A total of 280 cases of primary biliary cirrhosis were reported from 86 institutes in Japan, of whom 208 were middle aged women. Four clinical stages (asymptomatic, pruritus, icteric and terminal stage) were set up for analysing clinical and histopathological features based on the natural course of the disease. The clinical and histopathological findings were similar to the study reported from the United States and European countries. Out of 270 cases examined, 245 (90.7%), had mitochondrial antibodies. Concerning the prognosis 37 of 120 asymptomatic patients developed symptoms and the average symptom-free period in these patients was 28.7 months. Fifty-eight cases were fatal and causes of death were hepatic failure in 27, gastrointestinal bleeding in 20 and others in 11 cases. Patients were subdivided into three groups to elucidate the survival rate in patients with different symptoms. Asymptomatic patients showed almost the same survival rate as the patients with pruritus alone, showing about 50% survival 8 years after the diagnosis, in contrast to jaundiced cases with only 13.6% surviving 8 years after the onset of this symptom.

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We have successfully used retroviral gene transfer to correct the deficiency of the branched-chain alpha-oxo acid dehydrogenase complex in lymphoblasts from a homozygous Mennonite maple syrup urine disease (MSUD) patient. The mutation in Mennonites is a Tyr-393 to Asn substitution in the branched-chain alpha-oxo acid decarboxylase (E1)alpha subunit of the enzyme complex. This promotes improper assembly of mutant E1 alpha with E1 beta subunits, leading to degradation of both polypeptides. For transduction studies, a full-length human E1 alpha CDNA was inserted into the retroviral vector LXSN to produce the recombinant LSN-E1 alpha. High-titre [6 x 10(5) colony-forming units/ml] amphotropic retroviral preparations free of helper viruses were obtained by co-cultivation of infected GP+E86 with PA317 cells. Transduction of MSUD lymphoblasts from the Mennonite patient with LSN-E1 alpha viruses restored the decarboxylation of alpha-oxo[1-14C]isovalerate to the normal level. The normal decarboxylation activity in transduced MSUD cells remained stable without G418 selection during the 14 weeks studied. Southern-blot analysis indicated that the recombinant E1 alpha cDNA was integrated into the host genome. Northern and Western blotting showed that both the normal E1 alpha mRNA and the subunit were properly expressed in transduced MSUD cells. However, the level of E1 beta subunits is lower than that of normal cells, suggesting competition of the recombinant E1 alpha with the mutant form for assembly with E1 beta. The results provide a paradigm for the development of somatic gene therapy for disorders involving mitochondrial multienzyme complexes.

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