IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA.

BACKGROUND: Childhood neurodegenerative diseases often pose a challenge to clinicians to diagnose because of the degree of genetic heterogeneity and variable presentations. Here, we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia in which postmortem pathological analysis led to the diagnosis of interferon regulatory factor 2 binding protein like (IRF2BPL)-related disorder. METHODS: Detailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral-pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions. Follow up testing for the CAG repeat expansion at ATN1 was non-diagnostic. RESULTS: Subsequent exome sequencing reanalysis of the research exome identified a pathogenic de novo IRF2BPL variant. The IRF2BPL c.562C>T, p.(Arg188Ter) variant, distal to the polyQ repeat tract, results in variable mRNA levels depending on the cell type examined with decreased mRNA in the brain, as well as destabilization of the protein product and corresponding downstream molecular abnormalities in patient derived cells. CONCLUSION: We provide the first detailed pathological description for IRF2BPL-related disorder, termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures; Mendelian Inheritance in Man, 618088) and evidence for the inclusion of this condition in the differential diagnosis of spastic-ataxic neurodegenerative conditions, reminiscent of DRPLA. Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats. © 2024 International Parkinson and Movement Disorder Society.

Coexistence of dentatorubral-pallidoluysian atrophy and Parkinson's disease: An autopsy case report.

We report an autopsy case of a 56-year-old male patient with the coexistence of dentatorubral-pallidoluysian atrophy (DRPLA) and Parkinson's disease (PD). He presented with gait instability and dysarthria for 10 years. The removed brain showed general atrophy (988 g) with depigmentation of the substantia nigra. The neocortex and deep gray matter, including the red nucleus, subthalamic nuclei, and globus pallidus, were atrophic, and grumose degeneration of the cerebellar dentate nucleus was observed. Polyglutamine- and p62-positive neuronal inclusions were present and widespread in the areas mentioned above. Interestingly, this case also had brainstem-predominant PD pathology with α-synuclein-positive Lewy bodies and Lewy neurites. Generalized white matter atrophy with patchy loss of astrocytes in the white matter suggested glial dysfunction by elongated CAG repeats in the atrophin 1 gene (atrophin 1). Polymerase chain reaction (PCR) fragment analysis revealed increased CAG repeats (61) on atrophin 1 encoding atrophin 1. The patient had a family history of DRPLA, including his daughter, who was confirmed positive on genetic testing (CAG repeat: 65). His father, brother, and niece were suspected of having the disease. Clinicopathologically, all of the above findings are consistent with the coexistence of DRPLA and PD. So far, various overlapping neurodegenerative disorders have been reported, but the coexistence of DRPLA and PD has never been demonstrated in the published literature. Even though the exact time of PD development is unknown in this case, PD might develop after DRPLA, and the overwhelming symptoms of DRPLA might mask those of PD. Here, we report a clinicopathologically definite case of the coexistence of DRPLA and PD. White matter degeneration with patchy loss of astrocytes was another remarkable finding of this case.

Dentatorubral-pallidoluysian atrophy (DRPLA) with a small ganglioglioma component containing neurofibrillary tangles and polyglutamine aggregation.

Dentatorubral-pallidoluysian atrophy (DRPLA), one of the polyglutamine diseases, has not been reported in combination with ganglioglioma (GG). Herein, we report an autopsy case of a 72-year-old man with DRPLA with a small GG component harboring neurofibrillary tangles (NFTs) and polyglutamine aggregates. NFTs, cytoplasmic accumulations of hyper-phosphorylated tau, are mainly observed in Alzheimer's disease (AD) and other tau-associated neurodegenerative disorders. NFTs can also be present in normal aging, and are occasionally observed in low-grade central nervous system (CNS) neoplasms such as GG. In the present case, whole brain examination demonstrated widespread deposition of polyglutamine aggregates, including GG, whereas NFTs were restricted to the GG component. In addition, no other AD or aging-related neuropathological structures were detected throughout the CNS. These findings may provide us with clues to elucidate the pathogenetic mechanisms that neuronal neoplasms may have to develop NFTs regardless of aging, and that polyglutamine may accumulate in neoplastic neurons in polyglutamine disease.

Huntington disease and Huntington disease-like in a case series from Brazil.

The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non-HD cases. In HD, the median expanded (CAG)n (range) was 44 (40-81) units; R(2) between expanded HTT and age-at-onset (AO) was 0.55 (p=0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.

Dentatorubral-pallidoluysian atrophy: a case report and review of literature.

BACKGROUND: Dentatorubral-pallidoluysian atrophy is a rare autosomal dominant neurodegenerative disease. It is a rare disease in the world. Therefore, sharing clinical encounters of this case can deepen global awareness and understanding of the disease. CASE PRESENTATION: The patient was a 34-year-old male of Han nationality who was unmarried. The patient was admitted owing to weakness of the left lower limb with walking instability for 2 months and aggravation for 1 month. There was no dizziness, headache, numbness of limbs, convulsions, nausea, vomiting, abdominal pain, ataxia, nausea, vomiting, or abdominal pain. No nausea, vomiting, diarrhea, abdominal distension, tinnitus, hearing loss, fever, cough, expectoration. Personal history: worked in Cambodia 5 years ago, worked in Dubai 3 years ago, engaged in computer work, smoking or drinking habits. The patient was unmarried. Family history: the mother had symptoms similar to walking unsteadily (undiagnosed). Positive signs include a wide-base gait with a rotatory nystagmus that jumps upward in both eyes. Bilateral finger-nose instability test was quasi-positive, rapid alternating test was negative, and eye closure tolerance test was positive. Tendon reflexes were active in both upper limbs and hyperreflexia in both lower limbs. Stability of the heel, knee, and tibia. Genetic testing showed that the number of repeats in the dentatorubral-pallidoluysian atrophy ATN1 gene was 18 and 62, and the (CAG)n repeat sequence in the ATN1 gene was abnormal, with a repeat number of 62, and the patient was a pathogenic variant. The patient was diagnosed with dentatorubral-pallidoluysian atrophy. Dentatorubral-pallidoluysian atrophy remains a progressive neurodegenerative disease with no effective treatment. At present, the proband is taking 5 mg of buspirone three times a day, which has been reported to improve the symptoms. The patient was followed up for 6 months after taking buspirone, and there was no significant improvement in the temporary symptoms. At present, there are few cases of dentatorubral-pallidoluysian atrophy, and the characteristics of nystagmus in this disease have not been proposed in the past. This case reported the unusual presentation of nystagmus. CONCLUSION: Dentatorubral-pallidoluygur atrophy is a rare neurodegenerative disease with autosomal dominant inheritance. To the best of our knowledge, our present case report is the first case report of dentatorubral-pallidoluygur atrophy with specific nystagmus. We describe the special eye shake and its positive signs to increase dentatorubral-pallidoluysian atrophy clinical positive signs.

Establishing resources and increasing awareness to advance research on Dentatorubral-pallidoluysian atrophy toward a treatment: a patient organization perspective.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare neurodegenerative disorder characterized by ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations. This article delves into the multifaceted efforts of CureDRPLA, a family-driven non-profit organization, in advancing research, raising awareness, and developing therapeutic strategies for this complex condition. CureDRPLA's inception in 2019 led to the establishment of the DRPLA Research Program, and since then have funded research projects to advance the understanding of DRPLA including but not limited to human cellular and mouse models, a natural history and biomarkers study, and a patient registry. There are currently no disease-modifying treatments for DRPLA, motivating a concerted effort on behalf of CureDRPLA to hasten their development by funding and coordinating preclinical studies of therapies in multiple modalities. Of particular interest are therapies focused on lowering the expression (or downregulation) of ATN1, the mutant gene that causes DRPLA, in hopes of tackling the pathology at its root. As with many ultra-rare diseases, a key challenge in DRPLA remains the complexity of coordinating both basic and clinical research efforts across multiple sites around the world. Finally, despite the generous financial support provided by CureDRPLA, more funding and collective efforts are still required to advance research toward the clinic and develop effective treatments for individuals with DRPLA.

Funding research projects and activities to advance research towards treatments for dentatorubral-pallidoluysian atrophy (DRPLA) This article describes the journey of CureDRPLA, a family-driven non-profit organization dedicated to making strides against dentatorubral-pallidoluysian atrophy (DRPLA), an ultra-rare brain disorder. It describes CureDRPLA's tireless efforts to understand, treat, and raise awareness about DRPLA, a condition marked by movement difficulties (ataxia), intellectual disability, uncontrollable jerky movements (myoclonus), involuntary or irregular muscle movements (chorea) and seizures. This disorder is caused by a mutation in a gene called ATN1. The gene produces a protein called atrophin-1, and when the DRPLA-causing mutation is present, the protein becomes abnormal and can build up in the brain, affecting its normal functions. Since its founding in 2019, CureDRPLA has funded research projects to unravel the mysteries of the disease and provide support for affected individuals. CureDRPLA has funded projects to create models of DRPLA using human cells and mice, which helps scientists study the disease and test potential treatments. We have started a study to learn more about how DRPLA progresses in people and are building a global database of information from individuals with DRPLA. Due to the absence of a treatment or cure, CureDRPLA is focused on testing treatments. We are particularly interested in exploring different approaches to lower the levels of the abnormal protein in the brain. CureDRPLA is actively involving the DRPLA community worldwide, raising awareness through events, conferences, and social media. We aim to connect with medical professionals, researchers, and affected families to build a strong community focused on understanding and managing DRPLA. In summary, CureDRPLA is working hard to better understand DRPLA, support affected families, and accelerate the development of treatments for this challenging condition. Our collaborative efforts and dedication underscore the importance of a united global approach to address the complexities of DRPLA.

Understanding dentatorubral-pallidoluysian atrophy (DRPLA) symptoms and impacts on daily life: a qualitative interview study with patients and caregivers.

Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, neurodegenerative disorder with no disease-modifying treatments. There is a dearth of information in the literature about the patient and caregiver experience living with DRPLA. Objectives: This study aimed to (1) understand symptoms experienced by adult- and juvenile-onset DRPLA populations and their impact on daily life and (2) explore patient and caregiver treatment goals and clinical trial participation preferences. Design: The study was a qualitative interview study. Methods: Interviews were conducted remotely with adult patients with DRPLA and caregivers. Participants described patient symptoms and the impact of those symptoms on daily life, and they discussed treatment goals and potential clinical trial participation. There were 18 patients described in the interviews with two patients and seven caregivers. Some participants were caregivers to multiple patients with DRPLA. Results: Interview transcripts were coded for themes, and reported symptoms were summarized with descriptive statistics. Adult-onset patients (N = 7) experienced difficulty with ataxia (100%), cognition (100%), fine motor skills (100%), gross motor skills (100%), speech (100%), personality changes (100%), and seizures (57%). Juvenile-onset patients (N = 11) experienced difficulty with ataxia (100%), sleep (100%), speech (100%), jerking/twitching (83%), behavior (82%), cognition (82%), fine motor skills (82%), gross motor skills (82%), sensory sensitivity (75%), and seizures (64%). When considering aspects of DRPLA to target for future treatment, patients prioritized ataxia/mobility (100%), juvenile-onset caregivers prioritized ataxia/mobility (60%) and independence (60%), and adult-onset caregivers prioritized personality (60%). Almost all patients (93%) would participate in a clinical trial if given the opportunity, but travel to a clinical site could pose a participation barrier for half. Conclusion: This study found that there are symptom domains that are relevant across the DRPLA population, but there is heterogeneity within each domain based on the age of symptom onset and disease stage, which has implications for clinical trial design.

Understanding dentatorubral-pallidoluysian atrophy (DRPLA) symptoms and impacts on daily life through interviews with patients and caregivers Why was the study done? Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare and progressive brain disorder. Little is known about the patient and caregiver experience living with DRPLA and this lack of information has hindered the development of patient-focused treatments and the measurement of outcomes that are most meaningful to caregivers and patients. What did the researchers do? To address this problem, researchers conducted interviews with patients and caregivers of DRPLA to (1) better understand symptoms experienced by adult- and juvenile-onset DRPLA populations and their impact on daily life and (2) explore patient and caregiver treatment goals and clinical trial participation preferences. What did the researchers find? Eighteen patients were described in the interviews. Adult-onset patients (onset at age 20 or older) experienced difficulty with coordination, cognition, motor skills, speech, personality changes, and seizures. Juvenile-onset patients (onset before age 20) experienced difficulty with coordination, sleep, speech, jerking/twitching, behavior, cognition, motor skills, sensory sensitivity, and seizures. When considering symptoms to prioritize for future treatment, patients and caregivers identified coordination/mobility, independence, and personality as important. Nearly all participants indicated they would participate in a clinical trial if given an opportunity, however half expressed that travel to a clinical site could pose a barrier. What do the findings mean? This study provides a better understanding of the symptoms experienced by DRPLA patients and their impact on daily life. Additionally, it identifies important targets for treatment and considerations when designing clinical trials for DRPLA such as the barrier caused by travel to a clinical site.

Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity.

Among posttranslational modifications, directed proteolytic processes have the strongest impact on protein integrity. They are executed by a variety of cellular machineries and lead to a wide range of molecular consequences. Compared to other forms of proteolytic enzymes, the class of calcium-activated calpains is considered as modulator proteases due to their limited proteolytic activity, which changes the structure and function of their target substrates. In the context of neurodegeneration and - in particular - polyglutamine disorders, proteolytic events have been linked to modulatory effects on the molecular pathogenesis by generating harmful breakdown products of disease proteins. These findings led to the formulation of the toxic fragment hypothesis, and calpains appeared to be one of the key players and auspicious therapeutic targets in Huntington disease and Machado Joseph disease. This review provides a current survey of the role of calpains in proteolytic processes found in polyglutamine disorders. Together with insights into general concepts behind toxic fragments and findings in polyglutamine disorders, this work aims to inspire researchers to broaden and deepen the knowledge in this field, which will help to evaluate calpain-mediated proteolysis as a unifying and therapeutically targetable posttranslational mechanism in neurodegeneration.

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

BACKGROUND: Dentatorubral-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. METHODS: We 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. RESULTS: We 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). CONCLUSION: The 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.

The rare and the common: An Austrian DRPLA family harboring the European haplotype.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a CAG trinucleotide repeat expansion disorder with an autosomal-dominant mode of inheritance and very low prevalence in Europe. We herein report the clinical characteristics of the first Austrian DRPLA family. Genetic analysis revealed the presence of a common European haplotype, suggesting a founder mutation in Europe.

Juvenile Huntington's Disease and Other PolyQ Diseases, Update on Neurodevelopmental Character and Comparative Bioinformatic Review of Transcriptomic and Proteomic Data.

Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington's disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. In addition, we extended our bioinformatic transcriptomic analysis by proteomics data. We identified a group of 13 commonly downregulated genes and proteins in HD mouse models. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.

Universal RNAi Triggers for the Specific Inhibition of Mutant Huntingtin, Atrophin-1, Ataxin-3, and Ataxin-7 Expression.

The expansion of CAG repeats within the coding region of associated genes is responsible for nine inherited neurodegenerative disorders including Huntington's disease (HD), spinocerebellar ataxias (SCAs), and dentatorubral-pallidoluysian atrophy (DRPLA). Despite years of research aimed at developing an effective method of treatment, these diseases remain incurable and only their symptoms are controlled. The purpose of this study was to develop effective and allele-selective genetic tools for silencing the expression of mutated genes containing expanded CAG repeats. Here we show that repeat-targeting short hairpin RNAs preferentially reduce the levels of mutant huntingtin, atrophin-1, ataxin-3, and ataxin-7 proteins in patient-derived fibroblasts and may serve as universal allele-selective reagents for polyglutamine (polyQ) diseases.

The cerebellar white matter lesions in dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG nucleotide repeat expansion in atrophin 1. A previous report described cerebellar white matter lesions on magnetic resonance imaging (MRI) in elderly-onset DRPLA patients, but this finding has not been fully investigated in a total population of DRPLA patients, including juvenile or early-adult onset patients. Herein, we attempted to determine the frequency, distribution pattern, and features of the cerebellar white matter lesions in 30 consecutive DRPLA patients. We also assessed the relationships between the cerebellar white matter lesions and clinical parameters and other MRI findings. The cerebellar white matter lesions were found in 43% of the 30 DRPLA patients, and in 70% of the late adult-onset DRPLA patients. In approx. Two-thirds of the patients with cerebellar white matter lesions, the lesions were localized in the paravermal area (paravermal lesions). Multiple logistic regression analyses revealed that the Fazekas grade of 'cerebral' white matter lesions was independently associated with 'cerebellar' white matter lesions. In conclusion, cerebellar white matter lesions are one of the distinctive MRI features in DRPLA patients, especially in patients with older age at onset. Cerebellar white matter lesions, as well as cerebral white matter lesions, might originate from the disease process of DRPLA itself, and they often have a characteristic distribution of paravermal lesions.

Perampanel in lissencephaly-associated epilepsy.

We retrospectively investigated whether perampanel (PER) could serve as an alternative for treating drug-resistant seizures in lissencephaly. We investigated the following data: age at onset of epilepsy, age at start of PER, etiology, brain MRI findings, seizure type, seizure frequency, adverse effects, and concomitant anti-epileptic drugs. There were 5 patients with lissencephaly, including 2 with Miller-Dieker syndrome. Four out of five patients exhibited ≥ 50% seizure reduction. Myoclonic seizures disappeared in 1 patient. PER was an effective adjunctive anti-seizure drug in our series of patients with lissencephaly.

Dentatorubral-pallidoluysian Atrophy: An Update.

Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei. No disease-modifying or curative treatments are currently available. Methods: We performed an online literature search using PubMed for all articles published in an English Language format on the topics of DRPLA or ATN1 over the last 10 years. Where these articles cited other research as support for findings, or statements, these articles were also reviewed. Contemporary articles from related research fields (e.g., Huntington's Disease) were also included to support statements. Results: Forty-seven articles were identified, 10 were unobtainable and 10 provided no relevant information. The remaining 27 articles were then used for the review template: seven case reports, seven case series, six model system articles (one review article), four population clinical and genetic studies (one review article), two general review articles, and one human gene expression study. Other cited articles or research from related fields gave a further 42 articles, producing a total of 69 articles cited: 15 case series (including eight family studies), 14 model systems (one review article), 14 population clinical and genetic studies (two review articles), 10 case reports, eight clinical trials/guidelines, four genetic methodology articles, three general review articles, and one human gene expression study. Discussion: DRPLA remains an intractable, progressive, neurodegenerative disorder without effective treatment. Early recognition of the disorder may improve patient understanding, and access to services and treatments. Large-scale studies are lacking, but are required to characterize the full allelic architecture of the disorder in all populations and the heterogeneous phenotypic spectrum, including neuroimaging findings, possible biomarkers, and responses to treatment.

Spinocerebellar ataxias.

There are over 40 autosomal dominant spinocerebellar ataxias (SCAs) now identified. In this chapter we delineate the phenotypes of SCAs 1-44 and dentatorubral-pallidoluysian atrophy (DRPLA) and highlight the clinical and genetic features of the well characterised SCAs in detail in the main section of the chapter, along with their frequency and age at onset. We have included a section on the key phenotypic features of rare spinocerebellar ataxias and discuss rare and unusual presentations and genetic mechanisms of the ataxias and show differences between adult and paediatric presentations. We look at unusual mechanisms where knowledge is evolving in some dominant ataxias. For ease of reference we have tabulated historical aspects of the ataxias, major neurological diagnostic features, ataxias with predominant paediatric and infantile onset and list recognisable nerve conduction features. We comment on the anti-sense ataxia gene mechanisms and we discuss potential developments including exome sequencing and potential therapeutic options. A gene table listing all of the identified SCAs and DRPLA is also included with key references and gene locations and symbols with OMIM reference numbers for further reading.

Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA).

We administered perampanel (PER) to a bedridden 13-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA). The DRPLA diagnosis was based on the presence of a CAG trinucleotide repeat in the ATN1 gene. The patient experienced continuous myoclonic seizures and weekly generalized tonic-clonic seizures (GTCs). PER stopped the patient's myoclonic seizures and reduced the GTCs to fragmented clonic seizures. The patient recovered his intellectual abilities and began to walk again with assistance. We suggest that PER be considered as one of the key drugs used to treat patients with DRPLA.

Trinucleotide repeat disorders.

Trinucleotide repeat disorders comprise a variable group of inherited neurodegenerative diseases, with a large range in prevalence figures. There is a broad range in clinical presentations, but many of these diseases lead to some form of ataxia or other movement disorders, which are frequently combined with cognitive or psychiatric disturbances. This group can be divided into CAG- versus non-CAG-repeat diseases. Apart from spinocerebellar ataxia type 6 and 12 (SCA6 and SCA12), these CAG-repeat diseases, as well as Huntington disease-like 2 (HDL2) and SCA8, can be neuropathologically identified using 1C2 polyglutamine antibodies. In fragile X-associated tremor and ataxia, SCA6 and SCA12 ubiquitin/p62-positive and 1C2-negative inclusion bodies can be observed. In the other diseases proteinaceous inclusions are not found. For definite diagnosis genetic analysis is necessary.

Striatal glucose hypometabolism in preadolescent-onset dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is hereditary spinocerebellar degeneration presenting various symptoms in association with expansion of the CAG repeat in Atrophin-1 gene. The functional neuroimaging of DRPLA has been poorly investigated. The purpose of this study was to examine (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) findings of DRPLA. We retrospectively investigated the cases of 14 consecutive genetically confirmed DRPLA patients at our institute. Four juvenile-onset patients underwent (18)F-FDG-PET because of intractable seizures. Their (18)F-FDG-PET images, clinical profiles and MRI findings were evaluated. For quantitative comparison, 3 healthy volunteers also underwent (18)F-FDG-PET as controls. All four patients presented progressive myoclonus epilepsy without MRI abnormalities. Both the visual and quantitative assessments of their (18)F-FDG-PET findings demonstrated bistriatal hypometabolism in only the two preadolescent-onset patients with larger CAG repeat size, whereas the two other later-onset patients showed no hypometabolism in the striatum. Bistriatal glucose hypometabolism in preadolescent-onset DRPLA patients might reflect more severe degeneration. This finding could contribute to a better understanding of DRPLA.