Dopamine Beta-Hydroxylase Deficiency

Clinical characteristics.

Dopamine beta-hydroxylase (DBH) deficiency is characterized by lack of sympathetic noradrenergic function but normal parasympathetic and sympathetic cholinergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function that predispose to orthostatic hypotension. Although DBH deficiency appears to be present from birth, the diagnosis is not generally recognized until late childhood. The combination of ptosis of the eyelids in infants and children, together with hypotension, is suggestive of the disease. In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization; children have reduced exercise capacity. By early adulthood, individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis of the eyelids, and nasal stuffiness. Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain; symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Life expectancy is unknown, but some affected individuals have lived beyond age 60 years.

Diagnosis/testing.

The diagnosis of DBH is established in a proband with profound neurogenic orthostatic hypotension, minimal or absent plasma concentrations of norepinephrine and epinephrine, and a five- to tenfold elevation of plasma dopamine; it is confirmed with identification of biallelic pathogenic variants in DBH by molecular genetic testing.

Management.

Treatment of manifestations: Administration of L-threo-3,4-dihydroxyphenylserine (droxidopa) restores norepinephrine and alleviates the orthostatic hypotension and other symptoms. Affected individuals do not respond as well to standard therapeutic approaches for autonomic failure. Surgery can correct ptosis.

Surveillance: Renal function (measurement of plasma creatinine and BUN concentrations) is assessed every two years or more often if loss of renal function is evident; plasma magnesium and potassium should also be assessed. Yearly evaluation of efficacy of droxidopa against orthostatic hypotension as dosage adjustment may be required. Consultation with autonomic specialist prior to surgery or becoming pregnant.

Agents/circumstances to avoid: Untreated individuals should avoid hot environments, strenuous exercise, standing motionless, and dehydration.

Pregnancy management: Routine blood pressure monitoring during pregnancy and delivery, with adjustment of droxidopa dosage as needed; extra doses of droxidopa may be required during delivery and dose adjustment may be required post partum.

Genetic counseling.

DBH deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if both pathogenic variants in the family are known. Once the DBH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for DBH deficiency are possible.

Suggestive Findings

No formal testing strategy has been presented for DBH deficiency; a clinical assessment including orthostatic vital signs and an ophthalmic exam should be the initial step and, if indicated, this should be followed by autonomic function testing and plasma catecholamine analysis.

DBH deficiency should be suspected in individuals with the following clinical, physiologic, and laboratory findings [Vincent & Robertson 2002, Timmers et al 2004]:

Establishing the Diagnosis

The diagnosis of DBH is established in a proband with profound neurogenic orthostatic hypotension, minimal or absent plasma concentrations of norepinephrine and epinephrine, and a five- to tenfold elevation of plasma dopamine; the diagnosis is confirmed with identification of biallelic pathogenic variants in DBH by molecular genetic testing (see Table 2).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of dopamine beta-hydroxylase deficiency is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of dopamine beta-hydroxylase deficiency has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Dopamine beta-hydroxylase (DBH) deficiency is characterized by a lack of sympathetic noradrenergic function but normal parasympathetic and sympathetic cholinergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function, but apparently only subtle signs of central nervous system dysfunction [Robertson et al 1986, Man in 't Veld et al 1987, Timmers et al 2004, Jepma et al 2011].

Onset. Although DBH deficiency appears to be present from birth, the diagnosis is not generally recognized until late childhood, when orthostatic hypotension becomes more severe.

Features by age. The full clinical spectrum of DBH deficiency is not known because of the limited number of cases reported. Clinical features reported in 21 affected individuals (13 female, 8 male) are included in Table 3.

• Infancy:
  • In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization.
  • Delay in opening of the eyes has occurred and ptosis of the eyelids is seen in most affected infants.
• Childhood:
  • Children with DBH deficiency have markedly reduced exercise capacity, perhaps because of hypotension engendered by physical exertion.
  • The syncope associated with postural hypotension often suggests seizures and prompts trials of anticonvulsive medication despite lack of abnormalities on the electroencephalogram.
  • Mental and physical development are normal.
• Adolescence and early adulthood:
  • Symptoms generally worsen in late adolescence.
  • By early adulthood, affected individuals demonstrate profound orthostatic hypotension, fatigue, greatly reduced exercise tolerance, ptosis of the eyelids, and nasal stuffiness. Insulin resistance has been reported in an affected female age 15 years [Arnold et al 2017].
  • Males experience retrograde or prolonged ejaculation.

Clinical features of DBH deficiency are included in Table 3.

Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and occasionally chest pain. Symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Occasional bouts of unexplained diarrhea occur.

Renal function. Elevated blood urea nitrogen has been noted in six affected individuals in the USA [Garland et al 2005a, Garland et al 2009]. This may be evidence of a loss of renal function. A nephrologist who evaluated an individual age 16 years with a disproportionately high BUN (32 mg/dL) and slightly elevated creatinine (1.09 mg/dL) proposed that renal perfusion was reduced and that a BUN/Cr ratio <25 should be targeted. Although droxidopa acutely improved the ratio, the BUN/Cr ratio was further increased after a year of droxidopa treatment. The estimated GFR of an affected female age 57 years was reduced to 18 mL/min/1.73 m² [Emily Garland, personal observation]. Another patient with unexpectedly low eGFR and elevated creatinine was found, by electron microscopy, to have abnormal, fused mitochondria in the proximal, but not the distal, tubules. Associated problems with the glomerular-tubular balance can be at least partially reversed by treatment with droxidopa [Wassenberg et al 2017].

Cognitive function. Despite the lack of norepinephrine, persons with DBH deficiency apparently have relatively normal mental status. Five affected individuals and ten matched healthy unaffected participants underwent a comprehensive battery of neurocognitive testing in addition to brain MRI, pupillometry, and EEG. Performance of the affected individuals, whether on or off droxidopa treatment, was similar to that of the unaffected individuals in most respects, suggesting that other systems compensate for absent norepinephrine in affected individuals. Brain MRI studies revealed a smaller total brain volume in the affected individuals compared to unaffected individuals, although relative proportions of white and gray matter and cerebrospinal fluid were similar in the two groups. In addition, affected individuals had a temporal-attention deficit when they were not on treatment. During an attentional-blink task, participants were asked to identify two digits, separated by a variable number of letters. Attentional blink refers to the deficit in processing the second digit when it is presented within 200-400 msec of the first. Accuracy in identifying the second digit was impaired in affected individuals not on treatment but performance improved with droxidopa treatment [Jepma et al 2011].

Ptosis. Ptosis of the eyelids, defined as a reduction in the margin reflex distance, is common in individuals with DBH deficiency and can be noted at an early age. It was reported in the first descriptions of individuals with this disorder in the late 1980s and in more than 85% of all cases in the published literature. Levator function is intact. Some individuals undergo levator advancement surgery [Phillips et al 2013], which may mask this aspect of the phenotype.

Olfactory function is relatively unaffected in individuals with DBH deficiency, who have intact noradrenergic neurons, in contrast to the marked deficit in individuals with pure autonomic failure, who have peripheral neuronal degeneration [Garland et al 2011].

Hypoglycemia. Because so few individuals have been diagnosed with DBH deficiency, there has not been a clear explanation for the occurrence of hypoglycemic episodes in some of the individuals. It is not known if this is related to the absence of norepinephrine and epinephrine, or the elevated levels of dopamine. Investigators have speculated that it may result from loss of the counterregulatory actions of epinephrine that protect against hypoglycemia [Man in 't Veld et al 1987]. In contrast to the report of hypoglycemia during the perinatal period, a girl age 15 years studied with a hyperglycemic clamp had a normal fasting glucose level but insulin resistance [Shibao et al 2014]. Her hyperinsulinemia persisted after a year of droxidopa treatment, despite improved orthostatic tolerance and restoration of plasma norepinephrine [Arnold et al 2017].

High palate. Physicians who inspect the palate often report that patients with DBH deficiency have a high, arched palate [Man in 't Veld et al 1988, Cheshire et al 2006; Emily Garland, unpublished findings]. This, however, is generally a subjective determination; it is not known how frequently it is either not assessed or reported incorrectly.

Life span. Four persons with DBH deficiency are known to have died. A woman age 57 years had chronic kidney disease and was undergoing treatment for breast cancer. Her listed cause of death at an assisted living facility was cardiac arrhythmia. Autopsy of a male age 28 years reported "scattered pyknotic cerebral neurons, isolated microfoci of cortical gliosis, cardiac arteriolar smooth muscle hypertrophy, scattered fibrosis in the cardiac conduction system, and sclerotic renal glomeruli." Cardiac dysrhythmia, possibly related to fibrosis in the cardiac conduction system, may have contributed to the patient's sudden demise [Cheshire et al 2006]. One individual died at age 20 years, possibly by suicide. A person age 63 died of unknown causes. Other affected individuals are likely to be deceased, but there are no published reports of causes of death or of effects of the disorder on life span.

One individual was not diagnosed with DBH deficiency until age 73 years despite having long-lasting orthostatic hypotension [Despas et al 2010], suggesting that DBH deficiency may not necessarily shorten the life span.

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations.

Prevalence

The prevalence of DBH deficiency is unknown. Only 23 affected individuals, all of western European descent, have been reported in the literature, suggesting that it is a rare disorder.