1017 HLA ANTIGENS IN PATIENTS WITH
GENETIC CONTROL OF PROGRESSIVE
AUTONOMIC FAILURE: EVIDENCE FOR
PAF, PATIENTS WITH OTHER
DEGENERATIVE NEUROLOGICAL DISEASE, AND HEALTHY EUROPEAN CONTROLS*
ASSOCIATION WITH AN HLA ANTIGEN
JAMES MOWBRAY ROGER BANNISTER ALICK SIDGWICK Departments of Neurology and Experimental Pathology, St Mary’s Hospital Medical School, London W2 1PG Summary
patients with progressive autonomic
failure, a rare disease of unknown cause, the
frequency of the HLA antigen Aw32
was 13 times more in than common healthy controls, giving a relative risk of failure with Aw32 of 28·7. Such autonomic progressive to genetic predisposition the disease might cause a defect of catecholamine metabolism in the brain or possibly affect the immune response to a virus.
Introduction PROGRESSIVE autonomic failure (PAF) is a degenerative neurological disease usually appearing in the fourth or fifth decade of life and often associated with degeneration of other parts of the central nervous system.1,2 Although more than one member of a family can be affected, a genetic basis for the disease has not previously been found. The possibility of an infectious or immunological basis led us to look for an HLA association. Patients and Methods Patients The 16 patients studied were seen at St Mary’s Hospital or the National Hospital for Nervous Diseases. The diagnosis in each was made by R. B. and was based on clinical investigation and measurement of orthostatic hypotension. All 16 patients had PAF, and 12 had associated multiple-system atrophy (MSA).
Tissue typing was carried out for 16 HLA A-locus and 23 B-locus
antigens, with the standard NIH microcytotoxicity technique. Results
patients with progressive autonomic failure the frequencies of Aw32, A2, and B 12 were all higher than in 18 patients with other degenerative neurological disease without PAF and 280 racially matched controls without evidence of neurological disease (see table). Only the association with Aw32 remained statistically significant after correction for the number of antigens studied (p
chorea. The frequency ofAw32 in PAF is 13 - I times the frequency in the 280 healthy controls, and the relative risk is 28 - 7.
14 MacMahon B, Cole P, Lm TM, et al Age at first birth and breast cancer risk. Bull WHO 1970; 43: 209-21 5 Mornson AS, Lowe CR, MacMahon B, Warram JH, Yuasa S. Survival of breast cancer patients related to incidence risk factors. Int J Cancer 1972; 9: 470-76. 16 Office of Population Censuses and Surveys Cancer statistics, survival 1971-1975 England and Wales. London HM Stationery Office, 1982. Kinlen LJ Meat and fat consumption and cancer mortality: a study of strict religious orders in Britain. Lancet 1982, ii : 472-74.
*Only those antigens are shown which were increased in the PAF group. tstatistically significant after correction for number of antigens, p
Progressive autonomic failure is a rare neuronal degeneration of unknown cause. The pathological features are a unique degeneration of both pigmented catecholaminecontaining cells in the brainstem and cholinergic cells in the intermedio lateral columns, with more distal ganglionic and postganglionic degeneration. There is a pathological subgroup of PAF, the parkinsonian variety, in which there are hyaline eosinophilic cytoplasmic neuronal inclusions (Lewy bodies) in the brainstem. Patients with the later stages of the disease may show added features of parkinsonism or MSA. The degeneration of melanin-containing and catecholamine-containing cells in the brainstem suggests a genetic metabolic defect. One family with four members apparently with PAF and MSA was described by Lewis.4 The genetic predisposition to the disease shown here by the association with Aw32 may be not only with PAF but also with Parkinson’s disease and, conceivably, Huntington’s chorea. There are many references to disease association with B and D/Dr antigens,5 but a disease association with an A-locus antigen is unusual. Two known examples are idiopathic haemochromatosis and congenital adrenal hyperplasia.6,7 In the latter it is thought that the locus of the causal 21-hydroxylase gene lies closer to the A and B loci than to the D region. It is possible that PAF is the result ofa gene causing a biochemical defect of catecholamine metabolism in the brain and that this gene lies within the HLA region.8 The strong association with an A-locus antigen might make this more likely than an immunological cause. Correspondence should be addressed to R. B., Department of Neurology, St Mary’s Hospital, London W2 INY. REFERENCES
1. Shy GM, Drager GA. A neurological syndrome associated with orthostatic hypotension Arch Neurol 1960, 2: 27-51. 2. Bannister R, Oppenheimer DR. Parkinsonism, system degenerations and autonomic failure. In: Marsden CD, Fahn S, eds Movement disorders: Neurology 2. London: Butterworth Scientific, 1982: 174-90. 3. Forno LS. Pathology of Parkinson’s disease. In: Marsden CD, Fahn S, eds. Movement disorders: Neurology 2. London Butterworth Scientific, 1982: 25-40 4. Lewis P. Familial orthostatic hypotension Brain 1964, 87: 719-28. 5. Ryder LP, Andersen E, Svejgaard A. HLA and disease registry Tissue Antigens 1979 (suppl). 6. Fleishnick E, Awdeh ZL, Raum D, et al Extended MHC haplotypes in 21-hydroxylase deficiency congenital adrenal hyperplasia. shared genotypes in unrelated patients. Lancet 1983; i: 152-56 7. Simon M, Bourel M, Genetet B, Fauchet R. Idiopathic hemochromatosis demonstration of recessive transmission and early detection by family HLA typing 8.
N Engl J Med 1977; 297: 1017-21. Bannister, R. Introduction and classification. In Bannister R, ed Autonomic failure. Oxford: Oxford University Press, 1983: 1-13