Falls in degenerative cerebellar ataxias.

We retrospectively and prospectively assessed the frequency and characteristics of falls in patients with degenerative cerebellar ataxias. The results show that falls occur very frequently in patients with degenerative cerebellar ataxias and that these falls are serious and often lead to injuries or a fear of falling. Clinicians should be aware of this problem in ataxia patients and should try to prevent falls.     

Clinical features and molecular genetics of autosomal recessive cerebellar ataxias

Among the hereditary ataxias, autosomal recessive spinocerebellar ataxias comprise a diverse group of neurodegenerative disorders. Clinical phenotypes vary from predominantly cerebellar syndromes to sensorimotor neuropathy, ophthalmological disturbances, involuntary movements, seizures, cognitive dysfunction, skeletal anomalies, and cutaneous disorders, among others. Molecular pathogenesis also ranges from disorders of mitochondrial or cellular metabolism to impairments of DNA repair or RNA processing functions. Diagnosis can be improved by a systematic approach to the categorisation of these disorders, which is used to direct further, more specific, biochemical and genetic investigations. In this Review, we discuss the clinical characteristics and molecular genetics of the more common autosomal recessive ataxias and provide a framework for assessment and differential diagnosis of patients with these disorders.     

The genetic nomenclature of recessive cerebellar ataxias

The recessive cerebellar ataxias are a large group of degenerative and metabolic disorders, the diagnostic management of which is difficult because of the enormous clinical and genetic heterogeneity. Because of several limitations, the current classification systems provide insufficient guidance for clinicians and researchers. Here, we propose a new nomenclature for the genetically confirmed recessive cerebellar ataxias according to the principles and criteria laid down by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders. We apply stringent criteria for considering an association between gene and phenotype to be established. The newly proposed list of recessively inherited cerebellar ataxias includes 62 disorders that were assigned an ATX prefix, followed by the gene name, because these typically present with ataxia as a predominant and/or consistent feature. An additional 30 disorders that often combine ataxia with a predominant or consistent other movement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usually present with complex nonataxia phenotypes, but may occasionally present with cerebellar ataxia. These are listed separately without the ATX prefix. This new, transparent and adaptable nomenclature of the recessive cerebellar ataxias will facilitate the clinical recognition of recessive ataxias, guide diagnostic testing in ataxia patients, and help in interpreting genetic findings. © 2018 International Parkinson and Movement Disorder Society     

Autosomal recessive cerebellar ataxias

Introduction

Autosomal recessive cerebellar ataxias (ARCA) are heterogeneous and complex inherited neurodegenerative diseases that may affect the cerebellum and/or the spinocerebellar tract, the posterior column of the spinal cord and the peripheral nerves. Cerebellar ataxia is frequently proeminent and mostly associated with several neurological or extra-neurological signs, leading to a major disability before the age of 30.

State of art

Friedreich's ataxia (FRDA) is clearly the most frequent ARCA and several rarer entities have been described during the past fifteen years such as ataxia with oculomotor apraxia type 1 (AOA1) and type 2 (AOA2), ataxia with vitamin E deficiency (AVED) and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The ACAR are characterized by both allelic and non-allelic genetic heterogeneity. They may be divided into three groups: spino-cerebellar ataxia with pure sensory neuropathy; cerebellar ataxia with sensori-motor axonal neuropathy; pure cerebellar ataxia (i.e. ataxia of purely cerebellar origin that may be associated with other symptoms). Common physiological pathways are involved in several ARCA, such as DNA repair deficiency (AOA1, ataxia telangiectasia [AT]…), RNA termination disorder (AOA2), mitochondrial defect (FRDA, sensory ataxic neuropathy with dysarthria and ophthalmoplegia [Sando]…), lipoprotein assembly defects (AVED, abetalipoproteinemia [ABL]), chaperon protein disorders (ARSACS, Marinesco-Sjögren syndrome [MSS]) or peroxysomal diseases (Refsum disease [RD]).

Perspectives

New nanotechnology methods and high throughput gene analysis as well as bioinformatics should lead to the identification of several new ARCAs in the next few years despite the rarity of these entities. However, the challenge of the next decades will be the discovery of efficient treatments for these disabling neurodegenerative disorders.

Conclusion

Clinicians should be aware of the more frequent ARCAs, especially FRDA, in addition to ARCAs for which treatment is available (FRDA, AVED, ABL and RD for instance).     

Autosomal dominant cerebellar ataxias

Cerebellar ataxias with autosomal dominant transmission (ADCA) are far rarer than sporadic cases of cerebellar ataxia. The identification of genes involved in dominant forms has confirmed the genetic heterogeneity of these conditions and of the underlying mechanisms and pathways. To date, at least 28 genetic loci and, among them, 20 genes have been identified. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes more complex multisystemic neurological deficits. Seven ADCA (SCA1, 2, 3, 6, 7, 17, and dentatorubro-pallido-luysian atrophy) are caused by repeat expansions in the corresponding proteins; phenotype-genotype correlations have shown that repeat size influences the progression of the disease, its severity and clinical differences among patients, including the phenomenon of anticipation between generations. All other ADCA are caused either by non-coding repeat expansions, conventional mutations or large rearrangements in genes with different functions. This review will focus on the genetic features of ADCA and on the clinical differences among the different forms.     

The inherited cerebellar ataxias: an update

Journal of Neurology - This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and...     

Classification of hereditary cerebellar ataxias

The hereditary cerebellar ataxias are one of the most complex group of neurogenetic diseases. A review of the several attempts do classify the heredoataxias is presented. The classifications based on clinical and genetic grounds are the most useful. The recent advances in molecular genetics are prone to give important clues for elucidation and understanding of the pathogenesis of heredodegenerative cerebellar diseases.     

Milestones in genetics of cerebellar ataxias

neurogenetics - Cerebellar ataxias (CAs) comprise a group of rare, neurological disorders characterized by extensive phenotypic and genetic heterogeneity. The core clinical feature is the...     

Planned gait termination in cerebellar ataxias

This study set out to characterise the pattern of planned gait termination in a sample of patients with cerebellar diseases. The gait termination phase was recorded, using a motion analysis system, in ten patients with primary degenerative cerebellar disease and in ten controls. The subjects were instructed to walk at different gait speeds and to stop in response to an acoustic signal. Time-distance parameters (step length, step width, double support duration, time-to-slow, stopping time, centre of mass velocity and number of steps) and stability index-related parameters (distance between the "extrapolated centre of mass" (XCoM) and centre of pressure (CoP)) were measured at both matched and self-selected gait speeds. At matched speed the patients, compared with the controls, showed a reduced step length, a greater first and second step width and used more steps to stop. At self-selected speed, almost all the parameters differed from those of the controls. Furthermore, the patients showed an increased stability index, suggesting that they need to maintain a "safety margin" between the XCoM and CoP during the gait termination. Patients develop a series of compensatory strategies in order to preserve balance during planned gait termination, e.g. increasing their step width and number of steps. Ataxic patients need to maintain a safety margin in order to avoid instability when stopping. Given the potential risk of falls when stopping, walking ataxic patients may benefit from a rehabilitation treatment focused on preserving and improving their ability to terminate gait safely.     

Polyneuropathy in autosomal dominant cerebellar ataxias: phenotype-genotype correlation.

Autosomal dominant cerebellar ataxias (ADCAs) are clinically and genetically heterogeneous neurodegenerative disorders. The aim of this study was to evaluate electrophysiologically peripheral nervous system involvement in each of the groups studied and its correlation with the number of CAG repeats. Forty patients with ADCA were clinically and electrophysiologically investigated. Thirty-five patients belonged to the ADCA type I group (SCA1, 12; SCA2, 10; SCA3, 13) and five to the ADCA type II group. Axonal sensory or sensorimotor polyneuropathy was found in 42% of the SCA1 patients, 80% of the SCA2 patients, and 54% of the SCA3 patients, whereas electrophysiological studies were normal in all those with ADCA type II. The number of CAG repeats was significantly higher in SCA1 patients with polyneuropathy than in those without polyneuropathy (P = 0.01), whereas the reverse was observed in SCA3/MJD (Machado-Joseph disease) patients (P = 0.05). We conclude that axonal polyneuropathy is often associated with ADCA type I, but its frequency varies according to factors such as the locus responsible and the number of CAG repeats.     

Autosomal recessive cerebellar ataxias with oculomotor apraxia

INTRODUCTION: Autosomal recessive cerebellar ataxias (ARCA) comprise a phenotypically and genetically heterogeneous group of diseases. Recently, a subgroup of ARCA associated with oculomotor apraxia has been delineated. STATE OF THE ART: The ataxias with oculomotor apraxia (AOA) include four distinct genetic entities at least: ataxia-telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia type 1 (AOA1) and type 2 (AOA2). The responsible genes, ATM, MRE11, APTX and SETX respectively, are implicated in DNA-break repair mechanisms. CONCLUSION: We describe the phenotypic and genetic characteristics of these ataxias, based on a review of the literature and a personal study of AOA1 and AOA2 patients.     

Peripheral neuropathies associated with hereditary cerebellar ataxias

Inherited cerebellar ataxias constitute a complicated and heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or spinocerebellar tract, spinal cord and peripheral nerves. A peripheral neuropathy is frequently seen in inherited cerebellar ataxias although it rarely reveals the disease. Moreover, the peripheral neuropathy is helpful for the diagnostic procedure and contributes to the functional prognosis of the disease. Thus, electroneuromyography is essential in the algorithm for the diagnosis of inherited cerebellar ataxias, as well as brain MRI (looking especially for cerebellar atrophy) and the assessment of several biomarkers (alpha-foetoprotein, vitamin E, albumin, LDL cholesterol, lactic acid, phytanic acid).     

The neurological update: therapies for cerebellar ataxias in 2020

Journal of Neurology - Cerebellar ataxias (CAs) represent a heterogeneous group of sporadic or inherited disorders. The clinical spectrum of CAs is continuously expanding. Our understanding of the...     

New autosomal recessive cerebellar ataxias with oculomotor apraxia

Autosomal recessive cerebellar ataxias (ARCAs) are a phenotypically and genetically heterogeneous group of diseases. Recently, a subgroup of ARCA associated with oculomotor apraxia (AOA) has been delineated. It includes at least four distinct genetic entities: ataxia-telangiectasia, ataxia-telangiectasia-like disorder, and ataxia with oculomotor apraxia type 1 (AOA1) and type 2 (AOA2). The phenotypes share several similarities, and the responsible genes, ATM, MRE11, APTX, and SETX, respectively, are all implicated in DNA break repair. As in many other DNA repair deficiencies, neurodegeneration is a hallmark of these diseases. Recently, the genes for two new autosomal recessive cerebellar ataxias with oculomotor apraxia, AOA1 and AOA2, were identified. Here, we report the phenotypic characteristics, genetic characteristics, and the recent advances concerning AOA1 and AOA2.     

Increased GABA receptor binding in dominantly-inherited cerebellar ataxias

We measured gamma-aminobutyric acid (GABA) receptor binding in the cerebellar cortex of 14 patients with dominantly-inherited cerebellar ataxias. Most of these patients had moderate to marked Purkinje cell loss as judged from the subnormal dentate nucleus GABA levels. Mean GABA receptor binding (at 25 nM GABA concentration) was elevated significantly by 37% in the total group of 14 patients studied and by 60% in the largest subgroup (n=6) analyzed. Possible explanations for the enhanced binding include glial proliferation, exposure of normally unexposed receptor sites consequent to neuronal degeneration, and/or denervation supersensitivity.     

Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6.

BACKGROUND: Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders. The mutational basis for most of these disorders is an expanded CAG repeat sequence within the coding regions of the genes involved. The prevalence of SCA in the ethnic Chinese on Taiwan remains unclear. Moreover, there has been no report of SCA type 6 (SCA6) among Chinese people. OBJECTIVES: To characterize the prevalence of SCA in the ethnic Chinese on Taiwan, and to specifically characterize Chinese patients with SCA6 in terms of clinical and molecular features. PATIENTS AND METHODS: Using a molecular approach, we investigated SCA in 74 Taiwanese families with dominantly inherited ataxias and in 49 Taiwanese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 12 patients from 8 families and in 2 sporadic cases. Furthermore, the intragenic polymorphic marker D19S1150 was amplified by polymerase chain reaction to analyze for linkage disequilibrium. RESULTS: Machado-Joseph disease-SCA3 was the most common type of autosomal dominant SCA in the Taiwanese cohort, accounting for 35 cases (47.3%), followed by SCA6 (8 [10.8%]), SCA2 (8 [10.8%]), SCA1 (4 [5.4%]), SCA7 (2 [2.7%]), dentatorubropallidoluysian atrophy (1 [1.4%]), and SCA8 (0%). The genes responsible for 16 (21.6%) of Taiwanese dominantly inherited SCA cases remain to be determined. Among the 49 patients with sporadic ataxias in the present series, 2 (4.1%) were found to harbor SCA6 mutations. In the families with SCA6, we found significant anticipation in the absence of genetic instability on transmission, indicating that some other mechanism might account for the anticipation. The same frequent allele of the intragenic DNA marker (D19S1150) was shared by 7 of 10 Taiwanese families with SCA6. CONCLUSIONS: Although SCA6 has, so far, not been reported in mainland Chinese, we found a geographic cluster of families with SCA6 on Taiwan. Genotyping studies suggest a founder effect in the Taiwanese patients with SCA6.     

Thiamin contents of cerebrospinal fluid, plasma and erythrocytes in cerebellar ataxias.

Free thiamin and thiamin monophosphate have been found in the cerebrospinal fluid, plasma and in erythrocytes of patients suffering from ataxia of different origins. In erythrocytes, thiamin pyrophosphate was also measured. In a limited number of cases, uptake of 14C-thiamin by erythrocytes was found as well. Controls were hospitalized patients affected by chronic neurological diseases without any clinical sign of thiamin deficiency. The results showed a significant decrease in thiamin and thiamin monophosphate in the cerebrospinal fluid and in the plasma of ataxic subjects, in comparison to controls. In erythrocytes, only thiamin pyrophosphate levels had decreased. The uptake of 14C-thiamin by erythrocytes was similar in both ataxic and control groups. These results were comparable to those observed in thiamin-deficient individuals, like alcoholic patients, and prompted further investigation into thiamin metabolism in these diseases.