Congenital eyelid ptosis, decreased glomerular filtration, and orthostatic hypotension: Answers

Excerpt

The combination of congenital eyelid ptosis and severe orthostatic hypotension with preserved heart rate acceleration suggests sympathetic failure with intact parasympathetic function. Sweating, sympathetically mediated by acetylcholine, was intact, which implies that there was isolated absence of noradrenergic sympathetic function. Indeed, noradrenaline and adrenaline in plasma at rest and after standing were below detection limits (<0.01 nmol/L, normal values 0.4–3 nmol/L and 0.012–0.2 nmol/L respectively), whereas the dopamine level was greatly increased (1.1 nmol/L, normal values 0.02–0.19 nmol/L). These very low plasma levels of noradrenaline and adrenaline with an increased level of dopamine in this young adult patient are typical of dopamine beta hydroxylase (DBH) deficiency. DBH deficiency in this patient was genetically confirmed, with homozygous known pathogenic variants (IVS1 + 2 T > C) of the DBH gene (chromosome locus 9q34.2) [1]. As shown in Fig. 1, DBH is the enzyme that converts dopamine to noradrenaline. Noradrenaline can then be further converted to adrenaline. DBH deficiency is an extremely rare metabolic disorder of catecholamine synthesis, described in less than 20 patients worldwide. It leads to a lack of sympathetic noradrenergic function with normal parasympathetic and cholinergic-mediated sympathetic function, as is extensively reviewed by Robertson and Garland [2]. In DBH deficiency, the autonomic nervous system is structurally intact, but functionally impaired by the lack of noradrenaline, which leads to profound orthostatic hypotension and mild eyelid ptosis, but has no effect on sweating. In most patients, baroreflex afferents to the heart are at least partially intact, as demonstrated by the increase in heart rate on standing [3].

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