SDHA Variants Can Only Be Classified as Causative Once Their Pathogenicity Has Been Proven

With interest, we read the article by Ürey et al. [2023] on 2 patients with mitochondrial disorder due to the compound heterozygous variants c.1328G>A and c.872A>C in SDHA in patient 1 and the compound heterozygous variants c.1946del and c.1909-12_1909-11del in SDHA in patient 2 [Ürey et al., 2023]. The phenotype of patient 1 was classified as Leigh syndrome and the phenotype of patient 2 as myocardiopathy [Ürey et al., 2023]. It was concluded that a mitochondrial disorder should be suspected in patients with intellectual disability, developmental delay, epilepsy, progressive external ophthalmoplegia, ataxia, myoclonia, and cardiomyopathy [Ürey et al., 2023]. The study is excellent but has limitations that are cause of concerns and should be discussed.

The main limitation of the study is that the pathogenicity of the variants in patient 1 and patient 2 remained unproven. All four detected variants were classified as variants of unknown significance by in silico assessment. All variants have not been reported in the literature before. Furthermore, succinate dehydrogenase (SDH) deficiency, which is to be expected in pathogenic SDHA variants, has not been documented either in histological or immunohistological or in biochemical studies of the muscle homogenate. There is also no evidence that the described variants segregated with the phenotype within the two families. Therefore, it remains unconfirmed that the presented SDHA variants were truly pathogenic in the two index cases. Another argument against the causality of the SDHA variants, at least in patient 2, is that one of the variants was localized in an intron. We should know how to explain the pathogenicity of the variant when it is not in an exon.

Patient 1 had elevated urine lactate but surprisingly normal serum lactate [Ürey et al., 2023]. This is unusual and requires an explanation. Usually, serum lactate is also elevated when there is elevation of urine lactate. Patient 2 had extensively high serum lactate [Ürey et al., 2023]. We should know whether repeated measurement of serum lactate confirmed this baseline value and whether the patient presented clinically with symptoms of metabolic acidosis such as tachypnea, impaired consciousness, nausea, emesis, tiredness, or headache.

Patient 1 was described with “encephalopathy” without defining what the authors mean [Ürey et al., 2023]. Encephalopathy can have different meanings. Some authors use the term synonymously with epilepsy, some for cerebral disorders without morphological abnormalities, and some for nonspecific cerebral manifestations in the presence of morphological changes on imaging.

Patient 2 obviously manifested with myopathy [Ürey et al., 2023]. We should know the results of needle electromyography of clinically affected muscles, whether the electromyography was myogenic, neurogenic, or nonspecific, and whether the patient also presented with muscle wasting, cramping, or hypotonia. It would also be interesting to know whether the muscle homogenate was tested for respiratory chain functions, particularly complex-II of the respiratory chain.

Overall, the interesting study has limitations that call the results and their interpretation into question. Addressing these issues would strengthen the conclusions and could improve the status of the study. Before SDHA variants are classified as causative, their pathogenicity must be proven.