. 2020 Nov 9;29(3):533–538. doi: 10.1038/s41431-020-00757-x

Table 1.

Clinical characterization of Pts1, 2 and 3.

Patient, sex, origin, age at the follow-up	FARS2 variants	Clinical summary at onset and during follow-up	Brain MRI	Biochemistry
Pt1, Female, French and Chinese origin 8 years	Compound heterozygous c.[1256G>A]; [1269_1276dup] p. [(Arg419His)]; [(Ser426*)]	Regular pregnancy. BW: 2471 g (<5th percentile), BL: 44.5 cm (<5th percentile); BHC: 32.5 cm (<5th percentile); Apgar score 7–9. Presentation <1 month with axial hypotonia and developmental delay; Head control was acquired at 10 months and she could sit at 2 years. No signs of liver failure. No epileptic seizures. EEG recording (repeated during the follow-up): normal background activity and physiological organization during sleep and wakefulness. Electromyography and nerve conduction were normal. At 8 years: spastic tetraparesis, dystonic movements, and axial hypotonia. Unable to walk unassisted. Dysarthric language, able to write using a keyboard. No psychomotor regression episodes, but stagnation periods concomitant with febrile episodes during the first 3 years of life.	Normal at 1 and 2.2 years Mild ventriculomegaly, no enlargement of the subarachnoid spaces (3.5 years)	Transient increase in PL: 1.4–2.9 mmol/l (normal range 0.7–1.8) PP: 0.12–0.15 mmol/l (normal range 0.08–0.17) Lactate/pyruvate ratio: 16–19 (normal range 6–14) OXPHOS: ↓CI in muscle ↓CI+IV in fibroblasts
Pt2, Female, French origin, 16 years	Compound heterozygous c.[989G>A]; [1113G>T] p. [(Arg330His)]; [(Leu371Phe)]	Regular pregnancy. Normal growth parameters at birth; Apgar score 10/10. 6 weeks: neurological distress, global hypotonia. No signs of liver failure. Severe psychomotor delay. No head control. No visual contact. Can react to auditive stimuli. From 19 months, started to present myoclonic focal and generalized seizures that were resistant to antiepileptic treatment composed by phenytoin, vigabatrin, topiramate, lamotrigine, and clonazepam in variable combinations. EEG showed spikes and poly-spikes discharges predominating on occipital regions, activated by intermittent photic stimulation (IPS). At 16 years: spastic tetraparesis and severe muscular atrophy predominating on inferior limbs. Mild scoliosis.	Marked ventriculomegaly, enlargement of the subarachnoid spaces due to white matter loss, especially in the sylvian fissures, abnormal T2 hyperintensities in the lentiform nuclei and dorsal brainstem (4 months, 15 years), cerebellar atrophy. Proton MR spectrum from the basal ganglia shows elevated lactates (15 years).	PL 2.5–4.8 mmol/l (<2.20 mmol/l) PP: 0.21 mmol/l (normal range 0.08–0.17) Lactate/pyruvate ratio: 13.7–16.6 (normal range 6–14) CSF -L: 9.3 mmol/l (normal range: 1.4–2.2) OXPHOS: ↓CIV in muscle and fibroblasts
Pt3, Male, French origin, 5 years	Compound heterozygous c.[1256G>A]; [251A>C] p. [(Arg419His)]; [(His84Pro)]	Regular pregnancy. Normal growth parameters at birth; Apgar score: 10/10. Global hypotonia since birth. No signs of liver failure. Severe psychomotor delay. Partial head control at 10 months. Myoclonic generalized and focal seizures since the first year of life that were partially controlled by levetiracetam, clonazepam and piracetam. EEG showed spikes and poly-spikes discharges predominating on occipital regions. At 5 years: global hypotonia and lumbar mild scoliosis. He cannot sit unaided, has good contact, but no verbal language. He has nasogastric feeding.	Moderate ventriculomegaly and enlargement of the subarachnoid spaces. Dentate nuclei, brainstem, and pallidal T2 hyperintensity at the age of 1 and 3 years. Normal spectroscopy.	PL: 2.6–4.8 mmol/l (normal range 0.7–1.8) PP: 7.8 mmol/l (normal range 0.08–0.17) CSF-L: 5.8 mmol/l (normal range: 1.4–2.2) Normal liver enzymes OXPHOS: ↓CIV in fibroblasts

Patient, sex, origin, age at the follow-up

FARS2 variants

Clinical summary at onset and during follow-up

Brain MRI

Biochemistry

Pt1,

Female,

French and Chinese origin

8 years

Compound heterozygous

c.[1256G>A];

[1269_1276dup]

p. [(Arg419His)]; [(Ser426*)]

Regular pregnancy. BW: 2471 g (<5th percentile), BL: 44.5 cm (<5th percentile); BHC: 32.5 cm (<5th percentile); Apgar score 7–9.

Presentation <1 month with axial hypotonia and developmental delay;

Head control was acquired at 10 months and she could sit at 2 years.

No signs of liver failure. No epileptic seizures.

EEG recording (repeated during the follow-up): normal background activity and physiological organization during sleep and wakefulness. Electromyography and nerve conduction were normal.

At 8 years: spastic tetraparesis, dystonic movements, and axial hypotonia.

Unable to walk unassisted. Dysarthric language, able to write using a keyboard.

No psychomotor regression episodes, but stagnation periods concomitant with febrile episodes during the first 3 years of life.

Normal at 1 and 2.2 years

Mild ventriculomegaly, no enlargement of the subarachnoid spaces (3.5 years)

Transient increase in PL: 1.4–2.9 mmol/l

(normal range 0.7–1.8)

PP: 0.12–0.15 mmol/l (normal range 0.08–0.17)

Lactate/pyruvate ratio: 16–19 (normal range 6–14)

OXPHOS: ↓CI in muscle

↓CI+IV in fibroblasts

Pt2,

Female,

French origin,

16 years

Compound heterozygous

c.[989G>A];

[1113G>T]

p. [(Arg330His)]; [(Leu371Phe)]

Regular pregnancy. Normal growth parameters at birth; Apgar score 10/10.

6 weeks: neurological distress, global hypotonia.

No signs of liver failure.

Severe psychomotor delay. No head control. No visual contact. Can react to auditive stimuli.

From 19 months, started to present myoclonic focal and generalized seizures that were resistant to antiepileptic treatment composed by phenytoin, vigabatrin, topiramate, lamotrigine, and clonazepam in variable combinations.

EEG showed spikes and poly-spikes discharges predominating on occipital regions, activated by intermittent photic stimulation (IPS).

At 16 years: spastic tetraparesis and severe muscular atrophy predominating on inferior limbs. Mild scoliosis.

Marked ventriculomegaly, enlargement of the subarachnoid spaces due to white matter loss, especially in the sylvian fissures, abnormal T2 hyperintensities in the lentiform nuclei and dorsal brainstem (4 months, 15 years), cerebellar atrophy. Proton MR spectrum from the basal ganglia shows elevated lactates (15 years).

PL 2.5–4.8 mmol/l (<2.20 mmol/l)

PP: 0.21 mmol/l (normal range 0.08–0.17) Lactate/pyruvate ratio: 13.7–16.6 (normal range 6–14)

CSF -L: 9.3 mmol/l (normal range: 1.4–2.2)

OXPHOS: ↓CIV in muscle and fibroblasts

Pt3,

Male,

French origin,

5 years

Compound heterozygous

c.[1256G>A];

[251A>C]

p. [(Arg419His)]; [(His84Pro)]

Regular pregnancy.

Normal growth parameters at birth; Apgar score: 10/10.

Global hypotonia since birth.

No signs of liver failure.

Severe psychomotor delay. Partial head control at 10 months.

Myoclonic generalized and focal seizures since the first year of life that were partially controlled by levetiracetam, clonazepam and piracetam.

EEG showed spikes and poly-spikes discharges predominating on occipital regions.

At 5 years: global hypotonia and lumbar mild scoliosis. He cannot sit unaided, has good contact, but no verbal language.

He has nasogastric feeding.

Moderate ventriculomegaly and enlargement of the subarachnoid spaces.

Dentate nuclei, brainstem, and pallidal T2 hyperintensity at the age of 1 and 3 years.

Normal spectroscopy.

PL: 2.6–4.8 mmol/l (normal range 0.7–1.8)

PP: 7.8 mmol/l (normal range 0.08–0.17)

CSF-L: 5.8 mmol/l (normal range: 1.4–2.2)

Normal liver enzymes

OXPHOS: ↓CIV in fibroblasts

Accession numbers: FARS2 cDNA: NM_001318872.1; mtPheRS: NP_001305801.1, The normal ranges for the different biochemical indicators are indicated in the brackets.

BW birth weight, BL birth length, BHC birth head circumference, CSF-L lactate in cerebral-spinal fluid, PL plasma lactate, PP plasma pyruvate.