Table 1.
Phenotypes Associated with Compound Heterozygous or Homozygous POLG Mutations
| Nucleotide Change | Amino Acid Change | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No | Gender | Onset (yrs) |
DD or Dementia |
Sz | Liver | PEO | Lact | Dx | Other Symptoms | Allele 1 | Allele 2 | Allele 1 | Allele 2 | Domains |
| 1 | F | 23 | - | + | + | NA | NA | Alpers | Ataxia, neuropathy, hearing loss, valproate-associated liver failure |
c.1399G>A | c.1399G>A | p.A467T | p.A467T | L/L |
| 2 | M | 1 | + | + | + | - | + | Alpers | Stroke, hypotonia | c.1399G>A | c.2157+5_+ 6 gc>ag | p.A467T | c.2157+5 _+6 gc>ag splice? | L/L |
| 3 | F | 2 | + | + | + | - | - | Alpers | Ataxia | c.1399G>A | c.2542G>A | p.A467T | p.G848S | L/P |
| 4 | F | 2 | + | + | + | - | + | Alpers | Stroke | c.1399G>A | c.2542G>A | p.A467T | p.G848S | L/P |
| 5 | F | 1.5 | + | + | + | - | + | Alpers | Cortical atrophy, hypoglycemia |
c.1399G>A | c.2542G>A | p.A467T | p.G848S | L/P |
| 6 | F | 9 | + | + | + | - | - | Alpers | Stroke, ataxia, exercise intolerance |
c.1399G>A | c.2542G>A | p.A467T | p.G848S | L/P |
| 7 | M | 0.8 | + | + | - | - | - | Alpers | Hypotonia, failure to thrive |
c.1399G>A | c.2542G>A | p.A467T | p.G848S | L/P |
| 8 | M | 2 | + | + | + | - | - | Alpers | c.1399G>A | c.2542G>A | p.A467T | p.G848S | L/P | |
| 9 | M | 1 | + | + | - | - | - | Alpers | Family history of acute liver failure |
c.1399G>A | c.1270_1271del CT | p.A467T | p.L424G fsX28 | L/L-null |
| 10 | M | 1 | + | + | + | - | - | Alpers | c.1399G>A | c.2657T>C | p.A467T | p.L886P | L/P | |
| 11 | F | 3 | + | + | + | - | - | Alpers | Ptosis, ataxia, visual hallucinations |
c.1399G>A | c.202C>T | p.A467T | p.Q68X | L/Exo-null |
| 12 | M | 4 | + | + | - | - | - | Alpers | c.1399G>A | c.2143C>T | p.A467T | p.Q715X | L/L-null | |
| 13 | F | 1.5 | + | + | + | - | + | Alpers | Chorea, microcephaly, leukodystrophy |
c.1399G>A | c.2544_2545 insC c.3708G>T | p.A467T | p.T849H(i nsC) fs868X- p.Q1236H | L/P-null |
| 14 | M | 2 | + | + | - | - | - | Alpers | Chorea, Family history of Alpers syndrome |
c.1399G>A | c.2740A>C | p.A467T | p.T914P | L/P |
| 15 | F | 2 | + | + | + | - | - | Alpers | c.1399G>A | c.2740A>C | p.A467T | p.T914P | L/P | |
| 16** | F | 10 | + | + | + | - | - | Alpers | Cortical blindness, hearing loss |
c.248T>C | c.2662G>A | p.L83P | p.G888S | Exo/P |
| 17** | F | 1 | + | + | + | - | - | Alpers | Family history of Alpers syndrome |
c.1491G>C c.2243G>C c.3428A>G |
c.2542G>A | p.Q497H-p.W748S-p.E1143G | p.G848S | L/P |
| 18 | M | 1 | + | + | + | - | - | Alpers | Family history of Alpers syndrome |
c.3286C>T c.3708G>T |
c.3286C>T c.3708G>T | p.R1096C-p.Q1236H | p.R1096C-p.Q1236H | P/P |
| 19 | M | 0.5 | - | - | - | - | - | Alpers | Family history of Alpers syndrome. Diagnosed pre-symptomatically. |
c.752C>T c.1760C>T |
c.2542G>A | p.T251I-p.P587L | p.G848S | Exo-L/P |
| 20 | F | 4 | + | + | + | - | + | Alpers | Muscle weakness, respiratory failure |
c.2243G>C, c.3428A>G |
c.2480+1 G>A | p.W748S-p.E1143G | C.2480+1 G>A splice | L/P |
| 21 | F | 17 | + | + | - | - | - | ANS | Hearing loss | c.1399G>A | c.1491G>C c.2243G>C c.3428A>G |
p.A467T | p.Q497H-p.W748S-p.E1143G | L/L |
| 22 | M | 17 | + | + | - | - | - | ANS | Ataxia, exercise intolerance, cerebellar atrophy, SCAE |
c.2590C>T | c.2584G>A | p.R964C | p.A862T | P/P |
| 23 | F | 15 | - | + | + | + | + | ANS | Stroke, chorea, ataxia, ptosis, retinitis pigmentosa, liver transplant |
c.2554C>T |
c.32G>A c.1880G>C |
p.R852C | p.G11D-p.R627Q | P/MTS-L |
| 24** | F | 32 | - | - | - | + | - | arPEO+ | Neuropathy, myopathy, SANDO |
c.1399G>A | c.1399G>A | p.A467T | p.A467T | L/L |
| 25** | M | 60 | - | - | - | + | - | arPEO+ | Ataxia, neuropathy, myopathy, hearing loss, cerebellar atrophy, SANDO/SCAE |
c.1399G>A | c.2209G>C | p.A467T | p.G737R | L/L |
| 26** | F | 48 | - | - | - | + | + | arPEO+ | Neuropathy, myopathy, ptosis, SANDO |
c.1399G>A | c.3412C>T | p.A467T | p.R1138C | L/P |
| 27** | M | 33 | - | - | - | + | + | arPEO+ | Neuropathy, myopathy, SANDO |
c.2243G>C, c.3428A>G |
c.2243G>C, c.3428A>G | p.W748S-p.E1143G | p.W748S-p.E1143G | L/L |
| 28 | F | 3 | + | - | - | - | + | MCHS | Renal tubulopathy, dysmorphic featues, cataract, short stature, myopathy |
c.2209G>C | c.2827C>T, c.3428A>G | p.G737R | p.R943C-p.E1143G | L/P |
| 29 | F | 1 | + | - | + | - | + | MCHS | Fatigue, pancreatitis, cyclic vomiting |
c.752C>T, c.1760C>T |
c.3572A>G | p.T251I-p.P587L | p.K1191R | Exo-L/P |
| 30* | F | 0.2 | + | - | - | - | + | MCHS | Microcephaly, failure to thrive, hearing loss, abnormal MRI |
c.752C>T, c.1760C>T |
c.2558G>A | p.T251I-p.P587L | p.R853Q | Exo-L/P |
| 31 | M | 8 | NA | NA | NA | NA | NA | U | NA | c.2243G>C, c.3428A>G |
c.2542G>A | p.W748S-p.E1143G | p.G848S | L/P |
| 32 | M | 1 | + | - | - | - | - | U | Myopathy, RRF, elevated CK |
c.1550G>T | c.3586G>A | p.G517V | p.D1196N | L/P |
| 33 | M | 1 | + | - | + | - | - | U | microcephaly | c.1550G>T | c.3383G>A | p.G517V | p.R1128H | L/P |
Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence NM_002693.1, according to journal guidelines (www.hgvs.org/mutnomen). The initiation codon is codon 1. Novel mutations are shown in bold and neutral variants are in shown in blue.
Abbreviations: MCHS= Myocerebrohepatopathy Spectrum, ANS = Ataxia Neuropathy Spectrum, MEMSA= Myoclonus Epilepsy Myopathy Sensory Ataxia arPEO+ = autosomal recessive Progressive External Ophthalmoplegia, MTS = mitochondrial targeting sequence; Exo = exonuclease domain; L = linker region; P = Polymerase domain; DD = Developmental Delay; Sz = Seizures; Lact = Elevated lactate; Dx = Diagnosis.
Patient recognized early on the basis of family history positive for liver failure in a sibling.
These cases have been described in more details elsewhere (Milone et al., submitted; Bao et al., 2008; Brunetti-Pierri et al., 2008).