Orthostatic Hypotensive Disorder, Streeten Type

Clinical Features

Bradykinin (BK) is a nonapeptide hormone (RPPGFSPFR) that is an important mediator of the physiologic response to injury and trauma. The local release of BK causes pain, plasma extravasation, and vasodilation, as well as smooth muscle contraction. BK may play a role in the pathogenesis of asthma, since it appears to be a mediator of hyperallergenic bronchoconstriction in asthmatic patients. Kininogen (612358), in both of its isoforms in plasma, contains a bradykinin moiety.

Hyperbradykininism is a familial disorder characterized by orthostatic light-headedness or syncope, facial erythema, excessive orthostatic fall in pulse pressure and rise in pulse rate, ecchymoses, and purple discoloration of the legs after standing (Streeten et al., 1972). Plasma concentrations of bradykinin were elevated. Impaired destruction of circulating bradykinin was suggested, because of low concentrations of bradykininase-I. Clinical improvement occurred with administration of propranolol, fluorocortisone or cyproheptadine ('Periactin'). Three families were described: a woman and her daughter; a 23-year-old female student, her 50-year-old father and 16-year-old brother; and another woman and her daughter.

In a study of 3 of the families originally reported by Streeten et al. (1972), DeStefano et al. (1998) classified individuals as affected if a drop of standing blood pressure of more than 18 mm Hg and rise in heart rate were observed. A high-level athlete who experienced no symptoms was classified as affected on the basis of these criteria; her good physical condition probably enabled her to compensate for her blood pressure changes. A single nonpenetrant individual, with an affected parent and offspring, was observed. DeStefano et al. (1998) reported that in the quarter century after the initial report by Streeten et al. (1972) measurements of plasma bradykinin from these patients had given apparently conflicting results, which is consistent with the fact that plasma bradykininase concentration can be variable.

Orthostatic hypotension as observed in the families reported by Streeten et al. (1972) is a notorious feature of diabetic neuropathy with involvement of the autonomic nervous system. It occurs also in amyloid polyneuropathy due to mutations in the TTR gene (176300), in the neuropathy of Fabry disease (301500), in deficiency of dopamine beta-hydroxylase (223360), and as a striking feature of familial dysautonomia (DYS; 223900). Shy-Drager syndrome (146500) is a disorder of progressive autonomic failure with orthostatic hypotension as a leading feature. The syndrome is probably genetically heterogeneous.

Mapping

In 3 of the families originally reported by Streeten et al. (1972), DeStefano et al. (1998) conducted linkage analyses with DNA markers, which identified a locus for the disorder on chromosome 18q. A maximum multipoint lod score of 3.21 in the 3 families was observed at D18S1367, although the smallest family had negative lod scores in the entire region. There was significant evidence of linkage in the presence of heterogeneity at 18q, with a maximum lod score of 3.92 at D18S1367 in the 2 linked families. DeStefano et al. (1998) suggested that identification of the gene responsible for the orthostatic hypotensive disorder in these families may advance understanding of the general regulatory pathways involved in the continuum, from hypotension to hypertension, of blood pressure.

Exclusion Studies

DeStefano et al. (1998) could find no evidence of linkage of orthostatic hypotension to regions containing hyperbradykininism candidate genes such as bradykinin receptors B1 (600337) and B2 (113503) (14q32.1-q32.2) and kallikrein (KLK1; 147910) (19q13.2-q13.4).

Molecular Genetics

Ranade et al. (2001) investigated whether nucleotide variation in the human renal urea transporter-2 (UT2; 601611) could be associated with variation in blood pressure. Seven single-nucleotide polymorphisms (SNPs) were identified, including val227 to ile and ala357 to thr. Over 1,000 hypertensive and low-normotensive individuals of Chinese origin were genotyped. The ile227 and ala357 alleles were associated with low diastolic blood pressure in men but not women, with odds ratios 2.1 (95% confidence interval 1.5-2.7, P less than 0.001) and 1.5 (95% confidence interval 1.2-1.8, P less than 0.001), respectively. There was a similar trend for systolic blood pressure, and odds ratios for the ile227 and ala357 alleles were 1.7 (95% confidence interval 1.2-2.3, P = 0.002) and 1.3 (95% confidence interval 1.1-1.6, P = 0.007), respectively, in men. The authors suggested that polymorphisms in UT2 may influence blood pressure, at least in men, and UT2 may be a candidate gene for OHDS.