Orthostatic hypotension-2 is an autosomal recessive disorder characterized by severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine leve...
Orthostatic hypotension-2 is an autosomal recessive disorder characterized by severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood. Some patients may also have renal dysfunction and reduced life expectancy. The disorder results from a defect in the biosynthesis of norepinephrine from dopamine due to a cofactor deficiency.
For a discussion of genetic heterogeneity of ORTHYP, see ORTHYP1 (223360).
▼ Clinical Features
Van den Berg et al. (2018) reported 2 pairs of adult sisters from 2 unrelated families of Dutch and American descent, with severe orthostatic hypotension apparent from infancy or early childhood. Symptoms included dizziness and occasional fainting on standing. The combination of orthostatic hypotension and lack of compensatory tachycardia suggested sympathetic dysfunction, and laboratory analysis of all patients showed decreased or undetectable plasma and urinary levels of norepinephrine, epinephrine, and their downstream metabolites. CSF analysis of one of the Dutch sisters showed low levels of the principal downstream metabolite of norepinephrine, with normal levels of dopamine and serotonin metabolites. In the Dutch family, the sisters had impaired renal function with decreased renal plasma flow and glomerular filtration rate, as well as secondary mild anemia. Echography of the kidneys was unremarkable. In the American family, the sisters had episodic hypoglycemia. In vitro studies showed normal plasma dopamine beta-hydroxylase (DBH; 609312) activity in all patients, and Sanger sequencing of the DBH gene showed no mutations. Neurologic examination was otherwise normal. The American sisters had a brother with comparable complaints who died at age 16 years of unknown cause, and 3 of the 4 affected women died between 37 and 59 years of age.
▼ Clinical Management
The patients with ORTHYP2 reported by van den Berg et al. (2018) responded favorably to treatment with L-dihydroxyphenylserine, which can be converted directly to norepinephrine; however, tolerance of the medication was an issue.
The transmission pattern of ORTHYP2 in the families reported by van den Berg et al. (2018) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 4 women from 2 unrelated families with ORTHYP2, van den Berg et al. (2018) identified homozygous mutations in the CYB561 gene (G88R, 600019.0001 and W44X, 600019.0002). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family from which parental DNA was available. Neurotransmitter analysis in patients and Cyb561-null mice (see ANIMAL MODEL), as well as molecular modeling, indicated that the mutations resulted in impaired CYB561 function, likely leading to a shortage of ascorbate recycling inside intracellular catecholamine secretory vesicles. As ascorbate is a cofactor for DBH, disrupted ascorbate recycling was suggested to cause functional DBH deficiency, defective norepinephrine synthesis from dopamine, and abnormal neurotransmitter metabolism.
▼ Animal Model
Van den Berg et al. (2018) found that Cyb561-null mice had significantly decreased amounts of norepinephrine and normetanephrine in the adrenal gland and brain. In contrast, dopamine levels were normal, although dopamine catabolites were increased in the adrenal gland. The findings showed that dopamine biosynthesis is normal, and that the defect is downstream of dopamine.