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Background Spastic Paraplegia type 7 (SPG7) is one of the most common autosomal recessive Hereditary Spastic Paraplegias (HSP); Spastic Paraplegias (SPGs) can present as hereditary ataxias. However, ataxia is frequently the symptom of presentation of many other hereditary/sporadic disorders, such as Multiple system atrophy type C (MSA-C), an α-synuclein sporadic neurodegenerative disorder, in which cerebellar ataxia is one of the main clinical features. Dopamine Transporter imaging (DAT-SCAN), associated with clinical features, can be a helpful tool in order to distinguish MSA-C from other causes of ataxia. Case-presentation We present the case of a 70-year-old man with gait difficulties over a period of 3 years and frequent backward/lateral falls. He also reported urinary urge incontinence, but no symptoms that are compatible with orthostatic hypotension. On neurological examination he showed ataxic gait, spasticity in the left lower limb and trunk and limb ataxia, especially on the left side. Mild hypokinesia was found in all 4 limbs, especially in the left foot. MRI revealed atrophy of the cerebellar hemispheres and vermis. DAT-SCAN imaging revealed bilateral nigro-striatal degeneration, which was compatible with a diagnosis of possible MSA-C. Considering the atypical disease course (the patient walked without any support after 3 years), we carried out a genetic investigation for Ataxia, and a mutation in SPG7 was found. Conclusions DAT-SCAN imaging, evaluated together with the clinical findings, can be useful for differentiating MSA from other possible causes of adult-onset Ataxia. Indeed, patients with MSA-C generally show a decreased uptake of dopamine transporters in DAT-SCAN imaging. Ours is the first case reported in the literature of a patient with SPG7 mutation with nigrostriatal degeneration and a clinical presentation of a possible MSA-C. Performing genetic investigations in patients with an atypical disease course is important to avoid MSA-mimicries. Identifying the correct diagnosis is important not only for prognostic reasons, but also for possible future genetic therapies.

Rhombencephalitis is an orphan disease of multiple causes that may manifest with facial palsy, limb ataxia and reduced consciousness. Up to now it is described after COVID-19 infection and in this (personal) case was found up to 8 weeks after Comirnaty vaccination. So far, we do not fully understand the pathophysiological characteristics of encephalitis associated with SARS-CoV-2. In rare cases, vaccination may cause an immunological reaction and delayed inflammation, the consequences of which we have not yet deciphered. Rhombencephalitis should be considered as a rare potential mRNA-associated vaccination side effect. Supplementary Information The online version contains supplementary material available at 10.1186/s42466-021-00156-7.

Spinocerebellar ataxia type 23 (SCA23) is a late‐onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by pathogenic variants in PDYN, which encodes prodynorphin (PDYN). PDYN is processed into the opioid peptides α‐neoendorphin and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signaling, stress‐induced responses and addiction. Variants causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYN R212W mice express human PDYN containing the SCA23 variant p.R212W. These mice show progressive motor deficits from 3 months of age, climbing fiber (CF) deficits from 3 months of age, and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely increased GABAergic interneuron connectivity and non‐cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Examining PDYN R212W cerebella during development, we uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height, leaving proximal PC dendrites open to be occupied by parallel fibers (PFs). The observed increase in vGlut1 protein—a marker for PF‐PC synapses—indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYN R212W cerebella. These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum., Cerebellar developmental deficits preceding neurodegeneration in a mouse model of spinocerebellar ataxia type 23. Deficits include reduced basket cell and climbing fiber synapses on Purkinje cells, and increased parallel fiber‐Purkinje cell contact.

Guillain-Barré (GBS) and Fisher (FS) syndromes rarely recur and the characteristics of recurrence have not been fully elucidated. We describe the cases of 2 patients with GBS or FS that recurred more than twice and who were subsequently diagnosed with aplastic anemia. Case 1 was a 66-year-old man who was diagnosed with aplastic anemia 10 months before admission with limb ataxia and a sensory disturbance of the distal limbs that developed 3 days after an upper respiratory tract infection. He had a history of double vision with ataxia at the ages of 38 and 56 years. Case 2 was a 66-year-old woman who had been treated for aplastic anemia 1 year previously. She had a history of upper limb weakness after upper respiratory tract infections at the ages of 39 and 60 years. Tendon reflexes were absent in both patients at the time of onset and they were respectively diagnosed with FS and GBS and treated with intravenous immunoglobulin. No neurological deficits persisted. Blood findings showed that both were positive for IgG type ganglioside antibodies and HLA-DR15. The positive HLA-DR15 might have been associated with the recurrent GBS or FS and the development of aplastic anemia.

The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.

Progressive supranuclear palsy (PSP) is characterized by supranuclear gaze palsy, dystonic rigidity of the neck and upper trunk, frequent falls and mild cognitive impairment. Cerebellar ataxia is one of the exclusion criteria given by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. As a result, pathologically proven PSP patients exhibiting cerebellar ataxia have often been misdiagnosed with spinocerebellar degeneration, specifically multiple system atrophy with predominant cerebellar ataxia (MSA-C). However, more recently, it has been recognized that patients with PSP can present with truncal and limb ataxia as their initial symptom and/or main manifestation. These patients can be classified as having PSP with predominant cerebellar ataxia (PSP-C), a new subtype of PSP. Since the development of this classification, patients with PSP-C have been identified primarily in Asian countries, and it has been noted that this condition is very rare in Western communities. Furthermore, the clinical features of PSP-C have been identified, enabling it to be distinguished from other subtypes of PSP and MSA-C. In this review, we describe the clinical and neuropathological features of PSP-C. The hypothesized pathophysiology of cerebellar ataxia in PSP-C is also discussed.

Introduction Amyotrophy in Creutzfeldt-Jakob Disease (CJD) is rarely a conspicuous clinical finding. The overlap of CJD (a prionopathy) and motor neuron disease is reported in the literature but it remains to be established whether the neuronopathy is an integral part of CJD presentation, or, whether this represents a distinct variety. Our case describes a male patient with clincopathological diagnosis of sporadic CJD along with evidence of motor neuronopathy on nerve conduction studies. Case Summary At presentation to our neurology service, the patient was a 72-year-old male, living at home with his wife. He was initially referred for progressive short-term memory loss, personality change, and gait disturbance. On review, it was noted that in addition to gait and limb ataxia, and cognitive impairment, he demonstrated prominent generalised fasciculation. Nerve conduction and electromyography studies showed normal nerve conduction but fasciculations in proximal and distal muscle groups of the left upper and lower limbs, in keeping with a motor neuronopathy. CSF 14-3-3 and EEG provided little bearing. MRI demonstrated progressive T2-hyperintense, diffusion-restricted lesions in the bilateral basal ganglia, thalami and medial frontal cortices consistent with CJD. Post-mortem examination demonstrated spongiform encephalopathy and immunohistological staining (12F10) in-keeping with diagnosis of CJD. Conclusion In our patient, the combination of clinical and neurophysiologic features of motor neuron disease and a confirmed diagnosis of Creutzfeldt-Jakob Disease raises the vexed question of whether this represents a distinct overlap syndrome or an infrequent manifestation of the same pathology. Further research is required to establish this.

Autoimmune and paraneoplastic movement disorders are increasingly recognized as a result of improved methods in detecting antibodies directed against intracellular, membrane, and other antigens.1 High concentrations of anti-glutamic acid decarboxylase 65 (GAD65) antibodies are associated with several neurologic syndromes including stiff-person syndrome, epilepsy, limbic encephalitis, and cerebellar ataxia.2 Anti-GAD65-associated cerebellar ataxia is typically generalized with prominent gait disturbance and eye movement abnormalities.1 Limb ataxia is present in 60-70% of patients.3 Here we present 2 unusual cases of hemiataxia associated with high concentrations of anti-GAD65 antibodies.

Friedreich's ataxia is a rare degenerative neuromuscular disorder, caused by a homozygous GAA triplet repeat expansion in the frataxin (FXN) gene, with a broad clinical phenotype characterized by progressive gait and limb ataxia, dysarthria, and loss of lower limb reflexes; cardiac involvement is represented by hypertrophic cardiomyopathy, ventricular arrhythmias, and sudden cardiac deaths. Currently, no definite therapy is available, while many drugs are under investigation; for this reasons, we need markers of short‐ and long‐term treatment efficacy acting on different tissue for trial evaluation. We describe the case of a 21‐year‐old patient affected by Friedreich's ataxia on wheel‐chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment‐related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich's ataxia.

Infarcts involving the thalamus can yield many deficits, including sensory syndromes, altered consciousness, and cognitive disturbances, depending on the thalamic vascular territory involved. Isolated truncal contrapulsion due to pure thalamic infarct has been rarely reported. Truncal lateropulsion is a compelling sensation of being pulled toward one side that cannot be explained by weakness or limb ataxia. It is commonly reported in lateral medullary infarcts. It may occur with lesions that involve the peripheral vestibular system, brainstem, cerebellum, basal ganglia, ponto-mesencephalic, and thalamic lesions. We hereby report a 64-year-old woman who presented with truncal contrapulsion as the sole manifestation of an acute right lateral thalamic infarct.

Background Neurodegenerative disorders are characterized by insidious progression with poorly-delineated long latent period. Antecedent clinical insult could rarely unmask latent neurodegenerative disorders. Here, we report an autopsy-proven case of corticobasal degeneration which was preceded by a lacunar infarction. Case presentation A 58-year-old man presented with acute ataxia associated with a lacunar infarction in the right paramedian pons. His ataxia persisted with additional progressive gait difficulty and left arm clumsiness. Six months later, a follow-up neurological examination showed asymmetrical bradykinesia, apraxia, dystonic posturing, postural instability, and mild ataxia of the left limbs. Cognitive examination revealed frontal executive dysfunction and visuospatial difficulties. Dopamine transporter imaging scan demonstrated bilateral reduced uptakes in mid-to-posterior putamen, more prominent on the right side. Levodopa-unresponsive parkinsonism, asymmetric limb dystonia, and ideomotor apraxia became more conspicuous, while limb ataxia gradually vanished. The patient became unable to walk without assistance after 1 year, and died 4 years after the symptom onset. Autopsy findings showed frontoparietal cortical atrophy, ballooned neurons, and phosphorylated tau-positive astrocytic plaques and neuropil threads with gliosis and neuronal loss, confirming the corticobasal degeneration. Conclusions The case illustrates that precedent clinical events such as stroke might tip a patient with subclinical CBS into overt clinical manifestations.

ObjectiveTo better characterize the neurologic and cognitive profile of patients with spinocerebellar ataxia 34 (SCA34) caused by ELOVL4 mutations and to demonstrate the presence of ELOVL4 cellular localization and distribution abnormalities in skin-derived fibroblasts.MethodsWe investigated a 5-generation French-Canadian kindred presenting with a late-onset cerebellar ataxia and recruited age- and education-matched controls to evaluate the presence of neurocognitive impairment. Immunohistochemistry of dermal fibroblasts derived from a patient's skin biopsy was performed.ResultsPatients had a late-onset slowly progressive cerebellar syndrome (mean age at onset 47 years; range 32–60 years) characterized by truncal and limb ataxia, dysarthria, hypometric saccades, and saccadic pursuits. No patient had past or current signs of erythrokeratodermia variabilis, which had previously been reported. MRI revealed cerebellar atrophy, with pontine atrophy (4 of 6 patients), and cruciform hypersignal in the pons (2 of 6 patients). Fluorodeoxyglucose-PET showed diffuse cerebellar hypometabolism in all 5 tested patients with subtle parietal hypometabolism in 3. Significant cognitive deficits were found in executive functioning, along with apparent visuospatial, attention, and psychiatric involvement. Immunohistochemistry of dermal fibroblasts showed mislocalization of the ELOVL4 protein, which appeared punctate and aggregated, supporting a dominant negative effect of the mutation on protein localization.ConclusionsOur findings support the pathogenicity of ELOVL4 mutations in cerebellar dysfunction and provide a detailed characterization of the SCA34 phenotype, with neurocognitive changes typical of the cerebellar cognitive-affective syndrome.

Background and Purpose: Strokes due to small (Methods: This study is a retrospective analysis of clinical and imaging features of a prospectively assessed series of 108 consecutive patients with acute cerebellar infarction admitted to Liverpool Hospital, Sydney, NSW, Australia, during 2011–2015. Results: The mean age of the patients was 67 years, and 33 (31%) had small cerebellar infarction. Compared to large cerebellar infarction, those with small cerebellar infarction had a comparable distribution of vascular risk factors but significantly less nausea and vomiting, gait disturbance, limb ataxia, and dysarthria. The posterior (n = 22, 67%) lobe was most commonly affected, followed by the anterior (n = 9, 27%) and flocculonodular (n = 2) lobes. Dizziness, limb ataxia, and nystagmus were significantly more common in patients with anterior lobe infarction. Vertebrobasilar disease was the presumed aetiology in 40 patients (37%), and was less commonly seen in small as compared to large cerebellar infarction. Cardioembolism affected 37% of the patients, irrespective of the size or topography of the cerebellar infarction, and there was no relation of supratentorial white matter lucencies (WMLs) to the size of cerebellar infarction. At 3 months, 65% of the patients were functionally independent (according to modified Rankin Scale scores of 0–2), and having a poor outcome was significantly related to moderate-to-severe supratentorial WML and large cerebellar infarction. Conclusions: Small cerebellar infarction accounted for one-third of the ischaemic strokes in this location, most often involved the posterior lobe, causing fewer clinical features, and had a better clinical outcome than large cerebellar infarction. Patients with small cerebellar infarction require appropriate vascular management including investigation for a cardioembolic source.

Background To date, 43 types of Spinocerebellar Ataxias (SCAs) have been identified. A subset of the SCAs are caused by the pathogenic expansion of a CAG repeat tract within the corresponding gene. Ethnic and geographic differences are evident in the prevalence of the autosomal dominant SCAs. Few descriptions of the clinical phenotype and molecular genetics of the SCAs are available from the African continent. Established studies mostly concern the South African populations, where there is a high frequency of SCA1, SCA2 and SCA7. The SCA7 mutation in South Africa (SA) has been found almost exclusively in families of indigenous Black African ethnic origin. Objective To present the results of the first clinical description of seven Zambian families presenting with autosomal dominant SCA, as well as the downstream molecular genetic analysis of a subset of these families. Methods The study was undertaken at the University Teaching Hospital in Lusaka, Zambia. Ataxia was quantified with the Brief Ataxia Rating Scale derived from the modified international ataxia rating scale. Molecular genetic testing for 5 types of SCA (SCA1, SCA2, SCA3, SCA6 and SCA7) was performed at the National Health Laboratory Service at Groote Schuur Hospital and the Division of Human Genetics, University of Cape Town, SA. The clinical and radiological features were evaluated in seven families with autosomal dominant cerebellar ataxia. Molecular genetic analysis was completed on individuals representing three of the seven families. Results All affected families were ethnic Zambians from various tribes, originating from three different regions of the country (Eastern, Western and Central province). Thirty-four individuals from four families had phenotypic features of SCA7. SCA7 was confirmed by molecular testing in 10 individuals from 3 of these families. The age of onset of the disease varied from 12 to 59 years. The most prominent phenotypic features in these families were gait and limb ataxia, dysarthria, visual loss, ptosis, ophthalmoparesis/ophthalmoplegia, pyramidal tract signs, and dementia. Affected members of the SCA7 families had progressive macular degeneration and cerebellar atrophy. All families displayed marked anticipation of age at onset and rate of symptom progression. The pathogenic SCA7 CAG repeat ranges varied from 47 to 56 repeats. Three additional families were found to have clinical phenotypes associated with autosomal dominant SCA, however, DNA was not available for molecular confirmation. The age of onset of the disease in these families varied from 19 to 53 years. The most common clinical picture in these families included a combination of cerebellar symptoms with slow saccadic eye movements, peripheral neuropathy, dementia and tremor. Conclusion SCA is prevalent in ethnic Zambian families. The SCA7 families in this report had similar clinical presentations to families described in other African countries. In all families, the disease had an autosomal dominant pattern of inheritance across multiple generations. All families displayed anticipation of both age of onset and the rate of disease progression. Further clinical and molecular investigations of the inherited ataxias in a larger cohort of patients is important to understand the natural history and origin of SCAs in the Zambian population.

Objectives: Neuroimaging is contributing to the rising costs of dizziness evaluation. This study examined the rate of central neurological causes of dizziness, relevant clinical predictors, and the costs and diagnostic yields of neuroimaging in dizziness assessment. Methods: We retrospectively reviewed the records of 521 adult patients who visited the hospital during a 12-month period with dizziness as the chief complaint. Clinical findings were analyzed using Fisher’s exact test to determine how they correlated with central neurological causes of dizziness identified by neuroimaging. Costs and diagnostic yields of neuroimaging were calculated. Results: Of the 521 patients, 1.5% had dizziness produced by central neurological causes. Gait abnormalities, limb ataxia, diabetes mellitus, and the existence of multiple neurological findings predicted central causes. Cases were associated with gait abnormalities, limb ataxia, diabetes mellitus, and the existence of multiple neurological findings . Brain computed tomography (CT) and magnetic resonance imaging (MRI) were performed in 42% and 9.5% of the examined cases, respectively, with diagnostic yields of 3.6% and 12%, respectively. Nine cases of dizziness were diagnosed from 269 brain scans, costing $607 914. Conclusion: Clinical evaluation can predict the presence of central neurological causes of dizziness, whereas neuroimaging is a costly and low-yield approach. Guidelines are needed for physicians, regarding the appropriateness of ordering neuroimaging studies. Abbreviations: OR: odds ratio; CI: confidence interval; ED: emergency department; CT: computed tomography; MRI: magnetic resonance imaging; HINTS: Head impulse, Nystagmus, Test of skew

Posterior inferior cerebellar artery (PICA) aneurysm is relatively rare. We report on a 74-year-old woman presenting with dizziness and right-side tilted gait caused by a right-side distal PICA aneurysm, which mimicked a right lateral medullary infarction. A neurological examination showed right-side limb ataxia and left-beating torsional nystagmus, similar to a right lateral medullary infarction. Magnetic resonance imaging revealed a distal PICA aneurysm in the right-side middle cerebellar peduncle region.

Pathological yawning is rarely observed in cerebral or spinal diseases. A 67-year-old woman was admitted with a seven-day progressive hemisyndrome with left-sided limb ataxia and hypesthesia. The patient yawned with a high frequency, partially in salve-like episodes. MRI showed a cervical myelitis over more than three vertebral segments up to the lower medulla and Aquaporin-4-antibodies were positive (diagnostic criteria for a Neuromyelitis optica spectrum disorder were fulfilled). Under treatment with methylprednisolone, followed by plasmapheresis and immunoadsorption, clinical symptoms were regressive and the frequency of yawning completely normalized. When observing pathological yawning, even in the absence of other cerebral or brainstem symptoms, one should be aware of NMOSD as a possible cause.

Background CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss) syndrome is caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. Other mutations in this gene can cause a spectrum of overlapping phenotypes including alternating hemiplegia of childhood, rapid onset dystonia parkinsonism, early infantile epileptic encephalopathy and fever induced paroxysmal weakness and encephalopathy. The phenotype is still mistaken for mitochondrial/metabolic disorders and follow up studies are scare. Case presentation We report a 20 year old Norwegian male with ataxia, sensorineural deafness and visual loss. Before the age of five he experienced three fever related episodes of acute neurological deterioration when he temporarily lost his acquired motor skills and developed persistent gait and limb ataxia. In childhood, he developed bilateral optic atrophy and bilateral sensorineural hearing loss. Motor skills improved and at age 20 the patient showed a mild ataxia, hearing loss and reduced vision. A c.2452G > A mutation in the ATP1A3 gene was identified and CAPOS syndrome was confirmed. Conclusions This is the first Norwegian patient reported with CAPOS syndrome. Our patient had a de novo, previously identified ATP1A3 mutation. The combination of recurrent episodes of fever related ataxia, loss of motor skills in early childhood, and early onset hearing and vision loss is typical of CAPOS syndrome. Previous reports suggest a gradual progression of the disease after the initial episodes, while this patient showed a good outcome with improvement of motor skills from adolescence long after the last deterioration episode. Electronic supplementary material The online version of this article (10.1186/s40673-019-0096-3) contains supplementary material, which is available to authorized users.

Mutations in the voltage-gated Cav2.1 P/Q-type calcium channel (CACNA1A) can cause a wide spectrum of phenotypes, including the episodic ataxia type 2. Beside the growing number of descriptions of novel CACNA1A mutations with episodic ataxia type 2 phenotype; there are only rare reports on interictal oculomotor signs other than nystagmus. We describe a novel CACNA1A mutation and an unclassified CACNA1A in-frame variant in a Swiss family presenting as the episodic ataxia type 2 phenotype associated with reduced saccade velocity. In this case series interictal clinical examination showed only minimal neurological findings as mild limb ataxia and nystagmus, but most interestingly saccade analysis of all three affected individuals demonstrated reduced mean saccade velocity. Genetic testing of CACNA1A revealed a de novo frame-shift mutation (c.2691dupC/p.Thyr898Leufs*170) in the index patient in addition to an unclassified in-frame variant (c.6657_6659dupCCA/p.His2220dup) segregating in all three affected individuals. The de novo frame-shift CACNA1A mutation and the unclassified in-frame CACNA1A variant were associated with the episodic ataxia type 2 phenotype and reduced mean saccade velocity, which suggests involvement of brainstem or neural pathways connecting brainstem and the cerebellum in this disease.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, visual defects, scoliosis, pes cavus and cardiomyopathy. It is caused by a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion in intron 1 of the frataxin gene (FXN) on chromosome 9q13-q21.1. Onset is usually in the first or second decade of life; however, late-onset cases of Freidreich ataxia (LOFA), after the age of 25 years, and very late-onset cases of Freidreich ataxia (VLOFA), after the age of 40 years, have been reported. VLOFA is quite rare and usually presents a milder progression of the disease. We report the case of a 64-year-old woman affected with VLOFA whose first symptoms (balance and gait disturbances) occurred at the age of 44 years. At the age of 62 years, she started complaining of a slowly progressive dysphonia showing the clinical aspects of laryngeal dystonia. Molecular analysis showed a 210- and 230-trinucleotide GAA repeat expansion in the two alleles of the FXN gene. Laryngeal dystonia has been reported only in very few cases of ataxia syndrome and never before in FRDA patients. It may represent a rare clinical manifestation of VLOFA thus confirming the high variability of the clinical spectrum of FRDA.

One hundred and fifty years since Nikolaus Friedreich's first description of the degenerative ataxic syndrome which bears his name, his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. Onset is typically around puberty with slow progression and shortened life-span often related to cardiac complications. Inheritance is autosomal recessive with the vast majority of cases showing an unstable intronic GAA expansion in both alleles of the frataxin gene on chromosome 9q13. A small number of cases are caused by a compound heterozygous expansion with a point mutation or deletion. Understanding of the underlying molecular biology has enabled identification of atypical phenotypes with late onset, or atypical features such as retained reflexes. Late-onset cases tend to have slower progression and are associated with smaller GAA expansions. Early-onset cases tend to have more rapid progression and a higher frequency of non-neurological features such as diabetes, cardiomyopathy, scoliosis and pes cavus. Compound heterozygotes, including those with large deletions, often have atypical features. In this paper, we review the classical and atypical clinical phenotypes of Friedreich's ataxia.

The most common causes of acute cerebellar ataxia are vascular disorders resulting in cerebellar ischaemia or haemorrhage. Most cerebellar haemorrhages are midline and therefore present with gait ataxia, truncal ataxia, dysmetria of lower extremities, saccadic intrusions and vertigo. Symptoms for cerebellar hemisphere lesions include dysdiadochokinesis, dysmetria of upper extremities, limb ataxia, intention tremor and scanning speech. Chronic progressive ataxias are most commonly degenerative and frequently hereditary in origin; they account for half the cases of adult onset ataxia.1 Developmental venous anomalies are commonly encountered congenital anatomical variations of the cerebral vasculature—a malformation of …

In the present study, eye movements are recorded in two patient groups with an autosomal dominantly inherited cerebellar disorder, i.e. spinocerebellar ataxia type 6 (SCA6) and familial cortical myoclonic tremor with epilepsy (FCMTE). In SCA6 and FCMTE patients striking similarities with the extensive Purkinje cell changes in the cerebellar cortex were described, but the two disorders have a distinctive clinical picture. SCA6 is a late-onset cerebellar syndrome, with relatively minimal brain stem and cerebral cortex symptoms. In contrast, FCMTE is clinically characterized by cortical symptomatology with a distal cortical myoclonic tremor and infrequent epileptic attacks without cerebellar dysarthria and limb ataxia. Comparison of oculomotor function of six FCMTE patients, five SCA6 patients and 18 healthy controls demonstrated both in SCA6 patients and FCMTE patients square wave jerks, downbeat nystagmus (DBN) and a stronger reduced downward smooth pursuit gain than an upward smooth pursuit gain. Only in SCA6 patients horizontal smooth pursuit gain was reduced. Except for the downward direction mean saccadic gain in both patient groups was reduced. This is consistent with cerebellar cortical pathology in both disorders. Subsequently, both patient groups showed increase of DBN with hyperventilation. As a novel finding, only the FCMTE patients showed a significantly increased amount of express saccades in the pro-saccade paradigm.

In spite of the considerable progress in clinical and molecular research, knowledge regarding brain damage in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) still is limited and the extent to which the thalamus is involved in both diseases is uncertain. Accordingly, we performed a pathoanatomical analysis on serial thick sections stained for lipofuscin granules and Nissl substance through the thalami of two genetically confirmed cases: one an SCA2 patient, the other an SCA3 patient. During this systematic study, we detected severe destruction of the reticular (RT), fasciculosus (FA), ventral anterior (VA), ventral lateral (VL), ventral posterior lateral (VPL), ventral posterior medial (VPM), cucullar (CU) and mediodorsal thalamic nuclei (MD), the lateral geniculate body (LGB) and inferior nucleus of the pulvinar (PU i) in the SCA2 case, and a severe neuronal loss in the RT, FA, VA and PU i of the SCA3 case. In the SCA2 patient, additional obvious neuronal loss was observed in all nuclei of the anterior and rostral intra laminar groups, in the lateral posterior nucleus (LP), the lateral (PU l) and the medial subnuclei of the pulvinar (PU m), whereas in the SCA3 patient only two of the nuclei that belong to the anterior thalamic group, the VL, VPL, VPM, LP, LGB, PU l and PU m, displayed marked neurodegeneration. These novel findings indicate that thalamic involvement in SCA2 and SCA3 patients has been underestimated in the past. In view of what is known about the functions of the affected thalamic nuclei, the present findings provide an appropriate pathoanatomical explanation for some of the disease-related symptoms seen in both of our and other SCA2 and SCA3 patients: gait, stance, truncal and limb ataxia, dysarthria or anarthria, falls, dysdiadochokinesia and bradykinesia, problems with writing, somatosensory deficits, saccadic dysfunctions, executive dysfunctions and abnormalities of visual evoked potentials.

Multiple system atrophy is a rare and fatal neurodegenerative disorder characterized by progressive autonomic failure, ataxia and parkinsonism in any combination. The clinical manifestations reflect central autonomic and striatonigral degeneration as well as olivopontocerebellar atrophy. Glial cytoplasmic inclusions, composed of α-synuclein and other proteins are considered the cellular hallmark lesion. The cerebellar variant of MSA (MSA-C) denotes a distinctive motor subtype characterized by progressive adult onset sporadic gait ataxia, scanning dysarthria, limb ataxia and cerebellar oculomotor dysfunction. In addition, there is autonomic failure and variable degrees of parkinsonism. A range of other disorders may present with MSA-C like features and therefore the differential diagnosis of MSA-C is not always straightforward. Here we review key aspects of MSA-C including pathology, pathogenesis, diagnosis, clinical features and treatment, paying special attention to differential diagnosis in late onset sporadic cerebellar ataxias.

Friedreich's ataxia (FA) is an autosomal recessive inherited disorder characterized by progressive gait and limb ataxia, hypertrophic cardiomyopathy, limb muscular weakness, and areflexia with positive extensor plantar response. Loss of vibratory and position sense, skeletal abnormalities, and dysarthria are common comorbid features. The wide spectrum of disease may lead to a diagnostic challenge, and in such a scenario, the inheritance pattern might be a clue to diagnosis. A rare and peculiar pattern observed in some families is the pseudodominant pattern that is usually characterized by phenotypic variation, which, in turn, could make it even harder to get to a correct diagnosis. This pattern, although seemingly similar to a true dominant pattern of inheritance, should be kept in mind whenever one is evaluating a family with FA. We evaluated a Brazilian family of Italian ancestry with variation of phenotype among affected siblings.

Friedreich ataxia (FA) is an autosomal-recessive hereditary ataxia with a prevalence of around 1 case per 30,000. It is a severely debilitating disease characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, muscular weakness and pyramidal signs, and is due to GAA triplet expansion in the frataxin (FXN) gene located on chromosome 9q13 [1]. Patients usually begin the disorder at puberty or before the age of 25 years in most studies, but rare cases of ‘Late-Onset Friedreich ataxia’ (LOFA) have been described. LOFA patients were recognized to have a median age of onset of 28.8 years (range of 25.5–48), have a milder phenotype and often retained lower limb reflexes [2, 3]. Very late–Onset Friedreich ataxia (VLOFA) has also been reported [4, 5], with the first manifestations appearing in the seventies. Here we report an 82-year-old lady who presented with balance difficulties that led to some loss of independence. Symptoms began at about age 80 with subsequent mild dysarthria. She denied any similar familial history, rending autosomal dominant disease unlikely. On examination, cognition was normal, but she had hypometric ocular saccades, dysarthria, generally brisk deep tendon reflexes except for bilateral absent ankle jerks and a bilateral Babinski sign. There was also reduced ability for rapid, alternating motor tasks. There was no loss of sensations, including proprioception. The patient also showed important gait ataxia. The Scale for the Assessment and Rating of Ataxia (SARA) was rated 15 (gait: 3; stance: 1; sitting: 1; speech disturbance: 2; finger chase: 1; nose-finger test: 2; fast altering hand movements: 2; heel-sheen slide: 3). There was no pes cavus, scoliosis, deafness or diabetes. The nerve conduction study was normal, including amplitude of the sural nerve action potentials. Cardiac echography and EKG were normal. Friedreich ataxia was considered as a diagnosis based on ataxia with a bilateral Babinski sign and absent Achilles reflexes and normal blood vitamin E levels with undetectable serum antinuclear auto-antibodies (against Hu, Yo, Ma2, CV2/CRMP5, Ri, Tr, and GAD). The diagnosis was confirmed when an unstable GAA triplet expansion was demonstrated on both alleles of the FXN gene, with 170 and 1,300 tri-nucleotides, respectively. The small GAA expansion probably explains why the patient developed FA in her eighties, as other studies suggest a correlation between the size of the expanded tri-nucleotide repeats and severity of the disease and an inverse correlation with the age of onset [6, 7]. To our knowledge (excluding one possible but not proven case) [8], this lady represents the highest age of onset for a diagnosed FA patient. Even though FA is typically encountered in young patients, this report confirms that it cannot be excluded based on the advanced age of the patient, and should remain a possible differential diagnosis of older patients with ataxia, along with other genetic causes, such as SCA6 [9].

An outbreak of enzootic ataxia among sheep raised in the northeastern region of Brazil is described. Copper (Cu) deficiency was diagnosed in a herd of 56 sheep, among which five presented characteristic clinical symptoms of enzootic ataxia. The symptoms began 30 days after birth, with a clinical condition that included locomotion difficulty, limb ataxia, tremors, and continual falls. Liver biopsies were performed and blood was collected to determine hepatic and plasmatic Cu, iron (Fe), and zinc (Zn) concentration, respectively. The laboratory results showed that the animals presented low copper concentrations in the plasma and liver, without difference between the clinically healthy animals and those affected by enzootic ataxia. Even after supplementation with adequate Cu levels had been recommended, it was found on a new visit to the farm four months later that one animal still presented a clinical condition and that the hepatic Cu levels of the herd had not risen. Despite the low copper content of the diet, the high hepatic Fe levels found suggest that antagonism due to this element may have been an important factor in triggering copper deficiency in these animals, and thus, additional copper supplementation may be necessary for these animals.

A 60-yr-old man developed progressive gait disturbance and limb ataxia at the age of 52. Family history was absent for neurological disorders. Examinations showed pure cerebellar syndrome. There was no retinal degeneration for 7 yr. A brain MRI done at the age of 56 showed atrophy of the cerebellar hemispheres and vermis. Genetic test confirmed the spinocerebellar ataxia type 7 with CAG repeat number of 42.

Spinocerebellar ataxias (SCAs) are dominantly inherited neurodegenerative disorders characterized by progressive cerebellar ataxia and dysarthria We have identified missense mutations in prodynorphin (PDYN) that cause SCA23 in four Dutch families displaying progressive gait and limb ataxia PDYN is the precursor protein for the opioid neuropeptides alpha neoendorphin, and dynorphins A and B (Dyn A and B) Dynorphins regulate pain processing and modulate the rewarding effects of addictive substances Three mutations were located in Dyn A a peptide with both opioid activities and nonoproid neurodegenerative actions Two of these mutations resulted in excessive generation of Dyn A in a cellular model system In addition two of the mutant Dyn A peptides induced toxicity above that of wild type Dyn A in cultured striatal neurons The fourth mutation was located in the nonoproid PDYN domain and was associated with altered expression of components of the oproid and glutamate system, as evident from analysis of SCA23 autopsy tissue Thus, alterations in Dyn A activities and/or impairment of secretory pathways by mutant PDYN may lead to glutamate neurotoxicity, which underlies Purkinje cell degeneration and ataxia PDYN mutations are identified in a small subset of ataxia families, indicating that SCA23 is an infrequent SCA type (similar to 0 5%) in the Netherlands and suggesting further genetic SCA heterogeneity

We report the case of a 40-year-old right-handed German-speaking man who presented with ischemic stroke in the territories of the right superior cerebellar artery and posterior inferior cerebellar artery. The objective of the present study was to investigate the consequences of this cerebellar damage with regard to higher cognitive functions. On admission to the stroke unit, the patient presented with dysarthria, right-sided appendicular ataxia, gait ataxia, and right-sided horizontal nystagmus (National Institutes of Health Stroke Scale, NIHSS, score 4). When examined 10 days after his stroke using a set of neuropsychological tests, he showed a marked deficit in the ability to remember when and in which context he had previously encountered verbal material. This aspect of memory, so-called ‘source memory’, is known to be mediated mainly by frontal and medial temporal structures. The present case suggests the existence of a strong functional connectivity between cerebellum and cortical regions underlying specific memory processes.

Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy. This life threatening symptom can be ameliorated by the administration of idebenone, a short chain quinone antioxidant, supporting additional evidence that oxidative stress plays a major role in the pathogenesis of this disease. In this study we analyze the combinatorial effect of different antioxidants on cell viability of FRDA fibroblasts and of RAT-1 immortalized fibroblasts exposed to oxidative stress. We find that an equimolar mixture of idebenone and vitamin E is more potent than each of the compound alone. Increased potency was also obtained with a novel synthetic antioxidant (Fe-Aox29) combining the active groups from both idebenone and vitamin E. These results indicate, that idebenone and vitamin E might act synergistically to counteract oxidative stress in fibroblasts from FRDA patients.

Background: Limb ataxia is classically attributed to cerebellar hemispheric lesions, although isolated lesions of the inferior cerebellar peduncle (ICP) in the medulla may also cause this sign. It is still unclear why only some patients with acute cerebellar infarcts in the posterior inferior cerebellar artery (PICA) territory present with limb ataxia. The proximal intracranial posterior circulation (P-PC) territory includes structures fed by the intracranial vertebral arteries (ICVAs): the medulla, supplied by small ICVAs branches, and posterior inferior portion of the cerebellum, fed by PICA. ICP and PICA territory cerebellar infarcts most often occur independently but occasionally occur together. Objective: To identify structures responsible for limb ataxia in acute P-PC brain infarcts correlating clinical and topographical findings. Methods: Sixteen patients (8 women) were included with ages ranging from 30 to 82 years (mean age, 62 years) with isolated acute strokes in the P-PC territory. Results: The cases reported here indicate that limb ataxia in acute P-PC territory infarcts may be associated with a damage to the ICP in the dorsolateral medulla, regardless of a hemispheric cerebellar lesion. In fact among the 9 patients with PICA stroke, limb ataxia was observed only in the 2 patients who also presented a damage to the dorsolateral medulla involving the ICP. Of the 7 patients with isolated dorsolateral medullary infarct, only 5 patients with an ICP damage had limb ataxia. Conclusions: When correlating limb ataxia and acute P-PC infarcts it is important to take in account the entire ICVA territory.

Superficial siderosis of the CNS is a rare syndrome of progressive cerebellar ataxia and sensorineuronal deafness associated with haemosiderin deposition from chronic subarachnoid bleeding.1 We describe a patient with typical features of superficial siderosis and an anterior horn cell syndrome, a combination that to our knowledge has never been previously reported. A 59 year old man presented with a 4 year progressive history of unsteadiness of gait, bilaterally impaired hearing, and weakness which had begun in the left hand, spreading to involve the left arm and leg, and right hand. He had a 2 year history of cerebellar dysarthria, bladder hesitancy with postmicturition dribbling, and impotence. Examination disclosed a broad based ataxic gait with left sided limb ataxia. Apart from bilateral sensorineuronal deafness the cranial nerves were normal. There were fasciculations in the arms and legs. In the upper limbs he had asymmetric wasting and weakness of the intrinsic hand muscles, biceps, and triceps bilaterally. In the left lower limb there was wasting and weakness of the hip flexors and quadriceps. Sensory examination was normal. The deep tendon reflexes were all present and symmetric. The abdominal reflexes were present and the plantar responses were flexor. Magnetic resonance imaging of the brain and spinal cord demonstrated haemosiderin deposition around the cerebellar folia, …

Progressive myoclonic epilepsies are rare, genetically transmitted diseases characterized by epileptic seizures, myoclonus, and progressive neurologic deterioration. Unverricht-Lundborg disease, Lafora's disease, neuronal ceroid lipofuscinosis, mitochondrial disorders, and sialidosis are included in this group. Lafora's disease is a progressive disorder of the central nervous system with onset in the late first or second decade of life and is inherited in an autosomal-recessive pattern. The first clinical manifestation is generalized tonic-clonic seizures, myoclonus, or both, usually seen between the ages of 11 and 18 years. The other clinical manifestations are progressive dementia and limb ataxia. Diagnosis is based on showing the typical inclusions in the brain, liver, skin, or muscle tissue specimens. The case of a 6-year-old male patient, who was admitted with the clinical findings of third-degree atrioventricular block and dementia and eventually diagnosed with Lafora's disease, is presented. ( J Child Neurol 1999;14:745-746).

SummaryThe autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. The clinical symptoms include cerebellar dysfunction and associated signs from dysfunction in other parts of the nervous system. So far, five spinocerebellar ataxia (SCA) genes have been identified: SCA1, SCA2, SCA3, SCA6, and SCA7. Loci for SCA4 and SCA5 have been mapped. However, approximately one-third of SCAs have remained unassigned. We have identified a Mexican American pedigree that segregates a new form of ataxia clinically characterized by gait and limb ataxia, dysarthria, and nystagmus. Two individuals have seizures. After excluding all known genetic loci for linkage, we performed a genomewide search and identified linkage to a 15-cM region on chromosome 22q13. A maximum LOD score of 4.3 (recombination fraction 0) was obtained for D22S928 and D22S1161. This distinct form of ataxia has been designated “SCA10.” Anticipation was observed in the available parent-child pairs, suggesting that trinucleotide-repeat expansion may be the mutagenic mechanism.