Ind J Clin Biochem DOI 10.1007/s12291-013-0391-3
CASE REPORT
Fatty Acid Oxidation Disorder with Secondary Mitochondrial Energy Production Defect: A Case Report Seema Pavaman Sindgikar • Deepthi Raran Veetil Rathika D. Shenoy • Vijaya Shenoy
•
Received: 26 July 2013 / Accepted: 20 September 2013 Ó Association of Clinical Biochemists of India 2013
Abstract The presentation of long-chain fatty acid oxidation disorders (FAOD), unlike short and medium-chain disorders can be with secondary defects in mitochondrial function along with typical features of FAOD. We report an infant with Reye-like presentation and acylcarnitine profile suggestive of very-long-chain acyl-CoA dehydrogenase deficiency who had lactic acidosis and urine gas chromatographic pattern of mitochondrial defects. Keywords Lactic acidosis Reye-like Urine organic acids Very-long-chain acyl-CoA dehydrogenase deficiency
Introduction Fatty acid oxidation (FAO) is a pivotal pathway for energy homeostasis specifically in liver, heart and skeletal muscles during catabolic stress. Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a key enzyme involved in the early steps of long-chain FAO spiral in mitochondria. VLCAD deficiency (VLCADD) has heterogeneous clinical phenotypes with varying severity and the most common infantile onset hepatic form presents with hypoketotic hypoglycemia and hepatomegaly resembling Reye-syndrome [1]. The distinguishing feature of FAO disorders (FAOD) is absence of ketosis and lactic acidosis with specific blood acylcarnitine pattern and dicarboxylic aciduria. We discuss an infant with Reye-like presentation with lactic acidosis and
S. P. Sindgikar (&) D. R. Veetil R. D. Shenoy V. Shenoy Department of Pediatrics, K. S. Hegde Medical Academy, NITTE University, Derlakatte, Mangalore 575018, Karnataka, India e-mail: [email protected]
characteristic acylcarnitine profile of VLCADD and urine chromatography suggestive of defects in mitochondrial energy production and discuss the pathophysiology of the same.
Case Report A six-month old female was referred with fever and vomiting since 3 days and recurrent generalized tonic clonic convulsions since 1 day. She was second born to non-consanguineous couple at term with normal perinatal and developmental history. Two weeks prior she was hospitalized elsewhere for acute lower respiratory infection following which she was not able to hold her head steady or roll over. Family history was negative for developmental delay, cardiac illness or infant deaths. On examination her weight and head circumference were at third and length at 50th centiles. Her vitals were stable. Glasgow coma scale was 12/15 and fontanelle normal. Generalized hypotonia and hyporeflexia was present with firm hepatomegaly of span eight cm. Cardia was normal. Investigations showed low blood glucose (1.554 mmol/L), negative urine sugars and ketones, liver dysfunction with elevated transaminases (ALT 91U/L, AST 157U/L) and prolonged prothrombin time (INR-1.28). Sepsis screen was positive with smear showing neutrophilic leukocytosis with toxic granules and positive C-reactive protein. Electrolytes, anion gap and renal parameters were normal. CSF analysis was suggestive of partially treated meningitis with lymphocytic pleocytosis (135cells, L85 %), normal glucose (1.332 mmol/L) ratio and protein (290 mg/L). Blood and CSF cultures were sterile and neuroimaging normal. Further evaluation showed blood ammonia of 227.8 lmol/L (ref: 28–94) suggesting moderate hyperammonemia and mildly
123
Ind J Clin Biochem Table 1 Spectrometry analysis of blood for acyl carnitine and urine for organic acids
Discussion
Analyte
Reye-like presentation in children is seen with several metabolic disorders, central nervous system infections, toxins and drug ingestion. Though presentation suggested partially treated meningitis, a metabolic etiology specifically FAOD precipitated by crisis was considered in view of non-ketotic hypoglycemia, hepatomegaly and developmental regression. Defective synthesis of ketone bodies with increased utilization of glucose and impaired gluconeogenesis due to lack of acetyl CoA results in non/hypoketotic hypoglycemia in these disorders. Profound encephalopathy with moderate to severe lactic acidosis with abnormal neuro-imaging characterizes mitochondrial dysfunction. Moderate to severe lactic acidosis is reported in long-chain FAOD in contrast to medium-chain in the absence of anoxia or poor perfusion. Intra mitochondrial accumulation of long-chain acyl-CoA esters and reduced cofactors inhibits oxidative phosphorylation which constitutes the functional final common pathway of ATP production and pyruvate oxidation resulting in lactic acidosis [2]. The FAO spiral also requires ATP and reoxidised cofactors for its continued activation [2–4]. Thus the two pathways are mutually dependent on each other and hence the diagnosis of these disorders based on clinical presentation and investigations may be difficult in resource limited setting as in our case [5]. A specific acyl-carnitine profile in the blood is more definitive for the diagnosis of VLCADD [6, 7]. Urine organic acid pattern may be uninformative in VLCADD [8]. Urine gas chromatography in our case showed elevated levels of lactic acid and phosphoric acid suggestive of secondary mitochondrial energy defect. FAODs are usually missed as the biochemical parameters can be normal in between metabolic crises and the diagnosis is made only with strong suspicion during catabolic state. In addition to supportive management, bezafibrate an agonist of peroxisome proliferating activator receptor is a new treatment option in VLCADD [9]. In conclusion, it is important to consider metabolic disorder in an infant with Reye-like presentation and lactic
Result (lM) Trial 1
Reference range (lM)
Trial 2
Blood acyl carnitine profile by tandem mass spectrometry (MS/MS) C14
1.15
1.11
0.01–0.6
C14:1
0.77
0.74
0.05–0.5
C14:1/C16
0.43
0.42
0.01–0.2
% of internal standard
Cut-off (%)
Fold elevation
Urine organic acid profile by gas chromatography mass spectrometry 4 OH benzoic acid
296.96
22.38
38.07
Phosphoric acid
983.46
72.7
22.87
Ethyl malonic acid
28.94
7.45
4.67
Lactic Oxalic
19.32 3.21
6.70 1.00
4.11 3.21
Vanillic
13.08
5.79
2.26
0.55
0.50
1.37
Isobutyryl glycine
elevated lactate (3.108 mmol/L; ref: 0.44–2.22). Arterial blood gas was suggestive of compensated metabolic acidosis (pH: 7.34; pCO2: 3.5 kPa; HCO3: 15 mmol/L; base deficit: 8 mmol/L). Blood tandem mass spectrometry (MS/MS) revealed increased long-chain acylcarnitine esters of C14, C14:1 and C14:1/C16 suggestive of VLCADD (Table 1). Urine gas chromatography mass spectrometry (GC/MS) was suggestive of mitochondrial energy defect (Table 1; Fig. 1). Enzyme assay could not be done due to non-availability. Creatine kinase (108 U/L) and echocardiogram were normal. In addition to IV antibiotics, child was started on carnitine (100 mg/kg/day) with biotin (10 mg/day) and thiamine (100 mg/day), which were continued for 2 weeks. Avoidance of fasting, frequent feeding and medium chain triglyceride supplementation were advised at the time of discharge. Carnitine, thiamine and biotin were supplemented during intercurrent infections. In the 1 year follow up child has gained milestones with no crisis.
Fig. 1 Urine gas chromatography mass spectrometry (GC/MS) pattern
123
Ind J Clin Biochem
acidosis does not rule out FAOD. The prognosis is good in infantile onset hepatic form with diet management alone, hence the need for prompt diagnosis. Acknowledgments We acknowledge Neogen Labs Private Limited, Bangalore and Sandor Proteomics Pvt. Ltd., Hyderabad for their help in blood tandem mass spectrometry and urine GC/MS respectively.
References 1. Spiekerkoetter U. Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis. 2010;33:527–32. 2. Ventura FV, Ruiter JPN, Ijlst L, Tavares De Almeida I, Wanders RJA. Lactic acidosis in long-chain fatty acid b-oxidation disorders. J Inherit Metab Dis. 1998;21:645–54. 3. Hagenfeldt L. Compromised fatty acid oxidation in mitochondrial disorders. J Inherit Metab Dis. 1998;21:613–7.
4. Mochel F, Slama A, Touati G, Desguerre I, Giurgea I, Rabier D, et al. Respiratory chain defects may present only with hypoglycemia. J Clin Endocrinol Metab. 2005;90(6):3780–5. 5. Das AM, Fingerhut R, Wanders RJA, Ullrich K. Secondary respiratory chain defect in a boy with long-chain 3-hydroxyacylCoA dehydrogenase deficiency: possible diagnostic pitfalls. Eur J Pediatr. 2000;159(4):243–6. 6. Berry G, Goodman SI, Marsden D, Matern D, Nyhan W. Newborn screening ACT sheet (very-long-chain acyl-CoA dehydrogenase deficiency). American College of Medical Genetics ACT sheet. (May 1, 2008). Available from: http://www.acmg.net/resources/ policies/ACT/Visio-C14-1_(4-19-06).pdf. Accessed on 01 June 2013. 7. Van Hove JLK, Kahler SG, Feezor MD, Ramakrishna JP, Hart P, Treem WR, et al. Acylcarnitines in plasma and blood spots of patients with long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. J Inherit Metab Dis. 2000;23:571–82. 8. Wanders RJA, Vreken P, Den Boer MEJ, Wijburg FA, Van Gennip AH, Ijlst L. Disorders of mitochondrial fatty acyl-CoA b-oxidation. J Inherit Metab Dis. 1999;22:442–87. 9. Yamaguchi S, Li H, Purevsuren J, Yamada K, Furui M, Takahashi T, et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. J Mol Genet Metab. 2012;107(1–2):87–91.
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CASE REPORT
Fatty Acid Oxidation Disorder with Secondary Mitochondrial Energy Production Defect: A Case Report Seema Pavaman Sindgikar • Deepthi Raran Veetil Rathika D. Shenoy • Vijaya Shenoy
•
Received: 26 July 2013 / Accepted: 20 September 2013 Ó Association of Clinical Biochemists of India 2013
Abstract The presentation of long-chain fatty acid oxidation disorders (FAOD), unlike short and medium-chain disorders can be with secondary defects in mitochondrial function along with typical features of FAOD. We report an infant with Reye-like presentation and acylcarnitine profile suggestive of very-long-chain acyl-CoA dehydrogenase deficiency who had lactic acidosis and urine gas chromatographic pattern of mitochondrial defects. Keywords Lactic acidosis Reye-like Urine organic acids Very-long-chain acyl-CoA dehydrogenase deficiency
Introduction Fatty acid oxidation (FAO) is a pivotal pathway for energy homeostasis specifically in liver, heart and skeletal muscles during catabolic stress. Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a key enzyme involved in the early steps of long-chain FAO spiral in mitochondria. VLCAD deficiency (VLCADD) has heterogeneous clinical phenotypes with varying severity and the most common infantile onset hepatic form presents with hypoketotic hypoglycemia and hepatomegaly resembling Reye-syndrome [1]. The distinguishing feature of FAO disorders (FAOD) is absence of ketosis and lactic acidosis with specific blood acylcarnitine pattern and dicarboxylic aciduria. We discuss an infant with Reye-like presentation with lactic acidosis and
S. P. Sindgikar (&) D. R. Veetil R. D. Shenoy V. Shenoy Department of Pediatrics, K. S. Hegde Medical Academy, NITTE University, Derlakatte, Mangalore 575018, Karnataka, India e-mail: [email protected]
characteristic acylcarnitine profile of VLCADD and urine chromatography suggestive of defects in mitochondrial energy production and discuss the pathophysiology of the same.
Case Report A six-month old female was referred with fever and vomiting since 3 days and recurrent generalized tonic clonic convulsions since 1 day. She was second born to non-consanguineous couple at term with normal perinatal and developmental history. Two weeks prior she was hospitalized elsewhere for acute lower respiratory infection following which she was not able to hold her head steady or roll over. Family history was negative for developmental delay, cardiac illness or infant deaths. On examination her weight and head circumference were at third and length at 50th centiles. Her vitals were stable. Glasgow coma scale was 12/15 and fontanelle normal. Generalized hypotonia and hyporeflexia was present with firm hepatomegaly of span eight cm. Cardia was normal. Investigations showed low blood glucose (1.554 mmol/L), negative urine sugars and ketones, liver dysfunction with elevated transaminases (ALT 91U/L, AST 157U/L) and prolonged prothrombin time (INR-1.28). Sepsis screen was positive with smear showing neutrophilic leukocytosis with toxic granules and positive C-reactive protein. Electrolytes, anion gap and renal parameters were normal. CSF analysis was suggestive of partially treated meningitis with lymphocytic pleocytosis (135cells, L85 %), normal glucose (1.332 mmol/L) ratio and protein (290 mg/L). Blood and CSF cultures were sterile and neuroimaging normal. Further evaluation showed blood ammonia of 227.8 lmol/L (ref: 28–94) suggesting moderate hyperammonemia and mildly
123
Ind J Clin Biochem Table 1 Spectrometry analysis of blood for acyl carnitine and urine for organic acids
Discussion
Analyte
Reye-like presentation in children is seen with several metabolic disorders, central nervous system infections, toxins and drug ingestion. Though presentation suggested partially treated meningitis, a metabolic etiology specifically FAOD precipitated by crisis was considered in view of non-ketotic hypoglycemia, hepatomegaly and developmental regression. Defective synthesis of ketone bodies with increased utilization of glucose and impaired gluconeogenesis due to lack of acetyl CoA results in non/hypoketotic hypoglycemia in these disorders. Profound encephalopathy with moderate to severe lactic acidosis with abnormal neuro-imaging characterizes mitochondrial dysfunction. Moderate to severe lactic acidosis is reported in long-chain FAOD in contrast to medium-chain in the absence of anoxia or poor perfusion. Intra mitochondrial accumulation of long-chain acyl-CoA esters and reduced cofactors inhibits oxidative phosphorylation which constitutes the functional final common pathway of ATP production and pyruvate oxidation resulting in lactic acidosis [2]. The FAO spiral also requires ATP and reoxidised cofactors for its continued activation [2–4]. Thus the two pathways are mutually dependent on each other and hence the diagnosis of these disorders based on clinical presentation and investigations may be difficult in resource limited setting as in our case [5]. A specific acyl-carnitine profile in the blood is more definitive for the diagnosis of VLCADD [6, 7]. Urine organic acid pattern may be uninformative in VLCADD [8]. Urine gas chromatography in our case showed elevated levels of lactic acid and phosphoric acid suggestive of secondary mitochondrial energy defect. FAODs are usually missed as the biochemical parameters can be normal in between metabolic crises and the diagnosis is made only with strong suspicion during catabolic state. In addition to supportive management, bezafibrate an agonist of peroxisome proliferating activator receptor is a new treatment option in VLCADD [9]. In conclusion, it is important to consider metabolic disorder in an infant with Reye-like presentation and lactic
Result (lM) Trial 1
Reference range (lM)
Trial 2
Blood acyl carnitine profile by tandem mass spectrometry (MS/MS) C14
1.15
1.11
0.01–0.6
C14:1
0.77
0.74
0.05–0.5
C14:1/C16
0.43
0.42
0.01–0.2
% of internal standard
Cut-off (%)
Fold elevation
Urine organic acid profile by gas chromatography mass spectrometry 4 OH benzoic acid
296.96
22.38
38.07
Phosphoric acid
983.46
72.7
22.87
Ethyl malonic acid
28.94
7.45
4.67
Lactic Oxalic
19.32 3.21
6.70 1.00
4.11 3.21
Vanillic
13.08
5.79
2.26
0.55
0.50
1.37
Isobutyryl glycine
elevated lactate (3.108 mmol/L; ref: 0.44–2.22). Arterial blood gas was suggestive of compensated metabolic acidosis (pH: 7.34; pCO2: 3.5 kPa; HCO3: 15 mmol/L; base deficit: 8 mmol/L). Blood tandem mass spectrometry (MS/MS) revealed increased long-chain acylcarnitine esters of C14, C14:1 and C14:1/C16 suggestive of VLCADD (Table 1). Urine gas chromatography mass spectrometry (GC/MS) was suggestive of mitochondrial energy defect (Table 1; Fig. 1). Enzyme assay could not be done due to non-availability. Creatine kinase (108 U/L) and echocardiogram were normal. In addition to IV antibiotics, child was started on carnitine (100 mg/kg/day) with biotin (10 mg/day) and thiamine (100 mg/day), which were continued for 2 weeks. Avoidance of fasting, frequent feeding and medium chain triglyceride supplementation were advised at the time of discharge. Carnitine, thiamine and biotin were supplemented during intercurrent infections. In the 1 year follow up child has gained milestones with no crisis.
Fig. 1 Urine gas chromatography mass spectrometry (GC/MS) pattern
123
Ind J Clin Biochem
acidosis does not rule out FAOD. The prognosis is good in infantile onset hepatic form with diet management alone, hence the need for prompt diagnosis. Acknowledgments We acknowledge Neogen Labs Private Limited, Bangalore and Sandor Proteomics Pvt. Ltd., Hyderabad for their help in blood tandem mass spectrometry and urine GC/MS respectively.
References 1. Spiekerkoetter U. Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis. 2010;33:527–32. 2. Ventura FV, Ruiter JPN, Ijlst L, Tavares De Almeida I, Wanders RJA. Lactic acidosis in long-chain fatty acid b-oxidation disorders. J Inherit Metab Dis. 1998;21:645–54. 3. Hagenfeldt L. Compromised fatty acid oxidation in mitochondrial disorders. J Inherit Metab Dis. 1998;21:613–7.
4. Mochel F, Slama A, Touati G, Desguerre I, Giurgea I, Rabier D, et al. Respiratory chain defects may present only with hypoglycemia. J Clin Endocrinol Metab. 2005;90(6):3780–5. 5. Das AM, Fingerhut R, Wanders RJA, Ullrich K. Secondary respiratory chain defect in a boy with long-chain 3-hydroxyacylCoA dehydrogenase deficiency: possible diagnostic pitfalls. Eur J Pediatr. 2000;159(4):243–6. 6. Berry G, Goodman SI, Marsden D, Matern D, Nyhan W. Newborn screening ACT sheet (very-long-chain acyl-CoA dehydrogenase deficiency). American College of Medical Genetics ACT sheet. (May 1, 2008). Available from: http://www.acmg.net/resources/ policies/ACT/Visio-C14-1_(4-19-06).pdf. Accessed on 01 June 2013. 7. Van Hove JLK, Kahler SG, Feezor MD, Ramakrishna JP, Hart P, Treem WR, et al. Acylcarnitines in plasma and blood spots of patients with long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. J Inherit Metab Dis. 2000;23:571–82. 8. Wanders RJA, Vreken P, Den Boer MEJ, Wijburg FA, Van Gennip AH, Ijlst L. Disorders of mitochondrial fatty acyl-CoA b-oxidation. J Inherit Metab Dis. 1999;22:442–87. 9. Yamaguchi S, Li H, Purevsuren J, Yamada K, Furui M, Takahashi T, et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. J Mol Genet Metab. 2012;107(1–2):87–91.
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