those diseases, has motivated the use of human iPSC-derived motor neurons (hiPSC-MN) to study the neurobiological mechanisms underlying disease pathogenesis and to generate platforms for therapeutic discovery and testing. As our understanding of MNDs has grown, so too has our need to develop more complex in vitro models which include hiPSC-MN co-cultured with relevant non-neuronal cells in 2D as well as in 3D organoid and spheroid systems. These more complex hiPSC-derived culture systems have led to the implementation of new technologies, including microfluidics, multielectrode array, and machine learning which offer novel insights into the functional correlates of these emerging model systems.

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.

Typical amyotrophic lateral sclerosis (ALS) presents on neurological examination with specific signs of upper and lower motor neuron degeneration (Brooks et al, 1995), which can account for 85% of patients with ALS (Turner and Talbot, 2013). There are different types of clinical presentations, including progressive bulbar palsy (PBP), Limb-onset ALS, progressive muscular atrophy (PMA) and upper motor neuron (UMN) predominant ALS. PBP has mainly brainstem signs. There are a few case reports of dropped head syndrome in ALS, mainly in patients with the limb involvement variant. Case report. A 56 year old right-handed male, presented to the clinic with four months of dysphagia to liquids and solids, neck pain and progressive neck weakness causing constant drop head. No dysarthria or other neurological symptoms, no dyspnea. Neurological examination: Cranial Nerve (CN) CN XII: Nasal voice, bilateral atrophy of the tongue with tremor and fasciculations. Motor: Diffuse atrophy and decreased tone of the sternocleidomastoid and trapezii bilaterally, strength: 2/5 in neck flexors and extensors. Sensory: Hypoesthesia of the tongue. The rest of his neurological examination was normal. Labs: Routine blood work, thyroid function tests, collagen vascular work-up, and protein electrophoresis were normal. Creatine Phosphokinase (CPK) and Acetylcholine Receptor Antibodies (AChR Ab) were negative. Brain and Spinal Cord MRI: Showed mild brainstem, cerebellar and cervical spinal atrophy. Patients with ALS initially present with symptoms localized to the limbs or bulbar muscles. A very small percentage 1-2% of ALS patients had neck muscle weakness with head drop (Jokelainen et al, 1977; Gourie-Devi et al, 2003). However, in all the previously reported cases, the patients had limb involvement at the time of presentation which was absent in this case, and the head drop occurred after the onset of symptoms (Lange et al, 1986; Katz et al; 1996). Dropped head syndrome can be seen in inflammatory myopathies, myasthenia gravis, facioscapulohumeral muscular dystrophy, spinal muscular atrophy, nemaline myopathy and carnitine deficiency (Umapathy et al, 2003) but ALS should also be considered in patients with atypical presentations.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are distinct motor neuron disorders with overlapping molecular mechanisms. ALS involves progressive upper and lower motor neuron degeneration, while SMA primarily affects lower motor neurons. Mutations in SOD1 (superoxide dismutase 1), a well-established cause of familial ALS, have been identified in patients with atypical motor neuron disease phenotypes, suggestive of their broader role in motor neuron dysfunction. A 28-year-old male presented with progressive distal muscle weakness, atrophy, and a steppage gait, without upper motor neuron involvement. Electromyography confirmed chronic motor neuron dysfunction, raising suspicion of SMA. Genetic testing excluded SMN1 deletions but identified a pathogenic SOD1 mutation. Despite this, slow disease progression and phenotype were more consistent with adult-onset SMA type IV than ALS. This case highlights the diagnostic challenges posed by overlapping features of ALS and SMA. The findings emphasize the need for further research into the clinical features associated with SOD1 mutations and their potential contributions to SMA-like presentations, refining our understanding of motor neuron disorders.

Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. Depletions in dynein and dynactin-1, motor molecules regulating axonal trafficking, disrupt axonal transport in flies, and mutations in their genes cause motor neuron degeneration in humans and rodents. Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles indicate that dynactin-1 mRNA is downregulated in degenerating spinal motor neurons of autopsied patients with sporadic ALS. Dynactin-1 mRNA is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy, a motor neuron disease caused by triplet CAG repeat expansion in the gene encoding the androgen receptor. Pathogenic androgen receptor proteins also inhibit kinesin-1 microtubule-binding activity and disrupt anterograde axonal transport by activating c-Jun N-terminal kinase. Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases.