Intermittent episodes of metabolic ketoacidosis in a seven-year-old boy : Mitochondrial Beta-ketothiolase deficiency

A seven-year-old boy, the first born to second degree consanguineous parents, presented with a three days history of vomiting and low grade fever followed by drowsiness. Clinically child was afebrile, well hydrated, drowsy yet conscious with no focal neurological signs. Acidotic breathing was present. High anion gap metabolic acidosis was evident with initial investigations (Table 1). Urine ketone bodies were positive, but reducing substances were not detected.Analysis of cerebrospinal fluid was normal. Child recovered gradually with bicarbonate therapy and hydration with intravenous fluids. A similar episode has occurred at four years of age, managed at intensive care unit with ventilator support.


Introduction Case Report
(Keywords: Beta-ketothiolase deficiency, tandem mass spectrometry) Mitochondrial beta-ketothiolase deficiency (BKT) is a rare inborn error of metabolism.It was first reported in 1971 (1).Over 40 cases have been dealt with publications and more than 20 other cases have been reported worldwide (1).We report a child with BKT who was diagnosed recently at Lady Ridgeway Hospital for children.This is the first reported case in Sri Lanka.
A seven-year-old boy, the first born to second degree consanguineous parents, presented with a three days history of vomiting and low grade fever followed by drowsiness.Clinically child was afebrile, well hydrated, drowsy yet conscious with no focal neurological signs.Acidotic breathing was present.High anion gap metabolic acidosis was evident with initial investigations (Table 1).Urine ketone bodies were positive, but reducing substances were not detected.Analysis of cerebrospinal fluid was normal.Child recovered gradually with bicarbonate therapy and hydration with intravenous fluids.A similar episode has occurred at four years of age, managed at intensive care unit with ventilator support.
With the two episodes of intermittent metabolic acidosis the child was screened for metabolic disorders by tandem mass spectrometry (MS/MS) in India.Dried blood spot on a Guthrie card was analyzed for acylcarnitine to screen fatty acid oxidation disorders and organic acid disorders.3 hydroxyisovaleryl carnitine (C5OH) concentration was above normal and this elevation was attributed to the following inborn errors: 3-methyl  In contrast, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency is relatively a rare defect which present with predominantly neurological manifestations, although acute metabolic decompensation may occur in the early newborn period .Therefore, careful examination of urine organic acids is required for identification and differential diagnosis of these disorders, with awareness that the abnormalities may be subtle and variable (3). 3 In laboratory diagnosis of BKT, the elevated urinary metabolite most characteristic is 2-methyl-3-hydroxybutyric acid (Figure 1).This is often accompanied by elevation of 2-methylacetoacetic acid and its decarboxylation product 2-butanone.However, 2-methyl acetoacetic acid is usually not detected by GC / MS because, it is inherently labile and it rapidly decarboxylates to 2-butanone (4).Moreover, both 2-methyl acetoacetic acid and 2-butanone are highly volatile and always not detected, unless fresh samples are studied (4,5).Concurrently, in some known cases of BKT deficiency, there is very low excretion of 2-methyl acetoacetate or even nil at time especially in remission (5).Therefore, the absence of 2-methyl acetoacetate does not rule out BKT.
At the same time, 2-methylacetoacetic acid is not the most elevated metabolite seen in BKT, though it is the immediate substrate for the defective enzyme and might be expected to be most elevated (2).Rather, due to reversible reaction of 3-hydroxyacyl-CoA dehydrogenase and the normal high ratio of NADH to NAD, the reduced compound 2-methyl-3hydroxybutyric acid is more elevated (2).In this case 2-methyl-3-hydroxyl-butyric acid was slightly elevated giving a clue towards the diagnosis.Most patients with BKT also excrete significantly elevated amounts of tiglylglycine (2), as similarly occurred in this case.But in some cases of BKT this metabolite does not rise.In fact, the pattern and amount of excretion of all metabolites is variable (2).
With the above biochemical evidence and clinical correlation the most possible diagnosis was betaketothiolase deficiency.However, analysis of enzyme activity is preferred for confirmation of diagnosis if that was feasible.

Figure 1 :
Figure 1: Catabolism of isoleucine pathway.The structures and the names of intermediates of the pathway of catabolism of isoleucine are shown in the center, with the names of the enzymes on the left and the metabolites that may be elevated due to a deficiency of these enzymes shown on the right.