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Table of Contents
CLINICO-PATHOLOGICAL PEARLS
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 74-77

A challenging diagnosis of B-ketothiolase deficiency mimicking type 1 diabetes mellitus


1 Department of Pediatrics, Division of Pediatric Endocrinology, College of Medicine, King Khalid University Hospital, King Saud University; Department of Pediatrics, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
2 Department of Pediatrics, Division of Medical Genetics, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
3 Department of Pathology, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
4 Department of Pediatrics, Division of Pediatric Endocrinology, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

Date of Submission06-May-2020
Date of Decision20-Jul-2020
Date of Acceptance04-Aug-2020
Date of Web Publication09-Dec-2020

Correspondence Address:
Reem Abdullah Al-Khalifah
Department of Pediatrics, Division of Endocrinology, College of Medicine, King Khalid University Hospital, King Saud University, (39), P.O. Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_31_20

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  Abstract 


Beta-ketothiolase (BKT) deficiency is a disorder of ketone body metabolism and isoleucine catabolism. Patients with BKT deficiency have intermittent ketoacidosis attacks. In this report, we describe an unusual case that mimicked type 1 diabetes presentation. The patient is a 1-year-old boy who presented with clinical and biochemical evidence of diabetes ketoacidosis (DKA). After the resolution of DKA, he was commenced on subcutaneous insulin regimen. Insulin requirements decline over few weeks to 0.3 U/kg/day, and due to normalization of blood glucose coupled with frequent hypoglycemic episodes, insulin was stopped for few months. Later, he developed two additional DKA episodes with intermittent period of no insulin requirement. At 2 years of age, he presented with ketoacidosis and hypoglycemia. The unusual presentation of ketoacidosis accompanied with hypoglycemia prompted genetic testing. Genetic testing revealed a novel homozygous mutation in the ACAT1 gene. The patient was advised to avoid prolonged fasting and started on a low-protein diet. Since then, he had developed mild episodes of ketosis with illness required intravenous hydration. In conclusion, the pediatrician should maintain a high index of clinical suspicion when dealing with children presenting with unusual diabetic ketoacidosis. Delayed diagnosis of BKT, failure of management of acute crisis, and the unnecessary use of insulin can lead to high morbidity and mortality.

Keywords: B-ketothiolase deficiency, Type 1 diabetes mellitus, unusual diabetes ketoacidosis, diabetes ketoacidosis


How to cite this article:
Al-Hakami AA, Alghamdi MA, Sumaily K, Al-Khalifah RA. A challenging diagnosis of B-ketothiolase deficiency mimicking type 1 diabetes mellitus. J Nat Sci Med 2021;4:74-7

How to cite this URL:
Al-Hakami AA, Alghamdi MA, Sumaily K, Al-Khalifah RA. A challenging diagnosis of B-ketothiolase deficiency mimicking type 1 diabetes mellitus. J Nat Sci Med [serial online] 2021 [cited 2021 Jan 17];4:74-7. Available from: https://www.jnsmonline.org/text.asp?2021/4/1/74/303903




  Introduction Top


Beta-ketothiolase deficiency is caused by a defect of mitochondrial acetoacetyl-CoA thiolase (T2), which is required for ketone body metabolism and isoleucine catabolism. It is a rare metabolic disorder inherited as autosomal recessive condition, estimated to affect 1 in 1 million newborns. T2 is required in both ketolysis and ketogenesis, it characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone which could be used as a diagnostic metabolic profile.

Patients with T2 deficiency typically present at age of 5 months to 3 years with intermittent ketoacidotic attacks that are triggered by stress or infection. Typically, patients with T2 deficiency are euglycemic. However, mild hyperglycaemia reaching up to 14.1 mmol/L has been reported during the metabolic crisis. To our knowledge we report the first case of a child who presented with several episodes of significant hyperglycemia associated with metabolic ketoacidosis mimicking diabetic ketoacidosis (DKA) presentation and requiring insulin treatment for multiple times.

The institutional review board in our institute waived this report as the patient's confidentiality was maintained.


  Case Report Top


Our patient is a boy born at term with birth weight of 2.8 kg. His parents were second-degree cousins. He has a 6-year-old paternal cousin who has a history of recurrent acidosis and hypoglycemia but with no clear diagnosis yet. Our patient presented to a peripheral hospital at the age of 1 year with clinical and biochemical evidence of severe diabetes ketoacidosis (DKA) in addition to symptoms of upper respiratory tract infection (URTI). Laboratory investigation [Table 1] upon presentation showed a pH of 7.18, base excess of − 19.9, HCO3 9.8 mmol/l, serum blood glucose level 22 mmol/l, urine ketones + 4, and HbA1c 5.2%. He was managed in the pediatric intensive care unit with intravenous fluids and insulin as a case of DKA. Subsequently, he was transitioned to multiple daily injections of insulin detemir and aspart with the initial dose of 0.5 U/kg/day. Insulin requirement declined over few weeks to 0.3 U/kg/day, and due to normalization of blood glucose coupled with frequent hypoglycemia, insulin therapy was stopped for few months.
Table 1: Biochemical profile for two episodes

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Later, he developed two URTIs that were associated with DKA requiring intravenous insulin, followed by a brief period of subcutaneous insulin need up to 2 months after both events. In between the DKA attacks, blood glucose level ranged between 4.4 and 8.8 mmol/l, with occasional episodes of hyperglycemia during periods of infections reaching to 15 mmol/l that are managed with 1–2 units of insulin aspart.

At 2 years of age, he presented with ketoacidosis and hypoglycemia, blood glucose level of 2.2 mmol/l, and his HbA1c is 4.1%. Subsequently, he was referred to our center for second opinion. His neurodevelopment assessment was appropriate for his age. Weight 10 kg (−2.3 standard deviation [SD]), length 82 cm (−1.3 SD), and weight for length −1.47 SD he has normal cardiovascular, respiratory, and abdominal exam, and normal male genitalia. The unusual presentation of alternating hyperglycemia and hypoglycemia accompanied by ketoacidosis coupled with the lack of insulin needs for few months between episodes prompted investigation for metabolic disorders. [Table 2] summarizes the baseline biochemical and hormonal testing.
Table 2: Baseline endocrine workup

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Metabolic profile revealed normal ammonia, uric acid, lactate, plasma amino acids, serum acylcarnitine level, and total serum homocysteine. The urine organic acids showed abnormally increased urinary 2-methyl-3 hydroxybutyrate, 2-methylacetoacetic acid, and tiglylglycine [Figure 1]. This elevation is consistent with beta-ketothiolase (BKT) (T2) deficiency or 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency. However, given that the child has normal development, the diagnosis of MHBD deficiency was not highly suspected that prompted genetic confirmation by whole exome sequencing (WES) since there is no standard enzymatic assay that could be done to confirm the diagnosis. WES detected a novel homozygous variant in the ACAT1 gene, c.592G >A p.(Glu198Lys); Chr11(GRCh37):G.108010804G > A. There was no pathogenic variant in the HSD17B10 gene detected. Given this result and the good response to dietary modification, a diagnosis of alpha-methylacetoacetic aciduria was confirmed.
Figure 1: Metabolic profile in beta-ketothiolase (T2) deficiency

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The patient was started on a low-protein diet and was advised to avoid prolonged fasting. Since then, he had developed mild episodes of euglycemic ketosis during illness for which he was managed with intravenous hydration and supportive treatment with no need for insulin therapy.


  Discussion Top


BKT deficiency is a rare inherited metabolic disorder, which affects ketone body metabolism and isoleucine catabolism.[1] The clinical presentation is widely variable, the majority of the patients will only have one episode of ketoacidosis, and they will respond well to rehydration therapy. These mild cases of T2 can be explained by the degree of the T2 enzymatic activity that reduces the accumulation of the intermediates of the isoleucine catabolism.[2]

Hyperglycemia associated with metabolic ketoacidosis presents a diagnostic challenge for diabetologists and pediatricians. The most commonly encountered cause of such a presentation in childhood is Type 1 diabetes. However, some organic acidemias are reported to present similarly. Our patient presented with significant hyperglycemia 22 mmol/l mimicking type 1 diabetes, and the treatment of insulin was needed intermittently and treated as diabetic ketoacidosis, which is an unusual presentation for patients with T2 deficiency. Typically, type 1 diabetes DKA presentation is associated with academia, ketosis, and hyperglycemia. The acidosis can be severe to the extent of PH 6.8, bicarbonate 2. The insulin requirement is permanent, but they might go through a honeymoon period during which the insulin might not be needed. However, it is unusual for the honeymoon period to last for more than 1 year, or to be recurrent, and usually, glycemic control will be in a diabetic range.

Mild hyperglycemia has been reported in patients with BKT deficiency. Riudor et al. reported a 14-month-old girl which presented initially with asthma exacerbation and developed metabolic coma 48 h later. Her pH 6.89, pCO2 17.5, HCO3 3.4, base excess of −27, and ketonuria with blood glucose of 14.1 mmol/l. Urine organic acid analysis by GC-MS showed increased amounts (mmol/mol creatinine) of 3-hydroxybutyrate (13 × 103), acetoacetate (2.9 × 103), 2-methylacetoacetic acid 2MAA (48), 2-methyl-3-hydroxybutyrate (2M3HB) (409), and 3-hydroxyisovalerate (133). No tiglylglycine or 6-methyluracil (6MU) was found. Demir et al. reported an 8-month-old boy admitted with symptoms of respiratory tract infection and lethargy with significant acetone odor. His pH 6.88, pCO2 6.1 mmHg, bicarbonate 4.9 mmol/L, patient also had ketonuria, and mild hyperglycemia (blood glucose 12.2 mmol/l). During this metabolic disturbance period, sharp rises on acylcarnitines C5:1 and C5OH levels in addition to gross amounts of 3-hydroxy-n-butyrate, 2-methyl-3-hydroxybutyrate, and tiglylglycine excretion were detected in the blood and urine samples of the patient. BKT cases presenting with metabolic acidosis and hyperglycemia were managed with supportive care only, and none of the reported cases needed insulin treatment.[3],[4] Although insulin treatment for our case was considered appropriate at the time of the DKA presentation before the final diagnosis was reached, the continuation on daily subcutaneous insulin was unnecessary. It led to frequent hypoglycemia and delayed administration of appropriate therapy.

Mitochondrial 2-methylacetoacetyl-CoA or acetoacetyl-CoA thiolase is the only known enzyme that catalyzes the last step in the isoleucine degradation pathway; it reversibly converts 2-methylacetoacetyl-CoA into propionyl-CoA and acetyl-CoA. In the liver, it provides acetoacetyl-CoA, the substrate for ketogenesis. T2 has another important role in ketone body metabolism; it catalyzes acetoacetyl CoA to CoA to yield two acetyl-CoAs in the last step (ketolysis) in extrahepatic tissue. Accumulation of amino acid catabolic intermediates is a key point in clinical presentation and biochemical diagnosis of T2 deficiency.[5]

The diagnosis of T2 is done by urinary organic acid and blood acylcarnitine analysis during acute metabolic decompensation. An increase in urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine is consistent with the condition. Blood acylcarnitine profile usually reveals increased tiglylcarnitine (C5:1) and 2-methyl-3-hydroxybutyryl-carnitine. T2 deficiency can be confirmed by enzyme assay in cultured cells and DNA sequence analysis which reveals acetyl-CoA acetyltransferase 1 (ACAT1) gene mutation. Newborn screening using tandem mass spectrometry is a valuable tool for detecting metabolic disorders as T2 deficiency, although it may yield false-negative results, especially in mild cases.[6],[7],[8] [Figure 2] outlines a diagnostic approach for atypical DKA presentations.
Figure 2: Diagnostic approach for atypical diabetes ketoacidosis presentations

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Patients with severe phenotype have recurrent episodes of ketoacidosis accompanied with toxic encephalopathies such as vomiting, poor feeding, seizures, abnormal tone, lethargy, and even coma. These episodes are precipitated by infection, fasting, or increase dietary protein consumption. Impaired neurodevelopment and cardiac involvement in the form of mental disability, seizures, stroke, chorea, coma, left ventricular hypertrophy, atrial septal defect combined with a stenosis of the pulmonary artery, and tricuspid insufficiency have been described in T2 deficiency.[2],[9] Laboratory investigation during metabolic decompensation shows metabolic acidosis a median pH of 7.04 (range 6.80–7.25, n = 18) and a median base excess of −25.0 mmol/l. Mild hyperammonemia (median 93 μmol/l, range (64–207 μmol/l), hypoglycemic (median 1.3 mmol/l, range 0.9–2.1 mmol/l), and elevated aspartate aminotransferase activities were also reported. Urinary organic acid profile shows increase urinary excretion of 2-methyl-3-hydroxybutyrate and 2-methylacetoacetate during the acute metabolic crisis.[1]

The pediatrician should maintain a high index of clinical suspicion when dealing with an unusual presentation of metabolic disorders. Aggressive management of ketoacidotic attacks is a crucial step in managing metabolic disorders to prevent severe decompensation and complications as neurodevelopment impairment or even death. The management includes the administration of appropriate intravenous fluids, electrolyte, and glucose. In cases with blood, pH is <7.1, a small bicarbonate bolus (1 mmol/kg over 10 min) can be given, followed by continuous infusion. Cases with severe metabolic derangement may require L-carnitine supplementation or other supportive measures, such as peritoneal dialysis or mechanical ventilation. Long-term treatment includes avoidance of prolonged fasting combined with a low-protein diet and L-carnitine supplementation. The prognosis of such condition tends to be benign with minimal neurological sequel, particularly when diagnosed early, and when they receive the appropriate therapy.[1],[6]

Final diagnosis

BKT deficiency caused by a novel homozygous mutation in the ACAT1 gene with atypical presentation of severe hyperglycemia. The patient managed with a low-protein diet and avoiding prolonged fasting.

Clinicopathological pearls

  1. BKT deficiency is a rare metabolic disorder inherited as an autosomal recessive condition. It is caused by a defect of mitochondrial acetoacetyl-CoA thiolase (T2), which is required for ketone body metabolism and isoleucine catabolism
  2. Patients with T2 deficiency typically present at the age of 5 months to 3 years with intermittent euglycemic to mild hyperglycemic ketoacidotic attacks that are triggered by stress or infection
  3. T2 is required in both ketolysis and ketogenesis; it is characterized by urinary excretion of 2-methyl -3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone
  4. Patients with T2 deficiency are usually euglycemic. However, mild hyperglycemia reaching up to 14.1 mmol/L has been reported during the metabolic crisis and might need insulin therapy
  5. Aggressive management of ketoacidotic attacks is crucial, and long-term treatment includes avoidance of prolonged fasting combined with a low-protein diet.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Grünert SC, Schmitt RN, Schlatter SM, et al. Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency. Mol Genet Metab. 2017;122:67-75. doi:10.1016/j.ymgme.2017.06.012.  Back to cited text no. 1
    
2.
Fukao T, Scriver CR, Kondo N, t2 Collaborative Working Group. The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Mol Genet Metab 2001;72:109-14.  Back to cited text no. 2
    
3.
Riudor E, Ribes A, Perez-Cerda C, Arranz JA, Mora J, Yeste D, et al. Metabolic coma with ketoacidosis and hyperglycaemia in 2-methylacetoacetyl-CoA thiolase deficiency. J Inherit Metab Dis 1995;18:748-9.  Back to cited text no. 3
    
4.
Kose M, E. Canda, M. Kağnıcı, Rana Işgüder, A. Ünalp, S. K. Uçar, et al. “Two Siblings with Beta-Ketothiolase Deficiency: One Genetic Defect Two Different Pictures.” Journal of Pediatric Research 3 (2016): 113-116.  Back to cited text no. 4
    
5.
Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis 2014;37:541-51.  Back to cited text no. 5
    
6.
Abdelkreem E, Otsuka H, Sasai H, Aoyama Y, Hori T, Abd El Aal M, et al. Beta-ketothiolase deficiency: Resolving challenges in diagnosis. J Inborn Errors Metab Screen 2016;4:1-9.  Back to cited text no. 6
    
7.
Estrella J, Wilcken B, Carpenter K, Bhattacharya K, Tchan M, Wiley V. Expanded newborn screening in New South Wales: missed cases. J Inherit Metab Dis 2014;37:881-7.  Back to cited text no. 7
    
8.
Otsuka H, Sasai H, Nakama M, Aoyama Y, Abdelkreem E, Ohnishi H, et al. Exon 10 skipping in ACAT1 caused by a novel c. 949G&amp; gt; A mutation located at an exonic splice enhancer site. Mol Med Rep 2016;14:4906-10.  Back to cited text no. 8
    
9.
Wojcik MH, Wierenga KJ, Rodan LH, Sahai I, Ferdinandusse S, Genetti CA, et al. Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals. JIMD Rep 2018;39:45-54.  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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