Pyramidal Signs Research Articles

Sporadic Creutzfeldt Jakob disease: Case series in Peru.

A series of 6 cases with a probable diagnosis of sporadic CJD, treated in a Peruvian national reference hospital, are presented. The relevant clinical signs were rapidly progressive dementia and myoclonus, followed by akinetic mutism and pyramidal signs. Of the cases presented, 80% were men, with an average age of presentation of 65 years and duration from diagnosis to death of 6.5 months. Laboratory tests, images (Brain Resonance) and protein dosage 14.3.3 were performed to support the clinical suspicion. There is no effective treatment at the moment for said pathology. Creutzfeldt-Jakob disease (CJD) is a progressive, fatal, neurodegenerative disease of low prevalence and incidence. Great clinical suspicion and the exclusion of other etiologies are required. Currently there is no treatment for this entity and there is a high probability of death before one year.

Genetic and pathophysiological insights from autopsied patient with primary familial brain calcification: novel MYORG variants and astrocytic implications

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants.

Genetic profiles of multiple system atrophy revealed by exome sequencing, long-read sequencing and spinocerebellar ataxia repeat expansion analysis.

Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs. Although a few genetic factors have been reported to contribute to the disease, its mutational profiles have not been systemically studied. To address the genetic profiles of clinically diagnosed MSA patients, exome sequencing and triplet repeat detection was conducted in 205 MSA patients, including one familial case. The pathogenicity of variants was determined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. In the familial patient, a novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) was identified in the MSA pedigree. In the sporadic patients, 29 pathogenic variants were revealed in 21 genes, and the PARK7 p.Ala104Thr variant was significantly associated with MSA (p = 0.0018). Moreover, burden tests demonstrated that the pathogenic variants were enriched in cerebellar ataxia-related genes in patients. Furthermore, repeat expansion analyses revealed that two patients carried the pathogenic CAG repeat expansion in the CACNA1A gene (SCA6), one patient carried the (ACAGG)exp/(ACAGG)exp expansion in RFC1 and one carried the GAA-pure expansion in FGF14 gene. In conclusion, a novel COQ2 pathogenic variant was identified in a familial MSA patient, and repeat expansions in CACNA1A, RFC1 and FGF14 gene were detected in four sporadic patients. Moreover, a PARK7 variant and the burden of pathogenic variants in cerebellar ataxia-related genes were associated with MSA.

Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

Early Diagnosis of AP5Z1/SPG48 Spastic Paraplegia: Case Report and Review of the Literature.

Hereditary spastic paraplegias (HSPs) are a genetically heterogeneous group of neurodegenerative disorders clinically characterized by progressive lower limb spasticity with pyramidal weakness. Around a dozen potential molecular mechanisms are recognized. Childhood HSP is a significant diagnostic challenge in clinical practice. Mutations in AP5Z1, which are associated with spastic paraplegia type 48 (SPG48), are extremely rare and seldom described in children.We report the clinical, radiologic, and molecular studies performed in a child harboring novel biallelic mutations in AP5Z1.The child presented a neurodevelopmental disorder with slight lower limb pyramidal signs. Brain magnetic resonance imaging (MRI) showed minimal white matter changes in the frontal horns of the lateral ventricles and a normally shaped corpus callosum. Western blotting in cultured skin fibroblasts indicated reduced protein expression, which confirmed the genetic diagnosis and framed this as a case of protein reduction in a context of impaired autophagy.Our findings expand the spectrum of phenotypes associated with mutations in AP5Z1, highlighting their clinical and pathophysiologic overlap with lysosomal storage disorders. SPG48 should be considered in the differential diagnosis of neurodevelopmental disorders even when pyramidal signs are minimal and brain MRI not fully informative.

Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology

IntroductionCTNNB1 gene loss-of-function variants cause Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Although motor impairment represents a core feature of this condition, the motor phenotype remains poorly described. We systematically assessed a cohort of 14 patients with disease-causing CTNNB1 variants to better characterize the movement disorder phenotype. Methodspatients were enrolled at Bambino Gesù Children's Hospital in Rome, Italy, between January 2019 and February 2024. 14 participants were included and underwent extensive genetic and neurologic examination. Clinical features, neuroimaging and neurophysiological investigations were retrospectively analyzed from medical charts and video recordings. Results13 out of 14 patients showed motor disorders (one only showing mild coordination difficulties). 12 presented abnormal gait (11 patients with broad-based gait, one with narrow-based in-toeing gait, one with broad-based gait with unilateral intoeing). One did not achieve walking ability. 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13). Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients. ConclusionsCTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia.

Sporadic Creutzfeldt-Jakob disease in adults over 80years: a 10-year review of United Kingdom surveillance.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease with public health implications. Mean age of onset is 68years. Age-specific incidence declines after 80years. This may arise from under-ascertainment or other biological features of the disease. Accurate characterisation of late-onset sCJD is important for early diagnosis, avoiding unnecessary investigations and improving ascertainment for public health purposes. To phenotype the clinical features and investigation profile of sCJD in adults >80years. We analysed all probable and definite sCJD cases identified by the UK National CJD Research & Surveillance Unit over a 10-year period (2011-2021). Individuals were grouped by age of onset. Clinical features and investigation profiles were compared. 10.3% (123/1196) had an age of onset over 80. Median survival was shorter (3.2 vs 4.3months; P < 0.001). Pyramidal signs (48.3% vs 34.2%; P = 0.008) and akinetic mutism (55.1% vs 33.2%; P < 0.001) were more frequent. Psychiatric symptoms (26.3% vs 39.6%; P = 0.01) and cerebellar signs (65.4% vs 78.6%, P = 0.007) were less frequent. Cognitive impairment and myoclonus were highly prevalent regardless of age. Between age groups, the diagnostic sensitivity of cerebrospinal fluid real-time quaking-induced conversion (CSF RT-QuIC) (92.9% vs 91.9%, P = 0.74) was comparable, electroencephalography was superior (41.5% vs 25.4%; P = 0.006) and MRI was inferior (67.8% vs 91.4%; P < 0.001). Late-onset sCJD has distinct clinical features, shorter survival and a different profile of investigation sensitivity. CSF RT-QuIC, MRI brain and specialist CJD review is recommended in older adults with a rapidly progressive neurological disorder. Autopsy is valuable when the cause remains elusive.

Fisher Syndrome

Fisher syndrome is recognized as a variant of Guillain-Barré syndrome, encompassing acute onset immune-mediated neuropathies marked by the classical triad of ataxia, areflexia, and ophthalmoplegia. Generally, Fisher syndrome follows a self-limited course with a good prognosis. Ophthalmoplegia, typically bilateral, progresses to complete external ophthalmoplegia within 1-2 weeks. Ataxia, often very severe, may cause an inability to walk without support despite normal strength. Fisher syndrome is also frequently concomitant with additional clinical features, including ptosis, internal ophthalmoplegia, facial nerve palsy, sensory deficits, and bulbar palsy. The confirmation of an antecedent infection is often established. Among the ganglioside antibodies, anti-GQ1b antibodies exhibit positivity in over 80% of patients. The syndrome manifests in three distinct types: a partial subtype exhibiting only a subset of the triad symptoms, Bickerstaff's brainstem encephalitis marked by impaired consciousness and pyramidal tract signs, and an overlapping subtype with Guillain-Barré syndrome, characterized by weakness in the extremities.

Anti-IgLON5 disease as a differential diagnosis of multiple system atrophy

IntroductionAnti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a rare autoimmune encephalitis that can mimic progressive supranuclear palsy or corticobasal syndrome. Moreover, anti-IgLON5 disease can present with symptoms characteristic of multiple system atrophy (MSA), such as cerebellar ataxia and autonomic dysfunction. However, the clinical features of anti-IgLON5 disease resembling MSA have not been well established. MethodsWe enrolled 35 patients with suspected MSA for whom anti-IgLON5 antibody tests were requested. We evaluated immunoglobulin G (IgG) against IgLON5 using cell-based assays. We also summarized the clinical characteristics of patients who were positive for anti-IgLON5 antibodies. ResultsWe identified serum and cerebrospinal fluid anti-IgLON5 antibodies in three patients. These patients had many clinical features characteristic of MSA, including parkinsonism, cerebellar ataxia, severe orthostatic hypotension, acute respiratory failure, sleep parasomnia, vocal cord paralysis, and pyramidal tract signs. Clinical features atypical for MSA were myorhythmia, horizontal eye movement restriction, fasciculations, and painful muscle cramps. ConclusionAnti-IgLON5 disease may be an important differential diagnosis of MSA. A comprehensive physical examination, including assessments of eye movement, lower motor neuron signs, and atypical involuntary movements, is important to avoid misdiagnosis.

SYNE1 gene mutation: A recessive ataxic syndrome presenting with weakness and muscle atrophy. A case report

BackgroundAutosomal recessive spinocerebellar ataxia type 8 (SCAR8) is a rare neurodegenerative disease that can be manifest in a wide spectrum from ataxias and motoneuron syndromes. ObjectiveTo report a case of mutation in the SYNE1 gene with predominant motoneuron disease signs. MethodsIndex case medical report and literature review. ResultsA 32-year-old woman onset with pyramidal and lower motoneuron signs and symptoms during the second decade of life, with marked dysarthria showing associated cerebellar pattern. Clinical investigation with electroneuromyography showed chronic preganglionic disease and brain MRI showed cerebellar atrophy. Genetic testing confirmed pathogenic mutation in homozygosity in the SYNE1 gene. ConclusionsRare neurological condition that may be associated with signs of impairment of the pyramidal pathway and second motoneuron (amyotrophic lateral sclerosis-like syndrome), in addition to cerebellar ataxia in insidious course.

Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.

Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical and Imaging Profile of Patients with Cerebrotendinous Xanthomatosis - a Video Case Series from India.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX. This is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented. Five patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis. CTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.

Infratentorial superficial siderosis: report of six cases and review of the literature.

To investigate the etiology, clinical manifestations, imaging features, and treatment of patients with infratentorial superficial siderosis (iSS), enhance clinicians' comprehension of this rare disease, and conduct oral deferiprone intervention and subsequent monitoring. Six patients diagnosed with iSS based on magnetic resonance imaging (MRI) and susceptibility weighted imaging (SWI) were enrolled from 2021 to 2023 at the First Affiliated Hospital of Fujian Medical University. Their clinical datas were summarized, and the etiology and imaging characteristics were analyzed. Follow-up was conducted through telephone or outpatient visits. Among the 6 patients, there were 3 males and 3 females. The onset age ranged from 35 to 71 years, with an average onset age of 53 years. The clinical symptoms mainly included acoustic disturbances (6/6), gait imbalance (6/6), dysolfactory (6/6), cognitive impairment (2/6), epilepsy (2/6), and pyramidal tract sign (2/6). Evidence of superficial siderosis was observed on MRI across the cortex, brainstem, cerebellum, and spinal cord in all patients. T2-space sequence MRI revealed two instances of dural tear. During the follow-up period ranging from 1 month to 3 years, three patients who received oral deferiprone treatment showed improvement, whereas the remaining three patients who declined deferiprone treatment demonstrated progression. The primary clinical manifestations of iSS include bilateral sensorineural hearing disturbances, progressive cerebellar ataxia, and spinal cord lesions. The key diagnostic criteria involve the presence of linear hypointensity on T2-WI in the surface region of the nervous system. Dural tear caused by various factors is considered to be the most common cause of iSS, and its treatment mainly involves surgical intervention for hemorrhagic primary diseases as well as pharmacotherapy with deferiprone.

Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study.

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

Hot cross bun in pediatric age multi-system atrophy an unusual presentation

A 10-year-old female was brought to emergency department with complaint fever, cold, and cough for 5 days followed by weakness of upper limb weakness more than Lower limb associated with inability to walk/stand, brought to emergency with altered sensorium. Nervous system: Confused and altered, tone is normal, power: 3/3 in upper limbs 2/2 in lower limbs and reflexes in bilateral knee brisk, bilateral plantar-extensor; On general examination revealed hypomimia, dysarthria and bilateral bradykinesia along with ataxic gait and pyramidal signs. Blood investigation were normal and diagnosis made by neuroimaging s/o: Bilaterally symmetrical abnormal signal in both postero-medial thalami, bilateral insular cortices, pons and bilateral middle cerebellar peduncles. It is extending into pons involving transverse pontocerebellar tracts and median pontine raphe nuclei giving 'Hot cross bun sign' (HCBS). During course of treatment child had autonomic disturbances. Child was treated with supportive medication and methyl-presdnisolone followed by oral steroid. Child had responded to treatment given and child has been discharged with no neurological deficit on oral medications. We concluded autonomic dysfunction in any patient presenting with acute onset of weakness with short duration must evaluate for MSA and institute appropriate treatment.

Rare forms of autosomal recessive spinocerebellar ataxia associated with mutations in the ANO10 (ATX-ANO10) and SYNE1 (ATX-SYNE1) genes

To analyze clinical and genetic characteristics of patients with the verified rare forms of autosomal recessive spinocerebellar ataxias, ATX-ANO10 and ATX-SYNE1. Six unrelated patients with established diagnoses were examined: 4 patients with ATX-ANO10 and 2 patients with ATX-SYNE1. Brain MRI and nerve conduction study were performed. To screen for cognitive impairment, the scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) were used. Mutation screening included panel sequencing on the Illumina MiSeq platform. Six variants were found in the ANO10 gene: the previously described pathogenic nonsense mutations c.G1025A (p.W342X) and c.C1244G (p.S415X), as well as novel probably pathogenic variants c.1477-2A>G and c.G101T (p.W34L) and missense mutations c.A110C (p.N37T) and c.T104C (p.L35P) of undetermined significance. A novel nonsense mutation c.C8911T (p.Q2971X) and a previously described pathogenic variant c.C4939T (p.Q1647X) were found in the SYNE1 gene. The clinical presentation of the ATX-ANO10 and ATX-SYNE1 was typical presenting with slowly progressive cerebellar ataxia with pyramidal signs, with young onset and cerebellar atrophy according to brain MRI study. We provided first-ever data on clinical features and mutation spectrum In Russian patients with ATX-ANO10 and ATX-SYNE1. The phenotype of these ataxias is nonspecific, so the method of choice for molecular diagnostics is massive parallel sequencing.

Болезнь Галлервордена — Шпатца (пантотенат киназа-ассоциированная нейродегенерация)

The article presents a clinical case of a rare hereditary Hallervorden — Spatz disease with an atypical late form with onset in the fourth decade of life with a rapidly progressive course and unfavorable prognosis. The most characteristic signs of the disease in this patient were parkinsonism syndrome, pyramidal signs, various types of hyperkinesis, decreased cognitive functions, and depression. The diagnosis was confirmed by a clinical and a typical MRT signs in the form of the «tiger’s eye» symptom. There is no etiological and pathogenetic therapy for this disease; patients receive symptomatic treatment, the prognosis is unfavorable.

Two patients of immunotherapy-responsive autoimmune cerebellar ataxia fulfilled with criteria of multiple system atrophy

We report two patients with autoimmune cerebellar ataxia who fulfilled the diagnostic criteria of multiple system atrophy (MSA) and responded to immunotherapies. Patient 1 was a 72-year-old man who was diagnosed with clinically probable MSA according to Movement Disorder Society criteria. Patient 2 was a 68-year-old man who was diagnosed with clinically established MSA according to Movement Disorder Society criteria. Both patients showed cerebellar ataxia, autonomic dysfunction, and pyramidal tract signs; however, they also had atypical clinical features. Patient 1 exhibited self-‍limiting mild improvement of clinical symptoms and had inflammatory findings in his cerebrospinal fluid. Patient 2 showed a rapidly progressive clinical course. We therefore examined anti-neuronal antibodies using tissue-based immunohistochemical assays with frozen rat cerebellum sections. We detected autoantibodies that mainly reacted with the cytoplasm of Purkinje cells. The two patients then underwent immunotherapies, which led to substantial improvements in their clinical symptoms. Our findings indicate that some patients with autoimmune cerebella ataxia have clinical features that resemble MSA, and respond well to immunotherapies.

A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies

ObjectiveMitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. MethodsThis study summarizes the clinical, imaging, and molecular data of these patients for five years. ResultsThe three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. ConclusionsThe findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

Atypical presentations of autosomal dominant familial Alzheimer’s disease: insights into genetic, neuropathological and clinical heterogeneity

AbstractBackgroundAutosomal dominant familial Alzheimer’s disease (ADAD), caused by APP, PSEN1 and PSEN2 mutations, is clinically and pathologically similar to sporadic AD, with both typically presenting with memory impairment. However as in sporadic AD, atypical phenotypes and neuropathological heterogeneity occur, including variable vascular Aβ deposition as cerebral amyloid angiopathy (CAA). Investigating relationships between clinical, genetic and neuropathological heterogeneity in ADAD may provide insights into pathophysiological pathways relevant to AD in general.Methods256 symptomatic individuals from ADAD families seen at our Centre were included in a survival analysis, with detailed clinical phenotype data available for 138 (101 PSEN1, 37 APP). 33 of these individuals underwent brain donation (24 PSEN1, 9 APP), all demonstrating end‐stage AD pathology. Frontal and occipital cortex sections were stained immunohistochemically for Aβ and vessel counts used to determine the proportion of cortical and leptomeningeal blood vessels affected by CAA.ResultsAge at onset was, on average, seven years younger for PSEN1 than APP mutations and was influenced by mutation much more than survival was. Atypical (non‐amnestic) cognitive presentations with initial behavioral, language, dyscalculic or dysexecutive symptoms, and atypical clinical features (pyramidal, extrapyramidal and cerebellar signs) were more common in PSEN1 than APP cases, particularly those with post‐codon 200 mutations. Atypical cognitive presentations were associated with longer survival. There was some indication that APOE4 carriers had longer survival and that this effect may be restricted to PSEN1. In the post‐mortem cohort, atypical cognitive presentations occurred in 15%. Additional neurological features comprised myoclonus (45%), seizures (21%), pyramidal signs (21%) and extrapyramidal signs (15%), one individual had cerebellar signs. Increased frontal cortical and leptomeningeal CAA occurred in individuals with pyramidal and extrapyramidal signs, and in PSEN1 post‐codon 200 compared to pre‐codon 200 mutations. Atypical cognitive presentations were associated with increased frontal cortical CAA.ConclusionsPhenotypic heterogeneity in ADAD is influenced by causative gene and mutation type, and atypical clinical presentations are associated with increased CAA. Exploring mechanisms by which certain mutations drive Aβ deposition towards the vasculature, and how these may be impacted by other genetic factors and by therapies targeting Aβ, is an important direction for future research.