NEMMLAS Due to Biallelic WARS2 Variants

Abstract

With interest we read the article by Virdee et al about an 8-year-old female with neurodevelopmental disorder, mitochondrial, with abnormal movements, and lactic acidosis, with or without seizures (NEMMLAS) syndrome due to the compound heterozygote mutations c.797del and c.938A>T in the WARS2 gene. The patient did not develop seizures but benefited from a cocktail with coenzyme-Q (CoQ), lipoic acid, creatine-monohydrate, and vitamin E. We have the following comments and concerns. The first shortcoming of the study is that no detailed family history was provided. Except for exclusion of consanguinity, no further information about other family members was provided. Thus, we should be informed if any of the first-degree relatives also manifested with the disease, if the mother had a history of abortions or stillbirths, and if the culprit genetic defects were found in any of the relatives. A second shortcoming is that we do not know if the detected variants were inherited or sporadic. For future genetic counseling, it is crucial that the genetic status of probands from several generations is available and that not only the index case is genetically investigated. A third shortcoming of the study is that no prospective work-up for multisystem disease was carried out. From most of the mitochondrial disorders, it is well known that not only a single organ or tissue is affected but at least one other but usually several other organs. Because involvement of other organs may be subclinical at an early stage and because involvement of other organs may strongly determine the outcome, it is crucial investigating all patients with a mitochondrial disorder prospectively for multisystem involvement. Particularly excluded should be long-QT syndrome, arrhythmias, hypertrophic, dilated, restrictive, histiocytoid, Takotsubo, or noncompaction cardiomyopathy, epilepsy, retinopathy, optic atrophy, renal insufficiency, diabetes, and neuropathy. We do not agree with the statement that the cocktail applied was effective. No double-blind placebo controlled trial provides evidence that any of the four compounds is effective in mitochondrial disorders in general and particularly NEMMLAS. Only in case of primary CoQ-deficiency has the application of CoQ been shown to be effective. Because the improvement of some phenotypic features was attributed to the application of this cocktail, it should be specified which of the 4 compounds was the truly effective one. It is unclear which mitochondrial enzyme assay was used. It should be specified which assay was applied, which tissue was investigated, and what were the reference limits. If activity of respiratory chain enzymes in the muscle homogenate was measured, we should be informed about the technique applied and the exact values measured. Missing is the information about the lactate levels in the brain. Lactate should have been determined either directly in the cerebrospinal fluid or by means of magnetic resonance spectroscopy. Missing is a discussion about the pathogenicity of the variants found in the index case. Overall, this interesting report has a number of shortcomings, which need to be addressed before drawing final conclusions. Patients with mitochondrial disorders generally need to be closely and thoroughly managed to prevent deterioration from mitochondrion-toxic drugs, to detect treatable complications, and to provide comprehensive, decisive, and informative genetic counseling.