This is a study to determine the safety of dichloroacetate (DCA) with a low-tyrosine diet
given with or without nitisinone (NTBC) in children with chronic lactic acidosis (CLA).
DCA is being studied for the treatment of patients with CLA, which is a rare collection of
mitochondrial metabolism errors causing cellular energy failure and early death. DCA causes
reversible liver and peripheral nerve toxicity and it interrupts both tyrosine and heme
metabolism. The inhibitory effect of DCA on mammalian tyrosine metabolism elicits
biochemical changes similar to those observed in hereditary tyrosinemia type I (HT).
However, some reports and studies indicate substantial reduction in the biochemical and
clinical consequences of HT may occur when patients are treated concomitantly with a
low-tyrosine diet (LTD) and the chemical NTBC, which inhibits an early step in tyrosine
catabolism. Possibly, the same dietary and pharmacologic interventions may mitigate or
prevent toxicity associated with chronic DCA exposure.
Patients visit the Center 5 times over a 1-year period, usually for 2 to 3 days per visit,
for an extensive series of clinical and biochemical tests. Visit 1 is for baseline
examinations and blood and urine chemistries and to educate the patient on an LTD. This
visit lasts approximately 7 days to determine acceptable circulating tyrosine concentrations
for LTD formula at discharge. Patients are provided with tubes to take to local laboratories
every 2 weeks for blood work. Patients are readmitted in 1 month to determine adherence to
diet and serum tyrosine levels. Patients who evidence dietary compliance, no adverse
effects, and a willingness to continue are placed in 1 of 2 treatment arms: DCA plus an LTD
plus placebo or DCA plus an LTD plus NTBC. Thereafter, patients return during Months 5, 9,
and 13, which completes their 1-year treatment phase.
Completion date provided represents the completion date of the grant per OOPD records
- Biochemical or molecular genetic proof of a defect in mitochondrial enzyme of glucose
metabolism or oxidative phosphorylation.
- Clinical history consistent with CLA (e.g., basal hyperlactatemia, stroke-like
episodes, neuromuscular degeneration, and seizures).
- Ability to withstand an 8-hour fast (if 2 years old or younger) or a 12-hour fast
without developing hypoglycemia (blood glucose greater than or equal to 50 mg/dL).
- Secondary lactic acidosis due to impaired oxygenation or circulation.
- Hyperlactatemia associated with proven biotinidase deficiency or with enzyme
deficiencies of gluconeogenesis.
- Primary, defined organic acidurias other than lactic acidosis for which effective
therapy is available (e.g., propionic aciduria).
- Primary disorders of amino acid metabolism.
- Primary disorders of fatty acid oxidation.
- Malabsorption syndromes associated with D-lactic acidosis.
- Renal insufficiency.
- Serum creatinine greater than 1.2 mg/g.
- Creatinine clearance less than or equal to 60 mL/min.
- Primary hepatic disease unrelated to chronic lactic acidosis.
- In patients with pyruvate dehydrogenase enzyme complex deficiency, an inability to
maintain a diet greater than 50% calories from fat without biological and/or