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Background: Contactin-associated protein-like 2 (CASPR2) autoantibody disease has a variable clinical phenotype. We present a case report and performed a systematic review of the literature to summarize: (1) the clinical phenotype of patients with CASPR2 antibodies, (2) the findings in neurological investigations, and (3) the associated neuroimaging findings., Methods: A chart review was performed for the case report. A systematic review of the medical literature was performed from first available to June 13, 2018. Abstracts were screened, and full-text peer-reviewed publications for novel patients with CASPR2 positivity in serum or cerebrospinal fluid (CSF) were included. Selected publications were reviewed, and relevant information was collated. Data were analyzed to determine overall frequency for demographic information, clinical presentations, and investigation findings., Results: Our patient was a previously healthy 61-year-old male with both serum and CSF CASPR2 antibodies who presented with limbic encephalitis and refractory epilepsy. He was successfully treated with immunosuppression. For our systematic review, we identified 667 patients from 106 studies. Sixty-nine percent were male. Median age was 54 years (IQR 39-65.5). Median disease duration was 12 months (IQR 5.6-20). Reported overall clinical syndromes were: autoimmune encephalitis [69/134 (51.5%)], limbic encephalitis [106/274 (38.7%)], peripheral nerve hyperexcitability [72/191 (37.7%)], Morvan syndrome [57/251 (22.7%)], and cerebellar syndrome [24/163 (14.7%)]. Patients had positive serum [642/642 (100%)] and CSF [87/173 (50.3%)] CASPR2 antibodies. MRI was reported as abnormal in 159/299 patients (53.1%), and the most common abnormalities were encephalitis or T2 hyperintensities in the medial temporal lobes, or hippocampal atrophy, mesial temporal sclerosis, or hippocampal sclerosis. FDG-PET was abnormal in 30/35 patients (85.7%), and the most common abnormality was temporomesial hypometabolism. The most commonly associated condition was myasthenia gravis (38 cases). Thymoma occurred in 76/348 patients (21.8%). Non-thymoma malignancies were uncommon [42/397 (10.6%)]., Conclusions: Most patients have autoimmune or limbic encephalitis and corresponding abnormalities on neuroimaging. Other presentations include peripheral nerve hyperexcitability or Morvan syndromes, cerebellar syndromes, behavioral and cognitive changes, and more rarely movement disorders. The most commonly associated malignancy was thymoma and suggests a role for thymoma screening in CASPR2-related diseases.

Here we describe a clinical approach and differential diagnosis for chronic muscle diseases which include early respiratory failure as a prominent feature in their presentation (i.e. respiratory failure whilst still ambulant). These patients typically present to neurology or respiratory medicine out-patient clinics and a distinct differential diagnosis of neuromuscular aetiologies should be considered. Amyotrophic lateral sclerosis and myasthenia gravis are the important non-muscle diseases to consider, but once these have been excluded there remains a challenging differential diagnosis of muscle conditions, which will be the focus of this review. The key points in the diagnosis of these disorders are being aware of relevant symptoms, which are initially caused by nocturnal hypoventilation or diaphragmatic weakness; and identifying other features which direct further investigation. Important muscle diseases to identify, because their diagnosis has disease-specific management implications, include adult-onset Pompe disease, inflammatory myopathy, and sporadic adult-onset nemaline myopathy. Cases which are due to metabolic myopathy or muscular dystrophy are important to diagnose because of their implications for genetic counselling. Myopathy from sarcoidosis and colchicine each has a single reported case with this presentation, but should be considered because they are treatable. Disorders which have recently had their genetic aetiologies identified include hereditary myopathy with early respiratory failure (due to TTN mutations), the FHL1-related syndromes, and myofibrillar myopathy due to BAG3 mutation. Recently described syndromes include oculopharyngodistal muscular dystrophy that awaits genetic characterisation.

Background: Mutations in SPG7 are increasingly identified as a common cause of spastic ataxia. We describe a cohort of Irish patients with recessive SPG7-associated phenotype., Methods: Comprehensive phenotyping was performed with documentation of clinical, neurophysiological, optical coherence tomography (OCT) and genetic data from individuals with SPG7 attending two academic neurology units in Dublin, including the National Ataxia Clinic., Results: Thirty-two symptomatic individuals from 25 families were identified. Mean age at onset was 39.1 years (range 12-61), mean disease duration 17.8 years (range 5-45), mean disease severity as quantified with the scale for the assessment and rating of ataxia 9/40 (range 3-29). All individuals displayed variable ataxia and spasticity within a spastic-ataxic phenotype, and additional ocular abnormalities. Two had spasmodic dysphonia and three had colour vision deficiency. Brain imaging consistently revealed cerebellar atrophy (n = 29); neurophysiology demonstrated a length-dependent large-fibre axonal neuropathy in 2/27 studied. The commonest variant was c.1529C > T (p.Ala510Val), present in 21 families. Five novel variants were identified. No significant thinning of average retinal nerve fibre layer (RNFL) was demonstrated on OCT (p = 0.61), but temporal quadrant reduction was evident compared to controls (p < 0.05), with significant average and temporal RNFL decline over time. Disease duration, severity and visual acuity were not correlated with RNFL thickness., Conclusions: Our results highlight that recessive SPG7 mutations may account for spastic ataxia with peripheral neuropathy in only a small proportion of patients. RNFL abnormalities with predominant temporal RNFL reduction are common and OCT should be considered part of the routine assessment in spastic ataxia., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: MATR3-associated distal myopathy is a rare distal myopathy predominantly affecting lower legs as well as wrist- and finger extensors. Whilst most distal myopathies are clinically and genetically well characterized, diagnosis often remains challenging. Pattern-based magnetic resonance imaging (MRI) approaches offer valuable additional information. However, a consistent pattern of muscular affection is missing for most distal myopathies. Thus, the aim of the present study was to establish a disease-specific pattern of muscular involvement in MATR3-associated distal myopathy using whole-body MRI., Methods: 15 patients (25-79 years of age, 7 female) with MATR3-associated distal myopathy were subjected to whole-body MRI. The grade of fatty involution for individual muscles was determined using Fischer-Grading. Results were compared to established MRI-patterns of other distal myopathies., Results: There was a predominant affection of the distal lower extremities. Lower legs showed a severe fatty infiltration, prominently affecting gastrocnemius and soleus muscle. In thighs, a preferential involvement of semimembranous and biceps femoris muscle was observed. Severe affection of gluteus minimus muscle as well as axial musculature, mainly affecting the thoracic segments, was seen. A sufficient discrimination to other forms of distal myopathy based solely on MRI-findings of the lower extremities was not possible. However, the inclusion of additional body parts seemed to yield specificity., Interpretation: Muscle MRI of patients with MATR3-associated distal myopathy revealed a distinct pattern of muscular involvement. The usage of whole-body muscle MRI provided valuable additional findings as compared to regular MRI of the lower extremities to improve distinction from other disease entities.

Background: A recent international consensus panel proposed diagnostic criteria for optic neuritis and a new classification. We aimed to investigate the clinical relevance of these diagnostic criteria and classification, in a cohort of patients hospitalized for a suspected diagnosis of optic neuritis., Methods: We included all patients hospitalized between 2017 and 2022 in our tertiary center for (sub)acute loss of visual acuity suggestive of optic neuritis. Clinical and paraclinical criteria obtained within the first 3 months of symptoms were collected, as well as the final diagnosis which could be optic neuritis or non-optic neuritis. We constructed a contingency table comparing diagnoses based on physician experience to those based on the recently proposed criteria. The subtypes of optic neuritis based on the new classification were compared to subtypes based on the clinician experience., Results: Two hundred fifty-seven patients were included in this study. Prevalence of optic neuritis in our cohort was 88.3%. Sensitivity and specificity of a correct diagnosis using the new criteria were, respectively, 99.5% and 86.7%. The proposed diagnostic criteria overdiagnosed four patients with optic neuritis and missed the diagnosis in one patient. According to the recent classification, idiopathic optic neuritis and clinical isolated syndrome were reclassified mainly as single isolated optic neuritis., Conclusion: In our specific cohort of patients hospitalized for acute and subacute optic neuropathy highly suspect of optic neuritis, we found that recently proposed diagnostic criteria and classification of optic neuritis are relevant for our clinical practice. Our interpretation of clinical requirement for definite and possible optic neuritis diagnosis might explain our excellent sensitivity and our high percentage of definite optic neuritis, relative to previous publications. The moderate specificity (86.7%) underlines the importance to include all contextual data in consideration for the diagnosis. The simplification of subgroups is useful, but our study highlights the complexity to find the adequate subgroup for seronegative NMOSD., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients., (© 2024. The Author(s).)

2 Brain magnetic resonance imaging shows diffuse medullary and spinal atrophy (arrows) which can be seen in A, C the age of 49 and B, D age of 61 While there was no evidence of new acute brain lesions attributable to his vertigo symptoms, his vertigo could not be credited to a previous spinal cord injury. Neurological examination showed spontaneous direction-changing nystagmus, in which the duration of nystagmus in each direction was not periodic, nor was the duration of the null-point duration seen between nystagmus in each direction, which was consistent with aperiodic alternating nystagmus (right horizontal 15 s-null point 10 s-left beating nystagmus 135 s-null point 15 s-right beating nystagmus 75 s-left beating nystagmus 100 s-null point 15 s-right beating nystagmus 70 s-left beating nystagmus 70 s) (Fig. While rotatory chair tests were not performed in this patient, and caloric or video head impulse tests were within normal range, we believe that potential for combined vestibular nuclei/velocity storage disfunction likely coexists in this patient, given that both medullary and cerebellar involvement are possible in AOAD. Presuming that the patient's clinical presentation was related to trauma, MRI and electrophysiological findings were considered to be related to traumatic spinal cord injury. [Extracted from the article]

Dear Sirs, Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing selective loss of motor neurons in brain motor cortex and spinal cord in which muscle denervation and atrophy are associated with pyramidal involvement, typically spreading to contiguous muscular regions and leading eventually to a fatal paralysis. Here, we report two ALS cases carrying the m.11778A > G/ I MT-ND4 i (R340H) mitochondrial DNA (mtDNA) mutation pathogenic for Leber's hereditary optic neuropathy (LHON), a maternally inherited disease due to mtDNA mutations affecting complex I function and usually leading to isolated optic atrophy [[2]]. Pathogenic mtDNA mutations have been found in ALS phenocopies with a primary mitochondrial disorder [[12]] and, more recently, mutations in nuclear genes, such as I CHCHD10 i , have been associated with ALS and mitochondrial myopathy with accumulation of mtDNA multiple deletions [[13]]. [Extracted from the article]

Background: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. Methods: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. Results: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt–Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). Conclusion: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA. [ABSTRACT FROM AUTHOR]

Contactin-associated protein-like 2 (CASPR2) and leucine-rich glioma-inactivated 1 (LGI1) are essential components of the voltage-gated Kv1 potassium channel complex and are extensively expressed in both central and peripheral nervous system. Autoimmune CASPR2 and LGI1 disorders commonly present with Morvan syndrome (Mos) and/or limbic encephalitis, but whether Guillain–Barré syndrome (GBS) is a specific clinical phenotype is unknown. Here, we first reported an adult patient with dual CASPR2 and LGI1 antibodies in both serum and cerebrospinal fluid, who initially presented with a GBS-like syndrome and developed a typical MoS and respiratory paralysis, with a rapid resolution of his neurological symptoms and disappearance of autoantibodies after treatment with plasma exchange. Additionally, we also provided an overview of the previously reported GBS cases associated with CASPR2 or LGI1 antibodies. These cases expand the phenotypic spectrum of CASPR2 and LGI1 autoimmune syndromes, implying that these two antigens, especially CASPR2, are likely to participate in the etiology of GBS as a potential new target antigen, which deserves further exploration. [ABSTRACT FROM AUTHOR]

Introduction: Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. Methods: Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. Results: Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. Conclusion: Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice. [ABSTRACT FROM AUTHOR]

Adult-onset ataxias are a genetically and clinically heterogeneous group of movement disorders. In addition to nuclear gene mutations, sequence changes have also been described in the mitochondrial genome. Here, we present findings of mutation analysis of the mitochondrial gene MT-ATP6. We analyzed 94 patients with adult-onset spinocerebellar ataxia (SCA), including 34 sporadic cases. In all patients, common sequence changes found in SCAs such as repeat expansions and point mutations had been excluded previously. We found pathogenic MT-ATP variants in five of these patients (5.32%), two of whom were sporadic. Four of the five mutations have not previously been described in ataxias. All but one of these mutations affect transmembrane helices of subunit-α of ATP synthase. Two mutations (p.G16S, and p.P18S) disrupt transmembrane helix 1 (TMH1), one mutation (p.G167D) affects TMH5, and another one (p.L217P) TMH6. The fifth mutation (p.T96A) describes an amino acid change in close proximity to transmembrane helix 3 (TMH3). The level of heteroplasmy was either complete or very high ranging from 87 to 99%. The high prevalence of pathogenic MT-ATP6 variants suggests that analysis of this gene should be included in the routine workup of both hereditary and sporadic ataxias. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) are motor neuron diseases sharing clinical, pathological, and genetic similarities. While biallelic SPG7 mutations are known to cause recessively inherited HSP, heterozygous SPG7 mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rare SPG7 variants have not been studied in a larger ALS cohort. Here, whole-exome (WES) or targeted SPG7 sequencing was done in a cohort of 214 European ALS patients. The consequences of a splice site variant were analyzed on the mRNA level. The resulting protein alterations were visualized in a crystal structure model. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization. In 9 of 214 (4.2%) ALS cases, we identified five different rare heterozygous SPG7 variants, all of which were previously reported in patients with HSP or ALS. All detected SPG7 variants affect the AAA+ domain of the encoded mitochondrial metalloprotease paraplegin and impair its stability or function according to predictions from mRNA analysis or crystal structure modeling. ALS patients with SPG7 mutations more frequently presented with cerebellar symptoms, flail arm or leg syndrome compared to those without SPG7 mutations, and showed a partial clinical overlap with HSP. Brain MRI findings in SPG7 mutation carriers included cerebellar atrophy and patterns suggestive of frontotemporal dementia. Collectively, our findings suggest that SPG7 acts as a genetic risk factor for ALS. ALS patients carrying SPG7 mutations present with distinct features overlapping with HSP, particularly regarding cerebellar findings. [ABSTRACT FROM AUTHOR]

Leber hereditary optic neuropathy (LHON) typically presents as painless central or centrocecal scotoma and is due to maternally inherited mitochondrial DNA (mtDNA) mutations. Over 95% of LHON cases are caused by one of three mtDNA "common" point mutations: m.3460G>A, m.11778G>A, or m.14484T>C, which are all in genes encoding structural subunits of complex I of the respiratory chain. Intriguing features of LHON include: incomplete penetrance, tissue specificity, and male predominance, indicating that additional genetic or environmental factors are modulating the phenotypic expression of the pathogenic mtDNA mutations. However, since its original description as a purely ophthalmological disorder, LHON has also been linked to multisystemic conditions with variable neurological, cardiac, and skeletal abnormalities. Although double "common" mutations have been reported to cause LHON and LHON-plus, they are extremely rare. Here, we present a patient with an unusual double point mutation (m.11778 G>A and m.14484T>C) with a multisystemic LHON-plus phenotype characterized by: optic neuropathy, ptosis, ataxia, dystonia, dysarthria, and recurrent extensive transverse myelitis. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias (HSP) share as cardinal feature progressive spastic gait disorder. SPG4 accounts for about 25% of cases and is caused by mutations in the SPAST gene. Although HSP is an upper motor neuron disease, the relevance of non-motor symptoms is increasingly recognized because of the potential response to treatment. Our study sets out to evaluate non-motor symptoms and their relevance with regard to health-related quality of life. In 118 genetically confirmed SPG4 cases and age- and gender-matched controls, validated questionnaires were used to evaluate fatigue, depression, pain, and restless legs syndrome. In addition, self-reported medical information was collected concerning comorbidities and bladder, bowel, and sexual dysfunction. In a sub-study, cognition was evaluated using the CANTAB® test-battery and the Montreal Cognitive Assessment in 26 SPG4 patients. We found depression and pain to be significantly increased. The frequency of restless legs syndrome varied largely depending on defining criteria. There were no significant deficits in cognition as examined by CANTAB® despite a significant increase in self-reported memory impairment in SPG4 patients. Bladder, sexual, and defecation problems were frequent and seemed to be underrecognized in current treatment strategies. All identified non-motor symptoms correlated with health-related quality of life, which was reduced in SPG4 compared to controls. We recommend that clinicians regularly screen for depression, pain, and fatigue and ask for bladder, sexual, and defecation problems to recognize and treat non-motor symptoms accordingly to improve quality of life in patients with SPG4. [ABSTRACT FROM AUTHOR]

Objective: Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied.Methods: Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated.Results: Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF.Conclusions: Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history. [ABSTRACT FROM AUTHOR]

Background: Movement disorders can be associated with anti-neuronal antibodies., Methods: We conducted a systematic review of cases with documented anti-neuronal antibodies in serum and/or cerebrospinal fluid published in PubMed before April 1, 2020. Only patients with at least one movement disorder were included. We used random forests for variable selection and recursive partitioning and regression trees for the creation of a data-driven decision algorithm, integrated with expert's clinical feedback., Results: Three hundred and seventy-seven studies met eligibility criteria, totaling 844 patients and 13 antibodies: amphiphysin, GAD, GlyR, mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, NMDAR, LGI-1, CRMP5/CV2, ANNA-1/Hu, IgLON5, and DPPX. Stiffness/rigidity/spasm spectrum symptoms were more frequently associated with amphiphysin, GAD, and GlyR; ataxia with mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, and ANNA-1/Hu; dyskinesia with NMDAR and paroxysmal movement with LGI1; chorea/choreoathetosis with CRMP5/CV2, IgLON5, and NMDAR; myoclonus with GlyR and DPPX; tremors with ANNA2/Ri and anti-DPPX; and parkinsonism with IgLON5 and NMDAR. Data-driven classification analysis determined the following diagnostic predictions (with probability selection): psychiatric symptoms and dyskinesia predicted NMDAR (71% and 87%, respectively); stiffness/rigidity/spasm and ataxia, GAD (67% and 47%, respectively); ataxia and opsoclonus, ANNA-2/Ri (68%); chorea/choreoathetosis, CRMP5/CV2 (41%). These symptoms remained the top predictors in random forests analysis. The integration with an expert opinion analysis refined the precision of the approach. Breast and lung tumors were the most common tumors. On neuroimaging, cerebellar involvement was associated with GAD and Yo/PCA-1; temporal involvement with Caspr2, LGI-1, ANNA-1/Hu., Conclusion: Selected movement disorders are associated with specific anti-neuronal antibodies. The combination of data-driven and expert opinion approach to the diagnosis may assist early management efforts., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative ataxic disorders with autosomal dominant inheritance. We aim to provide an update on the recent clinical and scientific progresses in SCA where numerous novel genes have been identified with next-generation sequencing techniques. The main disease mechanisms of these SCAs include toxic RNA gain-of-function, mitochondrial dysfunction, channelopathies, autophagy and transcription dysregulation. Recent studies have also demonstrated the importance of DNA repair pathways in modifying SCA with CAG expansions. In addition, we summarise the latest technological advances in detecting known and novel repeat expansion in SCA. Finally, we discuss the roles of antisense oligonucleotides and RNA-based therapy as potential treatments. [ABSTRACT FROM AUTHOR]

Autosomal recessive ataxias (ARCA) represent a complex group of diseases ranging from primary ataxias to rare and complex metabolic disorders in which ataxia is a part of the clinical picture. Small number of ARCA manifest exclusively in adulthood, while majority of typical childhood onset ARCA may also start later with atypical clinical presentation. We have systematically searched the literature for ARCA with adult onset, both in the group of primary ataxias including those that are less frequently described in isolated or in a small number of families, and also in the group of complex and metabolic diseases in which ataxia is only part of the clinical picture. We propose an algorithm that could be used when encountering a patient with adult onset sporadic or recessive ataxia in whom the acquired causes are excluded. ARCA are frequently neglected in the differential diagnosis of adult-onset ataxias. Rising awareness of their clinical significance is important, not only because some of these disorders may be potentially treatable, but also for prognostic implications and inclusion of patients to future clinical trials with disease modifying agents., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

ALS is a relentlessly progressive and fatal disease, with no curative therapies available to date. Symptomatic and palliative care, provided in a multidisciplinary context, still remains the cornerstone of ALS management. However, our understanding of the molecular mechanisms underlying the disease has advanced greatly over the past years, giving new hope for the development of novel diagnostic and therapeutic approaches. Here, we have reviewed the most recent studies that have contributed to improving both clinical management and our understanding of ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement is often evident, neurological manifestation is the principal presentation in most cases. The multiple clinical phenotypes and the involvement of both the mitochondrial and nuclear genome make mitochondrial disease particularly challenging for the clinician. In this review article we cover mitochondrial genetics and common neurological presentations associated with adult mitochondrial disease. In addition, specific and supportive treatments are discussed. [ABSTRACT FROM AUTHOR]

Mitochondrial disease is complex and variable, making diagnosis and management challenging. The situation is complicated by lack of sensitive outcomes of disease severity, progression, contributing pathology and clinical efficacy. Gait is emerging as a sensitive marker of pathology; however, to date, no studies have quantified gait in mitochondrial disease. In this cross-sectional study, we quantified gait characteristics in 24 patients with genetically confirmed mitochondrial disease (m.3243A>G and m.8344A>G) and 24 controls. Gait was measured using an instrumented walkway according to a predefined model with five domains hypothesised to reflect independent features of the neural control of gait in mitochondrial disease, including: pace (step velocity and step length); rhythm (step time); variability (step length and step time variability); asymmetry (step time asymmetry); and postural stability (step width, step width variability and step length asymmetry). Gait characteristics were compared with respect to controls and genotype. Additional measures of disease severity, pathophysiology and imaging were also compared to gait to verify the validity of gait characteristics. Discrete gait characteristics differed between controls and mitochondrial disease groups, even in relatively mildly affected patients harbouring the m.3243A>G mutation. The pattern of gait impairment (increased variability and reduced postural control) was supported by significant associations with measures of disease severity, progression, pathophysiology and radiological evidence of cerebellar atrophy. Discrete gait characteristics may help describe functional deficits in mitochondrial disease, enhance measures of disease severity and pathology, and could be used to document treatment effects of novel therapies. [ABSTRACT FROM AUTHOR]

The article describes several cases of hereditary spastic paraplegia. The first patient had progressive gait disturbance and lower limb spasticity and her family history suggested autosomal dominant inheritance. The brother of the patient presented with slowly progressive spastic paraplegia and tiptoe walking. Several important points regarding genetic diagnosis based on such cases are also cited.

The article focuses on a case of SPG7-Paraplegin mutation in a 43 year old patient, who first experienced severe visual problems since his childhood. Topics discussed include the medical history of the patient including identification of moderate spastic paraparesis at age 43, as well as identification of the same mutation on his father. Also mentioned is the association of optic neuropathy and SPG7 mutations.