Portal de Periódicos da CAPES

A Novel AIFM1 ‐Related Disorder Phenotype Treated with Deep Brain Stimulation

2023; Wiley; Volume: 39; Issue: 1 Linguagem: Inglês

10.1002/mds.29616

1531-8257

Jordi Pijuan, Irina F. Sevrioukova, Óscar García‐Campos, Mar Hernaez, Laura Gort, Marta Gómez‐Chiari, Cristina Jou, Santiago Candela‐Cantó, Jordi Rumià, Rafael Artuch, Francesc Palau, Janet Hoenicka, Juan Darío Ortigoza‐Escobar,

RNA and protein synthesis mechanisms

Apoptosis-inducing factor (AIF) is a mitochondrial flavin adenine dinucleotide (FAD)-dependent oxidoreductase involved in oxidative phosphorylation (OXPHOS) and redox control.1-3 Pathogenic variants in the AIFM1 gene have been linked to combined OXPHOS deficiency,4 Cowchock syndrome,5 X-linked deafness,6 and X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy.7 Here, we report a 6-year-old boy presenting generalized chorea in wakefulness beginning in the first weeks of life, dystonic posturing, and orofacial dyskinesia. A marked developmental delay has been detected since 4 months of age. On physical examination at 6 years of age, we found acquired microcephaly, poor visual contact with severely altered comprehension, and absent spontaneous language. He had generalized hypotonia and difficulty maintaining head support. His muscular strength appeared normal, with normal tendon reflexes. He did not have sensorineural deafness or skeletal abnormalities. Initial biochemical studies, including plasma lactate, amino acids, and urinary organic acids, were normal. Brain magnetic resonance imaging confirmed microcephaly and showed agenesis of the corpus callosum and olfactory bulbs, hypomyelination, dysmorphic basal ganglia, and a hypoplastic pituitary gland (Fig. S1). Muscle biopsy displayed minimal nonspecific changes (Fig. S2). Whole-exome sequencing of the patient and his parents identified a new hemizygous missense variant in the AIFM1 gene (c.169 T>C, p.Ser57Pro) inherited from his mother. p.Ser57Pro, which is located outside structural domains for binding FAD and NADH, is a variant of uncertain significance (VUS) according to American College of Medical Genetics guidelines, and it has been predicted to be damaging by several in silico prediction tools (Fig. 1A, Table S1). Functional studies in the patient's muscle and fibroblasts showed decreased OXPHOS function and mitochondrial mass and also mitochondrial network defects in the presence of normal AIF levels in mitochondria (Fig. 1B–D, Table S2). In addition, staurosporine-treated fibroblasts showed p.Ser57Pro enhanced AIF nuclear translocation and increased sensitivity to apoptotic stimuli (Figs. 1E,F and S3). Nevertheless, recombinant AIFWT and AIFSer57Pro studies demonstrated comparable redox-linked properties, thus suggesting that AIFSer57Pro maintains oxidoreductase activity (Fig. 1G–I, Table S3, Figs. S4 and S5). Altogether, these results argued that p.Ser57Pro might affect both of the known functions of AIF. If this were the case, p.Ser57Pro would result in a particularly severe and unique phenotype among 63 clinically documented cases of AIFM1-related disorders (Table S4). The patient received a combination of biotin, coenzyme Q10, riboflavin, and tetrabenazine, resulting in partial improvement. He underwent internal globus pallidus (Gpi) deep brain stimulation (DBS) with final parameters as follows: left Gpi 2-c+, 2.8 V, 60 ms, 130 Hz; and right Gpi 9-c+, 2.8 V, 60 ms, 130 Hz. The motor part of the Burke–Fahn–Marsden Dystonia Rating Scale pre-DBS was 76.5/120 points and post-DBS at 6 months was 59/120 points (22% improvement). The abnormal involuntary movement scale pre-DBS was 21 points and post-DBS at 3 months was 14 points (33% improvement) (Video 1). Alongside these quantitative measurements, direct observations from his parents have documented a number of positive changes resulting from DBS therapy. These include enhanced ease in dressing the patient, enhanced sleep quality, and a significant reduction in feeding time as a result of decreased abnormal movements. Moreover, the specialized school has reported positive changes, including an increase in his attentiveness. Our results broaden the phenotypic spectrum of AIFM1-related disorders and suggest that DBS is an effective treatment for choreodystonia in these cases. The functional validation of VUSs of this gene is relevant given the clinical heterogeneity associated with AIFM1 defects. Notably, in this case, the reclassification of the p.Ser57Pro variant to ‘likely pathogenic’ highlights the significance of our findings in contributing to the understanding and management of such conditions. This case exemplifies expert analysis, gene identification, and tailored treatment—a glimpse into the future of neurostimulation therapies. The legal guardians gave their written consent to the recording of the patient for publication, and the study received ethical approval by the Ethics Committee. We thank the patient and his family. This work was supported by the CIBERER-ACCI 2019-16; the Generalitat de Catalunya and European Regional Development Fund grants SLT002/16/00174, 2015 FEDER/S21, and 2021/SGR-01610; the Fundación Isabel Gemio and the Torró Solidari-RAC1 i Torrons Vicens and FIS (PI20-00340). The CIBERER is an initiative of the Instituto de Salud Carlos III, and the Department of Genetic Medicine of Sant Joan de Déu Children's Hospital is part of the Centre Daniel Bravo de Diagnòstic i Recerca de Malalties Minoritàries. J.P. was the recipient of a postdoctoral research contract from CIBERER. Conceptualization, J.D.O.-E. and J.H.; acquisition of data and formal analysis, J.P., I.F.S., O.G.-C., M.H., L.G., M.G.-C., C.J., S.C.-C., J.R., R.A., F.P., J.H., and J.D.O.-E.; writing original draft: J.D.O.-E. and J.H.; funding acquisition, J.D.O.-E., F.P., and J.H. The authors declare that there are no additional disclosures to report. The data that support the findings of this study are available from the corresponding authors, upon reasonable request. TABLE S1. Predicted effect of the AIFM1 variant p.Ser57Pro. TABLE S2. Biochemical analysis of OXPHOS activities in patient's muscle. TABLE S3. Spectral and redox properties of human AIFWT and AIFSer57Pro. TABLE S4. Overview of the literature review of AIFM1-related disorders. FIGURE S1. Brain MRI at 30 months of age. FIGURE S2. Muscular biopsy studies. FIGURE S3. Apoptotic studies in (p.Ser57Pro) AIF patient. FIGURE S4. Absorbance spectra of the oxidized WT and AIFSer57Pro. FIGURE S5. Time course of FAD oxidation in CTCs formed by WT and AIFSer57Pro. DATA S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.