DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
EDITORIAL REVIEW
Impact of fatty acid oxidation disorders in child neurology: from Reye syndrome to Pandora’s box The study of inborn errors of metabolism has provided us with a unique perspective into the basic pathophysiological processes of disorders of human metabolism and the arising clinical, biochemical, and pathological phenotypes. They have also afforded us with the opportunity of developing pathophysiologically-based interventions to overcome the specific metabolic block, to provide the missing critical substrate, to reduce the toxicity of accumulated metabolites, and/or to utilize alternative pathways. Defects of bioenergetic metabolism most often present in infancy and early childhood as the metabolic demands of the developing brain are much higher than the young adult brain, which underlies its exquisite vulnerability to hypoxia, hypoglycemia, and hypoketonemia. The study of fatty acid oxidation (FAO) disorders has had an important historical impact in child neurology. These disorders are often clinically and biochemically silent during times of energy homeostasis but become manifest under specific stressors such as prolonged fasting, fever with infection, mild to moderate prolonged exercise, and cold exposure with shivering thermogenesis during which time FAO is stimulated. There are several physiologically-based reasons for an increased risk of problems with fasting adaptation in infants and young children.1,2 Notably, infants have a larger brain compared to body size, which is highly dependent upon glucose metabolism, and thus show an earlier activation of FAO with fasting.3 Secondly, infants have a larger ratio of surface area to body mass and thus have higher basal energy needs to maintain body temperature which depends upon shivering thermogenesis, which is highly dependent upon FAO. Thirdly, infants have lower activities of several key enzymes in energy production compared with the older child, leading to further impairment of the infant’s ability to maintain glucose homeostasis.4 In the prophetic words of Canadian physician Sir William Osler (1849–1919): ‘The value of experience is not in seeing much but in seeing wisely.’ Reye syndrome, which shares hallmark clinical, biochemical, and pathological features with FAO disorders, is named after R Douglas Reye who along with fellow physicians Graeme Morgan and Jim Baral in Australia published the first study of the syndrome. In 1963 in The Lancet5 they described encephalopathy with neuronal swelling, hypoglycemia, and an enlarged fatty liver with minimal inflammation, largely affecting children and rarely adults, though scattered reports of similar illnesses had appeared in the medical literature since 1929.6 In 1963, Johnson et al.7 described an outbreak of influenza B in a series of children in the US who developed neurological problems, several of whom had a clinical profile similar to Reye syndrome. In 1979, 304
Starko et al.8 conducted a case–control study during an outbreak of influenza A in Phoenix, Arizona and found a statistically significant link between aspirin use and the occurence of Reye syndrome. The attack rate for Reye syndrome approximated 30 to 60 cases per 100 000 influenza B infections, 2.5 to 4.3 cases per 100 000 influenza A infections, and 0.3 to 0.4 cases per 100 000 varicella infections.9 In 1980, after the Centers for Disease Control cautioned physicians and parents about the association between Reye syndrome and the use of salicylates in children under 18 years with viral illnesses or varicella, the incidence of this syndrome in the US began to decline significantly. Subsequently, it was noted that certain intoxications (e.g. hypoglycins in Jamaican vomiting sickness) and inborn errors of metabolism could mimic Reye syndrome and De Vivo proposed that the primary metabolic disturbance related to an acute mitochondrial injury in all tissues.10 Trauner et al.11 shed light on the pathophysiology through an experimental model involving exposure of mice to influenza B virus and to salicylates, both of which were shown to cause a significant inhibition of long-chain (palmitate) FAO and had an additive effect, even in low doses, when given in combination. Subsequently, a hypothesis was put forth suggesting that the combination of these two risk factors could have an additive effect on the metabolic derangement leading to Reye syndrome. It is possible that previously asymptomatic children heterozygous for inborn errors of FAO, the urea cycle, or mitochondrial metabolism would be at increased risk for a single episode of Reye syndrome in the presence of specific additional synergistic risk factors such as influenza B virus and salicylate exposure. Recurrent Reye-like syndrome with hypoglycemia, hypoketonemia, hepatic encephalopathy, and microvesicular steatosis of liver and other tissues became the pathological signature of FAO disorders. Toxins also known to be associated with a Reye-like syndrome included the commonly used anticonvulsant, valproic acid (VPA), which is a medium-chain fatty acid that acts much like a ‘Trojan horse’ in its inhibition of FAO.12–14 The incidence of the idiosyncratic fatal Reyelike hepatotoxicity with VPA was 1 in 500 for infants less than 2 years of age with a chronic neurological disorder who were receiving multiple anticonvulsants versus 1 in 37 000 for adults on VPA monotherapy.15 It was speculated that this fatal hepatotoxicity was the result of multiple synergistic factors related to the young age, low tissue carnitine reserves, an underlying metabolic disorder, and the metabolic toxicity of VPA.12,16 This careful observation led to a change in practice whereby physicians were cautioned about the use of VPA in children under 2 years of © 2015 Mac Keith Press
age. Furthermore, it was advised that all children on VPA who have laboratory or clinical evidence of serum or tissue carnitine deficiency be supplemented with L-carnitine.12 The first description of a genetic FAO defect was published in 1970 by Engel et al.17 and the first enzyme defect, identified in 1973 by DiMauro and DiMauro,18 carnitine palmitoyltransferase II (CPT II) deficiency which is the most common cause of recurrent myoglobinuria in children. Recognition of FAO disorders became important for the child neurologist as they could present with a spectrum of clinical disorders including progressive lipid storage limb girdle myopathy, exercise intolerance, recurrent myoglobinuria, neuropathy, progressive cardiomyopathy, recurrent hypoglycemic hypoketotic encephalopathy or Reye-like syndrome, seizures, neuronal migration abnormalities, and potential cognitive delays. Notably, fats are the most important efficient fuel for oxidative metabolism, are the largest reserve of fuel in the body, and become the predominant substrate for oxidation quite early in fasting.19 Highly energy-dependent tissues such as skeletal muscle, heart, and kidney are thus highly dependent upon FAO. The partial oxidation of fatty acids to ketones by the liver is the critical alternate fuel for almost all tissues and particularly the brain during times of hypoglycemia.20 Also, the high rates of hepatic gluconeogenesis and ureagenesis needed for maintaining fasting homeostasis are sustained by the production of energy (ATP), reducing equivalents and metabolic intermediates derived from FAO.3 FAO disorders constitute a critical group of diseases for the child neurologist as they are potentially rapidly fatal and a source of major neurological morbidity and mortality. There is frequently a family history of sudden infant death syndrome (SIDS) in siblings. All known conditions are autosomal recessive in inheritance. There are currently at least 25 enzymes and specific transport proteins in the pathway of b-oxidation and 18 have been associated with human disease. Medium-chain acyl-CoA dehydrogenase deficiency is the most common defect and was found to have an incidence of 1 in 8930 live births in one series.21 The institution of newborn screening programs for the identification of serum acylcarnitines by electrospray ionization-tandem mass spectrometry of dried blood spots on filter paper has significantly enhanced the early recognition of these disorders which may have an important impact on their prognosis.22 Novel phenotypes which should also elicit a search for an underlying FAO defect in a child include a family history of SIDS, particularly in the case of microvesicular steatosis of organs on necropsy. Another novel phenotype is the homozygous or compound heterozygous child of a mother who suffers from acute fatty liver of pregnancy. We now know that not only children with long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiencies23,24 but those with carnitine palmitoyltransferase 1A25 or short-chain acyl-CoA dehydrogenase (SCAD) deficiency26 may have mothers with this life-threatening presentation which
should prompt early delivery and investigation of the child for a potential FAO disorder. Overall, early recognition and prompt institution of therapy and appropriate preventative measures and in certain cases, specific therapy, may be life-saving and may significantly decrease long-term morbidity, particularly with respect to central nervous system sequelae. Treatments include avoidance of precipitating factors such as mild to moderate prolonged exercise, fasting, and cold exposure as well as the prompt treatment of infections with fever control.20 Early institution of intravenous glucose during vomiting is essential. Dietary manipulation generally involves increasing the ratio of carbohydrates to fats with frequent meals and supplementation with essential fatty acids.20 Specific therapies may include the use of docosahexaenoic acid for the retinopathy and neuropathy of LCHAD deficiency and riboflavin for the acyl-CoA dehydrogenase deficiencies.20 Currently, studies are underway to evaluate the efficacy of peroxisome proliferator-activated receptor (PPAR) agonists such as bezafibrate to increase mitochondrial FAO and the activities of CPT II and very long-chain acyl-CoA dehydrogenase in cases of milder mutations.27,28 In the flavin adenine dinucleotide-linked acyl-CoA dehydrogenases and NAD-linked LCHAD, there is a possibility of free radical generation which may benefit from the use of antioxidants. Furthermore, there is evidence that hyperthermia and protein misfolding may reduce the activity of mutant SCAD enzymes and lead to oxidative stress which respond in vitro in fibroblasts to temperature reduction, antioxidants, and PPAR agonists.29–31 Today as we open the Pandora’s box of whole genome sequencing and stand at the threshold of a virtual tsunami of genetic information with disease-causing mutations, disease-susceptibility polymorphisms, variants of unknown significance, and epigenetic factors, we need, more than ever, the astute clinician who is able to recognize the relevant clinical phenotype, hand in hand with the biochemist, who is able to study the activity and expression of the mutant protein and to evaluate its impact on cellular metabolism. As no one centre is likely to have sufficient numbers of cases of a specific metabolic disorder, the development of international multicentre prospective, randomized, double-blind control studies will be essential for the objective evaluation of the efficacy of new therapies. Through the International Child Neurology Association (ICNA) and our ICNApedia website (www.ICNApedia.org), we hope to provide research portals that will facilitate such collaborations by combining the expertise of clinicians phenotyping populations with high prevalence of a given disorder, with the expertise of investigators in tertiary laboratories who can provide in vitro biochemical investigations of the effects of the identified mutations on protein expression and activity combined with molecular genetic analysis; as well as the development of in vitro and in vivo disease models to study disease pathogenesis, for the development and evaluation of targeted interventional therapies, which can then be translated Editorial Review
305
back to the affected clinical populations. Such collaborations should benefit the affected children, their families, the treating clinicians, and the investigators in furthering knowledge of the disease etiopathogenesis and its effective treatment and prevention as well as expanding our knowledge of basic neurometabolism to optimize the developing brain.
INGRID TEIN Division of Neurology, Department of Pediatrics, Laboratory Medicine and Pathobiology, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario, Canada. doi: 10.1111/dmcn.12717
REFERENCES 1. Bier DM, Leake RD, Haymond MW, et al. Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977; 26: 1016–23. 2. Aynsley-Green A. Hypoglycemia in infants and children. Clin Endocrinol Metab 1982; 11: 159–94.
acid-associated carnitine deficiency. Pediatr Res 1993; 34: 281–7. 13. Kesterson JW, Granneman GR, Machinist JM. The
23. Isaacs JD Jr, Sims HF, Powell CK, et al. Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel
hepatotoxicity of valproic acid and its metabolites in
maternal mutant allele. Pediatr Res 1996; 40: 393–8.
rats. I. Toxicologic, biochemical and histopathologic
24. Sims HF, Brackett JC, Powell CK, et al. The molecular
studies. Hepatology 1984; 4: 1143–52.
basis of pediatric long chain 3-hydroxyacyl-CoA dehydro-
3. Hale DE, Bennett MJ. Fatty acid oxidation disorders: a
14. Turnbull DM, Bone AJ, Bartlett K, Koundakjian PP,
new class of metabolic diseases. J Pediatr 1992; 121: 1–
Sherratt HS. The effects of valproate on intermediary
of pregnancy. Proc Natl Acad Sci USA 1995; 92: 841–5.
11.
metabolism in isolated rat hepatocytes and intact rats.
25. Bennett MJ, Santani AB. Carnitine palmitoyltransferase 1A
4. Pagliara AS, Karl IE, Haymond M, et al. Hypoglycemia in infancy and childhood. I. J Pediatr 1973; 82: 365–79. 5. Reye RD, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera. A disease entity in childhood. Lancet 1963; 2: 749–52. 6. Brain WR, Hunter D, Turnbull HD. Acute meningoencephalitis of childhood: report of 6 cases. Lancet 1929; 9: 221–7. 7. Johnson GM, Scurletis TD, Carroll NB. A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. N C Med J 1963; 24: 464–73. 8. Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF. Reye’s syndrome and salicylate use. Pediatrics 1980; 66: 859–64. 9. De Vivo DC. Do animals develop Reye syndrome? Lab Invest 1984; 51: 367–72. 10. De Vivo DC. Reye syndrome: a metabolic response to an acute mitochondrial insult? Neurology 1978; 28: 105–
Biochem Pharmacol 1983; 32: 1887–92.
genase deficiency associated with maternal acute fatty liver
deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al.,
15. Dreifuss FE, Santilli N, Langer DH, Sweeney KP,
editors. GeneReviews. Seattle (WA): University of Wash-
Moline KA, Menander KB. Valproic acid hepatic fatali-
ington, Seattle; 1993–2014. 2005. http://www.ncbi.nlm.-
ties: a retrospective review. Neurology 1987; 37: 379–85. 16. Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol 1991; 6: 7–14. 17. Engel WK, Vick NA, Glueck CJ, et al. A skeletal-mus-
nih.gov/books/NBK1527/ (updated 2013 Mar 07). 26. Matern D, Hart P, Murtha AP, et al. Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 2001; 138: 585–8.
cle disorder associated with intermittent symptoms and a
27. Bonnefont JP, Bastin J, Lafor^et P, et al. Long-term fol-
possible defect of lipid metabolism. N Engl J Med 1970;
low-up of bezafibrate treatment in patients with the
282: 697–704.
myopathic form of carnitine palmitoyltransferase 2 defi-
18. DiMauro S, DiMauro PM. Muscle carnitine palmitoyltransferase deficiency and myoglobinuria. Science 1973; 182: 929–31. 19. Stanley CA. New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency. Adv Pediatr 1987; 34: 59–88. 20. Tein I. Disorders of fatty acid oxidation. Handb Clin Neurol 2013; 113: 1675–88.
ciency. Clin Pharmacol Ther 2010; 88: 101–8. 28. Djouadi F, Aubey F, Schlemmer D, et al. Potential of fibrates in the treatment of fatty acid oxidation disorders: revival of classical drugs? J Inherit Metab Dis 2006; 29: 341–2. 29. Pedersen CB, Zolkipli Z, Vang S, et al. Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria. J Inherit Metab Dis 2010; 33: 211–22.
21. Ziadeh R, Hoffman EP, Finegold DN, et al. Medium
30. Zolkipli Z, Pedersen CB, Lamhonwah AM, et al. Vulnera-
11. Trauner DA, Horvath E, Davis LE. Inhibition of fatty
chain acyl-CoA dehydrogenase deficiency in Pennsylva-
bility to oxidative stress in vitro in pathophysiology of mito-
acid beta oxidation by influenza B virus and salicylic acid
nia: neonatal screening shows high incidence and
chondrial short-chain acyl-CoA dehydrogenase deficiency:
in mice: implications for Reye’s syndrome. Neurology
unexpected mutation frequencies. Pediatr Res 1995; 37:
1988; 38: 239–41.
675–8.
8.
response to antioxidants. PLoS ONE 2011; 6: e17534. 31. Schmidt SP, Corydon TJ, Pedersen CB, Bross P, Gre-
12. Tein I, DiMauro S, Xie ZW, De Vivo DC. Valproic
22. Wilcken B. Fatty acid oxidation disorders: outcome
gersen N. Misfolding of short-chain acyl-CoA dehydro-
acid impairs carnitine uptake in cultured human skin fi-
and long-term prognosis. J Inherit Metab Dis 2010; 33:
genase leads to mitochondrial fission and oxidative
broblasts. An in vitro model for pathogenesis of valproic
501–6.
stress. Mol Genet Metab 2010; 100: 155–62.
306 Developmental Medicine & Child Neurology 2015, 57: 304–306
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EDITORIAL REVIEW
Impact of fatty acid oxidation disorders in child neurology: from Reye syndrome to Pandora’s box The study of inborn errors of metabolism has provided us with a unique perspective into the basic pathophysiological processes of disorders of human metabolism and the arising clinical, biochemical, and pathological phenotypes. They have also afforded us with the opportunity of developing pathophysiologically-based interventions to overcome the specific metabolic block, to provide the missing critical substrate, to reduce the toxicity of accumulated metabolites, and/or to utilize alternative pathways. Defects of bioenergetic metabolism most often present in infancy and early childhood as the metabolic demands of the developing brain are much higher than the young adult brain, which underlies its exquisite vulnerability to hypoxia, hypoglycemia, and hypoketonemia. The study of fatty acid oxidation (FAO) disorders has had an important historical impact in child neurology. These disorders are often clinically and biochemically silent during times of energy homeostasis but become manifest under specific stressors such as prolonged fasting, fever with infection, mild to moderate prolonged exercise, and cold exposure with shivering thermogenesis during which time FAO is stimulated. There are several physiologically-based reasons for an increased risk of problems with fasting adaptation in infants and young children.1,2 Notably, infants have a larger brain compared to body size, which is highly dependent upon glucose metabolism, and thus show an earlier activation of FAO with fasting.3 Secondly, infants have a larger ratio of surface area to body mass and thus have higher basal energy needs to maintain body temperature which depends upon shivering thermogenesis, which is highly dependent upon FAO. Thirdly, infants have lower activities of several key enzymes in energy production compared with the older child, leading to further impairment of the infant’s ability to maintain glucose homeostasis.4 In the prophetic words of Canadian physician Sir William Osler (1849–1919): ‘The value of experience is not in seeing much but in seeing wisely.’ Reye syndrome, which shares hallmark clinical, biochemical, and pathological features with FAO disorders, is named after R Douglas Reye who along with fellow physicians Graeme Morgan and Jim Baral in Australia published the first study of the syndrome. In 1963 in The Lancet5 they described encephalopathy with neuronal swelling, hypoglycemia, and an enlarged fatty liver with minimal inflammation, largely affecting children and rarely adults, though scattered reports of similar illnesses had appeared in the medical literature since 1929.6 In 1963, Johnson et al.7 described an outbreak of influenza B in a series of children in the US who developed neurological problems, several of whom had a clinical profile similar to Reye syndrome. In 1979, 304
Starko et al.8 conducted a case–control study during an outbreak of influenza A in Phoenix, Arizona and found a statistically significant link between aspirin use and the occurence of Reye syndrome. The attack rate for Reye syndrome approximated 30 to 60 cases per 100 000 influenza B infections, 2.5 to 4.3 cases per 100 000 influenza A infections, and 0.3 to 0.4 cases per 100 000 varicella infections.9 In 1980, after the Centers for Disease Control cautioned physicians and parents about the association between Reye syndrome and the use of salicylates in children under 18 years with viral illnesses or varicella, the incidence of this syndrome in the US began to decline significantly. Subsequently, it was noted that certain intoxications (e.g. hypoglycins in Jamaican vomiting sickness) and inborn errors of metabolism could mimic Reye syndrome and De Vivo proposed that the primary metabolic disturbance related to an acute mitochondrial injury in all tissues.10 Trauner et al.11 shed light on the pathophysiology through an experimental model involving exposure of mice to influenza B virus and to salicylates, both of which were shown to cause a significant inhibition of long-chain (palmitate) FAO and had an additive effect, even in low doses, when given in combination. Subsequently, a hypothesis was put forth suggesting that the combination of these two risk factors could have an additive effect on the metabolic derangement leading to Reye syndrome. It is possible that previously asymptomatic children heterozygous for inborn errors of FAO, the urea cycle, or mitochondrial metabolism would be at increased risk for a single episode of Reye syndrome in the presence of specific additional synergistic risk factors such as influenza B virus and salicylate exposure. Recurrent Reye-like syndrome with hypoglycemia, hypoketonemia, hepatic encephalopathy, and microvesicular steatosis of liver and other tissues became the pathological signature of FAO disorders. Toxins also known to be associated with a Reye-like syndrome included the commonly used anticonvulsant, valproic acid (VPA), which is a medium-chain fatty acid that acts much like a ‘Trojan horse’ in its inhibition of FAO.12–14 The incidence of the idiosyncratic fatal Reyelike hepatotoxicity with VPA was 1 in 500 for infants less than 2 years of age with a chronic neurological disorder who were receiving multiple anticonvulsants versus 1 in 37 000 for adults on VPA monotherapy.15 It was speculated that this fatal hepatotoxicity was the result of multiple synergistic factors related to the young age, low tissue carnitine reserves, an underlying metabolic disorder, and the metabolic toxicity of VPA.12,16 This careful observation led to a change in practice whereby physicians were cautioned about the use of VPA in children under 2 years of © 2015 Mac Keith Press
age. Furthermore, it was advised that all children on VPA who have laboratory or clinical evidence of serum or tissue carnitine deficiency be supplemented with L-carnitine.12 The first description of a genetic FAO defect was published in 1970 by Engel et al.17 and the first enzyme defect, identified in 1973 by DiMauro and DiMauro,18 carnitine palmitoyltransferase II (CPT II) deficiency which is the most common cause of recurrent myoglobinuria in children. Recognition of FAO disorders became important for the child neurologist as they could present with a spectrum of clinical disorders including progressive lipid storage limb girdle myopathy, exercise intolerance, recurrent myoglobinuria, neuropathy, progressive cardiomyopathy, recurrent hypoglycemic hypoketotic encephalopathy or Reye-like syndrome, seizures, neuronal migration abnormalities, and potential cognitive delays. Notably, fats are the most important efficient fuel for oxidative metabolism, are the largest reserve of fuel in the body, and become the predominant substrate for oxidation quite early in fasting.19 Highly energy-dependent tissues such as skeletal muscle, heart, and kidney are thus highly dependent upon FAO. The partial oxidation of fatty acids to ketones by the liver is the critical alternate fuel for almost all tissues and particularly the brain during times of hypoglycemia.20 Also, the high rates of hepatic gluconeogenesis and ureagenesis needed for maintaining fasting homeostasis are sustained by the production of energy (ATP), reducing equivalents and metabolic intermediates derived from FAO.3 FAO disorders constitute a critical group of diseases for the child neurologist as they are potentially rapidly fatal and a source of major neurological morbidity and mortality. There is frequently a family history of sudden infant death syndrome (SIDS) in siblings. All known conditions are autosomal recessive in inheritance. There are currently at least 25 enzymes and specific transport proteins in the pathway of b-oxidation and 18 have been associated with human disease. Medium-chain acyl-CoA dehydrogenase deficiency is the most common defect and was found to have an incidence of 1 in 8930 live births in one series.21 The institution of newborn screening programs for the identification of serum acylcarnitines by electrospray ionization-tandem mass spectrometry of dried blood spots on filter paper has significantly enhanced the early recognition of these disorders which may have an important impact on their prognosis.22 Novel phenotypes which should also elicit a search for an underlying FAO defect in a child include a family history of SIDS, particularly in the case of microvesicular steatosis of organs on necropsy. Another novel phenotype is the homozygous or compound heterozygous child of a mother who suffers from acute fatty liver of pregnancy. We now know that not only children with long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiencies23,24 but those with carnitine palmitoyltransferase 1A25 or short-chain acyl-CoA dehydrogenase (SCAD) deficiency26 may have mothers with this life-threatening presentation which
should prompt early delivery and investigation of the child for a potential FAO disorder. Overall, early recognition and prompt institution of therapy and appropriate preventative measures and in certain cases, specific therapy, may be life-saving and may significantly decrease long-term morbidity, particularly with respect to central nervous system sequelae. Treatments include avoidance of precipitating factors such as mild to moderate prolonged exercise, fasting, and cold exposure as well as the prompt treatment of infections with fever control.20 Early institution of intravenous glucose during vomiting is essential. Dietary manipulation generally involves increasing the ratio of carbohydrates to fats with frequent meals and supplementation with essential fatty acids.20 Specific therapies may include the use of docosahexaenoic acid for the retinopathy and neuropathy of LCHAD deficiency and riboflavin for the acyl-CoA dehydrogenase deficiencies.20 Currently, studies are underway to evaluate the efficacy of peroxisome proliferator-activated receptor (PPAR) agonists such as bezafibrate to increase mitochondrial FAO and the activities of CPT II and very long-chain acyl-CoA dehydrogenase in cases of milder mutations.27,28 In the flavin adenine dinucleotide-linked acyl-CoA dehydrogenases and NAD-linked LCHAD, there is a possibility of free radical generation which may benefit from the use of antioxidants. Furthermore, there is evidence that hyperthermia and protein misfolding may reduce the activity of mutant SCAD enzymes and lead to oxidative stress which respond in vitro in fibroblasts to temperature reduction, antioxidants, and PPAR agonists.29–31 Today as we open the Pandora’s box of whole genome sequencing and stand at the threshold of a virtual tsunami of genetic information with disease-causing mutations, disease-susceptibility polymorphisms, variants of unknown significance, and epigenetic factors, we need, more than ever, the astute clinician who is able to recognize the relevant clinical phenotype, hand in hand with the biochemist, who is able to study the activity and expression of the mutant protein and to evaluate its impact on cellular metabolism. As no one centre is likely to have sufficient numbers of cases of a specific metabolic disorder, the development of international multicentre prospective, randomized, double-blind control studies will be essential for the objective evaluation of the efficacy of new therapies. Through the International Child Neurology Association (ICNA) and our ICNApedia website (www.ICNApedia.org), we hope to provide research portals that will facilitate such collaborations by combining the expertise of clinicians phenotyping populations with high prevalence of a given disorder, with the expertise of investigators in tertiary laboratories who can provide in vitro biochemical investigations of the effects of the identified mutations on protein expression and activity combined with molecular genetic analysis; as well as the development of in vitro and in vivo disease models to study disease pathogenesis, for the development and evaluation of targeted interventional therapies, which can then be translated Editorial Review
305
back to the affected clinical populations. Such collaborations should benefit the affected children, their families, the treating clinicians, and the investigators in furthering knowledge of the disease etiopathogenesis and its effective treatment and prevention as well as expanding our knowledge of basic neurometabolism to optimize the developing brain.
INGRID TEIN Division of Neurology, Department of Pediatrics, Laboratory Medicine and Pathobiology, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario, Canada. doi: 10.1111/dmcn.12717
REFERENCES 1. Bier DM, Leake RD, Haymond MW, et al. Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977; 26: 1016–23. 2. Aynsley-Green A. Hypoglycemia in infants and children. Clin Endocrinol Metab 1982; 11: 159–94.
acid-associated carnitine deficiency. Pediatr Res 1993; 34: 281–7. 13. Kesterson JW, Granneman GR, Machinist JM. The
23. Isaacs JD Jr, Sims HF, Powell CK, et al. Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel
hepatotoxicity of valproic acid and its metabolites in
maternal mutant allele. Pediatr Res 1996; 40: 393–8.
rats. I. Toxicologic, biochemical and histopathologic
24. Sims HF, Brackett JC, Powell CK, et al. The molecular
studies. Hepatology 1984; 4: 1143–52.
basis of pediatric long chain 3-hydroxyacyl-CoA dehydro-
3. Hale DE, Bennett MJ. Fatty acid oxidation disorders: a
14. Turnbull DM, Bone AJ, Bartlett K, Koundakjian PP,
new class of metabolic diseases. J Pediatr 1992; 121: 1–
Sherratt HS. The effects of valproate on intermediary
of pregnancy. Proc Natl Acad Sci USA 1995; 92: 841–5.
11.
metabolism in isolated rat hepatocytes and intact rats.
25. Bennett MJ, Santani AB. Carnitine palmitoyltransferase 1A
4. Pagliara AS, Karl IE, Haymond M, et al. Hypoglycemia in infancy and childhood. I. J Pediatr 1973; 82: 365–79. 5. Reye RD, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera. A disease entity in childhood. Lancet 1963; 2: 749–52. 6. Brain WR, Hunter D, Turnbull HD. Acute meningoencephalitis of childhood: report of 6 cases. Lancet 1929; 9: 221–7. 7. Johnson GM, Scurletis TD, Carroll NB. A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. N C Med J 1963; 24: 464–73. 8. Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF. Reye’s syndrome and salicylate use. Pediatrics 1980; 66: 859–64. 9. De Vivo DC. Do animals develop Reye syndrome? Lab Invest 1984; 51: 367–72. 10. De Vivo DC. Reye syndrome: a metabolic response to an acute mitochondrial insult? Neurology 1978; 28: 105–
Biochem Pharmacol 1983; 32: 1887–92.
genase deficiency associated with maternal acute fatty liver
deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al.,
15. Dreifuss FE, Santilli N, Langer DH, Sweeney KP,
editors. GeneReviews. Seattle (WA): University of Wash-
Moline KA, Menander KB. Valproic acid hepatic fatali-
ington, Seattle; 1993–2014. 2005. http://www.ncbi.nlm.-
ties: a retrospective review. Neurology 1987; 37: 379–85. 16. Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol 1991; 6: 7–14. 17. Engel WK, Vick NA, Glueck CJ, et al. A skeletal-mus-
nih.gov/books/NBK1527/ (updated 2013 Mar 07). 26. Matern D, Hart P, Murtha AP, et al. Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 2001; 138: 585–8.
cle disorder associated with intermittent symptoms and a
27. Bonnefont JP, Bastin J, Lafor^et P, et al. Long-term fol-
possible defect of lipid metabolism. N Engl J Med 1970;
low-up of bezafibrate treatment in patients with the
282: 697–704.
myopathic form of carnitine palmitoyltransferase 2 defi-
18. DiMauro S, DiMauro PM. Muscle carnitine palmitoyltransferase deficiency and myoglobinuria. Science 1973; 182: 929–31. 19. Stanley CA. New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency. Adv Pediatr 1987; 34: 59–88. 20. Tein I. Disorders of fatty acid oxidation. Handb Clin Neurol 2013; 113: 1675–88.
ciency. Clin Pharmacol Ther 2010; 88: 101–8. 28. Djouadi F, Aubey F, Schlemmer D, et al. Potential of fibrates in the treatment of fatty acid oxidation disorders: revival of classical drugs? J Inherit Metab Dis 2006; 29: 341–2. 29. Pedersen CB, Zolkipli Z, Vang S, et al. Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria. J Inherit Metab Dis 2010; 33: 211–22.
21. Ziadeh R, Hoffman EP, Finegold DN, et al. Medium
30. Zolkipli Z, Pedersen CB, Lamhonwah AM, et al. Vulnera-
11. Trauner DA, Horvath E, Davis LE. Inhibition of fatty
chain acyl-CoA dehydrogenase deficiency in Pennsylva-
bility to oxidative stress in vitro in pathophysiology of mito-
acid beta oxidation by influenza B virus and salicylic acid
nia: neonatal screening shows high incidence and
chondrial short-chain acyl-CoA dehydrogenase deficiency:
in mice: implications for Reye’s syndrome. Neurology
unexpected mutation frequencies. Pediatr Res 1995; 37:
1988; 38: 239–41.
675–8.
8.
response to antioxidants. PLoS ONE 2011; 6: e17534. 31. Schmidt SP, Corydon TJ, Pedersen CB, Bross P, Gre-
12. Tein I, DiMauro S, Xie ZW, De Vivo DC. Valproic
22. Wilcken B. Fatty acid oxidation disorders: outcome
gersen N. Misfolding of short-chain acyl-CoA dehydro-
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