Abnormal concentrations of acetylated amino acids in cerebrospinal fluid in acetyl‐CoA transporter deficiency

Acetyl‐CoA transporter 1 (AT‐1) is a transmembrane protein which regulates influx of acetyl‐CoA from the cytosol to the lumen of the endoplasmic reticulum and is therefore important for the posttranslational modification of numerous proteins. Pathological variants in the SLC33A1 gene coding for AT‐1 have been linked to a disorder called Huppke‐Brendel syndrome, which is characterized by congenital cataracts, hearing loss, severe developmental delay and early death. It has been described in eight patients so far, who all had the abovementioned symptoms together with low serum copper and ceruloplasmin concentrations. The link between AT‐1 and low ceruloplasmin concentrations is not clear, nor is the complex pathogenesis of the disease. Here we describe a further case of Huppke‐Brendel syndrome with a novel and truncating homozygous gene variant and provide novel biochemical data on N‐acetylated amino acids in cerebrospinal fluid (CSF) and plasma. Our results indicate that decreased levels of many N‐acetylated amino acids in CSF are a typical metabolic fingerprint for AT‐1 deficiency and are potential biomarkers for the defect. As acetyl‐CoA is an important substrate for protein acetylation, we performed N‐terminal proteomics, but found only minor effects on this particular protein modification. The acetyl‐CoA content in patient's fibroblasts was insignificantly decreased. Our data may help to better understand the mechanisms underlying the metabolic disturbances, the pathophysiology and the clinical phenotype of the disease.