Table 1. Patient cohort with POLG mutations.
| Mutation | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient | Nucleotide change | Amino-acid substitution | Domain | Index Sex | Age (onset) | Family history | Clinical features | Deceased | Histological analysis | Respiratory chain analysis | mtDNA analysis |
| Patients with two POLG1 mutations identified by sequencing | |||||||||||
| 1a | c.911T>G c.911T>G | p.Leu304Arg p.Leu304Arg | Exo | M | 15 years | Sporadic | SANDO | Yes | RRF, COX− (40%) | ↓ CI, II, III (f) | Multiple deletions (m) |
| 2a | c.1139G>A c.1399G>A | p.Gly380Asp p.Ala467Thr | Exo L | M | 63 years | Sporadic | CPEO, cerebellar ataxia, weakness of lower limbs, cognitive impairment | No | RRF, COX−, lipid accumulation | NA | Multiple deletions (m) |
| 3a | c.975-976 ins C c.1399G>A | p.Thr326fs p.Ala467Thr | Exo L | M | 4 years | Recessive | Alpers | No | NA | NA | Depletion (l) |
| 4a | c.911T>G c.2243G>C | p.Leu304Arg p.Trp748Ser | Exo L | F | 27 years | Sporadic | R-EPC, sensory and cerebellar ataxia, axonal sensory neuropathy, CPEO | No | RRF(30%), COX− (30%), lipid accumulation | No deficiency (m) | Multiple deletions (m) |
| 5a | c.2740A>C c.1399G>A | p.Thr914Pro p.Ala467Thr | Pol L | F | 15 months | Sporadic | Alpers | No | NA | NA | Depletion (l) |
| 6 | c,1391T>C c.2302 A>G | p.Met464Thr p.Lys768Glu | Pol L | F | <20 years | Sporadic | Axonal sensorimotor neuropathy, sensory ataxia | No | RRF, COX− (5%) | No deficiency (m), ↓CIV (f) | Multiple deletions (m) |
| 7 | c.752C>T c.2452G>A | p.Thr251Ile p.Gly848Ser | Exo Pol | F | 45 years | Sporadic | CPEO | No | RRF, COX− (20%) | ↓ CI, III, IV, V (m) | Multiple deletions (m) |
| 8 | c.1399G>A c.2243G>C | p.Ala467Thr p.Trp748Ser | L L | F | 17 years | Sporadic | R-EPC, axonal neuropathy, cerebellar ataxia, hyperintensity of rolandic, occipital and cerebellar cortex and dentate nucleus | No | No histological abnormalities | No deficiency (m, f) | No deletion nor depletion (m) |
| 9 | c.2243G>C c.2740A>C | p.Trp748Ser p.Thr914Pro | L Pol | M | 6 years | Sporadic | Refractory generalized epilepsy with status epilepticus, hepatic cholestasis and cytolysis, proximal tubulopathy, hyperintensity of thalamus | No | Lipid accumulation | No deficiency (m, f, k), ↓CIII and IV (l) | Depletion (m: 39% and l: 36%) |
| 10a | c.235C>T c.3239G>T | p.Leu79Phe p.Ser1080Ile | Exo Pol | F | 8 years | Recessive | Polyendocrinopathy with adrenocortical insufficiency and hypothyroïdy, refractory generalized status epilepticus, cerebral white matter lesions | Yes | Not done | No deficiency (f) | Not done |
| 10b | c.235C>T c.3239G>T | p.Leu79Phe p.Ser1080Ile | Exo Pol | F | 8 years | Recessive | R-EPC, cerebellar ataxia, ptosis, symmetrical signal abnormalities of thalami and parieto-occipital cortex | No | Not done | No deficiency (f) | Not done |
| 11 | c.2243G>C c.2243G>C | p.Trp748Ser p.Trp748Ser | L | M | 37 years | Sporadic | SANDO, parkinsonism | No | No histological abnormalities | No deficiency (m) | Multiple deletions (m) |
| Patients with one POLG1 mutation identified by sequencing and one by QMPSF | |||||||||||
| 12 | c.2243G>C | p.Trp748Ser | L | F | 2 years | sporadic | R-EPC, delayed psychomotor development | No | Lipid accumulation | ↓ CI, III, V (l), ↓ CII, III, V (m) | 25% mtDNA (m), 30% mtDNA(l) |
| Patients with one POLG1 mutation identified by sequencing | |||||||||||
| 13 | c.1399G>A | p.Ala467Thr | L | M | 60 years | sporadic | ALS-like, sensorimotor neuropathy | Yes | No histological abnormalities | ↓ CII, III, IV, V (m) | Multiple deletions (m), 39% mtDNA |
| 14 | c.3218C>T | p.Pro1073Leu | Pol | F | 5 years | sporadic | Myopathy, myoclonic epilepsy, tubulopathy | No | Lipid accumulation | No deficiency (m) | No deletion nor depletion |
| 15 | c.3559C>T | p.Arg1187Trp | Pol | M | 10 years | recessive | Hepatic failure, myopathy, psychomotor delay | No | NA | NA | NA |
| 16 | c.2923C>T | p.Gln975* | Pol | F | 6 years | sporadic | Seizures, psychomotor delay, dystonia, hyperintensity of thalami | No | NA | No deficiency (m) | No deletion nor depletion |
| 17a | c.695G>A | p.Arg232His | Exo | M | 25 years | ? | Axonal sensorimotor neuropathy, sensory ataxia, parkinsonism | No | Lipid accumulation | No deficiency (m) | Multiple deletions (m) |
| 17b | c.695G>A | p.Arg232His | Exo | F | 30 years | ? | Axonal sensorimotor neuropathy | No | Not done | Not done | Not done |
| 17c | c.695G>A | p.Arg232His | Exo | F | 20 years | ? | Axonal sensorimotor neuropathy, sensory ataxia | No | Not done | Not done | Not done |
| 18a | c.3550G>A | p.Asp1184Asn | Pol | M | 70 years | ? | CPEO, axonal sensory neuronopathy, parkinsonism | No | Not done | Not done | Not done |
| 18b | c.3550G>A | p.Asp1184Asn | Pol | M | 75 years | ? | CPEO, axonal sensory neuronopathy | No | Not done | Not done | Not done |
Abbreviations: M, male; F, female; CPEO, chronic progressive external ophtalmoplegia; SANDO, sensory ataxic neuropathy dysarthria and ophtalmoparesis; R-EPC, refractory epilepsia partialis continua; ALS, amyotrophic lateral sclerosis; L, linker domain; Exo, exonuclease domain; Pol, polymerase domain; RRF, ragged-red fibers; COX−-, cytochrome c oxidase-negative fibers; RC, respiratory chain; CI–CV, complex I–V of the RC; m, muscle; l, liver; f, fibroblasts; k, kidney; NA, not available; ?, unclear; ↓, decrease.
All histological analyses were performed on muscle tissue. Novel variants are written in bold.
a
Previously reported by Naïmi et al.11