Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/ deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.
We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on‐off fluctuations whilst receiving long‐term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32‐80 mg h‐1 (0.5‐1.3 mg kg‐1 h‐1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l‐1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3‐OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two‐compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on‐ off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.
Summary T,.nsion heaclache is canman, and treatment with ,i(.LtpLIlcture is frequently recommended,,tlthouglt the evidence of its cffcctivcncss is contradiclory. This small, randontised, controlled trial was desiEned as a pilot to tcst procedLlrcs in preparajan fot a multi centre trial invcstiEating the efiect al acupuncturc as a treatmcnt far tension headache. l, t) \oluFlpct\ -ttfler;Fp uottt, pi,odi,. ', n-',,n '1p-headache wcrc rccruited by local n-.\a,spaper articlcs. Patients were randontised lo receive either bricf nccdlinB la lender areas ar selected traditional points (Croup A), ot pressure lrcnt ;t cocktail stick supportcd withitl a guide tulrc to c|-.lin-^t1, nontcDder and non-aa:LtpLtncture areas (Group B). The palients' vi-.\t, ol the treatnent sites \,\,as obstructed so that no indicatian could be gained as to which [a]ftt of eattneDt was being given.Thrau?hout the period of the ttial, duration, frequency and intensity of headachcs wcrc rccorded, from which the mean weekly headachc lndex was calculated-There was no diflerence betv,ecn thc changes in weekly headache ind-.r iD the t\\,o Eroups, camparing scates beforc and after treatment, Howcvcr, Craup A experienced a caDsiderably highcr nuntber ol headach-.-lree weeks than Croup B.'fhe credibility ol the t\\,o procedures was tested usinB a slandatd ctedibility questionn;;ire aDd a "final verdicl". One sul)ject it1 Orctup B cctncluded that she had not rcceiveal Benuine acupun.ture, but overall there ! as ro -slatistic?/ difterence between the credibility of treatment in the two gr.,ups.
Acanthocytosis occurs because of ultrastructural abnormalities of the erythrocyte membranous skeleton resulting in reduced membrane fluidity. At least three hereditary neurological conditions are associated with it, although as yet the pathogenesis of the neurological features is unknown. In abetalipoproteinaemia, an autosomal recessive condition, vitamin E deficiency results in a progressive spinocerebellar syndrome associated with peripheral neuropathy and retinitis pigmentosa. Neuroacanthocytosis is also probably an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysarthria, areflexia, seizures and dementia. McLeod syndrome is an X-linked recessive disorder usually presenting in males as a benign myopathy with areflexia, in association with a particular abnormality of expression of Kell blood group antigens. However, occasionally the neurological features are more severe and indistinguishable from those of neuroacanthocytosis. Recent advances in molecular genetics may assist better understanding of the disease mechanisms and the search for more effective treatments.
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