RESUMEN
OBJECTIVE: To use the technique of complementation analysis to help define genotype and classify patients with clinical manifestations consistent with those of the disorders of peroxisome assembly, namely the Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). STUDY DESIGN: Clinical findings, peroxisomal function, and complementation groups were examined in 173 patients with the clinical manifestations of these disorders. RESULTS: In 37 patients (21%), peroxisome assembly was intact and isolated deficiencies of one of five peroxisomal enzymes involved in the beta-oxidation of fatty acids or plasmalogen biosynthesis were demonstrated. Ten complementation groups were identified among 93 patients (54%) with impaired peroxisome assembly and one of three phenotypes (ZS, NALD, or IRD) without correlation between complementation group and phenotype. Forty-three patients (25%) had impaired peroxisome assembly associated with the RCDP phenotype and belonged to a single complementation group. Of the 173 patients, 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts. CONCLUSIONS: At least 16 complementation groups, and hence genotypes, are associated with clinical manifestations of disorders of peroxisome assembly. The range of phenotype is wide, and some patients have mild involvement.
Asunto(s)
Adrenoleucodistrofia/genética , Microcuerpos/genética , Fenotipo , Enfermedad de Refsum/genética , Síndrome de Zellweger/genética , Aciltransferasas/deficiencia , Adrenoleucodistrofia/sangre , Adrenoleucodistrofia/enzimología , Adulto , Células Cultivadas , Niño , Ácidos Grasos , Femenino , Prueba de Complementación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Refsum/sangre , Enfermedad de Refsum/enzimología , Síndrome de Zellweger/sangre , Síndrome de Zellweger/enzimologíaRESUMEN
Biochemical studies with emphasis on peroxisomal functions were conducted in six patients with well-documented rhizomelic chondrodysplasia punctata (RCDP) and compared with findings in patients with Zellweger syndrome and neonatal adrenoleukodystrophy (ALD). Patients with RCDP had three characteristic biochemical abnormalities: (1) profound defect in plasmalogen (ether lipid) synthesis, which is significantly greater than the analogous defect in Zellweger syndrome or neonatal ALD; (2) reduction of phytanic acid oxidation activity to 1% to 5% of control, similar to that observed in Refsum disease, Zellweger syndrome, and neonatal ALD; (3) presence of the unprocessed form of peroxisomal 3-oxoacyl-coenzyme A thiolase in the postmortem liver of two patients. Other peroxisomal functions were normal, including levels of very long chain fatty acids, pipecolic acid, and bile acid intermediates, and immunoblot studies of peroxisomal acyl-CoA oxidase and bifunctional enzyme in postmortem liver. Unlike what is observed in Zellweger syndrome and neonatal ALD, catalase activity in cultured skin fibroblasts was sedimentable, indicating that peroxisome structure is not grossly deficient in RCDP. The biochemical abnormalities in RCDP were consistent and set it apart from all the other known peroxisomal disorders.
Asunto(s)
Condrodisplasia Punctata/metabolismo , Microcuerpos/metabolismo , Acetil-CoA C-Aciltransferasa/metabolismo , Adrenoleucodistrofia/metabolismo , Femenino , Fibroblastos/metabolismo , Humanos , Lactante , Recién Nacido , Hígado/metabolismo , Masculino , Ácido Fitánico/metabolismo , Plasmalógenos/biosíntesis , Enfermedad de Refsum/metabolismoRESUMEN
West Indians form a sizable minority of diabetics attending many inner city diabetic clinics. There are 554 diabetics of West Indian origin on our computer files--7% of the total recorded clinic population. Of these 554 patients (56% female, 44% male), 70% have been diagnosed within the past five years; and only 9% have had diabetes for over 10 years; in only five (1%) was diabetes diagnosed before the age of 20. Sixteen per cent were taking insulin, but only 4% of the total West Indian population were truly insulin dependent. Of 65 patients admitted in hyperglycaemic coma or precoma over the past three years, 10 were of West Indian origin; eight of these 10 had hyperosmolar coma compared with only six of the remaining 55. We conclude that diabetics of West Indian origin attending our clinic show differences in the distribution of age and duration of diabetes from the caucasian population. Most are non-insulin dependent, and the frequency of hyperosmolar coma is higher than that of ketoacidosis. Diabetics of West Indian origin may have a different pattern of disease from the rest of the clinic population.