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.

Hemiplegic migraine is a rare form of migraine with aura that involves motor aura (weakness). This type of migraine can occur as a sporadic or a familial disorder. Familial forms of hemiplegic migraine are dominantly inherited. Data from genetic studies have implicated mutations in genes that encode proteins involved in ion transportation. However, at least a quarter of the large families affected and most sporadic cases do not have a mutation in the three genes known to be implicated in this disorder, suggesting that other genes are still to be identified. Results from functional studies indicate that neuronal hyperexcitability has a pivotal role in the pathogenesis of hemiplegic migraine. The clinical manifestations of hemiplegic migraine range from attacks with short-duration hemiparesis to severe forms with recurrent coma and prolonged hemiparesis, permanent cerebellar ataxia, epilepsy, transient blindness, or mental retardation. Diagnosis relies on a careful patient history and exclusion of potential causes of symptomatic attacks. The principles of management are similar to those for common varieties of migraine, except that vasoconstrictors, including triptans, are historically contraindicated but are often used off-label to stop the headache, and prophylactic treatment can include lamotrigine and acetazolamide.

Sporadic and Familial Hemiplegic Migraine: Pathophysiological Mechanisms, Clinical Characteristics, Diagnosis, and Management

Nuclear receptor (NR) coregulators (coactivators and corepressors) are essential elements in regulating nuclear receptor-mediated transcription. In a little more than a decade since their discovery, these proteins have been studied mechanistically and reveal that the regulation of transcription is a highly controlled and complex process. Because of their central role in regulating NR-mediated transcription and in coordinating intercompartmental metabolic processes, disruptions in coregulator biology can lead to pathological states. To date, the extent to which they are involved in human disease has not been widely appreciated. In a complete literature survey, we have identified nearly 300 distinct coregulators, revealing that a great variety of enzymatic and regulatory capabilities exist for NRs to regulate transcription and other cellular events. Here, we substantiate that coregulators are broadly implicated in human pathological states and will be of growing future interest in clinical medicine.

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Nuclear receptor coregulators and human disease.

Migraine is an episodic neurovascular disorder that is clinically divided into two main subtypes that are based on the absence or presence of an aura: migraine without aura (MO) and migraine with aura (MA). Current molecular genetic insight into the pathophysiology of migraine predominantly comes from studies of a rare monogenic subtype of migraine with aura called familial hemiplegic migraine (FHM). Three FHM genes have been identified, which all encode ion transporters, suggesting that disturbances in ion and neurotransmitter balances in the brain are responsible for this migraine type, and possibly the common forms of migraine. Cellular and animal models expressing FHM mutations hint toward neuronal hyperexcitability as the likely underlying disease mechanism. Additional molecular insight into the pathophysiology of migraine may come from other monogenic syndromes (for instance cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is caused by NOTCH3 mutations), in which migraine is prominent. Investigating patients with common forms of migraine has had limited successes. Except for 5′,10′-methylenetetrahydrolate reductase, an enzyme in folate metabolism, the large majority of reported genetic associations with candidate migraine genes have not been convincingly replicated. Genetic linkage studies using migraine subtypes as an end diagnosis did not yield gene variants thus far. Clinical heterogeneity in migraine diagnosis may have hampered the identification of such variants. Therefore, the recent introduction of more refined methods of phenotyping, such as latent-class analysis and trait component analysis, may be certainly helpful. Combining the new phenotyping methods with genome-wide association studies may be a successful strategy toward identification of migraine susceptibility genes. Likely the identification of reliable biomarkers for migraine diagnosing will make these efforts even more successful.

Molecular genetics of migraine

Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late-onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17. To estimate the frequency of SCA17 among white SCA patients and to define the phenotypic variability, we determined the frequency of SCA17 in a large sample of 1,318 SCA patients. In total, 15 patients in four autosomal dominant SCA families had CAG/CAA repeat expansions in the TBP gene ranging from 45 to 54 repeats. The clinical features of our SCA17 patients differ from other SCA types by manifesting with psychiatric abnormalities and dementia. The neuropathology of SCA17 can be classified as a “pure cerebellar” or “cerebello-olivary” form of ataxia. However, intranuclear neuronal inclusion bodies with immunoreactivity to anti-TBP and antipolyglutamine were much more widely distributed throughout the brain gray matter than in other SCAs. Based on clinical and genetic data, we conclude that SCA17 is rare among white SCA patients. SCA17 should be considered in sporadic and familial cases of ataxia with accompanying psychiatric symptoms and dementia. Ann Neurol 2003;54:367–375

Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17)

nantly transmitted cases had (CAG)n expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)n expansions at the SCA8 (2%) gene, whereas (GAA)n expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. Conclusions: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)n expansions at the TBP gene may cause SCA17. Arch Neurol. 2002;59:623-629

https://jamanetwork.com/journals/jamaneurology/articlepdf/781773/NOC10245.pdf

Trinucleotide Repeats in 202 Families With Ataxia: A Small Expanded (CAG)n Allele at the SCA17 Locus

Almost all mutations in the SCN1A gene, encoding the α1 subunit of neuronal voltage-gated Nav1.1 sodium channels, are associated with severe childhood epilepsy. Recently, two mutations were identified in patients with pure familial hemiplegic migraine (FHM). Here, we identified a novel SCN1A L263V mutation in a Portuguese family with partly co-segregating hemiplegic migraine and epilepsy. The L263V mutation segregated in five FHM patients, three of whom also had epileptic attacks, occurring independently from their hemiplegic migraine attacks. L263V is the first SCN1A mutation associated with FHM and co-occurring epilepsy in multiple mutation carriers, and is the clearest molecular link between migraine and epilepsy thus far. The results extend the clinical spectrum associated with SCN1A mutations and further strengthen the molecular evidence that FHM and epilepsy share, at least in part, similar molecular pathways.

First Mutation in the Voltage-Gated Nav1.1 Subunit Gene SCN1A with Co-Occurring Familial Hemiplegic Migraine and Epilepsy

Mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na+,K+-ATPase, are associated with familial hemiplegic migraine type 2. The majority of ATP1A2 mutations were reported in patients with hemiplegic migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with hemiplegic migraine and interesting additional clinical features. The proband's of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to hemiplegic migraine; more severe mental retardation was observed in his brother, who also had hemiplegic migraine and carried the same mutation. Cell-survival assays clearly showed abnormal functioning of mutant Na+,K+-ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.

Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes.

João Paulo Pereira Barros

Papers

Trinucleotide Repeats in 202 Families With Ataxia: A Small Expanded (CAG)n Allele at the SCA17 Locus

First Mutation in the Voltage-Gated Nav1.1 Subunit Gene SCN1A with Co-Occurring Familial Hemiplegic Migraine and Epilepsy

Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes.