Metabolic Studies of Carnitine in a Child with Propionic Acidemia

Abstract

ABSTRACT. Carnitine metabolism was studied in a 7-y- CASE HISTORY old boy with propionic acidemia due to an almost total deficiency of propionyl-CoA carboxylase. The initial diagnosis was made at 3 wk of age followed by numerous episodes of metabolic acidosis despite a low-content branch-chain amino acid diet containing supplemental biotin. Although clinically stable and in a nonacidotic state, the plasma concentration of total carnitine was normal (38.9 fiM; normal = 46 f 10, mean f SD, n = 30) whereas free carnitine was decreased (5.7 pM, normal = 37 f 8) and short-chain acylcarnitines were increased (28.6 pM; normal = 5.7 2 3.5). Skeletal muscle and liver specimens obtained at open biopsy had low total and free carnitine contents and increased ratio of short-chain acylcarnitines to free carnitine. Short-chain acylcarnitine content was low in liver but increased in skeletal muscle. The liver contained fatty vacuoles, enlarged mitochondria with paracrystalline inclusions, and numerous peroxisomes whereas the skeletal muscle also had lipid vacuoles and an increase in number and size of mitochondria. A carnitine challenge test (100 mg L-carnitinelkg body wt via a gastrostomy tube) resulted in a peak plasma carnitine concentration at 120 min. With maintenance therapy of 100 mg L-carnitine/kg/day the plasma free carnitine remained relatively low, the plasma glycine concentration decreased, and urinary acylcarnitine excretion increased. This study demonstrates that the alterations in carnitine and its derivatives observed in plasma and urine reflect the same type of altered distribution in tissue and provides further data on the effects of L-carnitine therapy. (Pediatr Res 26: 63-66, 1989) Systemic carnitine insufficiency has been implied in patients with propionic aciduria and other primary disorders of organic acid metabolism based on measurement of carnitine and its derivatives in plasma and urine (1-9). These studies have provided some insight into the biochemical pathophysiology of these inborn errors of metabolism as well as a rationale for their treatment with L-carnitine.Our report of a patient with propionic acidemia shows that plasma and urinary measurements of carnitine and acylcarnitines reflect tissue levels of carnitine compounds. It also provides additional evidence of a generalized disturbance in carnitine metabolism in organic acidurias that is amenable to carnitine therapy.The patient was a 7-y-old boy with propionic acidemia due to an almost complete absence of propionyl-CoA carboxylase activity. He presented at 10 days of age with hyperammonemia and metabolic acidosis and was treated with peritoneal dialysis. Plasma and urinary glycine were elevated, and urinary organic acid analysis demonstrated prominent excretion of propionic acid metabolites, including methylcitrate. The enzymatic diagnosis was established in cultured fibroblasts in the laboratory of Dr. L. Sweetman, University of California, San Diego, and there was no clinical response to biotin therapy.He subsequently had numerous episo...

Propionyl-CoA carboxylase – A review

“…In humans, it is difficult but possible (unpublished data) to detect elevations in propionyl- CoA. However, the levocarnitine ester of propionyl-CoA, propionylcarnitine (C3), is readily detectable in plasma, serum, and urine [38]. In addition, individuals have elevations in methylcitrate (MC) and 3-hydroxypropionate (3OHPA) which are usually assayed from urine clinically [39, 40].…”

Acute management of propionic acidemia

“…Individuals with PA are at increased risk of secondary deficiencies of carnitine and so carnitine can be used to scavenge propionyl groups as well as replace if deficient [33,34,35,36,37]. Initial studies of carnitine in PA dosed it as an intermittent oral dose and continuous dosing [38].…”

“…G-tubes are useful in home management of a PA patient when ill. In addition, G-tubes can be used to meet daily metabolic nutrition therapy goals when a patient is anorexic as is often seen in patients with PA [47,48,37]. They are also useful in the administration of medications which are often unpalatable.…”

Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered byl-carnitine

“…Given the fact that CrAT is highly abundant in the heart and that CrAT has the highest activity for propionyl-CoA (3,27,37,44), L-carnitine may correct propionate-mediated CoA trapping. The idea of L-carnitine supplement has been proposed to patients with propionic acidemia (20). However, the detailed effect and biochemical mechanism are not fully elucidated, particularly in the heart.…”