Table 3.

Overview of reported FARS2 subjects.

Subject	Citation	Mutations	Age, gender	Age at onset	Clinical phenotype	Seizures	MRI and neuropathological findings	OXPHOS activity	Functional proof of pathogenicity
1.Epileptic phenotype
1	Shamseldin et al.	Y144C homozygous	22 months (deceased) F	35 days	Early-onset epilepsy, developmental delay	Myoclonic epilepsy Refractory	Severe cortical atrophy, abnormal signal intensities in putamen and nucleus caudatus (at 1.5 years)	Skeletal muscle: scattered fibers with intense NADH and SDH activity, no ragged red fibers or COX negative fibers	Yes (Elo et al.)
2	Shamseldin et al.	Y144C homozygous	< 3 months (deceased) M	/	Early-onset epilepsy, developmental delay	Myoclonic epilepsy Refractory	ND	ND	Yes (Elo et al.)
3	Shamseldin et al.	Y144C homozygous	< 3 months (deceased) M	/	Early-onset epilepsy, developmental arrest	Myoclonic epilepsy Refractory	ND	ND	Yes (Elo et al.)
4	Elo et al.	I329T D391V	8 months (deceased) F	2 days	Early-onset epilepsy, developmental arrest,	Myoclonic epilepsy, Multifocal seizures, Refractory	Severe central and cortical atrophy, slight bilateral signal abnormalities in putamina (at 3 m) Autopsy: microcephaly, almost total degeneration of frontal cortex, severe atrophy of hippocampus, basal ganglia and cerebellar cortex, Alpers syndrome	Severe complex IV deficiency in brain and skeletal muscle, Partial complex I deficiency in brain, No deficiency in cultured skin fibroblasts	Yes
5	Elo et al.	I329T D391V	21 months (deceased) F	4 days	Early-onset epilepsy, developmental delay, multiorgan failure	Refractory	ND	ND	Yes
6	Almalki et al.	D325Y microdeletion	30 months M	6 months	Early onset epilepsy, developmental delay	Infantile spasms, focal seizures, epilepsia partialis continua, prolonged seizures Refractory	Symmetrical subcortical white matter lesions. Thinning of corpus callosum	Complex IV deficiency in skeletal muscle and myoblast cell lines, Normal activities in cultured skin fibroblasts	Yes
7	Walker et al.	P85A H135D	15 years (deceased) F	/	Infantile onset motor and speech delay, refractory epilepsy, progressive neurological deterioration	Generalized tonic-clonic, focal seizures, epilepsia partialis continua, recurrent status epilepticus	Extensive signal abnormalities in left caudate, cortex and cerebellum Autopsy: almost total degeneration of occipital and frontal cortex, spongiform change in right thalamus, Alpers syndrome	No ragged-red fibers, no COX negative fibers, polarographic analysis: normal activities complex I-IV	Yes
8	Raviglione et al.	R386G microdeletion	3 years M	3 months	Early-onset epilepsy, axial hypotonia, developmental delay, strabismus, nystagmus, impaired visual fixation	Infantile spasms (3 months) Seizure free (20 months)	Microcephaly, severe brain atrophy, hyperintensity of T2 signal abnormalities in hemispheric white matter and dentate nuclei	In cultured skin fibroblasts: complex I 34% and complex IV 37% residual activity	No
9	Cho et al.	G309S homozygous	3 years M	3 months	Early-onset epilepsy, poor head control (11 months), severe motor delay, spastic legs, brisk deep tendon reflexes	Generalized tonic-clonic, myoclonic, status epilepticus	Diffuse brain atrophy	ND	No
10	Cho et al.	G309S homozygous	17 months F	4 months	Early-onset epilepsy, motor developmental delay	Myoclonic at right hand, generalized tonic-clonic, status epilepticus, Refractory	Thin corpus callosum and diffuse brain atrophy	ND	No
11	Cho et al.	G309S homozygous	8 months (deceased) M	4 months	Early-onset epilepsy	Infantile spasms, ·status epilepticus	Mild brain atrophy	ND	No
12	Cho et al.	G309S homozygous	4 months (deceased) F	3 months	Early-onset epilepsy, developmental delay	Generalized tonic–clonic, focal clonic, hemiclonic	Mild brain atrophy	ND	No
2.Spastic paraplegia phenotype
13	Vernon et al.	R419C microdeletion	13 years M	First weeks	Globally delayed, truncal hypotonia, scoliosis, ptosis, Dorsal rhizotomy surgery at 5 years of age	Complications in neonatal period, seizures only in the neonatal period	Two foci of signal abnormalities in periventricular and deep white matter of right posterior frontal lobe (13 years)	ND	No
14	Vernon et al.	R419C microdeletion	5 years F	2 months	Globally delayed, strabismus, truncal hypotonia, bilateral equinovarus, brisk deep tendon reflexes, intention tremor, dysarthric speech	One seizure at 2 months of age	Normal (at 3 years)	ND	No
15	Yang et al.	D142Y homozygous	41 years F	2 years	Progressive limb spasticity, pyramidal weakness, hyperreflexia, extensor plantar reflexes, scissors gait	No seizures	Normal	ND	Yes
16	Yang et al.	D142Y homozygous	30 years M	1 year	Same phenotype as 15	No seizures	Normal	ND	Yes
17	Yang et al.	D142Y homozygous	26 years F	5 years	Same phenotype as 15	No seizures	Normal	ND	Yes
18	Yang et al.	D142Y homozygous	23 years F	3 years	Same phenotype as 15	No seizures	Normal	ND	Yes
19	Proband 1	A154V P361L	19 years M	6 months	Developmental delay, spastic paraplegia, neurogenic bladder	Mild seizures only between 15 and 30 months of age	Signal abnormalities in anterior parts of mesencephalon Diffuse brain atrophy	Complex IV deficiency in skeletal muscle and cultured skin fibroblasts	Yes
20	Proband 2	V174del P361L	15 years F	10 months	Delayed motor development, spastic paraplegia	No seizures	Signal abnormalities in tegmentum and periaqueductal grey matter Mild progressive cerebellar atrophy	Complex I deficiency and low activity of complex IV in cultured skin fibroblasts Normal activities in skeletal muscle	Yes