Branched-chain Ketoacid Dehydrogenase Deficiency Research Articles

Earwax: A potentially useful medium to identify inborn errors of metabolism?

Earwax was investigated as a source to identify patients' different inborn errors of metabolism (IEMs). Acylcarnitines, amino acids, and guanidino metabolites were measured from 28 treated patients with 11 different metabolic disorders including 3 organic acidaemias, 2 fatty acid oxidation defects, 6 amino acid disorders, and 1 peroxisomal abnormality. On the basis of the ratio of different acylcarnitine species relative to free carnitine, isovaleric acidaemia, methylmalonic acidaemia, and long‐chain hydroxyacylCoA dehydrogenase deficiency could be discriminated from the other disorders. For amino acids, neither creatinine nor alternative amino acid proved suitable reference standards against which results could be expressed. However, argininosuccinate and alloisoleucine were present in significantly elevated concentrations in two patients with argininosuccinate lyase deficiency and two patients with branched‐chain ketoacid dehydrogenase deficiency. This study has raised the potential of earwax for investigation of IEMs and may also have role in postmortem investigations. In view of its limited invasiveness, earwax also may have a role as a material to monitor treatment responses and compliance in patients with IEMs.

Mild inborn errors of metabolism in commonly used inbred mouse strains

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, α-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkd1 mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkd1 mRNA, decreased DHTKD1 protein and α-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains.

Sensory‐motor polyneuropathy occurring in variant maple syrup urine disease

Maple syrup urine disease (MSUD; OMIM 248600) results from an inherited deficiency of the branched-chain ketoacid dehydrogenase (BCKD) complex. Approximately 20% of patients with BCKD deficiency are non-classic variants of MSUD with differing clinical severity. Outcomes for this cohort are generally favourable; episodes of metabolic decompensation do not appear to correlate with adverse events if acute management is promptly provided. A case of predominantly axonal sensory-motor neuropathy following metabolic decompensation which persisted for a number of months is presented in an adolescent girl with variant (intermediate type) MSUD. EMG and nerve conduction studies suggested a pre-existent asymptomatic chronic neuropathy, exacerbated by the acute decompensation. Peak leucine concentration at decompensation was 1083 μmol/L. The patient had laboratory signs of secondary mitochondrial respiratory chain dysfunction at presentation. She had been on a moderate dose of thiamine prior to decompensation; thiamine and pyridoxine blood concentrations were normal. This, to our knowledge, is the first report of a neuropathy presenting in a patient with a decompensation of variant MSUD. We propose that this presentation resembles the intermittent neuropathy observed in pyruvate dehydrogenase deficiency and may reflect secondary inhibition of pyruvate dehydrogenase activity by MSUD metabolites.

Brain Amino Acid Requirements and Toxicity: The Example of Leucine

Glutamic acid is an important excitatory neurotransmitter of the brain. Two key goals of brain amino acid handling are to maintain a very low intrasynaptic concentration of glutamic acid and also to provide the system with precursors from which to synthesize glutamate. The intrasynaptic glutamate level must be kept low to maximize the signal-to-noise ratio upon the release of glutamate from nerve terminals and to minimize the risk of excitotoxicity consequent to excessive glutamatergic stimulation of susceptible neurons. The brain must also provide neurons with a constant supply of glutamate, which both neurons and glia robustly oxidize. The branched-chain amino acids (BCAAs), particularly leucine, play an important role in this regard. Leucine enters the brain from the blood more rapidly than any other amino acid. Astrocytes, which are in close approximation to brain capillaries, probably are the initial site of metabolism of leucine. A mitochondrial branched-chain aminotransferase is very active in these cells. Indeed, from 30 to 50% of all alpha-amino groups of brain glutamate and glutamine are derived from leucine alone. Astrocytes release the cognate ketoacid [alpha-ketoisocaproate (KIC)] to neurons, which have a cytosolic branched-chain aminotransferase that reaminates the KIC to leucine, in the process consuming glutamate and providing a mechanism for the "buffering" of glutamate if concentrations become excessive. In maple syrup urine disease, or a congenital deficiency of branched-chain ketoacid dehydrogenase, the brain concentration of KIC and other branched-chain ketoacids can increase 10- to 20-fold. This leads to a depletion of glutamate and a consequent reduction in the concentration of brain glutamine, aspartate, alanine, and other amino acids. The result is a compromise of energy metabolism because of a failure of the malate-aspartate shuttle and a diminished rate of protein synthesis.

2-[fluorine-18] fluoro-2-deoxy-D-glucose PET scan of the brain in maple syrup urine disease.

2-[fluorine-18] fluoro-2-deoxy-D-glucose positron emission tomography (F-18 FDG PET) and MRI brain scans revealed bilateral basal ganglia, thalami, and brain-stem involvement in a 6-year-old girl with maple syrup urine disease, an autosomal-recessive disorder caused by the deficiency of branched-chain ketoacid dehydrogenase. She had acute metabolic decompensation as a neonate and later showed a slowly progressive encephalopathic course. The F-18 FDG PET study showed functional changes that were more extensive than the structural abnormalities shown by MRI and proved to be more sensitive and accurate in delineating the areas involved and better correlated with the patient's clinical course.