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The Cerebellar Ataxias and Hereditary Spastic Paraplegias
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
There are several forms of autosomal dominant ataxia in which ataxia occurs in intermittent attacks. In episodic ataxia with myokymia (EAM/EA type 1), the attacks start in early childhood and last seconds to minutes with myokymia (rippling of muscles, especially facial) evident between attacks. Persistent ataxia does not develop. Mutation analysis of the voltage gated potassium channel gene, KCNA1, on chromosome 12p has identified different mis-sense point mutations. The attacks may respond to acetazolamide or carbamazepine.In episodic ataxia with nystagmus (EAN/EA type 2), the attacks develop in later childhood or adolescence, last hours or days and may be accompanied by headache, nausea and vertigo; they are relieved by acetazolamide. There is no myokymia. In between the episodes, there may be nystagmus and mild gait ataxia; some patients do not experience any acute attacks. Cerebellar atrophy is seen on brain MRI. Similar neurological signs are seen in some patients with autosomal dominant familial hemiplegic migraine. Familial hemiplegic migraine and periodic ataxia without myokymia are allelic disorders on chromosome 19p13 caused by point mutations of the alpha 1A calcium channel gene (CACNL1A4). Trinucleotide CAG expansions within the same gene cause a mild autosomal dominant adult-onset cerebellar ataxia (SCA6, see below under Autosomal dominant cerebellar ataxia type III). Other point mutations of CACNL1A4 cause familial hemiplegic migraine which has similar symptoms to EA2.Episodic ataxia type 3 is rare; there is episodic acetazolamide-responsive ataxia, vertigo and tinnitus; myokymia can occur. There is linkage to a gene on chromosome 1q42.Episodic ataxia type 4 (periodic vestibulocerebellar ataxia) can also be associated with a mild persistent ataxia; it is not linked to episodic ataxia type 1, 2 or 3. There are attacks of ataxia, oscillopsia, diplopia and vertigo. A persisting ataxia may develop.Episodic ataxia type 5 has been seen in one family. It was caused by a mutation of the alpha 4 subunit of the calcium channel gene CACNB4 on chromosome 2q22–23. The same mutation rarely causes epilepsy.
Use of big data in drug development for precision medicine: an update
Published in Expert Review of Precision Medicine and Drug Development, 2019
Tongqi Qian, Shijia Zhu, Yujin Hoshida
Due to the fact that patients might have different genetic backgrounds, the therapeutic window of certain drugs would be also distinct, accordingly raising a more important concern about the personalized drug safety [79]. It could be exemplified by 6-mercaptopurine, which is a drug for acute lymphocytic leukemia and chronic myeloid leukemia. It may take on different side effects in patients with different genetic variants on TPMT, NUDT15, and ITPA [81–83]. Motivated by this fact, genetic tests are necessary to screen patients with specific allele variants beforehand. Theoretically, biomarkers could be learned to predict the drug toxicity for each individual patient, when given enough training datasets. One proof-of-concept example is from the DREAM challenge, in which by integrating genetic profiles of cell lines with the compound chemical information, the in silico methods could predict cytotoxicity phenotype [84], largely supporting the feasibility of prediction of individualized drug toxicity [85]. GWAS as a hypothesis-free method has successfully identified novel genes that are responsible for drug response or drug-induced toxicity [86]. For example, through GWA study, a genetic variant on the TCL1A gene was found to induce musculoskeletal adverse events, revealing the involvement of cytokine receptor genes in the inflammatory response [87]. A similar study found the significant association between the genetic variants on the CACNB4 gene and the drug-induced alopecia in breast cancer, suggesting the mechanism of the pathogenesis of alopecia involving ion channels [88].
Emerging drugs for the treatment of Dravet syndrome
Published in Expert Opinion on Emerging Drugs, 2018
Francesco Brigo, Pasquale Striano, Ganna Balagura, Vincenzo Belcastro
Verapamil is a voltage-gated L-type calcium channel blocker which is able to cross the brain-blood barrier. In the literature there are some reports suggesting a possible antiepileptic role of verapamil, which might be explained by following proposed mechanisms of action: (a) inhibition of the P-glycoprotein, an active efflux transporter protein expressed in normal tissue, including the brain, which is believed to contribute to the in situ phenomenon of multidrug resistance [60,61]; and (b) regulation of membrane depolarization induced by abnormal sodium channels functions by modulating the abnormal Ca(2+) influxes into neurons with subsequent cell resting” [60]. Levetiracetam, an antiepileptic drug effective against different seizure types in DS [24], can selectively modulate high-voltage-activated Ca(2+) currents both in vivo and in vitro [62,63]. Although mutations of SCN1A are the most frequent genetic cause of DS, it has been demonstrated that the CACNB4 gene, encoding the beta4 subunit of voltage-dependent calcium channel, can affects the phenotypic expression of DS and the pharmacological response [42]. It has therefore been hypothesized that the modulation of Ca(2+) currents may represent a mechanism contributing to the antiepileptic activity of both verapamil and levetiracetam in DS [64]. An open-label study (ClinicalTrials.gov Identifier: NCT01607073) has investigated the role of add-on of verapamil (initial dose 1 mg/kg/day with weekly dose increases to target dose of 4 mg/kg/d given thrice/day) in patients (aged 2–25 years) with drug-resistant epilepsy, including DS [65]. Four patients with DS (three of them with a documented abnormality on the SCN1A gene; two of them were a couple of identical twins) were included. The patient with DS without mutation of the SCN1A showed a 90% reduction in seizure frequency of all types in the initial 13 months, but following seizure worsening verapamil was withdrawn. The three patients with genetically confirmed DS also experienced a partial response for all types of seizures (60% reduction in 2 patients; 90% in the remaining); furthermore, parents reported an improvement in cognitive function which was not verified with appropriate tests. No adverse effects were observed.