Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathy

https://doi.org/10.1016/j.ymgme.2005.04.004Get rights and content

Abstract

A patient diagnosed at 9 months with a milder form of propionic acidemia was functioning at a near normal intellectual level and a normal neurological level at age 8. After 2-week history of feeling “poorly” but functioning normally, she became acutely ill and succumbed to heart failure and ventricular fibrillation in 12 h. At post-mortem the heart was hypertrophied and had low carnitine levels, despite carnitine supplementation and repeatedly normal plasma carnitine levels. The findings in this patient provide a possible mechanism for the cardiac complications that are becoming more apparent in propionic acidemia.

Introduction

Cardiac diseases, including heart failure and arrhythmias, have been recognized as important manifestations of disorders of energy metabolism for a number of years. Virtually all genetic abnormalities of the mitochondrial electron transport chain have been associated with cardiac disease [1]. Similarly, disorders of fatty acid oxidation are now recognized as placing patients at high risk of overt or occult heart disease, especially those conditions involving longer chain fatty acid oxidation [2]. Both systemic [3], [4] and muscle carnitine deficiency [4] have been well known to be associated with cardiomyopathy and cardiac arrhythmias for nearly a generation.

More recently Massoud and Leonard [5] have recognized and reported serious and life threatening cardiac abnormalities in patients with propionic acidemia, although anecdotes of heart failure and sudden death in patients with both propionic and methylmalonic acidemia had been circulating prior to that time and have been since. With the advent of carnitine therapy for these disorders, plasma-free carnitine could be maintained in the normal range and would seem to reduce the probability of carnitine deficiency as the basis for this problem. Thus, we have been left with vague but plausible notion that one or another substance accumulating was toxic to the heart as it seems to be to the brain. This was particularly plausible in those patients who demonstrated acute cardiac problem in association with episodic acidosis [5].

We report here the development of a fatal cardiomyopathy in the absence of an acute episode of decompensation in a patient with more mild and well-compensated propionic acidemia. The surprising findings of carnitine deficiency and a respiratory chain abnormality are the impetus for publishing this experience

Section snippets

Clinical summary

The patient, a product of a non-consanguineous union and a normal pregnancy had an uneventful perinatal period. She was diagnosed with propionic acidemia at the age of 9 months when she became ill and comatose after a minor infection. Analysis of the organic acids by GC/MS showed the characteristic pattern of propionic acidemia, with elevated levels of propionate, propionylglycine, and methylcitrate. Following intensive medical therapy and improvement of her metabolic condition, the patient was

Post-mortem examination

The autopsy revealed hepatomegaly and cardiac hypertrophy. There was bilateral pulmonary congestion. The liver weighed 1050 g (normal 778 g). The heart weighed 350 g (normal 116 g). The right ventricular wall was 0.3 cm in thickness, while the left ventricular wall was hypertrophied and 1.8 cm in thickness. The chambers were not dilated and the endocardial surfaces were smooth. There were no abnormalities of the cardiac valves. Microscopic examination of the heart showed increased myofiber size.

Biochemical analysis of carnitine on heart and skeletal muscle

Skeletal and heart muscle specimens were obtained within one hour of the patient’s death. They were quenched in 2-methylbutane chilled by liquid nitrogen. Free and esterified carnitine was determined in water homogenates of muscle by spectrophotometric enzymatic assay, after extraction with methanol. Results are summarized in Table 2.

Total and free carnitine in heart muscle was very low. Low esterified carnitine content suggests a major defect in acylation/esterification pathway. Free and total

Mitochondrial oxidative enzymes assay

The activity of carnitine palmityl transferase was assayed spectrophotmetrically as described by Bieber et al. using 40 μmol/L CoA substrate derivatives. The short and long-chain acyl-CoA dehydrogenase were assayed by the reduction of 2,6-dichlorophenolindophenol (DCPIP) at 600 nm using a modification of the method of Fong and Schulz [6] in which 0.1 mmol/L KCN substituted for N-methylmaleimide. The results are shown in Table 3.

Carnitine palmityl transferase activity was normal in heart and

Discussion

Cardiomyopathy as a complication of organic acidemias and particularly of propionic acidemia is now a well accepted phenomenon ([5]; internet communications). The presentation of acute decompensation in this patient was somewhat of a surprise because the patient had no obvious exacerbation of her metabolic condition. That the onset of the process occurred prior to the onset of symptoms was demonstrated by the severe cardiac hypertrophy.

Despite the severity of metabolic crises that occur in

Acknowledgments

This work was supported by the Mental Retardation Research Program at UCLA and USPHS Grants HD-06576, HD 04612, and HD-36415. The metabolic staff at Kaiser Permanente took excellent care of this patient. Dr. Julian Williams of Children’s Hospital of Los Angeles cared for this patient prior to her transfer to the Kaiser System.

References (9)

There are more references available in the full text version of this article.

Cited by (84)

  • Cardiac phenotype in propionic acidemia – Results of an observational monocentric study

    2020, Molecular Genetics and Metabolism
    Citation Excerpt :

    Different types of cardiomyopathies have been described in PA patients, mainly dilated CM [11] [13] [9]. Secondary multiple OXPHOS deficiency due to mtDNA depletion or ineffective mitophagy resulting in accumulation of dysmorphic and dysfunctional mitochondria or lack of carnitine are currently discussed as possible mechanisms [12] [14] [15]. Toxic metabolites may also play an important role in the development of aLQTS [16] [17].

  • Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia

    2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
    Citation Excerpt :

    The most frequent cardiac complications found in patients with PA are systolic dysfunction (decreased ejection fraction, a measure of the amount blood leaving the heart with each contraction), cardiac arrhythmias and structural remodeling [7,9,10]. Also, heart rhythm problems, including prolonged QTc interval, tachycardia, ventricular ectopic beats, bradycardia and conduction abnormalities, have been described in patients [1,9,11–16]. The development of a hypomorphic mouse model for PA that survives into adulthood has facilitated the study of the mechanisms involved in the disease pathophysiology.

View all citing articles on Scopus

Data presented in part at the 7th Triannual Meeting of the International Inborn Errors of Metabolism Societies. Vienna, May 1997: Mardach, R., Verity, M.A., and Cederbaum, S. Myocardial Carnitine Deficiency Associated with Cardiomyopathy in a Child with Propionic Acidemia.

View full text