. 2022 Jan 3;9(2):218–228. doi: 10.1002/mdc3.13398

TABLE 1.

Demographic, phenotypic, and genetic features of nine new and nine previously reported NDUFA12 cases

Pedigree	Case	Sex/AE (y)	Ethnicity	Consanguinity	FH	Perinatal history/NDM	AO (y)	Symptom(s) at onset	Clinical manifestations			Brain MRI	Findings from other investigations	NDUFA12 variants (NM_018838.5)	Ref
Pedigree	Case	Sex/AE (y)	Ethnicity	Consanguinity	FH	Perinatal history/NDM	AO (y)	Symptom(s) at onset	Neurological	Ophthalmological	Other	Brain MRI	Findings from other investigations	NDUFA12 variants (NM_018838.5)	Ref
Cases first reported in this study
A	1	F/10	Pakistani	Yes	No	Premature induced birth due to intrauterine growth restriction. Normal NDM.	6.5	Gait abnormality and left arm weakness	Trunk hypotonia; dystonic posturing; episode of status dystonicus.	Visual impairment	Febrile convulsion; scoliosis	T2 hyperintensities of the posterior putamen bilaterally (chronic gliotic scarring and acute cytotoxic oedema).	Optic atrophy. Normal paired plasma and CSF lactate. NCS/EMG: no evidence of peripheral neuropathy. MB: mild predominance of slow fibers. RCE: low complex I, normal complexes II‐III‐IV.	Hom c.178C > T (p.Arg60 ^§§ )	‐
B ^§	2	M/21	Turkish	Yes	Yes	Normal birth. Normal NDM.	7	Gait disturbance with unilateral intoeing	Generalized dystonia, including oromandibular and left foot dystonia which worsens with exercise; focal seizures (since age 12); cognitive decline.	None	Kyphoscoliosis	Atrophy and T2 hyperintensity of lentiform nucleus	Plasma lactate and pyruvate, ammonia, urinary organic acids, serum and urine amino acids, VLCFA: normal. MRS: neuronal loss in lentiform nucleus.	Hom c.121dupG (p.Glu41Glyfs ^§§ 10)	‐
B ^§	3	M/25	Turkish	Yes	Yes	Normal birth. Normal NDM.	10	Gait disturbance with unilateral intoeing	Left foot dystonia, which worsens with exercise; hyperreflexia lower limbs.	None	Kyphoscoliosis	Atrophy and T2 hyperintensity of lentiform nucleus bilaterally	Plasma lactate and pyruvate, ammonia, urinary organic acids, serum and urine amino acids, VLCFA: normal. MRS: neuronal loss in lentiform nucleus.	Hom c.121dupG (p.Glu41Glyfs ^§§ 10)	‐
C ^§	4	M/9	Egyptian	Yes	Yes	Normal birth. Motor developmental delay	2	Unilateral tip‐toe walking, recurrent falls	Right hand tremor; generalized Spasticity lower limbs Muscle weakness	None	Kyphoscoliosis	T2/FLAIR hyperintensity and T1 hypointensity of BG, with some cystic areas	Normal amino acid/acylcarnitine. Increased urine lactate. CK and ceruloplasmin: normal.	Hom c.178C > T (p.Arg60 ^§§ )	‐
C	5	F/20	Egyptian	Yes	Yes	Normal birth. Normal NDM.	16	Clumsiness and tremor of the right hand	Muscle weakness right hand	None	‐	T2 hyperintensity of GP	‐	Hom c.178C > T (p.Arg60 ^§§ )	‐
D	6	M/16	Saudi	Yes	Yes	Global delay of NDM	2	Gait unsteadiness and falls Spastic‐dystonic tetraparesis	Right hand dystonia	Visual impairment	‐	Bilateral symmetrical T2 hyperintensity of BG along with left BG encephalomalacia	Optic nerve atrophy. Normal plasma lactate. Increased plasma pyruvate.	Hom c.4G > T (p.Glu2 ^§§ )	‐
D	7	M/12	Saudi	Yes	Yes	Global delay of NDM	6	Gait unsteadiness and falls	Spastic quadriplegia	None	Recurrent UTI; mild attention deficit disorder.	Bilateral symmetrical T2 hyperintensity of BG	Increased plasma lactate.	Hom c.4G > T (p.Glu2 ^§§ )	‐
E	8	M/16	Syrian	Yes	No	Normal birth. Normal NDM.	15	Subacute visual loss	Absent direct and consensual pupillary light reflexes	Visual impairment	Depression	Normal	V.A. 20/1600 bilaterally. Optic atrophy. Normal plasma lactate. Serology for HIV, syphilis, HTLV: negative. Autoimmune screening: negative. CSF: mildly elevated proteins (63.9 mg/dL; r.i. <45 mg/dl).	Hom c.253G > T (p.Glu85 ^§§ )	‐
F	9	M/33	Turkish	Yes	No	Normal birth. Normal NDM.	28	Acute visual loss	None	Visual impairment	‐	Optic chiasm atrophy	V.A. 20/200 (age 30). Optic atrophy. OCT: markedly thickness of peripapillary nerve fiber layer. NGS gene panel for optic atrophy: negative.	Hom c.83del (p.Phe28Serfr ^§§ 11)	‐
Cases previously reported
G ^§§	10	F/21	Pakistani	Yes	No	Normal birth. Delayed early motor NDM.	2	Regression of motor abilities	Generalized dystonia with dystonic spasms Severe muscle atrophy Slight intellectual disability Dysphagia (PEG) Wheelchair bound	Visual impairment (detected on follow‐up at age 18)	Scoliosis (surgery at age 18) Growth retardation Hypertrichosis Strabismus	T2 hyperintensity of GP	MB: type 1 fiber atrophy and fiber type disproportion. RCE: low complex I, normal complexes II‐III‐IV. Brain MRS: elevated lactate in the whole cerebrum. V.A. 20/25 (right eye), 20/32 (left eye). Fundoscopy: pale optic discs. Plasma lactate: 4.9 mmol/l (r.i. <2.1). CSF lactate: 2.4 mmol/l (r.i. 1.1–1.8). Pale optic discs.	Hom c.178C > T (p.Arg60 ^§ )	1
H ^§§§	11	F/Birth	Mennonite	No	No	Symmetric intrauterine growth restriction ^§§§	Birth	Facial dysmorphisms, short limbs, persistent thrombocytopenia, direct hyperbilirubinemia, and poor feeding ^§§§	–	‐	Facial dysmorphisms (large ears with increased folding anteriorly, long philtrum, small mouth with prominent alveolar ridge, epicanthal folds), short upper and lower extremities with bowing of the tibia and fibula bilaterally, supinated ankles, and mild generalized hypertonia. Flexion wrist contractures, clenched fists. Thumbs were held between the second and third fingers, bilaterally. ^§§§		Elevated ALP; low serum vitamin D 25‐OH; direct hyperbilirubinemia. US abdomen: normal. Thrombocytopenia. Congenital infection screen: negative. US head: normal. Echocardiogram: patent ductus arteriosus and patent foramen ovale. Chest X‐ray: hypoinflated lungs, dysplastic bones throughout the thorax and visualized upper extremities. Skeletal survey: marked osteopenia, foreshortened long bones with thickened diaphyses, irregular “raggedy” metaphyses, and no wormian bones. ^§§§	Hom c.178C > T (p.Arg60 ^§ )	4
I	12	M/9	Italian	Yes	No	Birth: poor sucking, hypotonia. Mild global delay of NDM.	4	Sudden‐onset convergent strabismus	Strabismus, nystagmus, minimal ptosis in the left eye	None	None	Age 5: T2 hyperintensity of the brainstem (red nuclei and tegmental tract) Follow‐up MRIs: normal.	Brain MRS: normal. VEP: increased latency in both eyes. ERG: normal. BAEPs: normal. ECG/Ecocardiography: normal. Plasma lactate: 2.85 mmol/l (r.i. 0.5–2.2) on one occasion only. RCE (muscle homogenate): low complex I, normal complexes II‐III‐IV.	Hom c.86G > A (p.Arg29Lys)	3
L	13	F/15	Italian	Yes	No	Birth: respiratory distress. Normal NDM.	6	Dystonia right arm	Generalized dystonia Spastic‐dystonic gait evolving to spastic‐dystonic tetraparesis Oromandibular dystonia	None	Scoliosis	Typical Leigh syndrome pattern. Follow‐up MRI: lesions in the BG (putamen), partial agenesis of septum pellucidum, and mild enhancement of left optic nerve after gadolinium	Brain MRS: normal. VEP: abnormal in amplitude in both eyes. Cardiological evaluation: normal. Plasma lactate: 3.62 mmol/l (r.i. 0.5–2.2). Urine lactate: >400 mmol/l creatinine (r.i. <200). Plasma amino acids: increased alanine (852 mmol/l; r.i. 150–400). RCE (muscle homogenate): low complex I, normal complexes II‐III‐IV.	Hom c.395delA (p.Lys132Argfs ^§ 50)	3
M	14	F/13	Moroccan	Yes	Yes	Birth: respiratory distress. Normal NDM.	4	Sudden‐onset nystagmus, right hemiparesis	Generalized dystonia Trunk hypotonia Extrapyramidal syndrome Peripheral neuropathy	None	None	T2 hyperintensity of lentiform nucleus and brainstem	Brain MRS: lactate peak. Plasma lactate: 2.4 mmol/l (r.i. 0.5–1.95). CSF lactate: 2.8 mmol/l (r.i. 1–1.9). NCS: peripheral neuropathy. RCE (muscle homogenate): low complex I, normal complexes II‐III‐IV.	Hom c.224G > A (p.Trp75 ^§ )	3
M	15	F/9	Moroccan	Yes	Yes	Normal NDM.	9	Sudden‐onset visual impairment	Extrapyramidal syndrome	Visual impairment	None	T2 hyperintensity of lentiform nucleus	Hyperlactatorachia (lactate 2.8 mmol/L; r.i. 1–1.90, with normal plasma lactate	Hom c.224G > A (p.Trp75 ^§ )	3
M	16	F/7	Moroccan	Yes	Yes	Normal NDM.	7	Visual impairment	None	Visual impairment	None	Normal	Optic atrophy. Hyperlactatorachia (2.4 mmol/L; r.i. 1–1.90)	Hom c.224G > A (p.Trp75Ter)	3
N ^§	17	M/11	Syrian	Yes	Yes	Normal NDM.	5	Limb dystonia	Limb dystonia	None	Episodes of vomiting	T2/T2‐FLAIR hyperintensity of lentiform nucleus and red nucleus	FO, VEP, ERG, BAEPs: normal. Serum lactate: 2.6 mmol/L (r.i. 0.5–2.20) Brain MRS: normal.	Hom c.253G > T (p.Glu85 ^§ )	3
N ^§	18	F/4	Syrian	Yes	Yes	Normal birth. Normal NDM.	3.5	Limb dystonia	Limb and oromandibular dystonia. Rigidity. Tip‐toe walking.	None	None	N.A.	Serum lactate: 2.2 mmol/L (r.i. 0.5–2.20). Acylcarnitine profile and urinary organic acids: normal.	Hom c.253G > T (p.Glu85 ^§ )	3

Abbreviations: AE, age at last evaluation; ALP, alkaline phosphatase; AO, age of onset; BG, basal ganglia; CSF, cerebrospinal fluid; F, female; FH, family history; FO, fundus oculi; GP, globus pallidus; Hom, homozygote; M, male; MB, muscle biopsy; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; N.A., not available; NDM, neurodevelopmental milestones; OCT, optical coherence tomography; PEG, percutaneous gastrostomy; Ref, reference; r.i., reference interval; UTI, urinary tract infections; V.A., visual acuity; VLCFA, very long chain fatty acids; Y, years.

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