CASE REPORT
Death of a Neonate With a Negative Autopsy and Ketoacidosis A Case Report of Propionic Acidemia Adriana Krizova, MD, MSc, FRCPC and Jayantha C. Herath, MD, MSc, DLM, MD (Forensic), FRCPC(AP & FP) Abstract: Facing a sudden neonatal death in the forensic setting brings to mind enormous differential diagnostic possibilities. This case report demonstrates that at times, when no anatomical cause of death is apparent after a postmortem examination, ancillary testing can lead to diagnosis. In this case, ancillary testing showed ketosis and further workup showed presence of propionic acidemia in a 3-day-old neonate. Key Words: ketoacidosis in a neonate, propionic acidemia, Armanni-Ebstein lesion, negative autopsy, forensic pathologist, autopsy, pediatric, acidemia, fibroblast culture (Am J Forensic Med Pathol 2015;36: 193–195)
S
udden neonatal death investigations can be frustrating for a forensic pathologist when no anatomical cause of death is found after the postmortem examination. Our institutional standard for performing autopsies on children younger than 5 years includes multiple ancillary tests (skeletal survey/computed tomography scan of body, histology, microbiology, virology, toxicology, vitreous biochemistry, metabolic screen, and scene reconstruction) that many times do not reveal significant additional information. However, 2 days after the autopsy, vitreous fluid biochemistry showed high ketones.
CASE HISTORY The scene reconstruction revealed that this 3-day-old newborn girl was cosleeping on an adult bed with her mother and 5-year-old sister. She was found unresponsive in the mother's arms in the morning. The mother reported lethargy and difficulty rousing the baby within 24 hours before the newborn's death. She also noted that the newborn had “odd breathing pattern” of gasping every fourth to fifth breath along with no feeding overnight despite the mother's efforts to breastfeed her. The mother was a healthy 27-year-old woman. The newborn was delivered via uncomplicated vaginal delivery in a hospital. The birth weight was 6.4 lbs. The newborn appeared healthy. The mother and the baby were discharged the next day. No further pregnancy history was known. There was no known history of maternal illness, infection, and drug or alcohol use during pregnancy. The mother had a healthy 5-year-old daughter from the same consanguineous marriage (southeast Asian Arab family). At autopsy, the body was a clean and appropriately developed neonate without evidence of congenital abnormality or
Manuscript received May 30, 2014; accepted January 3, 2015. From the Provincial Forensic Pathology Unit, Toronto, Ontario, Canada. The authors report no conflict of interest. Reprints: Jayantha C Herath MD, MSc, DLM, MD (Forensic), FRCPC(AP & FP) Provincial Forensic Pathology Unit, 25 Morton Shulman Ave, Toronto, Ontario, Canada M3M 0B1. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0195-7910/15/3603–0193 DOI: 10.1097/PAF.0000000000000156
Am J Forensic Med Pathol • Volume 36, Number 3, September 2015
dysmorphic features. Her weight was at the fifth percentile for her age. Liver and spleen were smaller than expected. There was no evidence of significant recent injury, and the radiographic skeletal survey and the whole body computed tomography scan were unremarkable. Internal examination revealed healthy organs and tissues. Bacterial cultures of postmortem blood and tissue samples grew multiple organisms; however, in the absence of a detectable infectious source, the cultured microorganisms were considered to represent postmortem bacterial overgrowth or contamination. Testing for common viruses was negative. Vitreous fluid biochemistry showed presence of ketones (ketones, 8 mmol/L (normal value is negative); sodium, 136 mmol/L (normal range, 135–150 mmol/L); potassium, 21 mmol/L (normal range 91 pmol/min per mg protein), a finding consistent with PCC deficiency.
DISCUSSION The differential diagnostic considerations in a neonate with negative postmortem examination and high ketones in vitreous www.amjforensicmedicine.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
193
Am J Forensic Med Pathol • Volume 36, Number 3, September 2015
Krizova and Herath
FIGURE 1. The hematoxylin-eosin sections of the kidneys showed focal subnuclear vacuolation within the proximal tubules, Armanni-Ebstein lesion. Fat stain (osmium) showed fat accumulation in subnuclear vacuoles. Liver parenchyma showed steatosis.
fluid biochemistry are prolonged fasting, starvation, severe diarrhea, sepsis, shock, renal tubular acidosis, and inherited metabolic disorders, such as organic acid disorder, disorders of lactate and pyruvate metabolism, and oxidative phosphorylation or disorders of the Krebs cycle, such as fumarase deficiency and 2-ketoglutarate dehydrogenase deficiency. Other conditions to consider are poisonings, such as methyl alcohol or ethylene glycol toxicity among others. Propionic acidemia is one of the classic organic acid disorders caused by abnormal amino acid catabolism of branchedchain amino acids. The biochemical defect involves impaired conversion of propionyl-CoA to methylmalonyl-CoA by a mitochondrial enzyme PCC.5,6 The PCC deficiency is caused by mutations of either of the 2 genes that encode its subunits, PCCA or PCCB.7 The incidence of propionic acidemia is 1 in 100,000 babies born in Ontario.2 It is inherited in an autosomal recessive manner. Most of the affected individuals are compound
194
www.amjforensicmedicine.com
heterozygotes (having 2 different abnormal alleles at a particular locus); therefore, the attempts at genotypic-phenotypic correlations have been difficult. Although a family history of neonatal death in siblings of a proband (typically refers to a first individual diagnosed with a genetic disease in a particular family) should prompt consideration of an organic acidemia, a negative family history does not exclude the possibility. Most patients present in the neonatal period, three quarters within the first 5 days of life.8 Affected neonates are usually well at birth and for the first few days of life. Without treatment, the newborns can go into metabolic acidosis with encephalopathy progressing to coma and death. The usual clinical presentation of such a crisis includes vomiting, poor feeding, failure to thrive, abnormal tone, seizures, and lethargy progressing to coma. This decompensation is usually caused by catabolic stress, such as febrile illness, decreased oral intake, vomiting, and diarrhea. Asymptomatic patients and patients with neurological complications without metabolic crises have been described.9–11 Although propionic acidemia is one of the most common organic acidemias, long(er)-term outcomes of affected individuals are limited. Grunert et al.8,12,13 recently showed that the intellectual impairment is still the rule in propionic acidemia in children and young adults.8,12,13 In addition, cytopenias, long QT syndrome, cardiomyopathy, pancreatitis and multiple neurological and psychiatric complications are seen.8,14 Current treatments are aimed at dietary restrictions or liver transplantation. At the time of writing of this case report, the mother was in her first trimester of a new pregnancy. The results of the autopsy and enzymatic testing were provided to her and her obstetrician and genetic counselor for counseling and management of the new pregnancy. Clinicians have 3 possible approaches to prenatal diagnosis of propionic academia: (1) measure analytes in the amniotic fluid, (2) use cells obtained by amniocentesis or chorionic villous sampling to assay enzymatic activity of PCC, and/or (3) perform molecular genetic testing from the extracted DNA. The first-line molecular testing is typically sequence analysis; however, in this case, targeted mutation analysis could be first performed because there have been reports of a specific mutation in consanguineous marriages of Arab populations.15 As to the choice of testing, this will be discussed between the family and their clinical care providers. The couple also has a 5-year-old girl that could be a carrier of a disease-causing mutation. The optimal time for clarification of carrier status and potential discussion of her future family planning would be during her young adulthood. This unfortunate case is significant on 2 counts. First, diligence in collecting samples for ancillary testing is critical in the detection of rare diseases, such as organic acidemias. Appropriate sample collection including fibroblasts and DNA for banking in neonates and young children are crucial because confirmatory testing of organic acidemias involve assays of the activity of the deficient enzyme in cultured fibroblasts and/or molecular testing. Second, collection of DNA for genetic analysis can identify disease-causing mutations that can direct prenatal diagnosis of future pregnancies or ascertain carrier status in autosomal recessive diseases. This case is an example of how forensic autopsy results can be used in community forensic medicine and prevent deaths in the future through genetic counseling and targeted prenatal genetic testing. REFERENCES 1. Childs B, Nyhan WL, Borden M, et al. Idiopathic hyperglycinemia and hyperglycinuria: a new disorder of amino acid metabolism. Pediatrics. 1961:522–538.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Am J Forensic Med Pathol • Volume 36, Number 3, September 2015
2. Newborn Screening Ontario. http://www.newbornscreening.on.ca/.
A Case Report of Propionic Acidemia
9. Wolf B, Paulsen EP, Hsia YE. Asymptomatic propionyl-CoA carboxylase deficiency in a 13-year-old girl. J Pediatr. 1979;95:563–565.
3. Baumgartner MR, Horster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic academia. Orphanet J Rare Dis. 2014;9:130.
10. Surtees RAH, Matthews EE, Leonard JV. Neurologic outcome of propionic acidemia. Pediatr Neurol. 1992;8:333–337.
4. UCSD Biochemical Genetics Laboratory, 212 Dickinson St, CTF-B 213, San Diego 92103.
11. Sethi KD, Ray R, Roesel RA, et al. Adult-onset chorea and dementia with propionic acidemia. Neurology. 1989;39:1343–1345.
5. Hsia YE, Scully KJ, Rosenberg LE. Inherited propionyl-CoA carboxylase deficiency in “ketotic hyperglycinemia”. J Clin Invest. 1971:127–130. 6. Brandt IK, Hsia YE, Clement DH, et al. Propionic acidemia (ketotic hyperglycinemia): dietary treatment resulting in normal growth and development. Pediatrics. 1974:391–395. 7. A database of PCCA and PCCB mutations: http://cbs.lf1.cuni.cz/pcc/ pccmain.htm. 8. Grunert SC, Mullerleile S, De Silva L, et al. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis. 2013;8:6.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
12. Lehnert W, Sperl W, Suormala T, et al. Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr. 1994;153:S68–S80. 13. Van der Meer SB, Poggi F, Spada M, et al. Clinical outcome and long-term management of 17 patients with propionic acidaemia. Eur J Pediatr. 1996;155:205–210. 14. Pena L, Franks J, Chapman KA, et al. Natural history of propionic acidemia. Mol Genet Metab. 2012;105:5–9. 15. Kaya N, Al-Owain M, Albakheet A, et al. Array comparative genomic hybridization (aCGH) reveals the largest novel deletion in PCCA found in a Saudi family with propionic acidemia. Eur J Med Genet. 2008;51:558–565.
www.amjforensicmedicine.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
195
Death of a Neonate With a Negative Autopsy and Ketoacidosis A Case Report of Propionic Acidemia Adriana Krizova, MD, MSc, FRCPC and Jayantha C. Herath, MD, MSc, DLM, MD (Forensic), FRCPC(AP & FP) Abstract: Facing a sudden neonatal death in the forensic setting brings to mind enormous differential diagnostic possibilities. This case report demonstrates that at times, when no anatomical cause of death is apparent after a postmortem examination, ancillary testing can lead to diagnosis. In this case, ancillary testing showed ketosis and further workup showed presence of propionic acidemia in a 3-day-old neonate. Key Words: ketoacidosis in a neonate, propionic acidemia, Armanni-Ebstein lesion, negative autopsy, forensic pathologist, autopsy, pediatric, acidemia, fibroblast culture (Am J Forensic Med Pathol 2015;36: 193–195)
S
udden neonatal death investigations can be frustrating for a forensic pathologist when no anatomical cause of death is found after the postmortem examination. Our institutional standard for performing autopsies on children younger than 5 years includes multiple ancillary tests (skeletal survey/computed tomography scan of body, histology, microbiology, virology, toxicology, vitreous biochemistry, metabolic screen, and scene reconstruction) that many times do not reveal significant additional information. However, 2 days after the autopsy, vitreous fluid biochemistry showed high ketones.
CASE HISTORY The scene reconstruction revealed that this 3-day-old newborn girl was cosleeping on an adult bed with her mother and 5-year-old sister. She was found unresponsive in the mother's arms in the morning. The mother reported lethargy and difficulty rousing the baby within 24 hours before the newborn's death. She also noted that the newborn had “odd breathing pattern” of gasping every fourth to fifth breath along with no feeding overnight despite the mother's efforts to breastfeed her. The mother was a healthy 27-year-old woman. The newborn was delivered via uncomplicated vaginal delivery in a hospital. The birth weight was 6.4 lbs. The newborn appeared healthy. The mother and the baby were discharged the next day. No further pregnancy history was known. There was no known history of maternal illness, infection, and drug or alcohol use during pregnancy. The mother had a healthy 5-year-old daughter from the same consanguineous marriage (southeast Asian Arab family). At autopsy, the body was a clean and appropriately developed neonate without evidence of congenital abnormality or
Manuscript received May 30, 2014; accepted January 3, 2015. From the Provincial Forensic Pathology Unit, Toronto, Ontario, Canada. The authors report no conflict of interest. Reprints: Jayantha C Herath MD, MSc, DLM, MD (Forensic), FRCPC(AP & FP) Provincial Forensic Pathology Unit, 25 Morton Shulman Ave, Toronto, Ontario, Canada M3M 0B1. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0195-7910/15/3603–0193 DOI: 10.1097/PAF.0000000000000156
Am J Forensic Med Pathol • Volume 36, Number 3, September 2015
dysmorphic features. Her weight was at the fifth percentile for her age. Liver and spleen were smaller than expected. There was no evidence of significant recent injury, and the radiographic skeletal survey and the whole body computed tomography scan were unremarkable. Internal examination revealed healthy organs and tissues. Bacterial cultures of postmortem blood and tissue samples grew multiple organisms; however, in the absence of a detectable infectious source, the cultured microorganisms were considered to represent postmortem bacterial overgrowth or contamination. Testing for common viruses was negative. Vitreous fluid biochemistry showed presence of ketones (ketones, 8 mmol/L (normal value is negative); sodium, 136 mmol/L (normal range, 135–150 mmol/L); potassium, 21 mmol/L (normal range 91 pmol/min per mg protein), a finding consistent with PCC deficiency.
DISCUSSION The differential diagnostic considerations in a neonate with negative postmortem examination and high ketones in vitreous www.amjforensicmedicine.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
193
Am J Forensic Med Pathol • Volume 36, Number 3, September 2015
Krizova and Herath
FIGURE 1. The hematoxylin-eosin sections of the kidneys showed focal subnuclear vacuolation within the proximal tubules, Armanni-Ebstein lesion. Fat stain (osmium) showed fat accumulation in subnuclear vacuoles. Liver parenchyma showed steatosis.
fluid biochemistry are prolonged fasting, starvation, severe diarrhea, sepsis, shock, renal tubular acidosis, and inherited metabolic disorders, such as organic acid disorder, disorders of lactate and pyruvate metabolism, and oxidative phosphorylation or disorders of the Krebs cycle, such as fumarase deficiency and 2-ketoglutarate dehydrogenase deficiency. Other conditions to consider are poisonings, such as methyl alcohol or ethylene glycol toxicity among others. Propionic acidemia is one of the classic organic acid disorders caused by abnormal amino acid catabolism of branchedchain amino acids. The biochemical defect involves impaired conversion of propionyl-CoA to methylmalonyl-CoA by a mitochondrial enzyme PCC.5,6 The PCC deficiency is caused by mutations of either of the 2 genes that encode its subunits, PCCA or PCCB.7 The incidence of propionic acidemia is 1 in 100,000 babies born in Ontario.2 It is inherited in an autosomal recessive manner. Most of the affected individuals are compound
194
www.amjforensicmedicine.com
heterozygotes (having 2 different abnormal alleles at a particular locus); therefore, the attempts at genotypic-phenotypic correlations have been difficult. Although a family history of neonatal death in siblings of a proband (typically refers to a first individual diagnosed with a genetic disease in a particular family) should prompt consideration of an organic acidemia, a negative family history does not exclude the possibility. Most patients present in the neonatal period, three quarters within the first 5 days of life.8 Affected neonates are usually well at birth and for the first few days of life. Without treatment, the newborns can go into metabolic acidosis with encephalopathy progressing to coma and death. The usual clinical presentation of such a crisis includes vomiting, poor feeding, failure to thrive, abnormal tone, seizures, and lethargy progressing to coma. This decompensation is usually caused by catabolic stress, such as febrile illness, decreased oral intake, vomiting, and diarrhea. Asymptomatic patients and patients with neurological complications without metabolic crises have been described.9–11 Although propionic acidemia is one of the most common organic acidemias, long(er)-term outcomes of affected individuals are limited. Grunert et al.8,12,13 recently showed that the intellectual impairment is still the rule in propionic acidemia in children and young adults.8,12,13 In addition, cytopenias, long QT syndrome, cardiomyopathy, pancreatitis and multiple neurological and psychiatric complications are seen.8,14 Current treatments are aimed at dietary restrictions or liver transplantation. At the time of writing of this case report, the mother was in her first trimester of a new pregnancy. The results of the autopsy and enzymatic testing were provided to her and her obstetrician and genetic counselor for counseling and management of the new pregnancy. Clinicians have 3 possible approaches to prenatal diagnosis of propionic academia: (1) measure analytes in the amniotic fluid, (2) use cells obtained by amniocentesis or chorionic villous sampling to assay enzymatic activity of PCC, and/or (3) perform molecular genetic testing from the extracted DNA. The first-line molecular testing is typically sequence analysis; however, in this case, targeted mutation analysis could be first performed because there have been reports of a specific mutation in consanguineous marriages of Arab populations.15 As to the choice of testing, this will be discussed between the family and their clinical care providers. The couple also has a 5-year-old girl that could be a carrier of a disease-causing mutation. The optimal time for clarification of carrier status and potential discussion of her future family planning would be during her young adulthood. This unfortunate case is significant on 2 counts. First, diligence in collecting samples for ancillary testing is critical in the detection of rare diseases, such as organic acidemias. Appropriate sample collection including fibroblasts and DNA for banking in neonates and young children are crucial because confirmatory testing of organic acidemias involve assays of the activity of the deficient enzyme in cultured fibroblasts and/or molecular testing. Second, collection of DNA for genetic analysis can identify disease-causing mutations that can direct prenatal diagnosis of future pregnancies or ascertain carrier status in autosomal recessive diseases. This case is an example of how forensic autopsy results can be used in community forensic medicine and prevent deaths in the future through genetic counseling and targeted prenatal genetic testing. REFERENCES 1. Childs B, Nyhan WL, Borden M, et al. Idiopathic hyperglycinemia and hyperglycinuria: a new disorder of amino acid metabolism. Pediatrics. 1961:522–538.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Am J Forensic Med Pathol • Volume 36, Number 3, September 2015
2. Newborn Screening Ontario. http://www.newbornscreening.on.ca/.
A Case Report of Propionic Acidemia
9. Wolf B, Paulsen EP, Hsia YE. Asymptomatic propionyl-CoA carboxylase deficiency in a 13-year-old girl. J Pediatr. 1979;95:563–565.
3. Baumgartner MR, Horster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic academia. Orphanet J Rare Dis. 2014;9:130.
10. Surtees RAH, Matthews EE, Leonard JV. Neurologic outcome of propionic acidemia. Pediatr Neurol. 1992;8:333–337.
4. UCSD Biochemical Genetics Laboratory, 212 Dickinson St, CTF-B 213, San Diego 92103.
11. Sethi KD, Ray R, Roesel RA, et al. Adult-onset chorea and dementia with propionic acidemia. Neurology. 1989;39:1343–1345.
5. Hsia YE, Scully KJ, Rosenberg LE. Inherited propionyl-CoA carboxylase deficiency in “ketotic hyperglycinemia”. J Clin Invest. 1971:127–130. 6. Brandt IK, Hsia YE, Clement DH, et al. Propionic acidemia (ketotic hyperglycinemia): dietary treatment resulting in normal growth and development. Pediatrics. 1974:391–395. 7. A database of PCCA and PCCB mutations: http://cbs.lf1.cuni.cz/pcc/ pccmain.htm. 8. Grunert SC, Mullerleile S, De Silva L, et al. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis. 2013;8:6.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
12. Lehnert W, Sperl W, Suormala T, et al. Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr. 1994;153:S68–S80. 13. Van der Meer SB, Poggi F, Spada M, et al. Clinical outcome and long-term management of 17 patients with propionic acidaemia. Eur J Pediatr. 1996;155:205–210. 14. Pena L, Franks J, Chapman KA, et al. Natural history of propionic acidemia. Mol Genet Metab. 2012;105:5–9. 15. Kaya N, Al-Owain M, Albakheet A, et al. Array comparative genomic hybridization (aCGH) reveals the largest novel deletion in PCCA found in a Saudi family with propionic acidemia. Eur J Med Genet. 2008;51:558–565.
www.amjforensicmedicine.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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