Leigh Syndrome should only be Diagnosed if the Diagnostic Criteria are met and all Differential Diagnoses have been Ruled out

We read with interest the article by Behzadi et al. about a 6-year-old girl diagnosed with Leigh syndrome based on the clinical presentation of hypothyroidism, diabetes, paraparesis, demyelinating sensorimotor polyneuropathy and epilepsy, cerebral magnetic resonance imaging (MRI) with confluent white matter lesions in the frontotemporal lobes and a genetic test revealing an MT-ND1 mutation [1] , The patient was treated with glargine, aspartate, insulin and levothyroxine [1] .The study is remarkable, but some points should be discussed.The first point is that the classification as Leigh syndrome is not comprehensible.Unfortunately, no MRI images were shown, but the description of the confluent white matter lesion predominantly in the fronto-temporal lobes argues against the diagnosis of Leigh syndrome.Cerebral imaging in Leigh syndrome is characterized by symmetrical lesions in the brainstem, cerebellum or spinal cord.Therefore, the patient should be categorized as non-syndromic mitochondrial disease and not Leigh syndrome.The second point is that the exact mutation in MT-ND1 has not been reported [1] .Knowledge of the variant is crucial for assessing whether it is truly pathogenic.The heteroplasmy rate of the variant in the different affected tissues is also missing.The results of the genetic tests in the parents and other first-degree relatives are also missing.Knowing which relative carried the mutation is crucial for genetic counselling and assessment of disease progression.Since mtDNA variants are inherited through the maternal line in 75% of cases [2] , it is very likely that the mother also carried the variant found in the index patient.It should also be mentioned whether the parents were related by blood or not.The third point is that lower limb weakness following SARS-CoV-2 infection is more likely to be due to Guillain-Barre syndrome (GBS) affecting the lower limbs than Leigh syndrome.Did the CSF show cyto-albuminous dissociation at the time of onset of lower limb paraparesis?Were the nerve conduction studies at this time indicative of a proximal lesion?Did she develop bulbar signs?Were cytokines (e.g.IL-6), chemokines and glial factors elevated in the CSF?What was the outcome of the paraparesis?It was reported that the patient subsequently attended elementary school [1] .If the paraparesis has fully recovered, GBS is more likely than Leigh syndrome.The fourth point is that the CSF was not examined for elevated lactate levels, either by direct measurement of the CSF or by magnetic resonance spectroscopy (MRS).Most patients with Leigh syndrome have a negative lactate peak on MRS or an elevated CSF lactate on direct measurement [3] .The fifth point is that the patient obviously developed epilepsy [1] .Did she have only one seizure or did she experience multiple seizures?We should know the results of the cerebral MRI at that time and the results of the EEG recordings.Surprisingly, her current medication did not include anti-seizure medication.Has a stroke-like episode (SLE) been ruled out as the cause of the seizure?The final issue is that the article mentions Figures 1, 2 and 3 in the text, but no figures are shown in the article [1] .Were the figures published as a supplement?To summarize, this interesting study has limitations that affect the results and their interpretation.Addressing these limitations could strengthen the conclusions and support the message of the study.All open questions need to be clarified before readers uncritically accept the conclusions of the study.The diagnosis of Leigh syndrome should be based on the detection of an mtDNA or nDNA variant compatible with Leigh syndrome and typical imaging abnormalities.In patients carrying mtDNA variants, segregation of the variant within the family should be documented and the heteroplasmy rate and mtDNA copy number reported.