Alagille Syndrome | Alpha-1 Antitrypsin Deficiency | Bile Acid Synthesis Defects | > Mitochondrial Hepatopathies | PFIC (Progressive Familial Intrahepatic Cholestasis)

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Mitochondrial Hepatopathies

Etiology and Genetics

The hepatocyte mitochondrion functions both as a cause and as a target of liver injury. Most mitochondrial hepatopathies involved defects in the mitochondrial respiratory chain enzyme complexes (Figure 1). Resultant dysfunction of mitochondria yields deficient oxidative phosphorylation (OXPHOS), increased generation of reactive oxygen species (ROS), accumulation of hepatocyte lipid, impairment of other metabolic pathways and activation of both apoptotic and necrotic pathways of cellular death.  Since the mitochondria are under dual control of nuclear DNA and mitochondrial DNA (mtDNA), mutations in genes of both classes have been associated with inherited mitochondrial myopathies, encephalopathies, and hepatopathies.  Autosomal nuclear gene defects affect a variety of mitochondrial processes such as protein assembly, mtDNA synthesis and replication (e.g., deoxyguanosine kinase [dGK)] and DNA polymerase gamma [POLG]), and transport of nucleotides or metals. MPV17 (function unknown) and RRM2B (encoding the cytosolic p53-inducible ribonucleotide reductase small subunit) are two genes recently identified as also causing mtDNA depletion syndrome and liver failure. Most children with mitochondrial hepatopathies have identified or presumed mutations in these nuclear genes, rather than mtDNA genes. A classification of primary mitochondrial hepatopathies involving energy metabolism is presented in Table I. Drug interference with mtDNA replication is now recognized as a cause of acquired mtDNA depletion resulting in liver failure, lactic acidosis, and myopathy in human immunodeficiency virus infected patients and, previously, in hepatitis B virus patients treated with nucleoside reverse transcriptase inhibitors.  Current estimates suggest a minimum prevalence of mitochondrial disease of 11.5 cases per 100,000 individuals, or 1 in 8500 of the general population.

Additional hepatopathies are related to deficiencies of enzymes involved in mitochondrial fatty acid oxidation (b-oxidation), a pathway that activates free fatty acids to acyl-CoA esters then metabolizes them to acetyl-CoA. They are caused by autosomal recessive mutations in nuclear genes encoding nearly two dozen enzymes and transporter proteins (Figure 2 and Figure 3). Many of these disorders can be identified by screening of blood spots from newborns using tandem mass spectrometry. Recent data from newborn screening programs indicate an overall incidence for all fatty acid oxidation defects of 1-2 per 1,000 births in the general population. While most of these disorders can lead to fatty liver when patients are ill, true hepatocellular disease is common in only a few of them, which will be highlighted in this document.

Table 1: Classification of Primary Mitochondrial Hepatopathies Involving Mitochondrial Energy Metabolism

1. Electron transport (respiratory chain complex) defects
   
   • Neonatal liver failure:
     • Complex I deficiency (NADH: ubiquinone oxidoreductase)
     • Complex IV deficiency (cytochrome c oxidase)
     • Complex III deficiency (ubiquinol: cytochrome c oxidoreductase)
     • Multiple Complex deficiencies
   • Mitochondrial DNA depletion syndrome (dGK, MPV17, RRM2Band Polymerase-g mutations)
   • Delayed-onset liver failure: Alpers' disease (complex I deficiency, Polymerase-g mutations)
   • Pearson's marrow-pancreas syndrome (mtDNA deletion)
   • Mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) (TP mutations)
   • Chronic diarrhea (villous atrophy) with hepatic involvement (complex III deficiency)
   • Navajo neurohepatopathy (MPV17 mutations)
     
2. Fatty acid oxidation and transport defects
   
   • Carnitinepalmitoyltransferase1 and 2 deficiency (CPT1, 2; neonatal or early infancy form)
   • Very long chain acyl-CoA dehydrogenase deficiency (VLCAD; hepatic form)
   • Acyl-CoA dehydrogenase 9 deficiency (ACAD9)
   • Trifunctional protein and isolated long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency
   • Acute fatty liver of pregnancy (AFLP) and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, related to carrier status for mutations is any one of several of the b-oxidation genes.

Clinical Features

Defects in OXPHOS can affect any tissue, with the most energy-dependent organs being most vulnerable, resulting in heterogeneous clinical presentations. Symptoms may involve every organ system, with an increasing number of organs involved as the disease progresses over time. It is important to consider the diagnosis of a mitochondrial disorder in patients with progressive, multi-system symptoms that cannot be explained by a specific diagnosis. Mitochondrial hepatopathies, such as mtDNA depletion syndrome, may present as neonatal liver failure with lactic acidosis, jaundice, synthetic liver dysfunction, with or without neuromuscular involvement (hypotonia, developmental delay, seizures), and typically results in death in infancy from liver failure. In other conditions, chronic hepatic involvement may present with cholestasis, steatosis, and hepatomegaly. In Alpers' disease (cerebro-hepatic degeneration), a previously normal child develops loss of developmental milestones, hypotonia, vomiting and intractable seizures concurrent with the development of hepatic steatosis and synthetic failure. The onset of liver failure is frequently precipitated by treatment with valproic acid for control of seizures. Non-specific gastrointestinal symptoms, such as vomiting, diarrhea, constipation, failure to thrive, and abdominal pain, are commonly found in many mitochondrial disorders. Other gastrointestinal manifestations, such as chronic intestinal pseudo-obstruction and pancreatic exocrine insufficiency, are important cardinal manifestations of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and Pearson syndrome, respectively.

Disorders of mitochondrial fatty acid oxidation can present with hypoglycemia, myopathy, cardiomyopathy, and hepatic steatosis. Fulminant liver failure is less common and occurs predominantly when the patient is under physiologic stress (especially illness and fasting). Clinical symptoms for each enzyme deficiency tend to overlap and differentiation on clinical criteria is difficult. Moreover, children may be well until stressed when they exhibit acute symptoms. For these reasons laboratory investigations become key in correctly identifying the diagnosis. Mitochondrial trifunctional protein deficiency presents with the most unique clinical picture including skeletal and cardiomyopathy, peripheral neuropathy, and retinopathy with recurrent episodes of hypoglycemia and hyperammonemia. Patients with isolate LCHAD deficiency will have episodes of hypoglycemia and hyperammonemia and can show the characteristic retinopathy, but do not usually have significant myopathy or neuropathy. Hepatocellular dysfunction occurs only during acute metabolic decompensation. Patients with the severe neonatal forms of CPT1, CPT2, and VLCAD deficiency present with profound hypoglycemia +/– hyperammonemia, along with generalized hepatocellular failure. Acute fatty liver of pregnancy and maternal HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome can occur in pregnant women who are carriers of fatty acid oxidation defects, especially when the fetus is affected with the disorder. The mechanism for this phenomenon is unclear. ACAD9 deficiency is the newest defect of fatty oxidation identified and has been reported to present with isolated, acute, recurrent liver dysfunction or failure with intercurrent illness.

Pathogenesis of Liver Injury

Hepatic steatosis is characteristic of these disorders. Neutral lipid accumulates in the hepatocyte because of continued unbridled uptake by the hepatocyte of free fatty acids released from adipose tissue, impaired beta oxidation of the fatty acids resulting in their accumulation in the cell, and increased synthesis of stored triglycerides. The liver is dependent on a rich supply of ATP for its many energy-consuming biological and chemical functions. Thus, a deficiency in production of ATP caused by reduced or abnormal respiratory chain function, deficient replication of mtDNA or loss of functional mitochondria will severely impair many important liver functions and may cause hepatocyte apoptosis or necrosis, reducing the functional mass of hepatocytes even more. In Alpers' disease, a rapid loss of functional hepatocytes may suddenly occur for unknown reasons. Cholestasis in these disorders is caused by poor function of the ATP-dependent bile salt export pump, the canalicular protein providing the main driving force for bile flow, which may exacerbate the hepatocellular injury caused by the accumulation of lipid in the hepatocyte (steatosis). Increased reactive oxygen species (ROS) generation is also believed to be an important pathologic process in these disorders. Impaired electron transport in the respiratory chain (see Figure 1), in the face of continued delivery of reducing equivalents results in generation of superoxide and hydrogen peroxide, oxidation of lipids and thiol proteins in the mitochondrial membrane and secondary damage to mtDNA. This situation may create a vicious cycle, leading to further impairment of mitochondrial respiration and oxidative phosphorylation, increased ROS generation, and energy deficiency within the hepatocyte. In chronic, less severe respiratory chain disorders, hepatic fibrosis and micronodular cirrhosis become an important component of the hepatic pathology.

Liver biopsy findings are variable, however certain features are uniform. In respiratory chain defects, microvesicular, and less commonly macrovesicular, hepatic steatosis may be focal or generalized (Figure 4 and Figure 5). Periportal inflammation is variably present. Canalicular cholestasis with bile duct thrombi (Figure 6) and bile ductular reaction (proliferation) are common findings. In some cases periportal and centrilobular fibrosis and drop out of broad bands of hepatocytes lead to an appearance of micronodular cirrhosis. Glycogen depletion is common and increased hepatocyte iron overload may lead to confusion with a primary iron storage disorder. Electron microscopy of liver shows lipid droplets in hepatocytes, and may reveal normal mitochondria, usually in increased density in hepatocytes, or swollen, polymorphic mitochondria with decreased matrix density (Figure 7).

Liver biopsy findings in fatty acid oxidation defects typically show panlobular microvesicular or macrovesicular steatosis, generally without significant inflammation, fibrosis or hepatocyte necrosis. However, in some disorders portal fibrosis or frank cirrhosis may develop (such as VLCAD and LCHAD deficiencies). Electron microscopy may show enlarged and abnormally shaped mitochondria, linear crystalline bodies in the mitochondrial matrix, or a condensed matrix with widening of the intracristal spaces.

Diagnosis

Diagnosing a mitochondrial respiratory chain defect in patients with liver disease requires a high index of suspicion. Clinical scenarios that should suggest these disorders include a) association of neuromuscular symptoms with liver dysfunction, b) multi-system involvement in a patient with acute or chronic liver disease, particularly with hepatic steatosis and c) a rapidly progressive course of liver disease, particularly in the presence of lactic acidosis or ketonemia.

Laboratory findings in the blood and urine that indicate an altered redox status are suggestive of respiratory-chain defects. Persistent elevation of plasma lactate (>2.5 mM) with an elevated molar ratio of plasma lactate to pyruvate (L/P >20), and elevated ketone body ratio of b-hydroxybutyrate to acetoacetate (>2) are highly suggestive of respiratory chain disorders. However, lactic acid and these ratios are not elevated in all patients with respiratory chain defects. Elevated ratios are indicative of an increase in reducing equivalents (excess of NADH and lack of NAD) caused by impaired transfer of electrons from NADH to oxygen as a result of disrupted OXHPOS. The L/P ratio is a reflection of the NADH to NAD balance in the cytosol, and the beta-OHB/AA ratio is a reflection of the NADH to NAD ratio within the mitochondrion. After feeding, an exaggerated paradoxical production of ketones may occur in respiratory chain defects, compared to the normal decrease in ketone production that occurs after meals due to the suppressive effect of insulin on ketogenesis. Lactate/pyruvate molar ratios in the CSF may be helpful when no elevation in plasma lactate is observed, particularly in patients with CNS involvement.

Urine gas chromatography-mass spectrometry (GC-MS) can detect elevated urinary lactate, Krebs cycle intermediates (succinate, fumarate, and malate), and at times, 3-methyl-glutaconic acid in patients with mitochondrial disorders. These urine organic acids are characteristic of but not specific to respiratory chain disorders. Urine amino acids may be elevated in the presence of a proximal tubulopathy. 

A plasma acylcarnitine profile is the best screening test for a mitochondrial fatty acid oxidation disorder that causes liver disease, along with characteristic urinary organic acid excretion (dicarboxylic and 3-hydroxydicarboxylic acids) detected by GC-MS of urine. This can be augmented with acylcarnitine profiling of extracts or tissue culture medium from cultured skin fibroblasts.

These screening tests require tissue or molecular confirmation of the diagnosis. Therefore, searching for dysfunction or abnormal histology/biochemistry of the target organ (the liver) is essential. Definitive diagnostic tests for respiratory chain disorders include the following: quantitative measurement of enzymatic activity of respiratory chain complexes in the clinically affected tissues; histology and histochemical staining (e.g., cytochrome c oxidase) of muscle or liver; genotyping for mtDNA and nuclear DNA mutations/deletions; and testing for mtDNA depletion. The appropriate investigations should be carried out on the liver (thus the need for liver biopsy tissue) as well as more standard tissues, such as muscle, since defects can be tissue-specific. Several clinical and research laboratories in North America and Europe provide these analyses. In the last several years, several clinical genetics laboratories in North America now offer genotyping of both nuclear genes (dGK, MPV17, POLG) and mtDNA, which might be an appropriate means of establishing the diagnosis before obtaining tissue in selected cases. Fatty acid oxidation defects can usually be diagnosed by direct enzyme assay of cultured skin fibroblasts, liver, or skeletal muscle. Common mutations have been identified in the genes for some of these disorders and are amenable to rapid molecular analysis.

Treatment

Unfortunately, there is no ideal effective therapy for most patients with respiratory chain disorders, including those with liver failure or more slowly progressive liver disease. It is not clear that any currently available medical therapy significantly alters the course of severe disease; however, there are anecdotal reports suggesting an improvement of neuromuscular symptoms in some patients. Several treatment strategies have been proposed (Table 2). "Mitochondrial cocktails," alleged to promote mitochondrial health, are empiric combinations of various antioxidants, vitamins, cofactors, and electron acceptors. To date, no controlled trials have been performed on any of these "mitochondrial cocktails," and the few controlled clinical trials of individual pharmacological agents have not been encouraging. There is a great need for well-performed double-blind placebo-controlled randomized clinical trials with comparable groups of patients and with sufficient follow-up periods. Management of mitochondrial hepatopathies also includes avoidance of drugs and conditions known to have a detrimental effect on the respiratory chain. Dietary measures, such as avoidance of fasting and high fat intake, have also been advocated. Infections can precipitate rapid metabolic deterioration, and require prompt attention and treatment. Many drugs interfere with mitochondrial metabolism, and should be avoided in these patients. Seizure control should not include phenobarbital since it can inhibit OXPHOS. Valproic acid should likewise be used with caution because of its effects on respiration and fatty acid metabolism. Several nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit or uncouple OXPHOS, and may result in clinical deterioration. Aminoglycoside antibiotics must be avoided in patients with mtDNA mutations, particularly the A1555G rRNA mutation, because of the significant risk of aminoglycoside-induced ototoxicity.

Most mitochondrial b-oxidation defects are amenable to treatment with dietary manipulation (low fat intake) and sometimes carnitine supplementation. Patients with severe CPT1 and 2 deficiencies have done more poorly, often dying on initial presentation. Acute liver disease in trifunctional protein and isolated LCHAD, VLCAD, and ACAD9 deficiencies is a sign of acute metabolic decompensation and reverses with reestablishment of metabolic equilibrium. Deficiency of the essential fatty acid DHA may occur in LCHAD deficiency and at least in part cause or exacerbate the retinopathy seen in this disorder. Supplementation may stabilize or slow deterioration, but does not seem to prevent it.

Although the presence of neuromuscular or extra-hepatic involvement in respiratory chain disorders should preclude the use of liver transplantation, a number of patients with respiratory chain defects isolated to the liver have successfully undergone liver transplantation with excellent long-term outcomes and no extra-hepatic disease expression. Other patients have developed neurologic or other symptoms following liver transplantation and have a much more guarded prognosis. Extra-hepatic disease, especially neuromuscular, gastrointestinal and cardiac disease, should be ruled out before liver transplantation, however, it may be difficult to differentiate clinical signs of CNS involvement by the primary disorder from secondary signs that accompany liver failure. For patients with acquired mtDNA depletion caused by nucleoside analogue reverse transcriptase inhibitors, successful liver transplantation has been performed without recurrence of disease, as long as the offending agent has been discontinued. Liver transplant has not been pursued in the disorders of fatty acid oxidation. In the milder forms, it appears not to be necessary and in the more severe phenotypes, children have usually not survived to transplant. Given the systemic symptoms in trifunctional protein deficiency, liver transplant is not likely to be effective.

Table 2: Proposed Pharmacologic Treatments For Mitochondrial Disorders

Electron Acceptors and Cofactors:

  Antioxidants:

Other Mechanisms:

* Ped = Pediatric doses

Outcome and Prognosis

There is wide variation in clinical outcome and prognosis for individuals with mitochondrial diseases. If there is significant central nervous system or cardiac involvement, the patient generally shows a progressive course of neuromuscular disability with its attendant medical problems. If the liver is severely affected in an inherited disorder involving the respiratory chain, the outlook for recovery or response to current therapies is poor. Infants and young children presenting with lactic acidosis and liver failure caused by mitochondrial hepatopathies have a particularly poor prognosis and may die at a young age. But there are also patients who have only minor problems and have only mild, manageable symptoms of liver disease or problems with other organs. Liver transplantation can be successful in a limited subgroup of patients without evidence of other major organ involvement (central nervous system, muscle, heart, small intestine or colon, and kidney). However, following liver transplantation, there is always a possibility that extra-hepatic symptoms may develop over time and that the disease was not limited to the liver, but was more slowly progressive in the other involved organ systems. Thus, the long-term prognosis for patients undergoing a successful liver transplantation is always guarded. Clearly, there is a need for a better understanding of the pathophysiology of these disorders in order to develop improved therapies.

References

Respiratory Chain Disorders

Munnich A, Rotig A, Chretien D, et al: Clinical presentations and laboratory investigations in respiratory chain deficiency. Eur J Pediatr 155:262-74, 1996

Pessayre D, Mansouri A, Haouzi D, Fromenty B.  Hepatotoxicity due to mitochondrial dysfunction. Cell Biol Toxicol. 1999;15:367-73.

Uusimaa J, Remes AM, Rantala H, et al: Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders. Pediatrics 105:598-603, 2000

Chinnery PF, Turnbull DM: Epidemiology and treatment of mitochondrial disorders. Am J Med Genet 106:94-101, 2001

Sokol RJ, Treem WR: Mitochondrial hepatopathies. In Suchy FJ, Sokol RJ, Balistreri WF (eds): Liver Disease in Children, ed 2nd. Philadelphia: Lippincott, Williams & Wilkins, 2001, pp 787-810

Leonard JV, Schapira AH: Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet 355:299-304, 2000

Cormier-Daire V, Chretien D, Rustin P, et al: Neonatal and delayed-onset liver involvement in disorders of oxidative phosphorylation. J Pediatr 130:817-22, 1997

Thomson M, McKiernan P, Buckels J, et al: Generalised mitochondrial cytopathy is an absolute contraindication to orthotopic liver transplant in childhood. J Pediatr Gastroenterol Nutr 26:478-81, 1998

Sokal EM, Sokol R, Cormier V, et al: Liver transplantation in mitochondrial respiratory chain disorders. Eur J Pediatr 158 Suppl 2:S81-4, 1999

Narkewicz MR, Sokol RJ, Beckwith B, et al: Liver involvement in Alpers disease. J Pediatr 119:260-7, 1991

Gauthier-Villars M, Landrieu P, Cormier-Daire V, et al: Respiratory chain deficiency in Alpers syndrome. Neuropediatrics 32:150-2, 2001

Mandel H, Szargel R, Labay V, et al: The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29:337-41, 2001

Mandel H, Hartman C, Berkowitz D, et al: The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies. Hepatology 34:776-84, 2001

Salviati L, Sacconi S, Mancuso M, et al: Mitochondrial DNA depletion and dGK gene mutations. Ann Neurol 52:311-7, 2002

Nishino I, Spinazzola A, Papadimitriou A, et al: Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 47:792-800, 2000

Krahenbuhl S, Kleinle S, Henz S, et al: Microvesicular steatosis, hemosiderosis and rapid development of liver cirrhosis in a patient with Pearson's syndrome. J Hepatol 31:550-5, 1999

Cormier-Daire V, Bonnefont JP, Rustin P, et al: Mitochondrial DNA rearrangements with onset as chronic diarrhea with villous atrophy. J Pediatr 124:63-70, 1994

Vu TH, Tanji K, Holve SA, et al: Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome? Hepatology 34:116-20, 2001

Parra D, Gonzalez A, Mugueta C, et al: Laboratory approach to mitochondrial diseases. J Physiol Biochem 57:267-84, 2001

Ferrari G, Lamantea E, Donati A, Filosto M, Briem E, Carrara F, Parini R, Simonati A, Santer R, Zeviani M. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain. 2005;128:723-31

Naviaux RK, Nguyen KV. POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann Neurol. 2004;55:706-12

Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006;45:108-16.

Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chretien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, Nakamura Y, Munnich A, Rotig A. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 2007 May 7; [Epub ahead of print]

Sarzi E, Bourdon A, Chretien D, Zarhrate M, Corcos J, Slama A, Cormier-Daire V, de Lonlay P, Munnich A, Rotig A. Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. J Pediatr. 2007;150:531-4, 534.e1-6

Karadimas CL, Vu TH, Holve SA, Chronopoulou P, Quinzii C, Johnsen SD, Kurth J, Eggers E, Palenzuela L, Tanji K, Bonilla E, De Vivo DC, DiMauro S, Hirano M. Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Am J Hum Genet. 2006 ;79:544-8.

Fatty Acid Oxidation Defects

Bennett M, Rinaldo P, Strauss A. (2000). Inborn errors of mitochondrial fatty acid oxidation. Crit Rev Clin Lab Sci 37: 1-44.

Demaugre F, Bonnefont J-P, Mitchell G, Nguyen-Hoang N, Pelet A, Rimoldi M, DiDonato S, Saudubray J-M. (1988). Hepatic and muscular presentations of carnitine palmitoyl transferase deficiency: two distinct entities. Pediatr Res 24: 308-11.

He M, Rutledge S, Kelly D, Palmer C, Murdoch G, Majumder N, Nicholls R, Pei Z, Watkins PA, Vockley J. (2007). A new genetic disorder in mitochondrial fatty acid beta-oxidation, ACAD9 deficiency. Am J Hum Genet. 81: 87-103

Hug G, Bove KE, Soukup S. (1991). Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. N Engl J Med 325: 1862-4.

Mathur A, Sims HF, Gopalakrishnan D, Gibson B, Rinaldo P, Vockley J, Hug G, Strauss AW. (1999). Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation 99: 1337-43.

Roe CR, Ding J. Mitochondrial fatty acid oxidation disorders. in The Metabolic and Molecular Basis of Inherited Disease Scriver C, Beaudet AL, Sly W, Valle D, Eds. (McGraw-Hill, New York, 2001), pp. 2297-326.

Saudubray JM, Martin D, de Lonlay P, Touati G, Poggi-Travert F, Bonnet D, Jouvet P, Boutron M, Slama A, Vianey-Saban C, Bonnefont JP, Rabier D, Kamoun P, Brivet M. (1999). Recognition and management of fatty acid oxidation defects: A series of 107 patients. Journal of Inherited Metabolic Disease 22: 488-502.

Vockley J, Singh RH, Whiteman DA. (2002). Diagnosis and management of defects of mitochondrial beta-oxidation. Curr Opin Clin Nutr Metab Care 5: 601-9.

Vockley J, Whiteman DA. (2002). Defects of mitochondrial beta-oxidation: a growing group of disorders. Neuromuscul Disord 12: 235-46.

Wanders RJA, Vreken P, Den Boer MEJ, Wijburg FA, Van Gennip AH, IJlst L. (1999). Disorders of mitochondrial fatty acyl-CoA ??oxidation. J Inher Metab Dis 22 : 442-87.

Updated: 11 June 2007

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