Anion Gap Metabolic Acidosis of Unknown Etiology
Biochemical/Metabolic and Therapeutics
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Introduction
We describe a case of a child with type 1 diabetes mellitus (T1DM) who presented with recurrent episodes of severe anion gap metabolic acidosis not consistent with diabetic ketoacidosis requiring hospitalization and bicarbonate supplementation of unclear etiology with negative diagnostic testing to date.
Case Presentation
Our patient is a 32-month-old male with T1DM with recurrent episodes of severe AGMA, and persistent ketonuria not consistent with DKA on significant bicarbonate supplementation with 3-hydroxypropionate, 2-methylcitrate and tiglyglycine on urine organic acids. He was diagnosed with type 1 diabetes at the age of 20 months in setting of DKA. He was subsequently admitted at 30 months of age with suspected DKA but remained acidotic despite DKA treatment which was attributed to infectious diarrhea. He was placed on bicarbonate supplementation and discharged home. He was subsequently re-admitted two more times for severe acidosis despite resolution of diarrhea with negative tox screen and low suspicion for RTA. Urine organic acids (UOA) obtained during the first readmission showed a single 3-hydroxypropionic acid peak. A UOA during his final admission showed ketonuria, 3-hydroxypropionic acid, 2-methylcitrate and tiglyglycine. This prompted further evaluation and management as noted below.
Diagnostic Workup
The patient never had a newborn screen. An echocardiogram showed mild dilation of ascending aorta but no cardiomyopathy. His genome sequencing without CNV analysis did not show any causative variants. No variants were specifically identified in: ALDH6A1, ACACB, BTD, CA5A, HLCS, PCCA, PCCB, MMUT, SLC5A6 and genes related to other cobalamin disorders. He has had negative/normal testing as follows: acylcarnitine profile (no C3 elevation), plasma amino acids (no glutamine elevation), biotinidase activity, ammonia, lactate, and vitamin levels (i.e. biotin, vitamin E and pantothenic acid). His urine organic acid samples show intermittent ketonuria, 3-hydroxypropionic acid, 2-methylcitrate and tiglyglycine.
Treatment and Management
The patient was placed on biotin supplementation, protein restricted diet and bicarbonate treatment.
Outcome and Follow-Up
The patient has not responded to the above treatment. He remains on significant bicarbonate supplementation with mild ketosis. We are in the process of performing additional testing including propionyl CoA carboxylase enzyme activity, mitochondrial genome sequencing and other metabolomics.
Discussion
We have not identified a similar case in literature to date. There are reports of patients with propionic acidemia presenting like diabetic ketoacidosis; however, these patients demonstrated expected PA biochemical profiles and often a poor response to DKA treatment unlike in our patient. These patients have also been symptomatic while our patient has remained clinical asymptomatic despite his severe acidosis. We have performed several diagnostic studies but have been unable to identify an etiology for our patient’s anion gap metabolic acidosis.
Conclusion
We present this case as an unknown medical diagnostic dilemma. By presenting this case, we aspire to collaborate with other experts in the field to identify similar patients with diagnostic success.
We describe a case of a child with type 1 diabetes mellitus (T1DM) who presented with recurrent episodes of severe anion gap metabolic acidosis not consistent with diabetic ketoacidosis requiring hospitalization and bicarbonate supplementation of unclear etiology with negative diagnostic testing to date.
Case Presentation
Our patient is a 32-month-old male with T1DM with recurrent episodes of severe AGMA, and persistent ketonuria not consistent with DKA on significant bicarbonate supplementation with 3-hydroxypropionate, 2-methylcitrate and tiglyglycine on urine organic acids. He was diagnosed with type 1 diabetes at the age of 20 months in setting of DKA. He was subsequently admitted at 30 months of age with suspected DKA but remained acidotic despite DKA treatment which was attributed to infectious diarrhea. He was placed on bicarbonate supplementation and discharged home. He was subsequently re-admitted two more times for severe acidosis despite resolution of diarrhea with negative tox screen and low suspicion for RTA. Urine organic acids (UOA) obtained during the first readmission showed a single 3-hydroxypropionic acid peak. A UOA during his final admission showed ketonuria, 3-hydroxypropionic acid, 2-methylcitrate and tiglyglycine. This prompted further evaluation and management as noted below.
Diagnostic Workup
The patient never had a newborn screen. An echocardiogram showed mild dilation of ascending aorta but no cardiomyopathy. His genome sequencing without CNV analysis did not show any causative variants. No variants were specifically identified in: ALDH6A1, ACACB, BTD, CA5A, HLCS, PCCA, PCCB, MMUT, SLC5A6 and genes related to other cobalamin disorders. He has had negative/normal testing as follows: acylcarnitine profile (no C3 elevation), plasma amino acids (no glutamine elevation), biotinidase activity, ammonia, lactate, and vitamin levels (i.e. biotin, vitamin E and pantothenic acid). His urine organic acid samples show intermittent ketonuria, 3-hydroxypropionic acid, 2-methylcitrate and tiglyglycine.
Treatment and Management
The patient was placed on biotin supplementation, protein restricted diet and bicarbonate treatment.
Outcome and Follow-Up
The patient has not responded to the above treatment. He remains on significant bicarbonate supplementation with mild ketosis. We are in the process of performing additional testing including propionyl CoA carboxylase enzyme activity, mitochondrial genome sequencing and other metabolomics.
Discussion
We have not identified a similar case in literature to date. There are reports of patients with propionic acidemia presenting like diabetic ketoacidosis; however, these patients demonstrated expected PA biochemical profiles and often a poor response to DKA treatment unlike in our patient. These patients have also been symptomatic while our patient has remained clinical asymptomatic despite his severe acidosis. We have performed several diagnostic studies but have been unable to identify an etiology for our patient’s anion gap metabolic acidosis.
Conclusion
We present this case as an unknown medical diagnostic dilemma. By presenting this case, we aspire to collaborate with other experts in the field to identify similar patients with diagnostic success.
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