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ORTHOSTATIC HYPOTENSION 1; ORTHYP1

ORTHOSTATIC HYPOTENSION 1; ORTHYP1

Alternative titles; symbolsDOPAMINE BETA-HYDROXYLASE DEFICIENCY, CONGENITALNOREPINEPHRINE DEFICIENCYNORADRENALINE DEFICIENCY▼ DescriptionOrthostatic hypotension-...

Alternative titles; symbols

  • DOPAMINE BETA-HYDROXYLASE DEFICIENCY, CONGENITAL
  • NOREPINEPHRINE DEFICIENCY
  • NORADRENALINE DEFICIENCY

▼ Description
Orthostatic hypotension-1 (ORTHYP1) is an autosomal recessive disorder characterized by profound autonomic failure. In addition to severe orthostatic hypotension, ptosis, nasal stuffiness, impaired ejaculation, and a neonatal history of delayed eye opening are frequent findings. Biochemical features include undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and undetectable levels of dopamine beta-hydroxylase (summary by Kim et al., 2002).

Genetic Heterogeneity of Orthostatic Hypotension

See also ORTHYP2 (618182), caused by mutation in the CYB561 gene (600019) on chromosome 17q11.

▼ Clinical Features
Robertson et al. (1986) reported a 33-year-old woman of Scottish-Irish descent with isolated failure of autonomic noradrenergic neurotransmission caused by a defect in the beta-hydroxylation of dopamine in peripheral nerves. Clinical features included orthostatic hypotension, ptosis, nasal stuffiness, and a neonatal history of delayed eye opening. From age 2 years, she had had episodes of syncope, especially after exercise, and marked ptosis. Parasympathetic and sympathetic cholinergic functions were normal. Plasma norepinephrine levels were less than 10% of normal and plasma dopamine levels were 5 to 10 times normal. Increase in plasma dopamine with the upright posture and with administration of yohimbine indicated that dopamine was released by physiologic and pharmacologic sympathetic stimulation. The early onset and general character of the disorder suggested a genetic basis, but there was no family history.

Biaggioni et al. (1990) reported a 42-year-old man with lifelong severe orthostatic hypotension, ptosis, nasal stuffiness, and retrograde ejaculation due to DBH deficiency. He had an isolated deficiency of norepinephrine in both central and peripheral neurons.

Robertson et al. (1991) reviewed dopamine beta-hydroxylase deficiency in detail on the basis of the first 6 published cases. Affected neonates may show a delay in opening of the eyes, up to 2 weeks in some cases, and ptosis of eyelids. The infants have occasionally been so sickly at birth that parents were advised their survival was unlikely. Hypotension, hypoglycemia, and hypothermia may occur early in life. Postural hypotension occurring with exertion has limited the ability of DBH-deficient patients to exercise during childhood. The syncope associated with postural hypertension has led to trials of anticonvulsive medication. Symptoms generally worsen in late adolescence and early adulthood. Reduced exercise tolerance, ptosis of the eyelids, nasal stuffiness, and prolonged or retrograde ejaculation are features. Retrograde ejaculation is recognized by the presence of semen in the post-ejaculation urine void. The patients are distinguished from familial dysautonomia (223900) by (1) normal tearing, (2) intact corneal and deep tendon reflexes, (3) normal sensory function, (4) normal senses of taste and smell, and (5) lack of the cholinergic sensitivity and intradermal histamine response typical of the latter condition. Robertson et al. (1991) noted that at the time of their report, no patients had been of Ashkenazi Jewish extraction.

Patients with Orthostatic Hypotension without Known Mutations

Man in't Veld et al. (1987) described a similar case in a 21-year-old woman with severe orthostatic hypotension. Ptosis, skeletal muscle hypotonia, and recurrent hypoglycemia had been noticed from early childhood. There was virtually complete loss of noradrenergic innervation but intact cholinergic function. Noradrenaline and adrenaline were not detectable in plasma, urine, and cerebrospinal fluid, but dopamine was increased 7- to 12-fold in plasma, 4-fold in urine, and 20-fold in CSF. Measurements of catecholamine metabolites showed further evidence for impairment of noradrenaline and adrenaline biosynthesis due to deficient dopamine beta-hydroxylation. Dopamine beta-hydroxylase was undetectable in plasma and CSF. Physiologic and pharmacologic stimuli of sympathetic neurotransmitter release caused increases in plasma dopamine rather than in plasma noradrenaline. Man in't Veld et al. (1987) concluded that the patient had congenital dopamine beta-hydroxylase deficiency. There were no other affected individuals in the family, the parents were unrelated, and 2 sibs were in good health. As useful controls, 12 other patients with orthostatic hypotension, either idiopathic or due to other causes such as hereditary amyloidosis (see, e.g., 105200), primary amyloidosis, diabetic neuropathy (see 603933), multiple system atrophy (146500), or amyloidosis with multiple myeloma, were studied and found to have normal levels of dopamine in the plasma.

Mathias et al. (1990) described a brother and sister with long-standing symptoms of postural hypotension. In the male, erection was unaffected, but ejaculation was prolonged or absent. Autonomic function tests confirmed sympathetic adrenergic failure with normal sympathetic cholinergic and intact parasympathetic function. There were no other neurologic abnormalities. Plasma dopamine was elevated, but noradrenaline and adrenaline were undetectable in the plasma, as was dopamine beta-hydroxylase activity. In perivascular cutaneous tissue, DBH immunoreactivity was absent. The parents were clinically and biochemically normal.

▼ Clinical Management
Biaggioni and Robertson (1987) found remarkable improvement from administration of DL-dihydroxyphenylserine by mouth in 2 patients with lifelong orthostatic hypotension due to DBH deficiency. Both patients also had ptosis and nasal stuffiness all their lives. The therapeutic agent bypassed the DBH deficiency, since it was readily converted to noradrenaline by decarboxylation of the terminal carboxyl group.

In a brother and sister with DBH deficiency, Mathias et al. (1990) reported that treatment with dihydroxyphenylserine reduced symptoms and signs of postural hypotension, increased plasma levels of noradrenaline, and, in the brother, made ejaculation possible.

▼ Inheritance
Ross et al. (1973) concluded that the variation in plasma DBH levels is under genetic control; they found a higher concordance for level of DBH activity in monozygotic twins than in dizygotic twins. Schanberg et al. (1974) found that individuals showed a wide variation in levels of plasma dopamine beta-hydroxylase, with a 'low' group and a 'high' group. The high group tended to show higher and less stable levels of blood pressure. Ogihara et al. (1975) did not find a bimodal distribution for serum DBH in the population. They also did not find a relationship between plasma DBH activity and hypertension in any age group. However, highly significant correlations were found for the serum DBH of sib-sib pairs and mean parent-child pairs. No significant correlation was found for father-mother pairs, suggesting that genetic factors are more important than environmental factors.

Weinshilboum et al. (1975) determined plasma DBH activity in 841 healthy children aged 6 to 12 years and 227 adult blood donors. Approximately 4% of the children and 3% of adults had very low serum DBH activity. Detailed analysis showed a striking familial aggregation of very low serum DBH activity, and the authors concluded autosomal recessive inheritance. No correlation was found with DBH activity and blood pressure in the children.

Gershon and Goldin (1981) concluded that the family data are consistent with codominant inheritance.

▼ Mapping
Goldin et al. (1982) found evidence for linkage of DBH to ABO on chromosome 9 (maximum lod score of 1.82 at 0.0 and 10% recombination fractions for males and females, respectively). Elston et al. (1979) found a lod score of 2.32 at 0% recombination, giving a combined score of 2.32. Asamoah et al. (1987) studied DBH levels and polymorphic markers in 178 members of a family ascertained through 6 members who had myocardial infarction. The persons with infarction had lower levels of DBH than did others, but the difference was partly confounded with age differences. Segregation analysis suggested that a codominant gene for DBH was segregating in the family. The largest lod score yielded by linkage analysis was 0.53 with ABO at 20% recombination. Adding this to the lod scores obtained by Elston et al. (1979) and Goldin et al. (1982), Asamoah et al. (1987) obtained combined lod scores of 2.49 and 2.50 at 0.0 and 10% recombination, respectively.

Linkage analysis by Wilson et al. (1987, 1988) yielded a lod score of 5.88 at a recombination fraction of 0.0 for the linkage of DBH and ABO. The DBH gene was not polymorphic in a black family. In studies using RFLPs of the DBH gene, Perry et al. (1991) found no recombination with argininosuccinate synthetase (603470) and ABO blood group loci, with lod scores of 7.37 and 4.5, respectively, at theta = 0.0, confirming mapping of the DBH locus to chromosome 9q34.

▼ Molecular Genetics
In 2 unrelated patients with orthostatic hypotension due to dopamine beta-hydroxylase deficiency reported by Robertson et al. (1986) and Biaggioni et al. (1990), Kim et al. (2002) identified compound heterozygosity for mutations in the DBH gene (609312.0002-609312.0004).

Tags: 9q34.2