November/December 2000 · Vol. 2 · No. 6 Disorders of fatty acid transport and mitochondrial oxidation: Challenges and dilemmas of metabolic evaluation Piero Rinaldo, MD, PhD, and Dietrich Matern, MD Inborn errors of fatty acid transport and mitochondrial oxidation (FATMO) have drawn considerable attention in recent years for the rapid pace of discovery of new defects and an ever-increasing spectrum of clinical phenotypes. Several of these disorders are not detected by conventional biochemical investigations, even when a patient is symptomatic with fasting intolerance or functional failure of fatty acid dependent tissue(s). In our view, today's major challenges are the inclusion of FATMO disorders in newborn screening programs and the investigation of the role played by individual disorders in maternal complications of pregnancy, sudden and unexpected death in early life, and pediatric acute/ fulminant liver failure. Dilemmas are found in the debate over the limitations, if any, to be imposed on the expansion of newborn screening using tandem mass spectrometry, in the provision of prenatal diagnosis for otherwise treatable disorders, and in the diagnostic workup of "unclassified" cases. Genetics in Medicine, 2000:2(6):338-344. Key Words: fatty acid transport, mitochondrial oxidation, newborn screening, sudden death Mitochondrial fatty acid oxidation plays a major role in en­ ease, skeletal myopathy, dilated/hypertrophic cardiomyopa­ ergy production and homeostasis.' In response to fasting, thy, and sudden and unexpected death in early life. 2- 4 long-chain fatty acids are mobilized from adipose tissue and Today's most pressing challenges are found first and fore­ taken up by active transport in liver and muscle cells. Enzymes most in the expansion of newborn screening programs to in­ responsible for the {3-oxidation of longer chain species are as­ clude FATMO disorders. Second, the challenge is to under­ sociated with the inner mitochondrial membrane, while the stand the role specific disorders may play in the etiology of enzymes responsible for the metabolism of medium- and maternal complications of pregnancy, sudden and unexpected short-chain species are located within the mitochondrial ma­ death in early life, and acute/fulminant liver failure in child­ trix. A distinction between defects of membrane-bound and hood. Dilemmas, defined as difficult choices to be made be­ matrix enzymes has become increasingly relevant to the classi­ tween equally valid but contrasting solutions, are posed by the fication of inborn errors of this pathway because the number of application of the full diagnostic potential of tandem mass defects in each group is almost equal, and the two groups tend spectrometry to newborn screening, the provision of prenatal to manifest with different patterns of clinical manifestations diagnosis for treatable disorders, and by defining the bound­ and particularly biochemical phenotypes.2 aries of the diagnostic workup of "unclassified" cases. The pathogenetic mechanisms underlying the clinical man­ ifestations of FATMO disorders are similar to virtually all mi­ NEWBORN SCREENING OF FATMO DISORDERS: tochondrial inborn errors of metabolism, originating from ei­ THE CHALLENGE ther one of two basic mechanisms: intoxication and energy deficiency. ' In FATMO disorders, both mechanisms are in­ State-mandated newborn screening was initiated in the early volved (Fig. 1 ), and consequent signs and symptoms include 1960s for the identification of infants affected with phenylke­ hypoketotic hypoglycemia, transient to fulminant liver dis- tonuria (PKU), but soon was expanded to include additional genetic and nongenetic conditions. The goal of newborn screening is the presymptomatic diagnosis of treatable disor­ /-rotH tilt' r;,, ,dtt'llll t"al ( ''' llt'ftt":' I lll'flrti/Pr_r, f of /.a/,,H•I IHf\' I ;,·nl'fll"::i, flt'f•lrfiiiCIIt ''' ders frequent enough to allow for a positive cost-benefit ratio. I olhr·•r,l/oiiT .\k.lllt/1( ..: '· l'atholo_..:l ', A l t/1'11 ( 'Iiiii( ,/}/,{ 1-"cl lltldtllion. l:n!"h c-> lu. ;\ lillllt'.'c'l''· Tandem mass spectrometry (MS/MS) is a powerful multiana­ ,,, t/11 · \tl/111111 ,\ ln·Jmg ••{the .·\ matt,l/1 ;1'111'1/c ·;, Sf.\ II ) .'o C.'5Jclll. /',dm c ,i/,f,•nt tll ..\ !,n t h .!tJOIJ. lyte screening method which is ideally suited for population­ 5 Hnldfdrr. All'· fi!1l '· Hiodlt"llllflll f ;t'llt'llt·..; 330. Pcparflllt'lll d/ /.dl'­ wide testing. Since the early 1990s, MS/MS has made possible f'/!1/tiiT ill!"(- Plltlwlog)". Affl_l'(l ( '/mir rllltl hnllldrllinll, _!(}() , .. ,r:_;f :·it ratS. \V. , /\odiL'.\.• screening for several FATMO disorders based on the pro­ ft·r. ,\ft,: ; _;wo_-:; filing of acylcarnitines in blood spots (Table 1). Beyond the availability of a screening method amenable to population­ wide testing, compelling reasons for the inclusion of FATMO 338 IN Medicine Fatty acid transport and mitochondrial oxidation Intoxication Table 1 Energy Tandem mass spectrometry in newborn screening ofFATMO disorders Fatty acids Normal Intoxication deficiency Acylcarnitines Effectiveness Effectiveness Ammonia, lactic acid of early of A A Disorder treatment" MS/MSb Uric acid Disorders of membrane-bound enzymes Energy deficiency + l Carnitine transport defect +++ +I- Hypoglycemia B B +reducing equivalent to Long-chain fatty acid transport defect +§ OXPHOS B + CPT-I deficiency (liver) (+) + +ketone bodies to + CACT deficiency extrahepatic tissues I Clinical manifestations I + + CPT -II deficiency Fig.1 Metabolic effects of impaired fatty acid metabolism. A and B indicate a substrate and product, respectively, of a generic enzyme reaction; C indicates the product of an Neonatal onset + alternative pathway (for example, conjugation with carnitine and glycine). OXPHOS, Late onset oxidative phosphorylation. + + VLCAD deficiency + (+) ETF-QO deficiency (GA2) disorders in screening programs are a documented prevention Neonatal onset + of morbidity by early diagnosis, and simple and inexpensive Late onset + (+) treatment strategies. This situation, however, has sparked an LCHAD deficiency + (+) intense debate over the allocation of sufficient resources to provide treatment, follow-up care, and genetic counseling to a TFP deficiency (a, f3) +§ (+) far more diverse population of patients. Disorders of mitochondrial matrix enzymes To date, a consensus has been reached to screen without MCAD deficiency +++ + further delay at least for medium-chain acyl-CoA dehydroge­ SCAD deficiency + + nase (MCAD) deficiency and glutaric acidemia type 1. 6 MCAD deficiency is the most common fatty acid oxidation disorder Functional SCAD detlciency + and possibly one of the most frequent metabolic diseases over­ ETF detlciency (a, f3, GA2) all; according to recent estimates, it occurs in approximately Neonatal onset + 1:6,500-1:17,000 live births.l Although growth and develop­ Late onset + (+) ment are not affected, the manifestations of acute episodes of decompensation include severe liver dysfunction, hypoglyce­ Riboflavin responsive form(s) (GA2) +++ (+) mic coma, and sudden, unexpected death. The first acute epi­ SCHAD detlciency (muscle) + sode usually occurs early in life, but affected individuals may SCHAD deficiency (tlbroblasts) + +I- 8 present at any age, including adulthood. Sudden and unex­ SCHAD detlciency (liver) +§ pected death is the first manifestation of MCAD deficiency in M/SCHAD detlciency +§ (+) 18% ofpatients,9 an outcome which could be prevented, with almost no exceptions, by simple dietary treatment and basic MCKAT detlciency + (+) preventive measures. 2,4-Dienoyl-CoA reductase deficiency (+) HMG-CoA synthase detlciency + HMG-CoA lyase detlciency + + NEWBORN SCREENING OF FATMO DISORDERS: Abbreviations are as follows, in alphabetical order: CACT, carnitine acylcar­ nitine translocase; CPT, carnitine palmitoyltransferase; ETF, electron transfer THE DILEMMA flavoprotein; ETF-QO, electron transfer flavoprotein ubiquinone-oxi­ doreductase; GA2, glutaric acidemia type II; HMG, 3-hydroxy 3-methylglu­ The reliability of screening by MS/MS for the majority of taryl; LCHAD, long-chain L-3-hydroxy acyi-CoA dehydrogenase; MCAD, me­ FATMO disorders, particularly long-chain L-3-hydroxy acyl­ dium-chain acyl-CoA dehydrogenase; MCKA T, medium-chain 3-ketoacyl­ CoA dehydrogenase (LCHAD) deficiency, has not been CoA thiolase; M/SCHAD, medium/short chain L-3-hydroxy acyl-CoA dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase; SCHAD, short­ proven conclusively based on the prospective detection of a chain L-3-hydrox)' acyl-CoA dehydrogenase; TFP, trifunctional protein; significant number of affected cases (Table 1). Obviously, any VLCAD, very long-chain acyl-CoA dehydrogenase. questions about the specificity and sensitivity of a screening "Effectiveness of treatment: + + +, demonstrated; +, dietary and preventive measures; -, no effective treatment; §, liver transplantation; ?, insufficient method lead to concerns of encountering high rates of false­ information. negative (missed diagnosis) and false-positive (unnecessary ofMS/MS: +,demonstrated in blood spots; (+),expected to be follow up) results, with a corollary of potential malpractice and effective, but not yet conclusively demonstrated; + /-, questionable effective­ ness; -, not effective. liability issues. Despite some reassuring reports, 10 the finding of only one case with LCHAD deficiency among almost one 2888 Viilo No. 6 339 Rinaldo and Matern million newborns screened by the laboratory with the largest ROLE OF FATMO DISORDERS AS CAUSE