Norepinephrine and epinephrine are crucial determinants of minute-to-minute neural regulation of blood pressure and are also present at crucial central nervous system sites likely to be involved in a variety of behaviors. Norepinephrine and epinephrine thus seem so important to human beings that it seemed unlikely for many years that subjects without these catecholamines would survive the perinatal period and develop to adulthood.
This view has changed with recognition of a congenital syndrome of severe orthostatic hypotension, noradrenergic failure, and ptosis of the eyelids in two young adults. The syndrome differs from familial dysautonomia and various other autonomic disorders seen in adults in that the defect can be localized to the noradrenergic and adrenergic tissues. There is virtual absence of norepinephrine, epinephrine, and their metabolites. However, there is greatly increased dopamine in plasma, cerebrospinal fluid, and urine.
Parents of DBH deficient patients have appeared normal, but there has usually been a history of spontaneous abortions and stillbirths in the mothers of affected patients. There has been delay in opening of the eyes in neonates and persistent ptosis of the eyelids in several patients. There has also been hypoglycemia, hypotension, and hypothermia in the prenatal period. It is possible that excessive CNS dopamine contributed to the hypothermia in these patients and may also have contributed to the recurrent vomiting observed in the first year of life in two patients. With severe hypoglycemia or hypotension, seizures have occasionally been seen in adults.
As children, DBH deficient patients have had a markedly reduced ability to exercise, perhaps because of hypotension engendered by the physical exertion. Because of occasional syncope, anticonvulsive medications have been given in some patients, even though no abnormality was seen on the electroencephalogram. Symptoms have generally worsened in late adolescence and by early adulthood, patients complain of profound orthostatic hypotension, especially early in the day and during hot weather or after alcohol ingestion. In addition to ptosis of the eyelids, there is reduced exercise tolerance, a tendency for nasal stuffiness to occur, especially in the supine posture. A male patient had appropriate erectal function, but retrograde rather than antegrade ejaculation. Presyncopal symptoms in these patients have included dizziness, blurred vision, dyspnea, nuchal discomfort, and occasionally chest pain. The mechanism of the chest pain is not understood, but has been replicated in one patient by the administration of isoproterenol during the supine posture. It is therefore possible that it is somehow related to excessive pumping action of the heart associated with the intact parasympathetic withdrawal accompanying upright posture.
Many specialized tests differentiate these patients from those with familial dysautonomia. Cholinergic sensitivity as assessed by conjunctival methacholine was normal in that there was no response. Intradermal histamine evoked a typical flare reaction, whereas this does not occur in familial dysautonomia. These patients are further distinguished from familial dysautonomia in having normal tearing, intact corneal and deep tendon reflexes, normal sensory function and normal senses of taste and smell. Also, subjects thus far recognized have not been of Ashkenazi Jewish extraction. Atrial fibrillation, quite resistant to therapy, developed in one patient at age 40.
These patients have no response even to high doses of tyramine, which normally increases blood pressure by releasing neuronal norepinephrine. Even the most severely affected pure autonomic failure patients respond to tyramine with at least some increase in blood pressure. Yet, in DBH-deficient patients, norepinephrine remained undetectable after tyramine administration, while dopamine increased. This is consistent with the hypothesis that in these patients, dopamine instead of norepinephrine is present in neuron terminals, and acts as a 'false neurotransmitter.'
A final feature of these patients is that central autonomic regulation as well as catecholamine release mechanisms are intact. Dopamine levels increase on assumption of the upright posture, during sustained handgrip, and after tyramine administration, while they decrease after clonidine administration. Also, muscle sympathetic nerve traffic, as measured by direct intraneuronal recordings, is present in excess under basal conditions but is otherwise normally modulated by baroreflex mechanisms in these patients. Therefore, primary autonomic neuronal pathways are intact and respond to appropriate stimuli, but dopamine instead of norepinephrine is present in noradrenergic nerve terminals. The excessive microneurographic sympathetic nerve traffic appeared to be due to insufficient central alpha-2 adrenoreceptor stimulation.
There is absence of pressor responses to cold exposure and sustained handgrip, and absence of a blood pressure overshoot on release of the Valsalva maneuver. However, sympathetic cholinergic function is intact, as assessed by normal sweating. Parasympathetic function is also preserved, as assessed by intact sinus arrhythmia, normal heart rate increase during Valsalva, and tachycardia after atropine.
The DBH gene is located at 9q34. In 2000, the genomic basis of DBH deficiency was elucidated. Kim et al. identified seven novel variants, including four potentially pathogenic mutations, in the human DBH gene of two unrelated DBH deficient patients and their families. Both patients had a IVS1+2TC mutation, an intronic mutation that can lead to aberrant splicing. However, this mutation generates both aberrant and properly spliced DBH messages, and patients with DBH deficiency have no DBH gene product, even when a polyclonal antibody against DBH is used to measure it. It is possible that another variant at DBH is necessary to produce the DBH deficiency phenotype.
While DBH deficiency is probably a rare disease in adults, it could be more common in the perinatal period. Medical histories of DBH deficient patients include near fatal illness during the neonatal period due to hypotension, hypoglycemia, and hypothermia. We suspect that many DBH deficient infants succumb at this point, and thus fail to survive into childhood and adulthood. The successful development of DBH knockout mice in April 1995 by Palmiter's group, requiring as it did the pharmacological support of the mother by dihydroxyphenylserine, the agent we introduced into the treatment of the clinical disorder, supports the view that DBH deficiency is a near-lethal condition in utero. Since norepinephrine and its receptor sites have long been postulated to play a role in a number of psychiatric disorders, the essentially normal mood and mental status of adult DBH-deficiency subjects so far encountered has elicited great interest among investigators in the area of depression and schizophrenia.
Efforts to treat DBH deficiency have also led to surprising observations. Fludrocortisone at relatively high doses has successfully raised blood pressure with some benefit. Indomethacin has also been of modest benefit in raising blood pressure, but one patient had aggressive ideation while receiving this drug. The monoamine oxidase inhibitor tranylcypromine also produced paranoid thinking in one patient. There has been a reasonable pressor response to phenylpropanolamine (25 and 50 mg), perhaps because of the hypersensitive alpha-adrenoreceptors in these patients.
Once the specific enzymatic defect had been elucidated, investigators knew that a better treatment for DBH deficiency could be devised. DBH deficient patients possessed all the machinery to handle neurotransmitters effectively, but simply had a 'false neurotransmitter', dopamine, instead of the physiological neurotransmitter, norepinephrine. Their alternative therapeutic approaches were to reduce the former (with metyrosine) or increase the latter (with dihydroxyphenylserine).
Metyrosine is an inhibitor of tyrosine hydroxylase and reduces the synthesis of catecholamines, both in the periphery and in the central nervous system. Drs. Robertson and Biaggioni, in consultation with Dr. Otto Kuchel, hypothesized that these patients might have such high dopamine levels that dopaminergic depressor effects would be manifest. Since metyrosine was depressor in normal individuals, a failure of metyrosine to affect blood pressure, or a reduction in blood pressure with metyrosine, would not support a role for dopamine in maintaining low blood pressure in these patients. On the other hand, a rise in blood pressure with metyrosine would suggest that dopamine was indeed exerting a depressor effect and that this effect could be attenuated by an agent which resulted in reduced synthesis and release of dopamine. It was found that metyrosine exerted a dramatic pressor response. Over a period of days, the pressor response was so great that it was considered prudent to discontinue the medication at its usual dose. The caution in this case was motivated by the fact that the investigators did not know if the vasculature in this disorder could withstand raised blood pressure normally. Metyrosine also significantly reduced urinary and plasma dopamine levels in DBH deficiency.
A more favorable long-term result has been achieved with L-dihydroxyphenylserine (L-DOPS). This agent is a prodrug acted upon by endogenous dopa decarboxylase to yield norepinephrine DBH is not required for the conversion of DOPS to norepinephrine and, thus, this enzyme could be bypassed by DOPS in patients in whom it was defective. The investigators hypothesized that there would be a restoration of norepinephrine following the administration of DOPS. This appears to have been correct. The administration of DOPS to these patients resulted in dramatic increases in blood pressure and in the restoration of plasma and urinary levels of norepinephrine toward normal. There was a decline in the associated dopamine levels, as though the provision of norepinephrine to intraneuronal sites might be reducing the enhanced activity of tyrosine hydroxylase. The increase in plasma norepinephrine was highly correlated with the increase in mean arterial blood pressure. In the DBH deficient patients to whom this drug has now been administered, it has been extraordinarily effective in normalizing blood pressure. Long-term experience with this drug indicates continued efficacy at the 250 mg or 500 mg tid regimen.
DBH deficiency and its successful treatment by DOPS has provided valuable lessons in catecholamine pharmacology and encourages us to hope that other autonomic disorders may one day also yield to genuinely effective therapeutic intervention. Indeed, other newly recognized genetic autonomic and catecholamine disorders are now being recognized, including tetrahydrobiopterin deficiency, dopa decarboxylase deficiency , Menkes disease, monoamine oxidase deficiency and other disorders of dopamine metabolism.