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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. [ABSTRACT FROM AUTHOR]

Twenty six consecutive patients with neuroleptic-induced Parkinson's syndrome (NIPS) are described. Their median age was 61 years, 60% were female, and most had received chronic neuroleptic medication for psychiatric indications. The clinical features were indistinguishable from idiopathic Parkinson's disease, except for the presence of co-existing orofacial chorea, limb dyskinesia or akathisia which provided an aetiological clue in 11 cases. Complete resolution of NIPS occurred in only two patients, one of whom later developed Parkinson's disease. Sixteen patients were treated with 300-1000 mg levodopa/benserazide for up to 4 years with few adverse effects but therapeutic response was disappointing. [ABSTRACT FROM AUTHOR]

A 28-year-old woman presenting with subacute onset of a tetraplegia is described who was shown to have active systemic lupus erythematosus in association with high circulating anticardiolipin binding and lupus anticoagulant activity. The patient later developed severe symptomatic systemic and pulmonary hypertension and required emergency resuscitation. This case provides further support for an association between antiphospholipid antibodies and the clinical features of central nervous system (CNS) involvement and pulmonary hypertension in SLE. [ABSTRACT FROM PUBLISHER]

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.

A case is described in which non-convulsive status epilepticus (NCSE) prompted further investigation leading to the diagnosis of Lafora body disease (LBD). The onset of NCSE was temporally related to the withdrawal of sodium valproate and introduction of carbamazepine, which may have been precipitating factors. NCSE has not previously been reported in LBD. Implications for its drug management are discussed., (Copyright 1999 Lippincott Williams & Wilkins.)

Objectives: To compare the dose-sparing effect of medetomidine on the propofol induction dose and concentration of halothane for maintenance of anesthesia during laparoscopy and to provide guidelines for effective and safe use of these anesthetics in dogs to ensure desirable perioperative analgesia., Animals: 14 purpose-bred dogs., Procedure: Cardiopulmonary and electroencephalographic responses were determined during 2 anesthesia protocols in dogs scheduled for laparoscopy. Fifteen minutes before anesthesia induction, all dogs received atropine sulfate (0.02 mg/kg of body weight, i.m.). Seven dogs were then given propofol (6.6 mg/kg, i.v.); anesthesia was maintained with halothane in oxygen. The other dogs were given medetomidine hydrochloride (10 micrograms/kg, i.m.) 5 minutes after administration of atropine sulfate; anesthesia was then induced by administration of propofol (2.8 mg/kg, i.v.) and was maintained with halothane in oxygen., Results: The halothane concentration required for laparoscopy was lower in dogs given medetomidine. Anesthetic requirements were significantly increased during abdominal manipulation in both groups. Total amplitude of the electroencephalograph in medetomidine-treated dogs was not significantly lower than that in dogs not given medetomidine. Pulmonary responses were stable throughout all procedures. The primary cardiovascular response was an increase in blood pressure associated with the medetomidine-atropine preanesthetic combination. Significant differences in total amplitude or frequency shifts (spectral edge) of brain wave activity were not associated with surgical stimulation., Conclusion: Lack of neurologic changes during laparoscopy supports the efficacy of either medetomidine-propofol-halothane or propofol-halothane combinations at higher concentrations to provide desirable analgesia and anesthesia in this group of dogs.

A two-year-old, female Chinese shar pei was presented with a one-year history of ataxia involving the pelvic limbs. The neurological lesion was localized to the thoracolumbar region of the spinal cord. A cyst involving the dorsal subarachnoid space at the level of the 12th thoracic vertebral body was identified with myelography. The diagnosis of a meningeal cyst was made, and surgical treatment consisting of a dorsal laminectomy and cyst fenestration was performed. The pelvic-limb ataxia improved, and the owners considered the dog to be normal three months after surgery. The classification, etiology, clinical signs, diagnostic techniques, treatment, and histology of meningeal cysts are reviewed.

The biochemical holding strength and histological characteristics of a laparoscopic stapled gastropexy (LG) adhesion were compared with that of an incisional gastropexy (IG) adhesion. An LG was performed in 14 dogs and an IG was performed in six dogs. During the LG procedure, the abdomen was insufflated with carbon dioxide and three cannulae were placed in the caudal aspect of the right side of the abdomen. A 35 mm laparoscopic stapler was used to staple the gastric antrum to the adjacent right lateral abdominal wall. The IG procedure was performed through ventral midline celiotomy. A 35 mm IG was made by apposing the gastric antrum to the adjacent right lateral abdominal wall with two continuous rows of suture. Half of each group of dogs was euthanatized at 7 and 30 days after surgery. The mean tensile load to failure at 7 days was 44.86 +/- 18.54 N for the LG group and 85.33 +/- 23.59 N for the IG group (P < .05). At 30 days the values were 72.39 +/- 18.01 N for the LG group and 71.17 +/-12.11 N for the IG group (P = .41). The gastropexy adhesions in the 7-day postoperative group contained variable amounts of fibrin, hemorrhage, mononuclear cell inflammation, loose fibrovascular tissue, and mature collagenous connective tissue. Adhesions in the 7-day postoperative group were divided subjectively into three histological subgroups based on the relative amounts of mature connective tissue within the adhesion. The LG and IG adhesions were randomly distributed among these subgroups (P = 1.0). Adhesions in the 30-day postoperative group contained well-organized fibrous connective tissue. No difference in the amount of connective tissue could be detected histologically in the LG or IG adhesions. Complications with the LG procedure included stomach perforation (2 cases), splenic puncture (2 cases), and subcutaneous emphysema (4 cases).

Nineteen cases are described, including 12 cases from three different families and 7 nonfamilial cases, in which multisystem neurological disease was associated with acanthocytosis in peripheral blood and normal plasma lipoproteins. Mild acanthocytosis can easily be overlooked, and scanning electron microscopy may be helpful. Some neurologically asymptomatic relatives with significant acanthocytosis were identified during family screening, including some who were clinically affected. The mean age of onset was 32 (range 8-62) yrs and the clinical course was usually progressive but there was marked phenotypic variation. Cognitive impairment, psychiatric features and organic personality change occurred in over half the cases, and more than one-third had seizures. Orofaciolingual involuntary movements and pseudobulbar disturbance commonly caused dysphagia and dysarthria that was sometimes severe, but biting of the lips or tongue was rarely seen. Chorea was seen in almost all symptomatic cases but dystonia, tics, involuntary vocalizations and akinetic-rigid features also occurred. Two cases had no movement disorder at all. Computerized tomography often demonstrated cerebral atrophy. Caudate atrophy was seen less commonly, and nonspecific focal and symmetric signal abnormalities from the caudate or lentiform nuclei were seen by magnetic resonance imaging in 3 out of 4 cases. Depression or absence of tendon reflexes was noted in 13 cases and neurophysiological abnormalities often indicated an axonal neuropathy. Sural nerve biopsies from 3 cases showed evidence of a chronic axonal neuropathy with prominent regenerative activity, predominantly affecting the large diameter myelinated fibres. Serum creatine kinase activity was increased in 11 cases but without clinical evidence of a myopathy. Postmortem neuropathological examination in 1 case revealed extensive neuronal loss and gliosis affecting the corpus striatum, pallidum, and the substantia nigra, especially the pars reticulata. The cerebral cortex appeared spared and the spinal cord showed no evidence of anterior horn cell loss. Two examples of the McLeod phenotype, an X-linked abnormality of expression of Kell blood group antigens, were identified in a single family and included 1 female. The genetics of neuroacanthocytosis are unclear and probably heterogeneous, but the available pedigree data and the association with the McLeod phenotype suggest that there may be a locus for this disorder on the short arm of the X chromosome.

On-off fluctuations have been studied in twenty patients with Parkinson's disease on long-term levodopa treatment. The pattern of fluctuations was related to the timing of oral levodopa ingestion in all patients. 'Predictable' fluctuators were characterized by fewer daily doses taken at longer intervals than 'unpredictable' fluctuators in whom individual dose responses tended to overlap. Most patients at least once a day experienced an unexplained failure of an oral dose to take effect. Administration of levodopa by intravenous infusion at a constant rate brought about a dramatic extension in the duration of mobility and reduced the frequency of fluctuations compared with oral therapy; apomorphine consistently reversed off phases when administered shortly after their onset, whereas lisuride was less often effective. We conclude that the development of a sustained-release formulation of levodopa would lead to improved control of the response fluctuations seen with conventional levodopa preparations.

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.

Acanthocytes have a distinct morphology and are not normally found in peripheral blood. They occur in association with at least three neurological syndromes. In abetalipoproteinaemia, a progressive spinocerebellar ataxia and retinopathy occurs secondary to malabsorption of vitamin E. Cases with chorea are often familial, with orofacial dyskinesia and an axonal neuropathy causing areflexia and muscle wasting. Areflexia and a subclinical myopathy also occur in the McLeod syndrome, in which there is abnormal expression of Kell blood group antigens. The exact mechanism of acanthocytosis in each disorder remains uncertain: passive changes in membrane lipids, surface receptor/ligand interactions, and a primary membrane defect are among the possibilities.

The clinical pharmacology concerned in the evolution of deprenyl as an adjuvant in the treatment of Parkinson's disease is briefly reviewed, with an assessment of its therapeutic potential. Experiments to clarify its mode of action are described, indicating that its clinical effects do not depend upon its amphetamine metabolites.

The main problems in long-term treatment of Parkinson's disease with levodopa are: 1. progressive decline in efficacy; 2. psychiatric complications; 3. the development of motor fluctuations. These are discussed, and important unanswered questions addressed, including when levodopa therapy should be started and at what dose; whether levodopa is in fact harmful in any way; what is the pharmacological role of O-methyl-dopa, present in such high concentrations; and the best management of motor fluctuations.