Table 3.
Reported cases with MMDS type 3.
| Ref. | Nb of Patients (Nb and Origin of Families) | Age at Onset/Age at Death | Metabolic Findings | Impaired Mitochondrial Proteins | Ophthalmological Findings | Clinical Feature | Brain MRI/Spectroscopy | Genotype (IBA57: NM_001010867) |
|---|---|---|---|---|---|---|---|---|
| [78] | 2 (1F, Morocco) | Antenatal/1 d, 15 d | Increased lactate (bl) and glycine (bl, CSF) levels | Complexes I, II, and IV, lipoylated proteins, IBA57 protein | NA | Polyhydramnios, microcephaly, severe hypotonia | Cerebral atrophy, polymicrogyria, CC hypoplasia | c.[941A > C]; [941A > C], p.[(Gln314Pro)]; [(Gln314Pro)] |
| [79] | 12 (1F, Palestine) | After 3 y/alive (12–65 y) | Normal lactate level | Complexes I, II, lipoylated proteins | Optic atrophy | Peripheral neuropathy, progressive spastic paraplegia | Hyperintensity in WM, cystic cavitation. Cerebellar, CC, CSC atrophy | c.[678A > G]; [678A > G], p.[Gly227Valfs]; [Gly227Valfs] |
| [80] | 1 (Morocco) | 6 m/17 m | Increased lactate and glycine levels (bl, CSF) | Complexes I, II, and IV, lipoylated proteins, | NA | FD with vomiting, opistothonos crises, progressive hypotonia, skills regression | Central and PV LE involving CC IC, USC, and cerebellar WM/lactate peak | c.[436C > T]; [436C > T], p.[(Arg146Trp)]; [(Arg146Trp)] |
| [50] | 2 (2F, unknown) | 3 w–8 m/2–11 m | High lactate level (bl, CSF) | Complexes I, II, lipoylated proteins, PDHc | NA | Hypotonia, with recurrent myoclonus, pyramidal syndrome, apnea | PV LD, myelination delay | c.[335T > G]; [437G > C], p.[(Leu112Trp)]; [(Arg146Pro)] c.[316A > G]; [738C > G]; p.[(Thr106Ala)]; [(Asn246Lys)] |
| [81] | 3 (2F, unknown) | 11 m–2 y/alive at 6–7 y | Intermittent high lactate level (bl, CSF) | Complexes I, II, lipoylated proteins, IBA57 protein level | NA | Spasticity, axial hypotonia, PMR | PV and CC LE with cysts or cavitation | c.[323A > C]; [940C > T], p.[(Tyr108Ser)]; [(Gln314*)] c.[323A > C]; [150C > A], p.[(Tyr108Ser)]; [(Cys50*)] |
| [75] | 4 (4F, Tunisia, unknown) | 4–18 m/2 y (n = 2) or alive at 12–16 y | High lactate and pyruvate levels (bl or CSF, 3/4) | Complex II (fib: 3/4, muscle 2/3)), complex I fib (1/4) | Nystagmus (2/4), abnormal VEP (3/3) | Severe PMR (4/4), FD (3/4), spastic tetraparesis (3/4), severe hypotonia (1/4), epilepsy (1/4) | Cavitating LE or LD (3/4), cerebral and cerebellar WM involvement (3/4)/lactate peak (3/4) | c.[586T > G]; [c.686C > T], p.[(Trp196Gly]; [Pro229Leu] c.[87insGCCCAAGGTGC]; [313C > T], p.[(Arg30Alafs)]; [(Arg105Trp)] c.[706C > T]; [706C > T], p.[(Pro236Ser)]; [(Pro236Ser)] c.[316A > G]; [757G > C]; p.[(Thr106Ala]; [(Val253Leu)] |
| [69] | 2 (2F, unknown)) | 18–20 m/alive at 19–31 m | NA | NA | NA | Milestones loss, difficulty in standing, progressive quadriparesis | Large hyperintense lesions in FP WM (2/2), in CC, and multiple WM cysts (1/2) | c.[738C > G]; [802C > T], p.[(Asn246Lys)]; [(Arg268Cys)] c.[656A > G]; [706C > T], p.[(Tyr219Cys)]; [(Pro236Ser)] |
| [82] | 3 (2F, Israel, Japan) | 7–20 m/alive at 7–19–29 y | Normal lactate level (1/1) | Normal RCC activity (1/1) | Reduced vision with pale discs (2/3), pendular nystagmus (1/3); no (1/3) | No neurological signs (1/3), spasticity with learning disabilities (1/3), PMR, spasticity, seizures, severe hypotonia and PMD (1/3) | PV WM hypersignal, thin optic nerves, PV rarefaction with thin CC (2/3), progressive WM atrophy, and cystic degeneration (1/3) | c.[335T > C]; [c.588dup], p.[(Leu112Ser)]; [(Arg197Alafs)] c.[386A > T]; [731A > C], p.[(Asp129Val)]; [(Glu244Ala)] |
| [83] | 11 (9F, China) | 5–15 m/Alive at 11 m to 10 y | High blood lactate level (2/11) | NA | Nystagmus (3/11), visual impairment 3/11 | Spasticity and motor regression (11/11), seizures (2/11) | Cavitating lesions in the frontal, parieto-occipital WM, CC (7/11), temporal (4/11), cerebellar, or IC (1/11) | c.[286T > C]; [316A > G], p.[(Tyr96His)]; [(Thr106Ala)] (n = 2) c.[701A > G]; [782T > C], p.[(Asp234Gly)]; [(Ile261Thr)] c.[286T > C]; [697C > T], p.[(Tyr96His)]; [(Arg223*)] (n = 3) c.[188G > A]; [286T > C], p.[(Gly63Asp)]; [(Tyr96His)] c.[286T > C]; [307C > T], p.[(Tyr96His)]; [(Gln103*)] (n = 2) c.[286T > C]; [754G > T], p.[(Tyr96His)]; [(Gly252Cys)] c.[22C > T]; [286T > C], p.[(Arg8*)]; [(Tyr96His)] |
| [84] | 17 (unknown, China) | NA | NA | NA | Visual impairment (8/17) | NA | No progressive cavitating LE: involving diffuse (12/17 or deep WM (5/17), | c.[22C > T]; [286T > C], p.[(Arg8*)]; [(Tyr96His)] c.[188G > A]; [286T > C], p.[(Gly63Asp)]; [(Tyr96His)] (n = 2) c.[236C > T]; [307C > T], p.[(Pro79Leu)]; [(Gln103*)] c.[286T > C]; [697C > T], p.[(Tyr96His)]; [(Arg223*)] (n = 4) c.[286T > C]; [307C > T], p.[(Tyr96His)]; [(Gln103*)] (n = 2) c.[286T > C]; [316A > G], p.[(Tyr96His)]; [(Thr106Ala)] (n = 2) c.[286T > C]; [522_523del], p.[(Tyr96His)]; [(Leu175Alafs)] c.[286T > C]; [589_590del], p.[(Tyr96His)]; [(Arg197Alafs)] c.[286T > C]; [754G > T], p.[(Tyr96His)]; [(Gly252Cys)] c.[286T > C]; [1053G > A], p.[(Tyr96His)]; [(Trp351*)] c.[701A > G]; [782T > C], p.[(Asp234Gly)]; [(Ile261Thr)] |
| [85] | 2 (2F, China) | 5–15 m/unknown | Normal lactate level | NA | NA | PMR | LE | c.[286T > C]; [697C > T], p.[(Tyr96His)]; [(Arg223*)] c.[286T > C]; [589_590del], p.[(Tyr96His)]; [(Arg197Alafs)] |
Bl: blood; CC: corpus callosum; CSC: cervical spinal cord; CSF: cerebrospinal fluid; d: day(s); F: families; FD: feeding difficulties; fib: fibroblast; FP: frontoparietal; IC: internal capsule; LD/LE: leuko-dystrophy/encephalopathy; m: month(s); MRI: Magnetic resonance imaging; NA: not available; PMR/D: psychomotor regression/delay; PV: periventricular; RCC: respiratory chain complexes; USC: upper spinal cord; VEP: visual evoked potentials; w: week(s); WM: white matter; y: year(s).