Table 1.
Demographic, molecular, and clinical data of MMA subjects.
| # | Age (years) | Sex | Race | Transplant | Gene | Variant 1 | Variant 2 | Serum MMA (μM) | % 1-13C3 dose metabolized (60 and 120 minutes) | Tmax Δ13C (minutes) | eGFR (mL/min/1.73 m2) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 4.2 | M | W | - | MMUT | c.1207C>T, p.Arg403Ter | Unknown | 774 | 12.51 | 18.97 | 30 | 110.1 |
| 2 | 5.4 | M | A | - | MMUT |
c.1630_1631delinsTA p.Gly544Ter |
c.1106G>A, p.Arg369His | 1,465 | 5.70 | 11.82 | 45 | 37.4 |
| 3 | 8.7 | M | M | - | MMUT | c.682C>T, p.Arg228Ter | c.322C>T, p.Arg108Cys | 2,011 | 6.43c | 13.92c | 25 | 40.2 |
| 4 | 8.8 | M | W | - | MMUT | c.1106G>A, p.Arg369His | c.1324G>C, p.Ala442Pro | 4,170 | 11.16 | 25.52 | 60 | 26.1 |
| 5 | 9.6 | F | B | - | MMUT | c.91C>T, p.Arg31Ter | c.250G>T, p.Glu84Ter | 167 | 12.31 | 20.39 | 30 | 92.4 |
| 6 | 9.7 | M | W | - | MMUT | c.52C>T, p.Gln18Ter | c.1038_1040del, p.Leu347del | 2,992 | 11.79 | 23.66 | 50 | 35.8 |
| 7 | 11.2 | M | W | - | MMUT | c.1106G>A, p.Arg369His | c.1324G>C, p.Ala442Pro | 1,702 | 18.69 | 35.35 | 45 | 52.5 |
| 8 | 11.4 | F | B | - | MMUT | c.682C>T, p.Arg228Ter | c.1108A>C, p.Thr370Pro | 258 | 8.89 | N/A | 50 | 118.3 |
| 9 | 11.7 | M | A | - | MMUT | c.1560G>C, p.Lys520Asn | c.1560G>C, p.Lys520Asn | 596 | 16.07 | 31.14 | 45 | 60.2 |
| 10 | 11.8 | M | W | - | MMUT | c.372_374dup p.Lys124_Asp125insGlu | c.146_147ins279d | 1,407 | 6.74 | 18.59 | 90 | 46.4 |
| 11 | 13.6 | F | H | - | MMUT | c.1196_1197del p.Val399GlufsTer24 | c.1106G>A, p.Arg369His | 1,530 | 16.78 | 35.65 | 60 | 40.8 |
| 12 | 13.7 | M | W | - | MMUT | c.1741C>T, p.Arg581Ter | c.753 + 2T>A, p.splice | 3,127 | 0.63c | 7.20c | 90 | 51.0 |
| 13 | 14.2 | F | W | - | MMUT | c.1924G>C, p.Gly642Arg | c.1924G>C, p.Gly642Arg | 3,092 | 14.19c | 31.25c | 45 | 31.9 |
| 14 | 14.4 | F | A | - | MMUT | c.682C>T, p.Arg228Ter | c.785G>T, p.Ser262Ile | 1,399 | 5.11 | N/A | 60 | 54.0 |
| 15 | 15.1 | F | W | - | MMUT | c.91C>T, p.Arg31Ter |
c.2053_2055dup p.Leu685dup |
341 | 21.38c | 41.37c | 45 | 51.1 |
| 16 | 15.6 | F | A | - | MMUT | c.2179C>T, p.Arg727Ter | c.2179C>T, p. Arg727Ter | 2,147 | 6.21 | 16.81 | 60 | 31.9 |
| 17 | 15.7 | F | W | - | MMUT | c.682C>T, p.Arg228Ter | c.607G>A, p.Gly203Arg | 551 | 8.52c | 20.24c | 40 | 54.0 |
| 18 | 16.5 | F | B | - | MMUT | c.281G>T, p.Gly94Val | c.1108A>C, p.Thr370Pro | 234 | 19.85 | 34.55 | 30 | 36.9 |
| 19 | 16.8 | F | A | - | MMUT | c.2078del, p.Gly693AspfsTer12 | c.2078del, p.Gly693AspfsTer12 | 1,239 | 11.80 | N/A | 45 | 91.4 |
| 20 | 18.0 | F | W | - | MMUT | c.323G>A, p.Arg108His | c.1867G>C, p.Gly623Arg | 400 | 6.38 | N/A | 60 | 58.3 |
| 21 | 18.8 | F | A | - | MMUT | c.643G>T, p.Gly215Cys | c.643G>T, p. Gly215Cys | 1,094 | 16.35 | 29.96 | 30 | 47.8 |
| 22 | 19.5 | F | W | - | MMUT | c.29dup, p.Leu10PhefsTer39 | c.1658del, p.Val553GlyfsTer17 | 2,260 | 6.12c | 15.09c | 60 | 70.3 |
| 23 | 23.7 | M | B | - | MMUT | c.1207C>T, p.Arg403Ter | c.1360G>A, p.Gly454Arg | 730 | 14.24 | 27.01 | 45 | 103.9 |
| 24 | 25.1 | M | W | - | MMUT | c.572C>A, p.Ala191Glu | c.655A>T, p.Asn219Tyr | 2,123 | 6.19 | 15.81 | 60 | 38.5 |
| 25 | 28.1 | F | W | - | MMUT | c.623_624del, p.Val208AlafsTer2 | c.322C>T, p.Arg108Cys | 1,157 | 14.29 | 25.94 | 52 | 33.1 |
| 26 | 33.7 | M | W | - | MMUT | c.753 + 2T>A, p.splice | c.1560 + 1G>T, p.splice | 4,754 | 7.02 | 16.13 | 60 | 45.8 |
| 27 | 3.4 | M | W | - | MMUT | c.372_374dup, p.Lys124_Asp125insGlu | c.842T>C, p.Leu281Ser | 36 | 39.46 | 48.23 | 15 | 76.0 |
| 28 | 4.8 | M | B | - | MMUT | c.91C>T, p.Arg31Ter | c.2150G>T, p.Gly717Val | 19.5 | 18.42 | 26.93 | 25 | 22.3 |
| 29 | 5.9 | M | B | - | MMUT | c.88C>T, p.Gln30Ter | c.299A>G, p.Tyr100Cys | 47 | 38.81 | 50.65 | 30 | 84.2 |
| 30 | 8.5 | F | B | - | MMUT | c.88C>T, p.Gln30Ter | c.299A>G, p.Tyr100Cys | 266 | 28.89 | 40.86 | 33 | 108.2 |
| 31 | 9.2 | M | W | - | MMUT | c.1181T>A, p.Leu394Ter | c.1924G>C, p.Gly642Arg | 37 | 37.70c | 48.35c | 20 | 109.6 |
| 32 | 9.6 | F | B | MMUT | c.2150G>T, p. Gly717Val | c.281G>T, p.Gly94Val | 168 | 28.47 | 48.82 | 30 | 91.9 | |
| 33 | 4.2 | M | W | - | MMAA | c.433C>T, p.Arg145Ter | c.433C>T, p.Arg145Ter | 80 | 35.03 | 43.09 | 15 | 87.7 |
| 34 | 9.9 | M | M | - | MMAA | c.387C>A, p.Tyr129Ter | c.593_596del, p.Thr198SerfsTer6 | 27 | 35.10c | 51.79c | 30 | 116.6 |
| 35 | 10.8 | M | W | - | MMAA | c.433C>T, p.Arg145Ter | c.1076G>A, p.Arg359Gln | 36 | 34.90 | 52.86 | 15 | 101.9 |
| 36 | 13.7 | M | W | - | MMAA | c.433C>T, p.Arg145Ter | c.1075C>T, p.Arg359Ter | 18.3 | 38.33c | 54.39c | 15 | 114.7 |
| 37 | 19.1 | M | W | - | MMAA | c.433C>T, p.Arg145Ter | c.433C>T, Arg145Ter | 25 | 30.99 | 46.93 | 25 | 76.5 |
| 38 | 26.5 | M | W | - | MMAA | c.433C>T, p.Arg145Ter | c.593_596del, p.Thr198SerfsTer6 | 27 | 43.48 | 62.13 | 15 | 83.5 |
| 39 | 27.6 | M | W | - | MMAA | c.440G>A, p.Gly147Glu | c.450dup, p.Pro151AlafsTer19 | 50 | 28.38c | 40.65c | 30 | 78.5 |
| 40 | 41.8 | M | NAm | - | MMAA | c.433C>T, p.Arg145Ter | c.433C>T, p.Arg145Ter | 29 | 34.04c | 52.46c | 25 | 97.4 |
| 41 | 47.2 | M | W | - | MMAA | c.433C>T, p.Arg145Ter | c.433C>T, p.Arg145Ter | 56 | 31.81 | 47.74 | 30 | 85.5 |
| 42 | 3.7 | M | W | - | MMAB | c.556C>T, p.Arg186Trp | c.556C>T, p.Arg186Trp | 805 | 8.35 | 16.34 | 40 | 36.1 |
| 43 | 34.1 | M | W | - | MMAB | c.700C>T, p.Gln234Ter | c.556C>T, p.Arg186Trp | 279 | 32.75 | 47.22 | 17 | 39.3 |
| 44 | 17.2 | F | W | KT | MMUT | c.927G>A, p.Trp309Ter | c.983T>C p.Leu328Pro | 2,477 | 9.41 | 21.1 | 60 | 23.4 |
| 45 | 18.1 | F | W | KTa | MMUT | c.1924G>C, p.Gly642Arg | c.1924G>C, p.Gly642Arg | 688 | 13.42 | 28.75 | 60 | 58.9 |
| 46 | 32.2 | M | A | KTb | MMUT | c.1741C>T, p.Arg581Ter | c.1741C>T, p.Arg581Ter | 445 | 12.30 | 24.49 | 30 | 70.8 |
| 47 | 37.5 | M | W | KTa | MMUT | c.753 + 2T>A, p.splice | c.1560 + 1G>T, p.splice | 11,991 | 10.21 | 21.17 | 60 | 19.4 |
| 48 | 30.3 | M | M | KT | MMUT | c.1760A>C, p.Tyr587Ser | c.2150G>T, p.Gly717Val | 263 | 25.15 | 36.43 | 25 | 78.9 |
| 49 | 27.1 | F | W | KT | MMAA | c.433C>T, p.Arg145Ter | c.586C>T, p.Arg196Ter | 24 | 23.74 | 35.35 | 15 | 74.4 |
| 50 | 9.3 | F | W | LKT | MMUT | c.682C>T, p.Arg228Ter | c.1287C>G, p.Tyr429Ter | 231 | 42.12 | 60.83 | 30 | 75.6 |
| 51 | 10.7 | M | M | LKTa | MMUT | c.682C>T, p.Arg228Ter | c.322C>T, p.Arg108Cys | 121 | 34.31 | 45.76 | 20 | 77.7 |
| 52 | 11.7 | F | W | LKT | MMUT | c.878A>C, p.Gln293Pro | c.878A>C, p.Gln293Pro | 154 | 36.52 | 47.50 | 10 | 44.9 |
| 53 | 13.0 | M | A | LKT | MMUT | c.2179C>T, p.Arg727Ter | c.2179C>T, p.Arg727Ter | 96 | 31.80 | 42.74 | 15 | 80.9 |
| 54 | 13.5 | M | W | LKT | MMUT | c.682C>T, p.Arg228Ter | c.670G>T, p.Glu224Ter | 385 | 27.88 | 48.78 | 20 | 50.7 |
| 55 | 15.7 | M | M | LKT | MMUT | c.349G>T, p.Glu117Ter | c.1038_1040del p.Leu347del | 57 | 27.69 | N/A | 15 | 36.1 |
| 56 | 16.8 | M | W | LTa | MMUT | c.1741C>T, p.Arg581Ter | c.753 + 2T>A, p.splice | 402 | 28.59 | 48.68 | 45 | 66.5 |
| 57 | 18.5 | M | W | LKT | MMUT | c.1207C>T, p.Arg403Ter | c.1105C>T, p.Arg369Cys | 395 | 32.49 | 44.59 | 7 | 59.4 |
| 58 | 19.1 | M | A | LT | MMUT | c.1106G>A, p.Arg369His | c.1106G>A, p.Arg369His | 1,021 | 42.45 | 54.41 | 10 | 33.2 |
| 59 | 23.9 | F | W | LKTa | MMUT | c.29dup, p.Leu10PhefsTer38 | c.1658del, p.Val553GlyfsTer17 | 9.5 | 35.65 | 49.43 | 15 | 69.8 |
| 60 | 30.4 | F | W | pLKT | MMUT | c.1106G>A, p.Arg369His | c.1106G>A, p.Arg369His | 2,246 | 13.06 | 24.94 | 45 | 49.5 |
| 61 | 31.1 | F | W | LKT | MMUT | c.2053_2055dup p.Leu685dup | c.2053_2055dup p.Leu685dup | 382 | 27.88 | 39.92 | 15 | 95.5 |
| 62 | 37.2 | F | H | LKT | MMUT | c.826G>T, p.Glu276Ter | c.1106G>A, p.Arg369His | 255 | 24.88 | 36.57 | 20 | 49.8 |
Age at the time of stable isotope breath testing, as well as the molecular genetic analysis of the MMUT, MMAA, and MMAB genes and selected variables of the study are provided for each of the MMA subjects. Italics for mut0, bold for mut–, bold and italics for cblB (MMAB) individuals and underline for cblA (MMAA). Serum MMA concentration is provided in micromole/liter, μmol/L or μM (normal levels <0.4 μmol/L).
A Asian, B Black, eGFR estimated glomerular filtration rate, H Hispanic, KT kidney transplant, LT liver transplant, LKT combined liver–kidney transplant, M Mixed race, MMA methylmalonic acid, N/A data not available, W White.
aSubjects tested before and after liver and/or kidney transplantation.
bRepeat study after a second KT.
cDesignates subjects where in vitro 14C-propionate fibroblast enzymatic assays were also available, provided in detail in Supplemental Table 1.
dIndividual 10 has a large 279- bp insertion comprised of an 183- bp segment that aligns to the 3’UTR of the ENO1 gene on chromosome 1 (8861004_8861186) and a ~96- bp polyA repeat that result in no detectable messenger RNA (mRNA) (PMID: 27233228).