Expanding the genetic and phenotypic spectrum of branched‐chain amino acid transferase 2 deficiency

Abstract

The first step in branched‐chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched‐chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra‐rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low‐normal branched‐chain keto acids (BCKAs) with undetectable l‐allo‐isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide‐ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein‐restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.

Alzheimer’s disease: targeting the glutamatergic system

“…Moreover, treatment of the patient with vitamin B6 resulted in a sharp decline in valine levels compared with those of leucine and isoleucine. A more recent study identified several additional BCAT2 mutations that ranged between homozygous or compound heterozygous BCAT2 mutations (Knerr et al 2019). The authors reported similar biochemical profiles i.e.…”

“…Although the biological significance of these variants remains to be determined, P3 has been shown to act as a corepressor for thyroid hormone nuclear receptors. More recently, a clinically relevant mutant form of BCATm has been reported, which has homozygous or compound heterozygous BCAT2 mutations, discussed in Mutations of BCAT leads to mild cognitive impairment and brain lesions Section (Wang et al 2015a, b;Knerr et al 2019).…”

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

“…This theory is further supported by experimental data, demonstrating that intracerebroventricular delivery of BCAAs ameliorates autism-related phenotypes in mouse models [ 120 ]. Interestingly, one study also identified loss of function BCAT mutations in patients with autism [ 127 ]. Since BCAT activity generates BCKAs from BCAAs ( Figure 1 ), as expected, these patients had higher BCAA levels in plasma [ 127 ].…”

Association or causation: Symptoms and rare disease

“…On pp x-y, Knerr et al have expanded our knowledge of a rarely found deficiency, that of mitochondrial branchedchain amino acid transferase 2 (BCAT2). 1 They describe five new cases to add to the one already reported. In BCAT2, there is a distinctive biochemical profile: elevated branched-chain amino acids, normal branched-chain α-keto acids, and allo-isoleucine.…”

“…On pp x‐y, Knerr et al have expanded our knowledge of a rarely found deficiency, that of mitochondrial branched‐chain amino acid transferase 2 (BCAT2) . They describe five new cases to add to the one already reported.…”