Table 4.

Disorders with Orthostatic Hypotension to Consider in the Differential Diagnosis of Dopamine Beta-Hydroxylase (DBH) Deficiency

DisorderGene(s)MOIClinical Description / CommentsDistinguishing Clinical Features
Familial dysautonomia (FD)ELP1 1AR
  • Affects development & survival of sensory, sympathetic, & parasympathetic neurons
  • Debilitating disease present from birth; progressive neuronal degeneration continues throughout life
  • Gastrointestinal dysfunction; vomiting crises
  • Recurrent pneumonia
  • Altered sensitivity to pain & temperature
  • Cardiovascular instability
  • ~40% of individuals have autonomic crises
  • Age-related decline in renal function noted 2
In DBH deficiency:
  • Normal tearing; intact corneal & deep tendon reflexes; normal sensory function; normal senses of taste & smell
  • Lack of abnormal cholinergic sensitivity & intradermal histamine response
In FD:
  • Occurs almost exclusively in persons of Ashkenazi heritage
  • High rates of excretion of HVA & low rates of excretion of VMA; plasma DHPG concentration is low; plasma DOPA & DA concentrations are ↑ 3
ATP7A-related copper transport disorders
(Menkes disease & occipital horn syndrome)		ATP7A 4XLDBH is a copper-dependent enzyme & thus DBH activity is depressed in individuals w/ATP7A-related copper transport disorders, leading to:
  • High plasma & CSF concentrations of DOPA, DOPAC, & DA
  • Low concentrations of DHPG
  • Approximately normal concentrations of NE
  • In infants w/classic Menkes disease: loss of developmental milestones, hypotonia, seizures, failure to thrive at age 2-3 mos, & characteristic hair changes (short, sparse, coarse, twisted, often lightly pigmented); death usually by age 3 yrs
  • In OHS: "Occipital horns," distinctive wedge-shaped calcifications at sites of attachment of trapezius muscle & sternocleidomastoid muscle to occipital bone; lax skin & joints; bladder diverticula; inguinal hernias; vascular tortuosity; intellect normal or slightly ↓; serum copper & serum ceruloplasmin concentrations are low.
Familial transthyretin amyloidosis TTR AD
  • Slowly progressive peripheral sensorimotor neuropathy & autonomic neuropathy as well as non-neuropathic changes of nephropathy, cardiomyopathy, vitreous opacities, & CNS amyloidosis
  • Cardinal feature: slowly progressive sensorimotor & autonomic neuropathy
  • Autonomic neuropathy may be 1st clinical symptom.
In familial transthyretin amyloidosis:
  • Constipation alternating w/diarrhea; attacks of nausea & vomiting; delayed gastric emptying; sexual impotence; anhidrosis; urinary retention or incontinence
  • Onset typically in 3rd-5th decade, but may be later
Multiple system atrophy
(Shy-Drager syndrome)
(OMIM 146500)		 COQ2 5 AR
AD
  • Adult-onset neurodegenerative disorder causing combination of ataxia, parkinsonism, & autonomic dysfunction
  • Poor response to levodopa
  • Severe orthostatic hypotension w/out compensatory tachycardia
In multiple system atrophy:
  • Extrapyramidal or cerebellar findings
  • Erectile dysfunction, constipation/diarrhea, urinary symptoms, decreased sweating are prevalent.
  • Onset age >30 yrs; rapidly progressive to death w/in ~3 yrs of diagnosis
Cytochrome b561 deficiency (OMIM 618182)CYB561 6AR
  • Sympathetic dysfunction evident by severe symptomatic orthostatic hypotension from infancy or early childhood w/out compensatory tachycardia
  • Undetectable or very low plasma & urinary norepinephrine & epinephrine, w/normal dopamine
  • Impaired renal function, mild anemia, episodic hypoglycemia
  • Shortened life span
  • Can be treated w/droxidopa
In CYB561 deficiency:
  • No ptosis
  • No orthostatic tachycardia in response to drop in blood pressure
  • No skeletal muscle hypotonia

AD = autosomal dominant; AR = autosomal recessive; DA = dopamine; DHPG = dihydroxyphenylglycol; DOPA = 3,4-dihydroxyphenylalanine; DOPAC = 3,4-dihydroxyphenylacetic acid; HVA = homovanillic acid; MOI = mode of inheritance; NE = norepinephrine; OHS = occipital horn syndrome; VMA = 3-methoxy-4-hydroxymandelic acid; XL = X-linked

1.

Two pathogenic variants account for more than 99% of pathogenic alleles in individuals of Ashkenazi Jewish descent.

2.
3.
4.

Molecular genetic testing of ATP7A detects pathogenic variants in more than 95% of affected individuals.

5.

No genetic cause has been identified for the vast majority of affected individuals.

6.

From: Dopamine Beta-Hydroxylase Deficiency

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