Table 2.

Summary of clinical findings in individuals with NDUFAF6-related LS.

Patient and source of study	Proband B (this study)	A1; [18]	A2; [18]	B; [17,18]a	C; [18]	P1; [20]	P2; [20]	P3; [20]	C8orf38 Patient P1; [21]; [22]	C8orf38 Patient P2; [21]	Pt512; [23]	Pt 598; [23]	Pt 101; [23]	Pt 330; [23]
Gender	Male	Male	Female	Male	Male	Female	Male	Male	Female	Male	Female	Male	Male	Male
Age of onset	4 years	21 months	12 months	3.5 years	5 years	30 months	30 months	17 months	10 months	7 months	Newborn	2 months	6 years	17 months
Symptoms at onset	Febrile episode, and months later toe walking and focal hand dystonia	Febrile episode and temporary loss of autonomous gait	Insidious, limb dysmetria and trunk titubation	Insidious, gross motor and language difficulties, dystonic movements and decreased fine motor ability.	Insidious, gait unsteadiness and motor coordination problems	Insidious, toe walking and speech difficulties	Insidious, toe walking and speech difficulties	Insidious, toe walking and speech difficulties	Focal right hand seizures, ataxia, rigidity, decreased movement and strength.	Focal right hand seizures, ataxia, rigidity, decreased movement and strength.	NR	NR	NR	NR
Developmental abnormality	Motor regression	Psychomotor regression	Psychomotor delay	Motor regression. Difficulty in verbal fluency but verbal comprehension preserved.	Psychomotor regression	Neuromotor regression	Neuromotor regression	Neuromotor regression	Neuromotor regression.	Neuromotor regression.	Neurological regression	Neurological regression	Neurological regression	Muscle atrophy
Neurological and cerebellar findings	Dysarthria, ataxic gait, dystonia	Ataxic gait, fine tremor, dysmetria, drooling, hypertonia, dystonia	Ataxic gait, limb dysmetria, trunk titubation, dystonia	Dysarthria, dystonic movements, decreased fine motor abilities, dystonia	Drooling, dysarthria, oromandibular dystonia, extrapyramidal hypertonia, mild camptocormic gait, dystonia	Dysarthria, stuttering, dysphagia, dystonia	Dysarthria, stuttering, dysphagia, dystonia	Dysarthria, stuttering, dysphagia, dystonia	Focal right hand seizures, ataxia, rigidity, decreased movement and strength.	Focal right hand seizures, ataxia, rigidity, decreased movement and strength.	NR	NR	NR	NR
Brain MRI	Bilateral T2 hyperintensities in the putamina without mass effect or contrast enhancement. No white matter abnormalities.	T2 hyperintensities in putamen, dentate nuclei, superior cerebellar peducle and caudate nucleus. Hypotrophic Putamen	Bilateral T2 hyperintensities in dentate nucleus and superior cerebellar peduncle.	Bilateral T2 intensities (and T1 hypointensities) in utamen, caudate nuclei, dentate nuclei. Gradual putaminal cavitation.	Bilateral T2 hyperintensities in putamen. Putaminal hypotrophy (cavitation).	Bilateral T2 hyperintensities in putamen. Caudate spared.	Bilateral T2 hyperintensities in putamen, and partly in caudate. Mild putaminal volume loss (cavitation).	Bilateral T2 hyperintensities and volume loss in putamen and caudate.	“Neuroimaging consistent with Leigh syndrome.”	“Neuroimaging consistent with Leigh syndrome.”	NR	Abnormalities of the basal ganglia on brain MRI.	NR	Abnormalities of the basal ganglia on brain MRI.
State of life at last consultation, age	Alive (adult)	Alive, 5 years old	Alive, 3 years old	Alive, 8.5 years old	Alive, 11 years old	Alive, 11 years old	Alive, 8 years old	Alive, 6 years old	Died at 34 months (pneumonia)	Alive, 34 months	NR	NR	NR	NR
Complex I deficiency - muscle	NR	Reduced, 42%	NR	Normal	Normal	Reduced, 60%	Reduced, not quantified	Reduced, not quantified	Reduced, 36%	NR	NR	NR	NR	NR
Complex I deficiency - fibroblasts	126%	Reduced, 38%	NR	Reduced, 25%	Normal	NR	NR	Reduced, not quantified	Reduced, 14%	Reduced, 14%	Reduced, < 30%	Reduced, < 30%	Reduced, < 40%	Reduced, < 30%
Serum lactate; normal range is 0.580–2.10 mmol/L	Normal	Initially normal then elevated; 2.818 mmol/L	Elevated; 2.293 mmol/L	Normal, value not reported	Normal, value not reported	Normal; 1.63 mmol/L	1.59 mmol/L	NR	Elevated, value not reported	Elevated, value not reported	Elevated, value not reported	NR	NR	NR
Serum pyruvate; normal range is 55–145 umol/L.	Normal	Initially normal then elevated; 181 umol/L	Elevated; 146 umol/L	Normal, value not reported	Normal, value not reported	NR	NR	NR	NR	NR	NR	NR	NR	NR
Consanguinity	No	No	No	No	No	No	No	No	Yes	Yes	No	No	No	No
Paternal NDUFAF6c variant	c.371 T > C (p.Ile124Thr)	c.532G > C (p.Ala178Pro)	c.532G > C (p.Ala178Pro)	c.532G > C (p.Ala178Pro)	NM_152416.3 c.532G > C (p.Ala178Pro)	c.371 T > C (p.Ile124Thr)	c.371 T > C (p.Ile124Thr)	c.371 T > C (p.Ile124Thr)	c.296A > G (p.Gln99Arg)	c.296A > G (p.Gln99Arg)	c.226 T > C (p.Ser76Pro)	c.371 T > C (p.Ile124Thr)	c.805C > G (p.His269Asp)	c.820A > G (p.Arg274Gly)
Maternal NDUFAF6c variant	c.420 + 2dup (produces abberant isoforms)	c.420 + 784C- > T (p.?; intron retention of ~124 nucleotides)	c.420 + 784C- > T (p.?; intron retention of ~124 nucleotides)	c.420 + 784C > - T (p.?; intron retention of ~124 nucleotides)	c.420 + 784C > - T (p.?; intron retention of ~124 nucleotides)	c.554_558delTTCTT (p.Tyr187AsnfsTer65)	c.554_558delTTCTT (p.Tyr187AsnfsTer65)	c.554_558delTTCTT (p.Tyr187AsnfsTer65)	c.296A > G (p.Gln99Arg)	c.296A > G (p.Gln99Arg)	c.805C > G (p.His269Asp)	c.206A > T (p.Asp69Val)	c.371 T > C (p.Ile124Thr)	c.820A > G (p.Arg274Gly)

“+” denotes the presence of a feature; “− “denotes the absence of a feature; “NR” represents not reported.

^a, Patient B initially reported in Biancardi et al. 2016 [17]; the second variant and biochemical abnormalities are reported by Catania et al.

^b, also reported in McKenzie et. al. 2011 [22].

^c, Variant nomenclature in NDUFAF6 based on NM_152416.3.