Ketogenic diet attenuates cerebellar atrophy progression in a subject with a biallelic variant at the ATAD3A locus [Response to Letter]

Ashraf Al Madhoun Fahad Alnaser Motasem Melhem Rasheeba Nizam Tala Al-Dabbous Fahd Al-Mulla 1Genetics 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, Kuwait Dear editor It is with great interest to read the comments of Dr. Josef Finsterer on our recent article, “Ketogenic diet attenuates cerebellar atrophy progression in a subject with a biallelic variant at the ATAD3A locus by Al Madhoun et al, 2019,” which has received a substantial article-level metrics and respond to the queries raised single nucleotide polymorphisms and deletion mutations within ATAD3 are lethal at embryonic stage or postnatally and the few survivors are living with low quality of life. Accordingly, ATAD3 genotyping enable prediction of genotype/phenotype relationship. Desai et al (2017) associated ATAD3 function with cholesterol homeostasis and maintenance of the mitochondrial genome stability. We thought that Ketogenic Diet (KD) may modulate mitochondrial biogenesis especially that it has proven efficacy in mitochondriopathies-mediated neurological disorders. Thus, it is not unrealistic to include KD treatment in a disease that is caused by ATAD3 gene mutations. The girl described in our paper is unique. She has been clinically evaluated extensively in Canada, but unfortunately, the family was not given a formal diagnosis. We diagnosed her with Harel-Yoon syndrome after discovering a novel pathogenic missense homozygous mutation in the ATAD3 gene (rs546711654 c.251C>T; p.Thr84Met). Globally, the variant allele frequency of rs546711654 is 0.0002 (https://www.ncbi.nlm.nih.gov/clinvar/variation/452865/). This information means that the disease is rare and therefore it is not possible to study other children harboring the same mutation. In response to KD, we never claimed an increase in the relative sagittal length of the cerebellum. But rather, an obvious slowing of her cerebellar atrophy. The KD was applied between the 2nd and 3rd MRI examination at the age of 4 and 5.5 years old. It has been reported that KD lowers the blood pH, increases ATP by shifting from glucoseto ketone-based metabolism. Although all body tissues are influenced by KD, the most prominent effect is on the nervous system activities. Accordingly, we do not exclude a positive effect on the muscle function. KD increases mitochondrial biogenesis. We agree that a real-effect of KD can only be assessed reliably in double-blind randomized clinical trials, but this is Correspondence: Fahd Al-Mulla Head of Genetics and Bioinformatics Department, Dasman Diabetes Institute, Dasman, 15462 Kuwait City, Kuwait Tel +9 652 224 2999 Ext. 2211 Email fahd@al-mulla.org The Application of Clinical Genetics Dovepress open access to scientific and medical research