Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population. METHODS: Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations. RESULTS: Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of < 0.00067-0.00084%. CONCLUSIONS: This study reveals the first extensive genotype-phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.

Sound Propagation in a Bose-Fermi Mixture: From Weak to Strong Interactions.

Particlelike excitations, or quasiparticles, emerging from interacting fermionic and bosonic quantum fields underlie many intriguing quantum phenomena in high energy and condensed matter systems. Computation of the properties of these excitations is frequently intractable in the strong interaction regime. Quantum degenerate Bose-Fermi mixtures offer promising prospects to elucidate the physics of such quasiparticles. In this work, we investigate phonon propagation in an atomic Bose-Einstein condensate immersed in a degenerate Fermi gas with interspecies scattering length a_{BF} tuned by a Feshbach resonance. We observe sound mode softening with moderate attractive interactions. For even greater attraction, surprisingly, stable sound propagation reemerges and persists across the resonance. The stability of phonons with resonant interactions opens up opportunities to investigate novel Bose-Fermi liquids and fermionic pairing in the strong interaction regime.

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Observation of fermion-mediated interactions between bosonic atoms.

In high-energy and condensed-matter physics, particle exchange has an essential role in the understanding of long-range interactions and correlations. For example, the exchange of massive bosons leads to the Yukawa potential1,2, and phonon exchange between electrons gives rise to Cooper pairing in superconductors3. Here we show that, when a Bose-Einstein condensate of caesium atoms is embedded in a degenerate Fermi gas of lithium atoms, interspecies interactions can give rise to an effective trapping potential, damping, and attractive boson-boson interactions mediated by fermions. The latter, which is related to the Ruderman-Kittel-Kasuya-Yosida mechanism4, results from a coherent three-body scattering process. Such mediated interactions are expected to form new magnetic phases5 and supersolids6. We show that under suitable conditions, the mediated interactions can convert a stable Bose-Einstein condensate into a train of 'Bose-Fermi solitons'7,8. The predicted long-range nature of the mediated interactions opens up the possibility of correlating distant atoms and preparing new quantum phases.

Observation of a Degenerate Fermi Gas Trapped by a Bose-Einstein Condensate.

We report on the formation of a stable quantum degenerate mixture of fermionic ^{6}Li and bosonic ^{133}Cs in an optical trap by sympathetic cooling near an interspecies Feshbach resonance. New regimes of quantum degenerate Bose-Fermi mixtures are identified. With moderate attractive interspecies interactions, we show that a degenerate Fermi gas of Li can be fully confined in a Cs Bose-Einstein condensate without external potentials. For stronger attraction where mean-field collapse is expected, no such instability is observed. Potential mechanisms to explain this phenomenon are discussed.