This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

Symmetric abnormality involving the cerebellar white matter and posterior limb of the internal capsule is characteristic of heroin vapor inhalation toxicity, although involvement may be more extensive, depending on the severity of the condition. MR imaging and CT appear to be essential for making this diagnosis because clinical history is often unreliable and findings at physical examination are nonspecific.

Paroxysmal kinesigenic choreoathetosis (PKC) is a rare paroxysmal movement disorder characterized by recurrent and brief attacks of choreiform or dystonic movements triggered or exacerbated by sudden voluntary movements. Some patients with PKC also have a history of infantile afebrile convulsions. PKC can be sporadic, or familial with autosomal dominant inheritance. PKC has been mapped to the pericentromeric region of human chromosome 16 in several Japanese families and in an African-American family, to regions which overlap by 9.8 cM (centiMorgan). Both regions overlap by 3.4 cM with a region containing a gene responsible for 'infantile convulsions and paroxysmal choreoathetosis' (ICCA). We have identified a second PKC locus (EKD2) on the long arm of chromosome 16 in a large Indian family with PKC. A maximum two-point LOD score of 3.66 (recombination fraction = 0.00, penetrance = 0.80) was obtained between PKC and D16S419. Haplotype and recombinant analysis localized EKD2 to a 15.8 cM region between D16S685 and D16S503. This region does not overlap with that identified in Japanese families, or with the ICCA locus. These results exclude one locus on chromosome 16 which causes both the ICCA and PKC syndromes; this suggests that there may be a cluster of genes on human chromosome 16 which lead to paroxysmal disorders.

Alternative splicing is known to generate multiple functionally distinct calcium channel variants that exhibit unique spatial and temporal expression patterns. In humans, naturally occurring mutations in genes encoding calcium channel pore forming α 1 -subunits are associated with several severe hereditary disorders although it remains to be described whether there exists any relationship between the physiological effects of these mutations and calcium channel splice variation. In the present study, we systematically compare the biophysical effects of three type-1 familial hemiplegic migraine (FHM-1) mutations in two predominant splice variants of the neuronal Ca V 2.1 P/Q-type channel. All three FHM-1 mutations cause a greater hyperpolarizing shift in voltage-dependent properties when expressed in the short carboxyl terminus variant (Ca V 2.1 Δ47) compared to the long variant (Ca V 2.1 +47). Furthermore, the FHM-1 mutations also exhibit differential splice variant-specific effects on recovery from inactivation and accumulation of inactivation during tonic and burst firing. Our findings provide important insight concerning the role of calcium channel alternatively spliced variants and the molecular pathophysiology of FHM-1 and potentially of other calcium channelopathies.

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An association between leukoencephalopathy, a disease of the white matter of the brain, and smoking heroin is well recognized. This paper describes 27 cases of leukoencephalopathy identified in two cities in British Columbia, Canada 2001-2006; the largest number of geographically and temporally defined reported cases in North America.Twenty cases of leukoencephalopathy were identified in and around Vancouver with onset dates December 2001 to July 2003; seven further cases were identified in Victoria September 2005-August 2006. Twenty (74%) of all cases were male, two couples were reported and eleven cases (55%) had Asian ethnicity. One case reported smoking heroin on a single occasion and developed mild symptoms; all other cases were hospitalized. Thirteen (48%) cases died; all had smoked heroin for a minimum of 3 years. Testing of one available heroin sample identified no substance other than common cutting agents.Although a specific etiology was not identified our study supports the theory of an intermittent exposure to a toxic agent added to the heroin or a combustion by-product. It also suggests a dose response effect rather than genetic predisposition. Collaboration with public health, health professionals, law enforcement and persons who use illegal drugs, will facilitate the early identification of cases to enable timely and complete follow-up including obtaining samples. Testing of implicated heroin samples may allow identification of the contaminant and therefore prevent further cases. It is therefore important to ensure key stakeholders are aware of our findings.

Episodic ataxia type 2 (EA2) is an autosomal dominant condition characterized by paroxysmal attacks of ataxia, vertigo, and nausea, typically lasting minutes to days in duration. These symptoms can be prevented or significantly attenuated by the oral administration of acetazolamide; however, the mechanism by which acetazolamide ameliorates EA2 symptoms is unknown. EA2 typically results from nonsense mutations in the CACNA1A gene that encodes the alpha1A (Cav2.1) subunit of the P/Q-type calcium (Ca2+) channel. We have identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore-forming region of the P/Q-type Ca2+ channel. Functional analysis of P/Q-type channels containing the mutation show that the H1736L alteration affects several channel properties, including reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values. Although these findings are consistent with an overall loss of P/Q-type channel function, the mutation also caused some biophysical changes consistent with a gain of function. We also tested the direct effect of acetazolamide on both wild-type and H1736L mutated P/Q-type channels and did not observe any direct action on channel properties of this pharmacological agent used to treat EA2 patients.

The spinocerebellar ataxias (SCAs) are a large group of neurological disorders which may be hereditary or sporadic. The core clinical features of gait and limb ataxia are manifestations of degenerations of the cerebellum and its connections. Other neurological systems are variably involved producing features such as extraocular movement abnormalities, pyramidal tract dysfunction, sensory loss, bulbar dysfunction, and movement disorders such as parkinsonism, dystonia and tremor. The dominantly inherited SCAs were classified in the past according to a scheme suggested by Harding.1 In this system, the autosomal dominant cerebellar ataxias (ADCA) were separated clinically into three types. In addition to cerebellar ataxia, ADCA I patients had variable degrees of dementia, supranuclear ABSTRACT: Background: The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders. Relative frequencies vary within different ethnic groups and geographical locations. Objectives: 1) To determine the frequencies of hereditary and sporadic adult onset SCAs in the Movement Disorders population; 2) to assess if the fragile X mental retardation gene 1 (FMR1) premutation is found in this population. Methods: A retrospective chart review of individuals with a diagnosis of adult onset SCA was carried out. Testing for SCA types 1, 2, 3, 6, 7, and 8, Dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich ataxia and the FMR1 expansion was performed. Results: A total of 69 patients in 60 families were identified. Twenty-one (35%) of the families displayed autosomal dominant and two (3.3%) showed autosomal recessive (AR) pattern of inheritance. A positive but undefined family history was noted in nine (15%). The disorder appeared sporadic in 26 patients (43.3%). In the AD families, the most common mutation was SCA3 (23.8%) followed by SCA2 (14.3%) and SCA6 (14.3%). The SCA1 and SCA8 were each identified in 4.8%. FA was found in a pseudodominant pedigree, and one autosomal recessive pedigree. One sporadic patient had a positive test (SCA3).Dentatorubral-pallidoluysian atrophy and FMR1 testing was negative. Conclusion: A positive family history was present in 53.3% of our adult onset SCA patients. A specific genetic diagnosis could be given in 61.9% of dominant pedigrees with SCA3 being the most common mutation, followed by SCA2 and SCA6. The yield in sporadic cases was low. The fragile X premutation was not found to be responsible for SCA.RÉSUMÉ: Ataxie spinocérébelleuse débutant chez l'adulte dans une clinique de désordres du mouvement au Canada. Contexte: Les ataxies spinocérébelleuses (ASCs) constituent un groupe hétérogène de maladies neurodégénératives tant au point de vue génétique qu'au point de vue clinique. Leur fréquence relative est très variable selon le groupe ethnique et le lieu géographique. Objectifs: 1) déterminer la fréquence d'ASCs héréditaires et sporadiques débutant chez l'adulte chez des patients fréquentant une clinique de désordres du mouvement ; 2) évaluer si on r...