The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

Abstract

Background: Ketone bodies form a vital energy source for end organs in a variety of physiological circumstances. At different times, the heart, brain and skeletal muscle in particular can use ketones as a primary substrate. Failure to generate ketones in such circumstances leads to compromised energy delivery, critical end-organ dysfunction and potentially death. There are a range of inborn errors of metabolism (IEM) affecting ketone body production that can present in this way, including disorders of carnitine transport into the mitochondrion, mitochondrial fatty acid oxidation deficiencies (MFAOD) and ketone body synthesis. In situations of acute energy deficit, management of IEM typically entails circumventing the enzyme deficiency with replenishment of energy requirements. Due to profound multi-organ failure it is often difficult to provide optimal enteral therapy in such situations and rescue with sodium DL-3-hydroxybutyrate (S DL-3-OHB) has been attempted in these conditions as documented in this paper.

Results: We present 3 cases of metabolic decompensation, one with carnitine-acyl-carnitine translocase deficiency (CACTD) another with 3-hydroxyl, 3-methyl, glutaryl CoA lyase deficiency (HMGCLD) and a third with carnitine palmitoyl transferase II deficiency (CPT2D). All of these disorders are frequently associated with death in circumstance where catastrophic acute metabolic deterioration occurs. Intensive therapy with adjunctive S DL-3OHB led to rapid and sustained recovery in all. Alternative therapies are scarce in these situations.

Conclusion: S DL-3-OHB has been utilised in multiple acyl co A dehydrogenase deficiency (MADD) in cases with acute neurological and cardiac compromise with long-term data awaiting publication. The use of S DL-3-OHB is novel in non-MADD fat oxidation disorders and contribute to the argument for more widespread use.

Keywords: 3-hydroxybutyrate; 3-hydroxyl-3-methylglutaryl-CoA lyase deficiency (HMGCLD); Carnitine acyl-carnitine translocase deficiency (CACTD); Carnitine palmitoyl transferase II deficiency (CPT2D); Fat oxidation; Ketone body.

Fig. 1

a) Sagittal MRI Image of the brain on day 12 of case I with CACTD, indicating extensive abnormal T2 hyperintensity seen within the white matter of both cerebral hemispheres. b) T2 -weighted MRI of brain of case 1 at 16 months indicating mild white matter and cortical volume loss especially in the parietal region. Hyperintensity has substantially improved

Fig. 2

a) CT Scan of 16 yr old boy with HMGCL2D on day 1 of admission (top row) when GCS was 10 and on day 3 (bottom row) when GCS was 3, and pupils were dilated bilaterally indicating deteriorating cerebral oedema. b) Axial DWI (top row) and T2 (bottom row) images of 16 yr old boy with HMGCL2D on day 3 of admission when GCS was 3. There is infarction involving the occipital and temporal lobes, likely secondary to trans-tentorial herniation and compression of the posterior cerebral arteries. Note also the distended optic nerve sheaths and flattening of the posterior globes, in keeping with significantly elevated intracranial pressure. c) Axial T2 Flair images of case 2 with HMGCLD three years after acute life-threatening event (aged 19 years) continuing to demonstrate deep subcortical white matter abnormality with extensive occipital lobe changes leading to cortical blindness

Fig. 3

Axial FLAIR image of the brain of case 3 with CPT2D performed at four months of age, one month following her acute decompensation event. Selected image at the level of the lateral ventricles demonstrates prominence of the extra-axial CSF spaces overlying the frontal lobes. Myelin appearance is appropriate for age