Acetazolamide‐responsive episodic ataxia syndrome

Zasorin, N. L.; Baloh, Robert W.; Myers, Laura B.

doi:10.1212/wnl.33.9.1212

Cited by 75 publications

(35 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A downbeat nystagmus was observed in most of our patients and might alert clinicians to this genetic condition in children with refractory epilepsy. [33][34][35][36][37][38][39] Mechanistically, Ca V 2.1 channels are voltage-gated calcium channels expressed at the pre-synaptic and somatodendritic level of a variety of cerebral and spinal neuronal populations. 15,40,41 Ca V 2.1 channels have been shown to mediate synaptic release from a variety of neuronal cell types, both excitatory and inhibitory, in the cortex, hippocampus, thalamus and cerebellum.…”

Section: Discussionmentioning

confidence: 99%

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

et al. 2015

View full text Add to dashboard Cite

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of Ca V 2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

show abstract

Section: Discussionmentioning

confidence: 99%

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Acetazolamide (ATZ), a carbonic anhydrase inhibitor, is used empirically to reduce the severity and frequency of attacks of ataxia in episodic ataxia patients (23,24) and has been shown to ameliorate the stress-induced loss of motor coordination in a mouse model of EA1 (17). Injection of ATZ before the motor coordination tests abolished the reduction in latency of Pgu/ϩ and Pgu/Pgu mice to fall from the accelerating rotarod (Fig.…”

Section: Derivation Of the I402t Kv12 Mutation-the Foundermentioning

confidence: 99%

A New Kv1.2 Channelopathy Underlying Cerebellar Ataxia

Xie

Harrison

Clapcote

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

A forward genetic screen of mice treated with the mutagen ENU identified a mutant mouse with chronic motor incoordination. This mutant, named Pingu (Pgu), carries a missense mutation, an I402T substitution in the S6 segment of the voltage-gated potassium channel Kcna2. The gene Kcna2 encodes the voltage-gated potassium channel ␣-subunit Kv1.2, which is abundantly expressed in the large axon terminals of basket cells that make powerful axo-somatic synapses onto Purkinje cells. Patch clamp recordings from cerebellar slices revealed an increased frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents and reduced action potential firing frequency in Purkinje cells, suggesting that an increase in GABA release from basket cells is involved in the motor incoordination in Pgu mice. In line with immunochemical analyses showing a significant reduction in the expression of Kv1 channels in the basket cell terminals of Pgu mice, expression of homomeric and heteromeric channels containing the Kv1.2(I402T) ␣-subunit in cultured CHO cells revealed subtle changes in biophysical properties but a dramatic decrease in the amount of functional Kv1 channels. Pharmacological treatment with acetazolamide or transgenic complementation with wildtype Kcna2 cDNA partially rescued the motor incoordination in Pgu mice. These results suggest that independent of known mutations in Kcna1 encoding Kv1.1, Kcna2 mutations may be important molecular correlates underlying human cerebellar ataxic disease.Voltage-gated potassium channels play a key role in neuronal excitability and plasticity and are critical in establishing resting membrane potential and firing thresholds, repolarizing action potentials, and limiting excitability (1). Channels are unevenly distributed throughout the brain as a whole and also within individual neurons (2-10). Therefore, the particular utility of any given channel depends not only on its specific channel properties and stoichiometry but also on its particular localization and density within a cell or cellular compartment. In the cerebellum, the genes Kcna1 and Kcna2 encode the voltagegated potassium channel subunits Kv1.1 and Kv1.2, respectively, which contribute to the low voltage-activated potassium current I Kv1 and are coexpressed in the presynaptic GABAergic pinceaus of spontaneously firing basket cell interneurons that provide a strong inhibitory input to Purkinje cells (5-9). The shunting effect of this inhibitory conductance has been shown through modeling to have a steep correlation with the prolongation of Purkinje cell interspike intervals in vitro (11-13).The cerebellum is involved in the regulation of the initiation and timing of movements and is important for maintaining balance and posture (14). At the core of the cerebellar computational circuitry, the spontaneously spiking Purkinje cells integrate cerebral cortical and sensory, excitatory and inhibitory inputs encoding relevant information in their action potential discharge and communicate the information to the deep cerebell...

show abstract

“…[53][54][55][56] Its efficacy, discovered accidentally in a patient with EA 2 misdiagnosed as having periodic paralysis, 51 was later confirmed by others. 57,58 ACTZ effectively prevents or attenuates the attacks in approximately 50% to 75% of all patients. Clinical experience, however, shows that many patients stop treatment with this agent in the long run, because it is either no longer effective or they develop adverse effects (unpublished observation).…”

Section: Acetazolamidementioning

confidence: 99%

“…ACTZ also lowers serum bicarbonate levels and reduces the amount of brain lactate and pyruvate, resulting in subsequent brain acidosis. 58 The mechanism by which ACTZ prevents attacks-most likely via changes in pH-may be a key to understanding the disease pathomechanism, especially how the attacks are triggered.…”

Section: Acetazolamidementioning

confidence: 99%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

162

View full text Add to dashboard Cite

Summary: Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca V 2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

show abstract

Acetazolamide‐responsive episodic ataxia syndrome

Cited by 75 publications

References 0 publications

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

A New Kv1.2 Channelopathy Underlying Cerebellar Ataxia

Episodic Ataxia Type 2

Contact Info

Product

Resources

About