Summary Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474442204007379.pdf

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.

The cerebellum is an essential part of the neural network involved in adapting goal-directed arm movements. This adaptation might rely on two distinct signals: a sensory prediction error or a motor correction. Sensory prediction errors occur when an initial motor command is generated but the predicted sensory consequences do not match the observed values. In some tasks, these sensory errors are monitored and result in on-line corrective motor output as the movement progresses. Here we asked whether cerebellum-dependent adaptation of reaching relies on sensory or on-line motor corrections. Healthy controls and people with hereditary cerebellar ataxia reached during a visuomotor perturbation in two conditions: "shooting" movements without on-line corrections and "pointing" movements that allowed for on-line corrections. Sensory (i.e., visual) errors were available in both conditions. Results showed that the addition of motor corrections did not influence adaptation in control subjects, suggesting that only sensory errors were needed for learning. Cerebellar subjects were comparably impaired in both adaptation conditions relative to controls, despite abnormal and inconsistent on-line motor correction. Specifically, poor on-line motor corrections were unrelated to cerebellar subjects' adaptation deficit (i.e., adaptation did not worsen), further suggesting that only sensory prediction errors influence this process. Therefore adaptation to visuomotor perturbations depends on the cerebellum and is driven by the mismatch between predicted and actual sensory outcome of motor commands.

/pdf/sensory-prediction-errors-drive-cerebellum-dependent-1p06ibw5tx.pdf

Sensory Prediction Errors Drive Cerebellum-Dependent Adaptation of Reaching

Nicotinic acetylcholine receptors (AChRs) are a family of acetylcholine-gated cation channels that form the predominant excitatory neurotransmitter receptors on muscles and nerves in the peripheral nervous system. AChRs are also expressed on neurons in lower amounts throughout the central nervous system. AChRs are even being reported on unexpected cell types such as keratinocytes. Structures of these AChRs are being determined with increasing precision, but functions of some orphan subunits are just beginning to be established. Functional roles for postsynaptic AChRs in muscle are well known, but in neurons the post-, peri-, extra-, and presynaptic roles of AChRs are just being revealed. Pathogenic roles of AChRs are being discovered in many diseases involving mechanisms ranging from mutations, to autoimmune responses, to the unknown; involving cell types ranging from muscles, to neurons, to keratinocytes; and involving signs and symptoms ranging from muscle weakness to epilepsy, to neurodegenerative disease, to psychiatric disease, to nicotine addiction. Awareness of AChR involvement in some of these diseases has provoked new interests in development of therapeutic agonists for specific AChR subtypes and the use of expressed cloned AChR subunits as possible immunotherapeutic agents. Highlights of recent developments in these areas will be briefly reviewed.

Nicotinic acetylcholine receptors in health and disease.

Neurodegenerative disorders, which are chronic and progressive, are characterized by selective and symmetric loss of neurons in motor, sensory, or cognitive systems. Delineation of the patterns of cell loss and the identification of disease-specific cellular markers have aided in nosologic classification: senile plaques, neurofibrillary tangles, neuronal loss, and acetylcholine deficiency define Alzheimer's disease1,2; Lewy bodies and depletion of dopamine characterize Parkinson's disease3; cellular inclusions and swollen motor axons are found in amyotrophic lateral sclerosis4; and γ-aminobutyric acid–containing neurons of the neostriatum are lost in Huntington's disease.5 Mendelian inheritance can be demonstrated in many of these disorders . . .

Molecular basis of the neurodegenerative disorders.

Human motor behavior is constantly adapted through the process of error-based learning. When the motor system encounters an error, its estimate about the body and environment will change, and the next movement will be immediately modified to counteract the underlying perturbation. Here, we show that a second mechanism, use-dependent learning, simultaneously changes movements to become more similar to the last movement. In three experiments, participants made reaching movements toward a horizontally elongated target, such that errors in the initial movement direction did not have to be corrected. Along this task-redundant dimension, we were able to induce use-dependent learning by passively guiding movements in a direction angled by 8 degrees from the previous direction. In a second study, we show that error-based and use-dependent learning can change motor behavior simultaneously in opposing directions by physically constraining the direction of active movements. After removal of the constraint, participants briefly exhibit an error-based aftereffect against the direction of the constraint, followed by a longer-lasting use-dependent aftereffect in the direction of the constraint. In the third experiment, we show that these two learning mechanisms together determine the solution the motor system adopts when learning a motor task.

https://www.jneurosci.org/content/jneuro/30/15/5159.full.pdf

Use-Dependent and Error-Based Learning of Motor Behaviors

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the α1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.

Spinocerebellar ataxia type 6: Gaze‐evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset

The slow-channel syndrome is one of several congenital myasthenic syndromes that result from inherited abnormalities of the ion channel of the skeletal muscle acetylcholine receptor (AChR). The ion channel is formed by the second transmembrane domains (M2) of the four AChR subunits. We screened the genomic DNA of one family with the slow-channel syndrome for mutations in the coding sequences for the M2 domains of the four AChR subunits and report the identification of a missense mutation that causes a leucine-to-phenylalanine substitution at position 269 of the epsilon subunit in three affected members of a family with the slow-channel syndrome. We propose that this mutation may be responsible for the disease.

A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome.

Erratum: A β-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome (Annals of Neurology (1996) 39 (712- 723))

Jason T. Gammack

Papers

Spinocerebellar ataxia type 6: Gaze‐evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset

A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome.

Erratum: A β-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome (Annals of Neurology (1996) 39 (712- 723))

Gomez, C. M. et al. A -subunit mutation in the acetylcholine receptor gate causes severe slow-channel syndrome. Ann. Neurol. 39, 712-723