Purpose
To report the ophthalmic findings in young patients with dopamine β-hydroxylase deficiency and to assess them in the context of other reports in an attempt to discern if ophthalmic criteria may assist in early detection of this debilitating, yet treatable, disorder.
Design
Prospective, observational case series.
Methods
An ophthalmic examination, including measuring intraocular and systemic blood pressures while supine, sitting, and standing, and eyelid function and pupillary function testing, was completed on 3 young patients with recently documented dopamine β-hydroxylase deficiency at a single institution.
Results
Mean arterial blood pressures were 90.1 ± 18.5 mm Hg supine, 79.1 ± 25.7 mm Hg sitting, and 45.8 ± 11.6 mm Hg standing ( P = .021). Mean intraocular pressures in these patients were 15.8 ± 1.0 mm Hg supine, 15.0 ± 3.6 mm Hg sitting, and 7.7 ± 2.3 mm Hg standing ( P = .03). Mean palpebral fissure, levator function, and margin reflex distance were 8.2 ± 1.0 mm, 16.0 ± 0 mm, and 2.8 ± 0.6 mm, respectively. Measurable miosis was present in only 1 patient, and pupillary supersensitivity to 2.5% phenylephrine was not observed.
Conclusions
The ophthalmologic findings of the patients in this case series documented mild ptosis and striking orthostatic reductions in intraocular pressure and mean arterial blood pressure, as might be expected with a lack of intrinsic sympathetic function. Orthostatic intraocular pressure and mean arterial blood pressure may be a helpful early screening tool for autonomic dysfunction in children undergoing a ptosis evaluation.
Dopamine β-hydroxylase deficiency is a rare congenital type of autonomic failure caused by an abnormality in the enzyme that converts dopamine to norepinephrine. It is inherited in an autosomal recessive manner, so that both parents are asymptomatic carriers of 1 mutant allele for the Dbh gene, and siblings of affected individuals have a 25% chance of being affected. Dopamine β-hydroxylase deficiency was first described in 1986, with the absence of plasma norepinephrine and epinephrine and elevated levels of dopamine. Parasympathetic and sympathetic cholinergic functions remain intact, whereas sympathetic noradrenergic functions are affected. It can be treated successfully with L-threo-dihydroxyphenylserine, which is converted to norepinephrine without the presence of dopamine β-hydroxylase.
Although dopamine β-hydroxylase deficiency is present from birth, the diagnosis usually is not made until late in childhood or early adulthood. Infants may experience multiple episodes of dehydration, hypotension, hypothermia, hypoglycemia, and vomiting. Children have low exercise tolerance. Other signs and symptoms include significant orthostatic hypotension, nasal stuffiness, ptosis, and pupil abnormalities. The diagnosis of dopamine β-hydroxylase deficiency is still made based on a collection of clinical and laboratory findings indicative of impaired sympathetic noradrenergic function, intact sweating, and absent or minimal plasma norepinephrine with at least a 5-fold elevation of plasma dopamine. The combination of childhood ptosis and systemic hypotension is suggestive of dopamine β-hydroxylase deficiency. Therefore, 3 young patients with dopamine β-hydroxylase deficiency underwent an ophthalmologic examination to determine whether ocular findings could assist in the earlier detection and treatment of dopamine β-hydroxylase deficiency.
Methods
This was a prospective study design. The Vanderbilt University Institutional Review Board approved the protocol before the start of this study. The study and data accumulation were carried out in accordance with this approval. Written informed consent was obtained from each subject before participating in the study. This study is registered in the public database of the National Institute of Health-maintained site at http://www.clinicaltrials.gov with the following identifier: NCT00338065 . This study was conducted in compliance with regulations of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki. The medications of 3 patients with dopamine β-hydroxylase deficiency were discontinued, including L-threo-dihydroxyphenylserine, 1-deamino-8-D-arginine vasopressin, or fludrocortisone, during their admission to Vanderbilt’s Clinical Research Center inpatient unit. While medications were suspended, they underwent an ophthalmic examination including intraocular pressure (IOP) and blood pressure (BP) measurement while supine, sitting, and standing and eyelid function and pupillary function testing. Table 1 lists each patient’s demographic features. The mean age of the 3 patients was 18.7 ± 3.5 years with mean age at diagnosis of 17.7 ± 3.8 years and symptom onset during the first decade of life. A 1-way repeated measures analysis of variance was performed on the mean arterial blood pressures (MAPs), heart rates, and IOPs (SigmaStat software version 2.03; SPSS, Inc, Chicago, Illinois, USA).
| Patient 1 | Patient 2 | Patient 3 | |
|---|---|---|---|
| Age (y) | 19 | 17 | 23 |
| Sex | Female | Male | Male |
| Age of symptom onset | 3 years | Young age | 5 months |
| Age at diagnosis (y) | 16 | 17 | 23 |
| Prior eye surgery | None | None | Levator advancement |
| Medications on admission | L-threo-dihydroxyphenylserine 1-deamino-8-D-arginine vasopressin | Fludrocortisone | Fludrocortisone |
| Medications on discharge | L-threo-dihydroxyphenylserine 1-deamino-8-D-arginine vasopressin | L-threo-dihydroxyphenylserine | L-threo-dihydroxyphenylserine |
Patient 1
Patient 1 was a 19-year-old woman who experienced episodes of syncope at 3 years of age and was diagnosed with dopamine β-hydroxylase deficiency at 16 years of age. Her symptoms are controlled adequately with L-threo-dihydroxyphenylserine 400 mg twice daily and 1-deamino-8-D-arginine vasopressin 0.6 mg once daily. She is homozygous for c. [301G→A];[1033G→A] mutations in the Dbh gene.
Patient 2
Patient 2 was a 17-year-old boy who reported muscle weakness and fatigue “since a very young age.” Testing at the clinical research center confirmed dopamine β-hydroxylase deficiency. His symptoms initially were treated with fludrocortisone 0.1 mg twice daily before admission to the Clinical Research Center, but were controlled better when switched to L-threo-dihydroxyphenylserine 300 mg 3 times daily. He also has continuous nasal congestion without a seasonal pattern. His older brother also has dopamine β-hydroxylase deficiency and was Patient 3 in this case series.
Patient 3
Patient 3 was a 23-year-old man with type I diabetes with a similar presentation as his younger brother with regard to fatigue onset at a young age. At 5 months of age, he was hospitalized for aseptic meningitis and documented to have ptosis. Subsequently, he had levator advancement surgery for the ptosis. Like his brother, testing at the Clinical Research Center confirmed the preliminary diagnosis of dopamine β-hydroxylase deficiency. He was also treated with fludrocortisone 0.1 mg twice daily before admission to the clinical research center. Symptoms were controlled better when the medication was switched to L-threo-dihydroxyphenylserine 300 mg 3 times daily.
Patients 2 and 3 are compound heterozygotes for c. [348+2T→C];[1033G→A] in the Dbh gene.
Results
Blood Pressure and Intraocular Pressure
All 3 patients exhibited a profound reduction in orthostatic BP with MAP averaging 90.1 ± 18.5 mm Hg supine, 79.1 ± 25.7 mm Hg sitting, and 45.8 ± 11.6 mm Hg standing ( P = .021; Table 2 ). There were corresponding elevations in heart rates averaging 55 ± 6 beats per minute supine, 73 ± 8 beats per minute sitting, and 89 ± 1.7 beats per minute standing ( P = .028; Table 2 ). IOPs also were found to decrease markedly in all 3 patients with standing ( P = .03; Table 2 ). IOPs averaged 15.8 ± 1.0 mm Hg supine, 15.0 ± 3.6 mm Hg sitting, and 7.7 ± 2.3 mm Hg standing.
| Position | Patient 1 | Patient 2 | Patient 3 | MAP Average | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| IOP | HR | BP | MAP | IOP | HR | BP | MAP | IOP | HR | BP | MAP | |||||
| Right Eye | Left Eye | Right Eye | Left Eye | Right Eye | Left Eye | |||||||||||
| Standing | 9 | 9 | 88 | 46/34 | 38.9 | 10 | 8 | 88 | 55/33 | 40.3 | 6 | 4 | 91 | 73/49 | 59.0 | 45.8 ± 11.6 |
| Sitting | 12 | 12 | 65 | 97/58 | 49.5 | 20 | 19 | 72 | 129/73 | 91.7 | 14 | 13 | 81 | 126/81 | 96.0 | 79.1 ± 25.7 |
| Supine | 15 | 15 | 50 | 103/52 | 69 | 17 | 15 | 54 | 139/86 | 103.6 | 16 | 17 | 61 | 133/80 | 97.6 | 90.1 ± 18.5 |
Eyelid Function
The mean palpebral fissure width was 8.2 ± 1.0 mm ( Table 3 ). The margin reflex distance was reduced in all patients with a mean of 2.8 ± 0.6 mm ( Table 3 ). Patient 1 and Patient 2 ( Figure , Top) had mild ptosis, defined as a reduction in the margin reflex distance. Patient 3 ( Figure , Bottom) had palpebral fissures within the normal range, but he had a history of ptosis surgery as a child and his margin reflex distance remained slightly diminished. All 3 patients had intact levator function with a mean of 16 ± 0 mm ( Table 3 ). A small increase averaging 1.5 ± 0.5 mm in palpebral fissure width occurred after instillation of 2.5% phenylephrine ( Table 3 ).
| Patient 1 | Patient 2 | Patient 3 | ||||
|---|---|---|---|---|---|---|
| Right Eye | Left Eye | Right Eye | Left Eye | Right Eye | Left Eye | |
| Palpebral fissure (reference, 9 to 10 mm) a | 8 | 9 | 7 | 7 | 9 | 9 |
| Levator function (reference, 14 to 18 mm) a | 16 | 16 | 16 | 16 | 16 | 16 |
| Margin reflex distance (reference, 4 to 4.5 mm) a | 3 | 3 | 2 | 2 | 3 | 3.5 |
| Palpebral fissure after 2.5% phenylephrine a | 9 | 10 | 9 | 9 | 10 | 10 |
| Reaction to light under the following conditions b | ||||||
| Light | 4-4 | 4-4 | 6-4 | 6-4 | 3-2 | 3-2 |
| Dark | 7-5 | 7-5 | 7-4 | 7-4 | 4-2 | 4-2 |
| Accommodation | 5-3 | 5-3 | 6-4 | 6-4 | 3-2 | 3-2 |
| After 2.5% phenylephrine | 5-4 | 5-4 | 8-7 | 8-7 | 6-5 | 6-5 |
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