SLC33A1 – Huppke-Brendel syndrome

Huppke-Brendel syndrome is an autosomal recessive neurodevelopmental disorder caused by biallelic loss-of-function variants in SLC33A1, coding for the acetyl-CoA transporter-1 (Gene Symbol; Disease Name). A total of ten unrelated probands (nine pediatric, one adult) have been reported to date, with clinical features including congenital cataract, hearing impairment, global developmental delay, cerebellar hypoplasia, hypogonadism, hypotonia and spastic ataxia ([PMID:39512429]). Segregation in siblings further supports causality.

Genetic evidence: All reported patients harbor homozygous or compound heterozygous truncating or in-frame deletion variants. One recurrent deletion, c.542_543del (p.Val181GlyfsTer6), was identified in a consanguineous family and segregates with disease ([PMID:27306358]). Another family exhibited compound heterozygosity for c.817_819del (p.Thr273del) and c.1331T>C (p.Ile444Thr) in an adult presentation ([PMID:36119696]). In total, ten probands across four families, including one pair of affected siblings, meet ClinGen criteria for a Strong genetic evidence score.

Functional evidence: Metabolic profiling in cerebrospinal fluid and plasma from affected individuals revealed a consistent decrease in multiple N-acetylated amino acids, establishing a biochemical fingerprint for AT-1 deficiency ([PMID:35999711]). N-terminal proteomics and fibroblast assays showed minor perturbations in global protein acetylation and unchanged cellular acetyl-CoA content, indicating a primary transporter deficit rather than broad acetylation failure. Therapeutic trials with N-acetylcysteine and ketogenic diet failed to normalize metabolite levels, demonstrating the need for targeted interventions ([PMID:39512429]).

Mechanism: Loss of AT-1 function likely impairs endoplasmic reticulum acetyl-CoA import, disrupting posttranslational acetylation of secreted proteins including ceruloplasmin and other copper-binding enzymes, thereby leading to systemic copper deficiency and neurodevelopmental impairment.

No conflicting reports have been described to date. Functional concordance between human biochemistry and model systems supports a haploinsufficiency/LoF mechanism. Additional cases may enhance genotype–phenotype correlations and inform therapeutic development.

Key take-home: Biallelic truncating or in-frame deletion variants in SLC33A1 cause autosomal recessive Huppke-Brendel syndrome; N-acetylated amino acid profiles in CSF offer diagnostic biomarkers and underscore the clinical utility of targeted genetic testing.

References

• Metabolic brain disease • 2016 • Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1. PMID:27306358
• Frontiers in neurology • 2022 • Case report: Huppke-Brendel syndrome in an adult, mistaken for and treated as Wilson disease for 25 years. PMID:36119696
• Journal of inherited metabolic disease • 2022 • Abnormal concentrations of acetylated amino acids in cerebrospinal fluid in acetyl-CoA transporter deficiency. PMID:35999711
• JIMD reports • 2024 • Huppke-Brendel syndrome: Novel cases and a therapeutic trial with ketogenic diet and N-acetylcysteine. PMID:39512429

Evidence Based Scoring (AI generated)