Table 1.

Demographic and clinical review of the eight homozygous c.1100C > T, p. Thr367Ile VARS2 encephalopathy cases. Data on P1-P6 are obtained from literature (see references); cases A and B are described in present study

	Origin	Sex	First medical referral	Current age/death	Clinical and neurological signs	Lab tests	Brain MRI (spectroscopy)	OXPHOS study
P1a1	Italy (Sardinia)	M	First months	Death at 8 years	Developmental delay, microcephaly, seizures, nystagmus, facial dysmorphia	n.a.	T2 hyperintensity in insulae, right fronto-temporal cortex, periventricular WM (lactate in frontal WM)	Complex I deficiency (25% residual activity)
P22	Poland	F	Birth	Alive at 5 years	Hypotonia, developmental delay, ataxia, seizures, pathological visual evoked potentials	n.a.	T2/FLAIR WM-hyperintensity, cerebral atrophy (lactate)	n.a.
P3b2	Afghanistan	F	6 months	Death at 7 years	Microcephaly, severe hypotonia, developmental delay, nystagmus, seizures	Serum lactate 2.3 mmol/l (normal 0.55–2.00)	Cerebellar atrophy, T2 hyperintensity of dentate nuclei & thalami; thin corpus callosum	n.a.
P4b2	Afghanistan	F	6 months	Death at 8 years	Progressive microcephaly, hypotonia, developmental delay, limb spasticity, seizures	Serum lactate 2.8 mmol/l (normal 0.55–2.00)	Cerebellar atrophy, T2 hyperintensity of dentate nuclei & thalami; thin corpus callosum	n.a.
P5b2	Afghanistan	M	Birth	Alive at 5 months	Hypotonia, progressive microcephaly	Serum lactate 4.4 mmol/l (normal 0.55–2.00) CSF lactate 3.08 mmol/l (normal 1.2–2.1)	Cerebellar hypoplasia	n.a.
P63	Portugal	F	Birth	Death at 28 months	Developmental delay, nystagmus, severe hypotonia, spastic tetraparesis, microcephaly, seizures, feeding difficulties	Serum lactate 2.72 mmol/L (normal 0.55–2.00) CSF lactate 1.45 mmol/L (normal 1.2–2.1)	Global atrophy, diffuse T2 WM-hyperintensity	Complex II + III: 2.6 nmol/min/mg (normal 2.6–12)
A4	Italy (Sardinia)	F	11 months	6 years old	Motor and language delay, hypotonia, limb spasticity; dysmorphisms. No seizures	Normal serum lactate	T2 hyperintensity in deep WM and posterior internal capsule; corpus callosum hypoplasia and cortical cerebellar atrophy (increased lactate and decreased NAA in cerebellar WM lesions)	Complex I and III deficiency
B4	Italy (Sardinia)	F	2 years	5 years old	Developmental delay, nystagmus, hypotonia, limb spasticity; facial dysmorphisms; seizures	Slightly increased serum lactate	First MRI: mega-cisterna magna with slight cerebellar atrophy; cerebellar atrophy and vermis hypoplasia at follow-up MRI (normal spectroscopy)	n.a.

Legend: M male, F female, WM white matter, NAA N-acetyl-aspartate, n.a. not applicable

^a Clinical update on P1, subsequent to 2014 publication, was obtained from his medical records at the Unit of Child Neuropsychiatry, University Hospital of Sassari, where he has been treated

^bSiblings

¹ Diodato et al. [6]; ²Bruni et al. [3]; ³Pereira et al. [8]; ⁴Present study