Fluvoxamine, a selective serotonin reuptake inhibitor which modulates serotoninergic activities, is a useful drug for patients with an autistic disorder. Genetic variation of the serotonin receptor may influence the efficacy of fluvoxamine treatment. We studied the correlation between clinical responses to fluvoxamine and serotonin receptor gene polymorphism (5-HT2AR) in children with an autistic disorder. Eighteen patients completed a 12-week double-blind, placebo-controlled, randomized crossover study. Clinical global impression (CGI) by child neurologists and interviews for parents were assessed after 12 weeks of fluvoxamine treatment. Behavioral assessments consisting of 20 items by newly created Behavioral Assessment Scale (BAS) were obtained before as well as 6 and 12 weeks after treatment. For genotyping of 5-HT2AR, 102 T/C polymorphism was analyzed by the PCR method. Seven cases of T/T, 6 of T/C and 5 of C/C were identified. The patients with the genotype T/C responded more favorably when estimated by CGI and parents' report at 12 weeks of treatment. Although not significant statistically (p = 0.0578), the number of improved BAS items in these patients were larger after fluvoxamine than placebo treatment. On analyses of individual BAS items, the patients with the genotype C/C showed improvement of unnatural facial expression, which was significant at 6 weeks, but not at 12 weeks, of fluvoxamine treatment. In the patients with the genotype T/C, eye movements and emotional changes were significantly improved at 12 weeks of treatment. Our results suggested that genetic polymorphism of 102 T/C in the 5-HT2AR gene may have influence on the response to fluvoxamine treatment for patients with an autistic disorder. Because of the small numbers of subject studied here, further studies are needed. The methods of fluvoxamine treatment, such as appropriate dosage and treatment duration, should also be clarified.
Biochemical analysis using biopsied muscle specimens was performed on 72 cases who had symptoms suggesting metabolic myopathies. Sixteen out of 72 cases (22%) were diagnosed as having chemically confirmed metabolic defects. Of these 16 cases, 9 had defects in the glycolytic pathway (glycogen storage disease type II; 3 cases, type III; 1 case, type V; 3 cases, phosphoglycerate kinase deficiency; 1 case, phosphoglucomutase deficiency; 1 case) and 7 cases in mitochondrial metabolism (complex IV deficiency; 4 cases, carnitine deficiency; 3 cases). Among 14 cases who were strongly suspected as having a defect in the glycolytic pathway because of abnormal ischemic forearm test, 6 (43%) showed biochemically proved glycolytic defects. These data suggest that care should be taken when evaluating the results of ischemic forearm test. In addition, we should carefully interpret the muscle histochemistry, because histochemical stains including PAS might be fairly normal in the defects with second step glycolytic pathway.
Abstract We report two female patients with a history of alcohol abuse presenting with proximal painful muscle weakness following aversion therapy with emetine hydrochloride. Muscle biopsy of Case 1 showed a reversible floccular‐shaped loss of myosin ATPase and dehydrogenase, and accumulation of PAS positive material, and a normal lipid content. Repeat biopsy showed core change with no focal loss of myosin ATPase. In Case 2, muscle biopsy was taken 1 month after commencement of emetine therapy and revealed similar but milder changes to Case 1. Electron microscopy revealed Z‐band streaming with a decrease or loss of mitochondria. Sarcotubular systems appeared normal in shape and size. Anaerobic glycolysis on homogenate from the initial biopsy of Case 1 showed generalized reduction of lactate formation, which returned to normal in the repeat biopsy.
Causative genes have been identified only in four types of lipid storage myopathies (LSMs): SLC22A5 for primary carnitine deficiency (PCD); ETFA, ETFB, and ETFDH for multiple acyl-coenzyme A dehydrogenation deficiency (MADD); PNPLA2 for neutral lipid storage disease with myopathy (NLSDM); and ABHD5 for neutral lipid storage disease with ichthyosis. However, the frequency of these LSMs has not been determined. We found mutations in only 9 of 37 LSM patients (24%): 3 in SLC22A5; 4 in MADD-associated genes; and 2 in PNPLA2. This low frequency suggests the existence of other causative genes. Muscle coenzyme Q(10) levels were normal or only mildly reduced in two MADD patients, indicating that ETFDH mutations may not always be associated with CoQ(10) deficiency. The 2 patients with PNPLA2 mutations had progressive, non-episodic muscle disease with rimmed vacuoles. This suggests there is a different pathomechanism from other LSMs.
In nine patients aged 3 to 45 years with glycogen storage disease type III (GSD III) presenting muscle weakness, the clinical manifestations and biochemical subtype-classifications based on organ specificity or enzymatic varieties of debrancher enzyme were analyzed. All the patients developed muscle weakness since childhood. Five patients who showed muscle weakness beginning from childhood became apparently progressive during adult life. Cardiac involvements were noticed in six patients. Eight patients were diagnosed as having type IIIa and one type IIId. Our results suggest that progressive muscle weakness and cardiac symptoms are not rare in GSD III patients, especially in the patients with enzyme deficiency in muscle tissue as well as liver. Hence we recommend to measure debrancher activity in muscle tissue in order to predict the clinical prognosis of the patients with GSD III.
