Phenotype of NDUFV1-related Disease.

With interest we read the article by Incecik et al.[1] about a 10-year-old boy, born to consanguineous parents, with late-onset Leigh syndrome due to the variant c.1268C>T in the NDUFV1 gene who initially presented with gait ataxia. We have the following comments and concerns.

Leigh syndrome is characterized by symmetric T2-hyperintensities of the basal ganglia, the brainstem, or the cerebellum.[2] However, Figure 1 of the case report shows asymmetric hyperintensity of the caput of the caudate nucleus.[1] Did hyperintensities of the caudate nucleus become bilaterally symmetric during follow-up?

The patient presented with marked cerebellar signs (horizontal nystagmus, ataxic gait, dysarthria, dysmetria, dysdiadochokinesia, and bilateral intention tremor).[1] Since Figure 1 does show the cerebellum properly, it would be interesting to know if there was cerebellar atrophy or other cerebellar lesions on imaging? Was there involvement of the cerebellar cortex or the cerebellar nuclei?

It would be interesting to know why the NDUFV1 gene was tested. Did the authors apply exome sequencing or did they apply a targeted, single-gene approach? Since the parents were obviously asymptomatic, the trait of inheritance is most likely autosomal recessive. Did any of the two parents or both carry the mutation in the NDUFV1 gene of the index case?

Mutations in NDUFV1 are usually associated with deficiency of complex I of the respiratory chain. Were biochemical investigations of the muscle homogenate or another tissue carried out and was complex I deficiency detected?

Since Leigh syndrome is a progressive disease in the majority of the cases, it would be interesting to know for how long the patient was followed up and if there was progression of the clinical, radiologic, or spectroscopic findings. Did the patient develop epilepsy, spasticity, insomnia, tremor, dystonia, personality change, myopathy, and visual impairment, as has been previously reported in association with NDUFV1 mutations [Table 1].

Table 1

Phenotypic manifestations of NDUFV1 mutations

Organ	Manifestation	References
Cerebrum	Cystic leucoencephalopathy	Whadwa et al. (2018)[5]
	Regression of motor milestones	Zafeiriou et al. (2008)[6]
	Spastic diplegia	Zafeiriou et al. (2008)
	Infantile bilateral striatal necrosis	Lal et al. (2013)[7]
	Mental retardation	Bénit et al.[3]
	Apnea	Bénit et al.[3]
	Lethargy	Bénit et al.[3]
	Ataxia	Incecik et al.[1]
	Spasticity	Baertling et al. (2018)[8]
	Leucodystrophy	Schuelke et al. (1999)[9]
	Myoclonic epilepsy	Schuelke et al. (1999)
	Depression	Baertling et al. (2018)
	Insomnia	Baertling et al. (2018)
	Personality change	Baertling et al. (2018)
	Aphonia	Baertling et al. (2018)
	Cerebellar atrophy	Baertling et al. (2018)
	Tremor	Baertling et al. (2018)
	Dystonia	Laugel et al.[4]
Muscle	Ophthalmoplegia	Laugel et al.[4]
	Ptosis	Bénit et al.[3]
	Limb muscle weakness	Baertling et al. (2018)
	Lactic acidosis	Baertling et al. (2018)
Eyes	Leber’s optic neuropathy	Baertling et al. (2018)

Nothing is reported about any therapeutic intervention.[1] Did the patient receive coenzyme-Q, riboflavin,[3] a ketogenic diet,[4] or L-carnitine and was any of these measures effective in the index case? Which was the long-term outcome of the patient?

In conclusion, this interesting case could be more meaningful if clinical and genetic data of the consanguineous parents would have been provided, if biochemical investigations would have been carried out, if imaging data of the cerebellum would have been provided, and if applied therapeutic interventions would have been discussed.