Early-onset hereditary isolated non-neurogenic orthostatic hypotension in a Swedish family, 2023, Jan Fagius et al

Mij · Jul 20, 2023

Abstract
Purpose
Orthostatic hypotension is a common condition with heterogeneous and, in many cases, unclear underlying pathophysiology. Frequent symptoms are syncope and falls with a strong impact on daily life. A two-generation family with eight individuals segregating early-onset severe orthostatic hypotension with persistent tachycardia in upright position and repeated faints was identified. Our aim was to elucidate the underlying pathophysiology.

Methods
One severely affected individual underwent thorough investigation with neurophysiological and blood pressure (BP) measurements, including direct recording of baroreflex-governed sympathetic nerve signalling and induction of BP rise with phenylephrine. Family members underwent parts of the examination. Genetic analysis using exome sequencing was performed.

Results
Marked postural hypotension with greatly reduced cardiac preload was observed, but without signs of autonomic nervous system dysfunction: sympathetic nerve signalling was normal, as were catecholamine levels, and phenylephrine stimulation revealed a normal increase in BP. The results of the genetic analysis using exome sequencing comprising all known genes associated with the regulation of BP and catecholamine metabolism were normal.

Conclusion
The combined findings suggest an autosomal dominant form of early-onset orthostatic hypotension with variable clinical expression and without any additional autonomic dysfunction. It is possible that further investigation will reveal an as yet undescribed entity of orthostatic hypotension transmitted as an autosomal dominant trait.

https://link.springer.com/article/10.1007/s10286-023-00963-9

Hutan · Jul 20, 2023

Jan Fagius, Joakim Klar & Niklas Dahl
Uppsala University

Looks as those these researchers might be interested in further work on this.

While an understanding of such diseases has brought important information on mechanisms underlying OH, the specific causes of severe and early-onset OH forms remain elusive in many cases. Identification of familial cases with the disturbance may therefore open up for new insights into the regulation of orthostasis. In this framework, we report on a hereditary disorder, which to our knowledge has not previously been described, with extreme and rapidly evolving orthostatic intolerance without any signs of ANS pathophysiology and with preserved catecholamine levels. The disease showed an autosomal dominant inheritance pattern with variable expressivity
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I liked the careful way the researchers went about the investigation e.g.

Direct recording of sympathetic signals was performed with microneurography in the peroneal nerve. MNSA and, after electrode adjustment, SSNA, were recorded. Both types of activity occurred in the respective normal burst pattern: MSNA bursts displaying cardiac rhythmicity and an inverse relationship to BP fluctuations (Fig. 2c, D); SSNA bursts in an irregular pattern, with clear arousal response (Fig. 2E). MSNA outflow (burst frequency) at supine rest was 30 bursts/min (somewhat higher than mean outflow in subjects of the patient’s age [25, 26]. Apnoea induced an increase in MSNA with subsequent rise in BP (Fig. 2c), and a Valsalva manoeuvre brought about a normal pattern (Fig. 2D), i.e. a reduction in BP inducing an initial increase in MSNA, followed by an increase of BP during the ongoing manoeuvre, and a final inhibition of sympathetic outflow with normal post-manoeuvre rebound rise in BP. Strength of individual bursts, measured as mean amplitude (mm) in the neurogram, increased 59% during apnoea and 39% during Valsalva.
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Hutan · Jul 20, 2023

The severe inherited disorder familial dysautonomia (HSAN III, Riley-Day syndrome) is excluded by the present individuals’ phenotype, and this conclusion is supported by the normal cardiac rhythm of MSNA, which is lost in familial dysautonomia [38]. Other rare forms of inherited and isolated OH have been associated with dopamine β-hydroxylase (DHB) deficiency or cytochrome b561 (CYB561) mutations transmitted as autosomal recessive traits [10, 12, 14]. Our exome sequencing of the most severely affected family member (subject IV:1) did not reveal any pathogenic gene variants in DHB, CYB561 or in several other known genes associated with OH and catecholamine metabolism [13].

Given the dominant inheritance pattern in this family, the absence of DHB or CYB561 mutations were expected as these are associated with recessive inheritance. However, autosomal dominant transmission of orthostatic intolerance has been reported previously [39], although in this earlier study the affected individuals presented also with additional and many faceted symptoms.

Another report [40] presented five patients from four different and multiplex families with OH, tachycardia and blue-purple ankle discoloration and leg ecchymoses, i.e. with a partly different clinical presentation when compared to that of our family. A molecular genetic study on members of the latter four families suggested heterogeneity for a gene locus on chromosome 18q [41]. A later genome-wide scan of hypertensive siblings [42] suggested that genes on chromosome 18q might be involved in the regulation of systolic BP following a postural stressor, but the subjects were not selected on the basis of OH.
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Early-onset hereditary isolated non-neurogenic orthostatic hypotension in a Swedish family, 2023, Jan Fagius et al

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