Dopamine beta-hydroxylase deficiency (ORPHA:230)
A very rare primary monoamine neurotransmitter synthesis disorder with norepinephrine and adrenaline deficiency that leads to young-onset severe orthostatic hypotension and eyelid ptosis.
Epidemiology
The prevalence of dopamine beta-hydroxylase (DBH) deficiency is unknown. Only 25 patients have been reported to date.
Clinical description
DBH deficiency is mainly characterized by severe early onset orthostatic hypotension. In the neonatal period hypothermia and hypoglycemia can occur. First symptoms of orthostatic hypotension generally occur in early childhood with reduced exercise intolerance. Orthostatic hypotension is profound and can lead to syncope. Other symptoms and signs of the selective noradrenergic failure of the sympathetic nervous system are eyelid ptosis, nasal congestion, and primary enuresis. Sweating is normal. The central nervous system appears to be largely spared. Reduced kidney function, anemia and hypomagnesemia are common.
Etiology
DBH deficiency is caused by mutations in the DBH gene (9q34), encoding the enzyme dopamine beta hydroxylase which converts dopamine to noradrenaline. It results in undetectable levels of noradrenaline and adrenaline, and highly increased levels of dopamine in plasma, urine and cerebrospinal fluid.
Diagnostic methods
Plasma measurements of catecholamines shows undetectable levels of noradrenaline and adrenaline and increased levels of dopamine. Diagnosis is confirmed by genetic testing of the DBH gene. Diagnosis can be supported by testing DBH enzyme activity in plasma, however this can be falsely absent due to a common polymorphism in the healthy population.
Differential diagnosis
Orthostatic hypotension due to CYB561 mutations gives a comparable clinical picture but levels of dopamine are normal.
Antenatal diagnosis
Prenatal diagnosis is possible when the pathogenic variant has been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Excellent and sustained clinical response can be achieved by precursor therapy with L-threo-dihydroxyphenylserine (L-DOPS/ Droxidopa). Oral administration of 100 to 500 mg of L-DOPS, twice or three times a day, reverses the orthostatic intolerance. For children, a starting dose of 2 mg/kg/d in 2-3 doses eventually increasing to 5-10 mg/kg/d in 2-3 doses seems reasonable. Dose should be titrated individually based on clinical response. Blood pressure should be monitored regularly and (nightly) hypertension should be avoided (last dose of medication should be given more than 4 hours before bedtime). Regular follow-up of kidney function, electrolytes and hematological parameters is advised.
Prognosis
With L-DOPS treatment, clinical response is excellent and sustained, with improvement of quality of life and exercise intolerance. Mild ptosis can persist under treatment. Catecholamine profile in plasma does not normalize completely.

                            Last update: 
                            May 2021


                            - Expert reviewer(s): 
                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN* - Dr Tessa WASSENBERG | MetabERN*


                                * European Reference Network