Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.

SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS-expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.

Novel AHDC1 Gene Mutation in a Brazilian Individual: Implications of Xia-Gibbs Syndrome.

Xia-Gibbs syndrome (XGS) is a rare neurological disorder characterized by global developmental delay, hypotonia, intellectual disability, seizures, and sleep apnea. XGS is defined by monoallelic pathogenic variants in AHDC1. In this study, we identified a Brazilian patient carrying a likely de novo AHDC1 nonsense mutation (c.451C>T; p.Arg151*) which was absent in both parents. All disease-causative variants already associated with XGS have been reviewed and the mutation described here corresponds to the closest one to the N-terminal region. Our findings were discussed based on the suggested genotype-phenotype correlation of the disease.