# Branched-chain amino acid transferase 2 (BCAT2) deficiency: A case series and systematic review

## TL;DR

This study reports three new cases of BCAT2 deficiency and reviews existing literature, highlighting the condition's variable symptoms and potential treatment with pyridoxine.

## Contribution

The study provides new clinical insights and expands the genetic and phenotypic understanding of BCAT2 deficiency through case reports and a systematic review.

## Key findings

- Three patients with BCAT2 deficiency were homozygous for the c.600C > A variant and showed variable symptoms.
- Pyridoxine supplementation reduced BCAA levels, but only half of the patients showed clinical improvement.
- MRI revealed abnormal white matter findings in all imaged patients, and intellectual disability was common among cases.

## Abstract

Branched-chain amino acid transaminase 2 (BCAT2) deficiency is an autosomal recessive disorder that impairs branched-chain amino acid (BCAA) catabolism. Its clinical and metabolic features remain poorly understood due to limited reports in the literature.

We report three novel cases of BCAT2 deficiency from Slovenia: one diagnosed following symptom onset, one through cascade screening of parents, and one by newborn screening. Diagnosis was established through metabolic evaluation and confirmation of pathogenic variants in the BCAT2 gene. In addition, we performed a systematic review of all previously reported cases of BCAT2 deficiency.

All three patients were homozygous for the NM_001190.4:c.600C > A (p.Tyr200Ter) variant, with valine concentrations at presentation of 2093, 2589, and 794 μmol/L. Only one patient was symptomatic, presenting with headaches, developmental delay, and intellectual disability, while the remaining two were largely asymptomatic. Notably, insulin resistance was observed in one of the three patients and may be associated with elevated BCAA levels. Systematic literature review identified 8 additional cases of BCAT2 deficiency. Genetic variant c.600C > A was also found in two Pakistani individuals, while the remaining variants were each reported in only a single individual. The most common clinical characteristics were intellectual disability (55%), developmental delay and other neurological symptoms (36%). Abnormal white matter findings on MRI were observed in all patients who underwent imaging. BCAA levels decreased in all patients receiving pyridoxine supplementation; however, only 50% showed clinical improvement.

BCAT2 deficiency displays marked interindividual heterogeneity, ranging from asymptomatic cases to severe neurological impairment, which renders its pathogenicity uncertain.