Reversible end-stage renal disease in an adolescent patient with methylmalonic aciduria

Abstract

Sirs, Methylmalonic aciduria (MMA) is an inborn error of metabolism, characterized by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase or by defects in the synthesis of 5-deoxyadenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. Affected children suffer from lethargy, failure to thrive, and muscular hypotonia, and may have ketoacidotic, hypoglycemic, and hyperammonemic coma. Biochemically, the disease is characterized by accumulation of methylmalonate and, due to activation of alternative pathways of propionate oxidation, by accumulation of proprionate, 3-hydroxyproprionate, and 2-methylcitrate. Some of these organic acids have been suggested to act as endogenous toxins, inducing a synergistic inhibition of mitochondrial energy metabolism [1, 2]. Dietary and emergency therapy and thus outcome have substantially improved [3]. In brief, treatment is based on a restriction of natural protein and administration of precursor-free amino acid mixtures, as well as supplementation of carnitine. To avoid malnutrition and catabolism, affected patients require close monitoring during therapy. Secondary organ damage, however, remains insufficiently resolved, particularly if metabolic control is inadequate. Impairment of renal function is observed in a majority of patients [4]. It is characterized by tubulointerstitial nephritis with mononuclear cell infiltration, interstitial fibrosis, and tubular atrophy [5, 6, 7, 8]. Chronic renal failure (CRF) usually develops within the 1st or 2nd decade of life. However, adequate dietary control of protein metabolism is likely to slow the progression of renal disease, although this has not yet been investigated in prospective, observational studies. We report a 16-year-old male adolescent with vitamin B12-unresponsive MMA (mut ) and partially reversible end-stage renal disease, most likely due to improved metabolic control. In this patient, MMA was diagnosed shortly after birth, and a low-protein diet and carnitine supplementation was initiated. There were several episodes of metabolic decompensation due to inadequate metabolic control during infancy and childhood, resulting in neurological sequelae and CRF. Notably, a reduced glomerular filtration rate (GFR) was noted at 2.3 years of age. At 9 years of age, he developed spastic diplegia. CRF slowly progressed until puberty. At the age of 15 years, the patient was referred to our unit with a creatinine of 6.6 mg/dl and a GFR of 8 ml/min per 1.73 m (Fig. 1A). Transient hypercalcemia due to treatment of secondary hyperparathyroidism with 1, 25-dihydroxyvitamin D3 had resolved at the time of admission. Selective metabolic investigations revealed insufficient metabolic control, most likely due to inadequate adherence to the recommended dietary regimen. High-performance liquid chromatography analysis of plasma carnitine showed strongly elevated acylcarnitines, but free carnitine was within the normal range due to supplementation (Fig. 1B). Differentiation of acylcarnitines using tandem mass spectrometry of dried blood spots showed a predominant elevation of propionylcarnitine (Fig. 1B). Organic acid analysis of urine revealed a urinary excretion of methylmalonate, 2-methylcitrate, lactate, and pyruvate (Fig. 1C). ParathyC. P. Schmitt · O. Mehls · T. L. Weber Division of Pediatric Nephrology, Department of General Pediatrics, University Children’s Hospital, Heidelberg, Germany