Progressive Ataxia Research Articles

Emerging Therapies in Friedreich's Ataxia: A Review

Friedreich's ataxia (FRDA) is an inherited, neurodegenerative disease that typically presents in childhood and results in progressive gait and limb ataxia, with the extraneural features of hypertrophic cardiomyopathy, diabetes and scoliosis. The genetic defect results in a deficiency of frataxin protein, which is important for mitochondrial function, especially in the brain and heart. Drug development has approached FRDA through pathways addressing oxidative stress, mitochondrial dysfunction, frataxin protein deficiency and DNA transcriptional deficiency, paving the way for the first disease-modifying drugs for FRDA.

“Hot Cross Bun” Sign in a Patient With Kelch-like Protein 11 Rhombencephalitis

A 36-year-old man had progressive gait ataxia, diplopia, and hearing loss over 3 years. On examination, he had upper extremity ataxia, truncal ataxia, bradykinesia, and lower extremity spasticity. Brain magnetic resonance imaging revealed a “hot cross bun” sign (Figure). Kelch-like protein 11 (KLHL11) IgG was detected in serum and cerebrospinal fluid.1Dubey D. Wilson M.R. Clarkson B. et al.Expanded clinical phenotype, oncological associations, and immunopathologic insights of paraneoplastic Kelch-like protein-11 encephalitis [published correction appears in JAMA Neurol. 2020;77(11):1453].JAMA Neurol. 2020; 77: 1420-1429Crossref PubMed Scopus (40) Google Scholar Positron emission tomography revealed a hypermetabolic mediastinal mass. Subsequent biopsy revealed seminoma. The hot cross bun sign has been described in patients with multiple system atrophy as well as in a patient with KLHL11 encephalitis.2Massano J. Costa F. Nadais G. Teaching neuroImage: MRI in multiple system atrophy: “hot cross bun” sign and hyperintense rim bordering the putamina.Neurology. 2008; 71: e38Crossref PubMed Scopus (14) Google Scholar,3Ishikawa H. Mandel-Brehm C. Shindo A. et al.Long-term MRI changes in a patient with Kelch-like protein 11-associated paraneoplastic neurological syndrome.Eur J Neurol. 2021; 28: 4261-4266Crossref PubMed Scopus (3) Google Scholar Some KLHL11 rhombencephalitis cases have been misdiagnosed as multiple system atrophy.1Dubey D. Wilson M.R. Clarkson B. et al.Expanded clinical phenotype, oncological associations, and immunopathologic insights of paraneoplastic Kelch-like protein-11 encephalitis [published correction appears in JAMA Neurol. 2020;77(11):1453].JAMA Neurol. 2020; 77: 1420-1429Crossref PubMed Scopus (40) Google Scholar This case highlights the importance of considering KLHL11 IgG evaluation in men with progressive brainstem/cerebellar syndrome despite the radiological findings.1Dubey D. Wilson M.R. Clarkson B. et al.Expanded clinical phenotype, oncological associations, and immunopathologic insights of paraneoplastic Kelch-like protein-11 encephalitis [published correction appears in JAMA Neurol. 2020;77(11):1453].JAMA Neurol. 2020; 77: 1420-1429Crossref PubMed Scopus (40) Google Scholar

Spinocerebellar Ataxia Type 13: A report of a non-progressive disease

Introduction: Spinocerebellar ataxia type 13 is a rare autosomal dominant disease caused by point mutations in the KCNC3 gene coding for the Kv3.3 voltage-gated potassium channel. This disease can present different neurodevelopmental and neurodegenerative forms. Case report: We present a case of a child who had trunk and appendicular ataxia, exuberant gait ataxia, tremor, dysarthria, and dysrhythmic and scanning speech. She presented a delay and difficulty in acquiring fine motor skills. Cerebral magnetic resonance imaging showed moderate hypoplasia of the cerebellum. A pathogenic variant c1268 G>A p.(Arg423His) in heterozygosity in the KCNC3 gene was detected, allowing the diagnosis of Spinocerebellar Ataxia type 13. Later, the same diagnosis was established in the patient's father. However, he gradually improved his ataxia and motor function throughout his life. Discussion: Unlike most spinocerebellar ataxias, including the other spinocerebellar ataxia type 13 phenotypes, this one does not lead to progressive ataxia. Children with this disease should be follow-up by a multidisciplinary team and referred to an early intervention program. A regular neurologic examination is recommended to evaluate disease progression.

Dysfunction of cerebellar microglia in Ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging. ATM phosphorylates more than 1500 target proteins, which are involved in cell cycle control, DNA repair, apoptosis, modulation of chromatin structure, and other cytoplasmic as well as mitochondrial processes. In our quest to better understand the mechanisms by which ATM deficiency causes cerebellar degeneration, we hypothesized that specific vulnerabilities of cerebellar microglia underlie the etiology of A-T. Our hypothesis is based on the recent finding that dysfunction of glial cells affect a variety of process leading to impaired neuronal functionality (Song et al., 2019). Whereas astrocytes and neurons descend from the neural tube, microglia originate from the hematopoietic system, invade the brain at early embryonic stage, and become the innate immune cells of the central nervous system and important participants in development of synaptic plasticity. Here we demonstrate that microglia derived from Atm-/- mouse cerebellum display accelerated cell migration and are severely impaired in phagocytosis, secretion of neurotrophic factors, and mitochondrial activity, suggestive of apoptotic processes. Interestingly, no microglial impairment was detected in Atm-deficient cerebral cortex, and Atm deficiency had less impact on astroglia than microglia. Collectively, our findings validate the roles of glial cells in cerebellar attrition in A-T.

WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia

IntroductionSixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. MethodsSix individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. ResultsA relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10–12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient‐derived fibroblasts showed a markedly decreased expression of the full‐length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. ConclusionsThis study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.

Symptom burden of people with progressive ataxia, and its wider impact on their friends and relatives: a cross-sectional study.

Progressive ataxias are complex disorders that result in a wide variety of symptoms. Whilst we currently have a relatively good understanding of the symptom patterns associated with the various types of ataxia, and how these diseases progress over time, their impact on the person with ataxia is less well understood. In addition, little is known about how carers, friends and families are affected by them. This paper aims to provide preliminary information on the presence and impact of medical symptoms and day-to-day challenges on people with ataxia and their friends and relatives. Data were extracted from a survey by Ataxia UK for their members. The views of 366 people with ataxia and 52 friends and relatives are reported. Data were analysed for the entire groups, as well as for the three most common ataxia types represented in the sample, Friedreich's ataxia, inherited ataxia (excluding Friedreich's ataxia), and cerebellar ataxia of unknown cause. The survey confirmed the symptom patterns described in previous research, but further showed that the impact of these symptoms can vary across ataxia populations. Similar findings were observed for day-to-day challenges. Friends and relatives experienced similar challenges to people with ataxia, indicating that support provided has to consider those supporting people with ataxia as well as the patient. Respondents also highlighted limitations in terms of accessing support services, and not all services were able to cater fully to their specific needs. This study begins to provide information that can be used in further research to explore the needs of people with ataxia and their carers, friends, and relatives. Such research will support treatment trial design, ensuring patients' needs are considered, help to tailor support services to their needs, and ensure health care professionals have the necessary skills to fully address them.

Non-dysraphic Subpial Intramedullary Lipoma of Cervicothoracic Spine

Intramedullary spinal cord tumors are rare and comprise less than one percentage of all central nervous system (CNS) neoplasms. When encountered, most are found in the lumbosacral region with coinciding spinal dysraphism. Here, we discuss a case of isolated non-dysraphic intramedullary lipoma of cervicothoracic spine in an adolescent who was surgically managed with posterior decompression and subtotal resection via laminoplasty. A 21-year-old male adolescent, without a history of spinal dysraphism, presented with a progressive sensory ataxia. This manifestation was attributed to magnetic resonance documented intramedullary lipoma, extending from C7 to T2 spinal level. Patient underwent subtotal surgical resection of the lesion; and histopathology report was confirmed as spinal lipoma. Surgical management of this rare pathology has a wide variety of options depending on clinical presentation. In our case, a subtotal resection and laminoplasty was achieved with no further worsening of neurologic symptoms.

Pharmacotherapy of cerebellar and vestibular disorders.

Major therapeutic advances have been made in patients with episodic and progressive cerebellar ataxias, downbeat nystagmus and some vestibular disorders. We provide an update review on this subject highlighting important research findings from the last two years. Recently, the use of omaveloxolone for 2 years significantly improved upright stability in Friedreich's ataxia patients. In an open-label study, N-acetyl-l-leucine administered for 6-weeks significantly improved clinical impression of change, ataxia, and quality of life in patients with Niemann-Pick disease type C1. A 12-week treatment with dalfampridine was associated with improved standing balance in a subgroup of patients with multiple sclerosis. A gluten-free diet alone improved ataxia in half of patients with antiglutamic acid decarboxylase (GAD) ataxia, suggesting that gluten sensitivity might be part of the underlying pathogenesis in anti-GAD ataxia. In a head-to-head trial, both prolonged-release 4-aminopyridine (4-AP) and acetazolamide effectively reduced the attacks up to 60% in patients with episodic ataxia type 2 (EA2), albeit 4-AP had fewer adverse effects. Small observational studies have shown that patients with episodic vestibular syndrome who cannot be diagnosed as definite or probable vestibular migraine, might still improve vestibular symptoms following preventive treatment for migraine. The use of vitamin D supplementation in benign paroxysmal positional vertigo, steroids in acute unilateral vestibulopathy, and betahistine in Ménière's disease patients remains controversial. Although the use of several therapies is being established in the treatment of cerebellar and vestibular disorders, there is an urgent need for prospective controlled therapeutic trials.

Anti-Tr/DNER Antibody–Associated Cerebellar Ataxia: a Systematic Review

Rapidly progressive cerebellar ataxia is a classical paraneoplastic neurological syndrome associated with different autoantibodies and typical demographic characteristics, extracerebellar signs, tumor association, and prognosis. Anti-Tr/anti-Delta/Notch-like epidermal growth factor-related receptor (DNER) antibody is one of the associated antibodies. Given the rarity of this condition, our current knowledge is based on case reports and small case series. In order to improve our understanding of these conditions, we conducted a systematic review of the literature. Our study followed the PRISMA reporting guidelines. Studies of patients with the presence of anti-Tr/DNER antibodies in serum or cerebrospinal fluid (CSF) were included. We extract data information related to study characteristics, demographics, clinical symptoms, tumor association, neuroimaging, and cerebrospinal fluid analysis. Out of 131 records, we analyzed 17 papers, including a total of 85 patients with anti-Tr/DNER antibody-associated cerebellar ataxia. We confirmed that this disease occurred mostly in middle-aged males. Isolated cerebellar ataxia was the most common presentation. Extracerebellar features were rare (8%). Ninety-one percent of the patients presented an associated tumor, being Hodgkin lymphoma the most common. Abnormal neuroimaging patterns included cerebellar atrophy (19%) and cerebellar hypersignal (6%). Cerebrospinal fluid was inflammatory in 64% of the patients. Oncological response was complete in 88%, but neurological prognosis was poor with only 41% of the patients presenting significant neurological improvement at the last follow up. Anti-Tr/DNER antibodies should be tested in rapid progressive cerebellar ataxia. Oncological response is excellent; however, many patients do not improve from their cerebellar ataxia.

The complexities of CACNA1A in clinical neurogenetics.

Variants in CACNA1A are classically related to episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. Over the years, CACNA1A has been associated with a broader spectrum of phenotypes. Targeted analysis and unbiased sequencing of CACNA1A result not only in clear molecular diagnoses, but also in large numbers of variants of uncertain significance (VUS), or likely pathogenic variants with a phenotype that does not directly match the CACNA1A spectrum. Over the last years, targeted and clinical exome sequencing in our center has identified 41 CACNA1A variants. Ultimately, variants were considered pathogenic or likely pathogenic in 23 cases, with most phenotypes ranging from episodic or progressive ataxia to more complex ataxia syndromes, as well as intellectual disability and epilepsy. In two cases, the causality of the variant was discarded based on non-segregation or an alternative diagnosis. In the remaining 16 cases, the variant was classified as uncertain, due to lack of opportunities for segregation analysis or uncertain association with a non-classic phenotype. Phenotypic variability and the large number of VUS make CACNA1A a challenging gene for neurogenetic diagnostics. Accessible functional read-outs are clearly needed, especially in cases with a non-classic phenotype.

Pontocerebellar atrophy is the hallmark neuroradiological finding in late-onset Tay-Sachs disease.

Late-onset Tay-Sachs disease (LOTS) is a form of GM2 gangliosidosis, an autosomal recessive neurodegenerative disorder characterized by slowly progressive cerebellar ataxia, lower motor neuron disease, and psychiatric impairment due to mutations in the HEXA gene. The aim of our work was to identify the characteristic brain MRI findings in this presumably underdiagnosed disease. Clinical data and MRI findings from 16 patients (10F/6M) with LOTS from two centers were independently assessed by two readers and compared to 16 age- and sex-related controls. Lower motor neuron disease (94%), psychiatric symptoms-psychosis (31%), cognitive impairment (38%) and depression (25%)-and symptoms of cerebellar impairment including dysarthria (94%), ataxia (81%) and tremor (69%), were the most common clinical features. On MRI, pontocerebellar atrophy was a constant finding. Compared to controls, LOTS patients had smaller mean middle cerebellar peduncle diameter (p < 0.0001), mean superior cerebellar peduncle diameter (p = 0.0002), mesencephalon sagittal area (p = 0.0002), pons sagittal area (p < 0.0001), and larger 4th ventricle transversal diameter (p < 0.0001). Mild corpus callosum thinning (37.5%), mild cortical atrophy (18.8%), and white matter T2 hyperintensities (12.5%) were also present. Given the characteristic clinical course and MRI findings of the pontocerebellar atrophy, late-onset Tay-Sachs disease should be considered in the differential diagnosis of adult-onset cerebellar ataxias.

Клинический случай синдрома Луи-Бар с клинической картиной мозжечковой атаксии и EBV-индуцированного лимфопролиферативного синдрома

В данном описании клинического случая представлена история болезни ребенка в возрасте 2 лет и 6 месяцев с картиной синдрома Луи-Бар. Отмечались проявления прогрессирующей мозжечковой атаксии, бруксизма, глазодвигательной апраксии и доброкачественного лимфопролиферативного синдрома, вызванного вирусом Эпштейна — Барр. Признаков телеангиэктазий не отмечалось, что может быть объяснено возрастом ребенка. При иммунологическом исследовании идентифицированы признаки комбинированного иммунодефицита с лимфопенией, снижением количества Т-хелперов и цитотоксических Т-лимфоцитов в крови, а также низкой сывороточной концентрацией молекул IgA. Содержание альфа-фетопротеина в сыворотке крови превышало верхнюю границу нормы в 15 раз. Генетический тест выявил три мутации в гене АТМ, в частности две известные патогенные замены нуклеотидов в гетерозиготном состоянии — с.8147Т&gt;С (p.Val2716Ala) и c.8584 + 2T&gt; C (Splice donor) и одну неизвестную ранее мутацию — c.3178A&gt;G (p.fle1060Val) — неопределенного диагностического значения в гетерозиготном состоянии. Проводили лечение валганцикловиром для подавления репродуктивной активности EBV, препаратом диализата лейкоцитов крови и пропесом для компенсации иммунодефицита и комбинированной терапией цереброкурином и цитиколином по поводу неврологического дефицита с частичным положительным эффектом. Данный клинический пример ярко демонстрирует потенциал нейроиммунологического подхода к ведению пациентов, поскольку исследуемый ребенок страдал как иммунодефицитом, так и неврологической дисфункцией, что связано с плейотропными эффектами мутировавшего гена, который был причиной развития болезни.

Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases.

Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

A syndrome of progressive ataxia and palatal tremor in a patient with mild bilateral idiopathic hypertrophic olivary degeneration

A syndrome of progressive ataxia and palatal tremor in a patient with mild bilateral idiopathic hypertrophic olivary degeneration

Quantifying the Risk and Dosimetric Variables of Symptomatic Brainstem Injury After Proton Beam Radiation in Pediatric Brain Tumors

Brainstem toxicity after radiation is a devastating complication and a particular concern with proton radiation (RT), given the biological differences and range uncertainties at the distal edge of proton beam. Data from St. Jude's found a 3.7% risk of brainstem necrosis after photon-based RT, while the incidence with protons ranges from 0.7% - 31% across studies. We investigated the incidence and clinical correlates of brainstem injury in pediatric brain tumors treated with proton therapy.All patients < 18 years with infratentorial brain and pineal tumors, treated with proton beam RT at our institution from 2007 - 2019, with a brainstem Dmean of > 30 Gy and/or Dmax > 50.4 Gy were included. We excluded patients with primary brainstem tumors. Symptomatic brainstem injury (SBI) was defined as any new or progressive cranial neuropathy, ataxia, dysmetria and/or motor weakness with corresponding radiographic abnormality within the brainstem and was graded per the NCI Common Terminology Criteria for Adverse Events v5.0 (Grade 2: moderate symptoms, corticosteroids indicated; Grade 3: severe symptoms, medical intervention indicated; Grade 4: life-threatening; urgent intervention; and Grade 5: death).A total of 595 patients were reviewed and 362 (medulloblastoma = 209, ependymoma = 86, ATRT = 43, pineoblastoma = 9, others = 15) met our inclusion criteria. Median age at RT was 5 years (range 0.7 - 17.9 years) and median prescribed RT dose was 54 CGyE (range 39.6 - 59.4 CGyE). Median follow up was 40 months (range 1 - 152). Ten patients (2.7%) developed SBI, at a median of 4 months after RT (range 1-6). Grades 2,3,4 and 5 brainstem injuries were seen in 3, 4, 2 and 1 patient respectively. Mean brainstem Dmax in SBI and non-SBI patients was 55.9 Gy and 54.8 Gy (P = 0.30), while the mean Dmean was 43.3 Gy and 43.2 Gy (P = 0.48) respectively. Most common symptoms of SBI were ataxia, slurred speech, 6th cranial nerve palsy and bulbar palsy. All SBI patients required steroids for 1-5 months, while grade 3-5 injuries were also treated with bevacizumab and/or hyperbaric oxygen therapy. Asymptomatic imaging changes within brainstem were seen in 47 patients (13%) at a median of 4 months after RT, most common findings being increased T2 flair, focal enhancement and encephalomalacia. In 2014, our institution started using strict brainstem dose constraints (Dmax ≤ 57 Gy, Dmean ≤ 52.4 Gy and V54 ≤ 10%). The incidence of SBI has decreased from 4.2% (2007-2013) to 0.7% (2014-2019) (P = 0.047) while asymptomatic imaging changes remain similar (11.6% vs 15.1%, P = 0.33). Patients with SBI had a higher V45, V50-52 and D15 -D50; while the Dmax, Dmean, V53-60 and D1- D10 were similar.Our results suggest that there is a low risk of SBI after proton therapy for pediatric brain tumors. A lower incidence of SBI was seen after the use of strict brainstem dose constraints. Volumetric doses to brainstem may play a significant role in determining the risk of SBI and developing a dose response nomogram is warranted.

Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies.

Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.

DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?

BackgroundDentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant spinocerebellar ataxia caused by pathological expansion of CAG trinucleotide repeats in the ATN1 gene. Most cases were described in patients from Japanese ancestry who presented with adult-onset progressive cerebellar ataxia associated with cognitive impairment, choreoathetosis and other movement disorders. DRPLA has been rarely described in Brazilian patients. MethodsWe performed a retrospective observational multicentric study including six different Neurology Centers in Brazil. All patients with genetically confirmed diagnosis of DRPLA had their medical records evaluated and clinical, genetic and neuroimaging features were analyzed. ResultsWe describe of eight Brazilian patients (5 male, 3 female) from four nuclear families with genetically confirmed DRPLA. The most common neurological features included cerebellar ataxia (n = 7), dementia (n = 3), chorea (n = 2), psychiatric disturbances (n = 2), progressive myoclonic epilepsy (n = 2) and severe bulbar signs (n = 1). Progressive myoclonic epilepsy was observed in two juvenile-onset cases before 20-year. A large CAG trinucleotide length was observed in the two juvenile-onset cases and genetic anticipation was observed in all cases. Neuroimaging studies disclosed cerebellar atrophy (n = 6), as well as brainstem and cerebellar atrophy (n = 2) and leukoencephalopathy (n = 1). ConclusionThe patients described herein reinforce that clinical features of DRPLA are highly influenced by age of onset, genetic anticipation and CAG repetition lengths. There is a large complex spectrum of neurological features associated with DRPLA, varying from pure cerebellar ataxia to dementia associated with other movement disorders (myoclonus, choreoathetosis). DRPLA is an unusual cause of cerebellar ataxia and neurodegeneration in Brazilian patients.

Co-infection with Trypanosoma congolense and Trypanosoma brucei is a significant risk factor for cerebral trypanosomosis in the equid population of the Gambia

Trypanosomosis is a major cause of morbidity and mortality in working equids in The Gambia. Recently, a progressive, severe neurological syndrome characterised by a diffuse lymphoplasmacytic meningoencephalitis has been identified and associated with Trypanosoma brucei infection of the central nervous system. The pathogenesis of cerebral trypanosomosis is unclear and the clinical syndrome not well described. This observational cross-sectional study aimed to identify host and parasite related risk factors associated with the development of cerebral trypanosomosis and to describe the neurological syndrome associated with cerebral trypanosomosis. History, signalment, clinical and laboratory parameters were collected from 326 horses and donkeys presented to The Gambia Horse and Donkey Trust. Neurological derangements in affected animals were described. Species-specific polymerase chain reaction (PCR) for Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei was performed. The associations between signalment, clinical and laboratory parameters and PCR results were assessed using multivariable logistic regression. The overall prevalence of trypanosomosis was 50 %, with infections dominated by T. congolense (44.1 %) and a lower intensity of T. brucei (7.4 %) and T. vivax (6.5 %). Overall, 54.8 % of neurological cases were PCR positive for trypanosomosis. Within the neurological sub-population prevalence remained similar to the whole population for T. congolense (48.4 %) and T. vivax (6.5 %); whilst the prevalence increased markedly for T. brucei (32.3 %). Co-infections were identified in 32.3 % of neurological cases. Donkeys typically presented with progressive cerebral dysfunction and cranial nerve deficits, whereas in horses a progressive spinal ataxia was predominant. Mortality in affected animals was high (82.4 %). The final multivariable model identified a significant association between body condition score ≤2 (OR 11.4; 95 % CI 4.6–27.9; P = <0.001), and T. congolense and T. brucei. coinfection (OR 20.6; 95 % CI 1.71–244.1; P = 0.016) with the presence of neurological deficits. This study has provided clinically relevant information confirming the link between T. brucei and neurological disease outbreak in the equid population of The Gambia, and crucially identified co-infection with T. brucei and T. congolense as a major risk factor for the development of neurological trypanosomosis. Further research is required to identify the epidemiology of co-infection in equidae of The Gambia, so that cerebral trypanosomosis can be better prevented in this vulnerable population.

A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A‐related pathologies

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.

Sub-Acute Sclerosing Panencephalitis Manifesting as Psychiatric Illness: A Case Report

Subacute sclerosing panencephalitis (SSPE) is a chronic progressive inflammatory central nervous system disorder manifesting as a rare complication of measles viral infection in childhood resulting in fatality in all cases. It is likely to have possibility of subclinical or undiagnosed measles in early childhood in absence of prior overt measles infection. Measles vaccine has a protective effect against SSPE and high vaccination gap is associated with higher incidence of SSPE. Children residing in areas with poor vaccination coverage are at increased risk of developing the disease. It is characterised by progressive intellectual deterioration, seizures, myoclonus, ataxia and visual disturbances. The onset of SSPE is insidious and can manifest as significant psychiatric ailments. A 17 years old girl with history of progressive scholastic deterioration for a year presented with focal seizures, myoclonic jerks and psychiatric manifestations like emotional outburst followed by progressive unresponsiveness, altered sensorium and memory lapses since two weeks. A diagnosis of Subacute sclerosing panencephalitis (SSPE) was made on the basis of clinical symptoms, typical EEG changes and presence of anti-measles antibody in cerebrospinal fluid. Patient received treatment for myoclonic jerks, spasticity along with supportive care. SSPE is often a chronic inflammatory and life threatening disease of central nervous system with no cure despite development of antiviral and immunomodulator drugs. There is urgent need to advocate policies to enhance vaccination coverage and for extensive research in field for potential therapies for treatment of such patients to improve clinical outcomes.