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The ATPase AAA-domain protein 3 (ATAD3) is a ubiquitously expressed mitochondrial protein involved in mitochondrial dynamics, DNA-nucleoid structural organization, cholesterol transport and steroidogenesis. Mutations within the ancestral ATAD3A gene are strongly associated with neurological abnormalities due to alterations in the mitochondrial function and homeostasis. Here, we report the case of a subject diagnosed with developmental delay associated with ataxia and progressive atrophy of both cerebellar hemispheres and cerebellar vermis, despite exhibiting a normal biochemical profile. By whole exome sequencing, we identified two biallelic single nucleotide variants within the coding region of ATAD3A in the affected subject. Both variants were previously reported as monoallelic variants with uncertain clinical significance. Importantly, the variant ATAD3A c.251T>C leads to an amino acid change of a highly conserved residue across species and in silico analysis revealed structural alteration in the ATAD3A protein. Ketogenic diet was administered to the subject as a novel therapeutic approach. Notably, the treatment correlated with a reduction in cerebellum atrophy progression and the gradual enhancement of the subject's physical skills, vitality and personal interactions. Thus, we report the first subject with a homozygous status for the ATAD3A c.251T>C (p.Thr84Met) variant. We propose that this mutation led to an alteration of the mitochondrial function, causing the neurological symptoms observed in the subject. The symptoms were partially alleviated following ketogenic diet, improving the subject's quality of life.

Background: The association of mitochondrial DNA (mtDNA) variations with obesity has been investigated in diverse populations across the world. However, such obesity-associated mtDNA examinations are rarely conducted in Arab populations. Materials and methods: We re-sequenced mtDNA displacement loop (D-loop) region of 395 Arab individuals of Kuwait. We categorized the individuals based on their BMI scores as obese (n=232; BMI ≥30 kg/m2), overweight (n=110; BMI ≥25 kg/m2 and G, and m.523delAC were positively correlated with obesity, while m.310T>C, and m.16318A>T were negatively associated. All these variants, except m.16318A>T, remain statistically significant after adjusting for age and gender. We found that the variant m.73A>G increases the likelihood of being obese by 6-fold, whereas haplogroup H decreases the probability of being obese in Arab individuals of Kuwait. Haplotype analysis revealed that a haplotype, A263G-C309CT-T310C, defining the H2a clade of H haplogroup, reduces the probability of being obese. Conclusion: Our study reports, for the first time, the obesity-related mtDNA variants in Arabs of Kuwait. Based on the mtDNA D-loop region variations, we detected particular variants and haplogroup that are related with increased and decreased probability of being obese in the Kuwait Arab population.

Ashraf Al Madhoun,1,2 Fahad Alnaser,3 Motasem Melhem,1 Rasheeba Nizam,1 Tala Al-Dabbous,4 Fahd Al-Mulla11Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, 15462 Kuwait City, Kuwait; 2Animal and Imaging Core Facility Department, Dasman Diabetes Institute, Dasman, 15462 Kuwait City, Kuwait; 3Radiology Department, Ibn Sina Hospital, Ministry of Health, Kuwait City, Kuwait; 4Bayt Abdullah Children’s Hospice, NBK Children’s Cancer Hospital, Al-Adan ICU, Kuwait City, KuwaitIt is with great interest to read the comments of Dr. Josef Finsterer on our recentarticle, “Ketogenic diet attenuates cerebellar atrophy progression in a subject with abiallelic variant at the ATAD3A locus by Al Madhoun et al, 2019,” which hasreceived a substantial article-level metrics and respond to the queries raised singlenucleotide polymorphisms and deletion mutations within ATAD3 are lethal at embryonic stage or postnatally and the few survivors are living with low qualityof life.1–3 Accordingly, ATAD3 genotyping enable prediction of genotype/phenotyperelationship.This is in response to the Letter to the Editor

Background: The association of mitochondrial DNA (mtDNA) variations with obesity has been investigated in diverse populations across the world. However, such obesity-associated mtDNA examinations are rarely conducted in Arab populations. Materials and methods: We re-sequenced mtDNA displacement loop (D-loop) region of 395 Arab individuals of Kuwait. We categorized the individuals based on their BMI scores as obese (n=232; BMI ≥30 kg/m2), overweight (n=110; BMI ≥25 kg/m2 and G, and m.523delAC were positively correlated with obesity, while m.310T>C, and m.16318A>T were negatively associated. All these variants, except m.16318A>T, remain statistically significant after adjusting for age and gender. We found that the variant m.73A>G increases the likelihood of being obese by 6-fold, whereas haplogroup H decreases the probability of being obese in Arab individuals of Kuwait. Haplotype analysis revealed that a haplotype, A263G-C309CT-T310C, defining the H2a clade of H haplogroup, reduces the probability of being obese. Conclusion: Our study reports, for the first time, the obesity-related mtDNA variants in Arabs of Kuwait. Based on the mtDNA D-loop region variations, we detected particular variants and haplogroup that are related with increased and decreased probability of being obese in the Kuwait Arab population.