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Dionisi-Vici and colleagues (2000) published a case study of a boy who was 3½ years of age at the time of reporting. The patient had been born prematurely (33 weeks) but had a birth weight, length, and head circumference (an index of prenatal brain growth) expected for his gestational age. During the perinatal period, he suffered from respiratory distress and repeated episodes of hypoglycemia. As time went on, he began to show signs of hypotonia, hypokinesia (reduced movement), and difficulty in feeding. The child was examined further at 5 months of age, at which time he showed normal blood chemistry and EEG but moderately enlarged cerebral ventricles based on an MRI scan. Behaviorally, he exhibited prolonged periods of lethargy accompanied by excessive sweating, which alternated with periods of irritability and dystonia, including uncontrollable upward movements of the eyes.
At 22 months of age a spinal tap was performed to measure monoamine metabolites in the cerebrospinal fluid (CSF). The CSF level of HVA (DA metabolite) was undetectable, MHPG (NE metabolite) was detectable but very low, and 5-hydroxyindoleacetic acid (5-HT metabolite) was normal. These findings strongly pointed to a deficiency in TH activity and DA synthesis (the low level of MHPG is understandable since DA is the normal precursor to NE). Additional tests appeared to rule out problems with AADC activity or the TH co-factor tetrahydrobiopterin, suggesting a problem with TH itself. This was confirmed by genetic analysis revealing a homozygous point mutation in the TH gene that altered one specific amino acid in the TH protein. Remarkably, this single amino acid alteration led to the production of a TH molecule that expressed little or no ability to synthesize DA.
There is no cure for this genetic disorder, although researchers hope that gene therapy will eventually be developed for patients like this. Instead, pharmacotherapy is instituted to provide whatever symptomatic relief is possible. Accordingly, the child’s doctors began prescribing l-DOPA to replenish some of the missing DA by circumventing the missing TH step. Treatment also included carbidopa (trade name Lodosyn), which is a peripheral AADC inhibitor that blocks metabolism of l-DOPA before it reaches the brain. Carbidopa is commonly given along with l-DOPA in the treatment of patients with Parkinson’s disease (see Chapter 20). This treatment regimen led to increased muscle tone, less sweating, and disappearance of the previously observed periods of lethargy. Unfortunately, severe dystonic movements continued to occur. Delayed somatic and brain development (based on head circumference) were also evident as the child reached 3 to 4 years of age.
In a search for improved treatment outcome, doctors tried adding the MAO-B inhibitor selegiline to the l-DOPA/carbidopa regimen. This trial led to significant symptom improvement. In the words of the authors, “At age 4 years he is now able to sit with support and to reach for objects with both hands. Within 2 months of this treatment regimen growth also improved, with a weight gain of 1 kg and a height gain of 4 cm” (p. 561). The abilities described in the quotation may seem meager, but the fact that they were not present before the new treatment regimen emphasizes the severity of the motor disorder exhibited by this child.
This case study reveals the critical role for DA in mediating the control of voluntary movements. Interestingly, the lack of this transmitter during all of embryonic development did not obviously hamper prenatal growth, although we cannot know if it played a role in the premature birth. We also do not know if the child’s brain developed normally with respect to neural circuitry, synapse formation, and so forth. Soon after birth, motor dysfunction began to appear, and this dysfunction quickly worsened over time. Attempts to restore dopaminergic activity were only partially successful; however, we cannot rule out the possibility that greater benefit would have ensued if pharmacotherapy had been instituted at an earlier age.
Reference
Dionisi-Vici, C. et al. (2000). Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. J. Pediatr. 136, 560–562.