G14459A

# **General Information**

| **Position** | **14459** | **Variant** | **m.14459G\>A** | **Locus** | **MT\-ND6** | **Amino\-AcidChange** | **A72V** |
| --- | --- | --- | --- | --- | --- | --- | --- |
| **Homoplasmy** | \+ | **Heteroplasmy** | \+ | **APOGEE2** | Pathogenic | **Pathogenicity** | Cfrm \[P] |

"Pathogenicity" status is derived from published literature or predictions from bioinformatics tools. Researchers and clinicians are cautioned that additional data and/or analysis may still be necessary to confirm the pathological significance of these variants. For more information, please see [Mitofam Info](https://mitofam.com/doc/385/).

# **Pedigree Information**

The **m.14459G\>A** variant in MT\-ND6 has been reported in 29 pedigrees. To date, 52 carriers have been reported. Homoplasmy was reported in 13/52 carriers (25%), and 41/52 carriers (78\.8%) were affected. In one affected carrier, a marked tissue\-specific difference was observed, with higher mutation loads in muscle (94%), urine (88\.1%), and bone marrow (80\.8%) than in blood (39\.1%). The main clinical manifestations among affected carriers included leigh syndrome, dystonia, spasticity, cSF lactate, hypotonia, 0\.05, LHON, leigh disease, and other features.

| **No.** | **Position** | **Variant** | **Family ID** | **Nationality** | **Diseases** | **Unaffected Maternal Relatives** | **Affected Maternal Relatives** | **Publication Year** | **PMID/Ref** | **Note** |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 1 | 14459 | m.14459G\>A | G14459A\-F1 | USA | LHON plus dystonia | 0 | 1 | 1995 | [7654063](https://pubmed.ncbi.nlm.nih.gov/7654063/) |  |
| 2 | 14459 | m.14459G\>A | G14459A\-F2 | USA | LHON plus dystonia | 0 | 0 | 1995 | [7654063](https://pubmed.ncbi.nlm.nih.gov/7654063/) |  |
| 3 | 14459 | m.14459G\>A | [G14459A\-F3](https://mitofam.com/doc/2118/) | Hispanic\-American | LHON and dystonia | ND | ND | 1994 | [8016139](https://pubmed.ncbi.nlm.nih.gov/8016139/) |  |
| 4 | 14459 | m.14459G\>A | G14459A\-F4 | Australia | Leigh disease | 0 | 1 | 2000 | [10894222](https://pubmed.ncbi.nlm.nih.gov/10894222/) |  |
| 5 | 14459 | m.14459G\>A | G14459A\-F5 | Australia | Leigh disease | 0 | 0 | 2000 | [10894222](https://pubmed.ncbi.nlm.nih.gov/10894222/) |  |
| 6 | 14459 | m.14459G\>A | G14459A\-F6 | France | LHON with Leigh\-like encephalopathy | 0 | 0 | 2002 | [12205655](https://pubmed.ncbi.nlm.nih.gov/12205655/) |  |
| 7 | 14459 | m.14459G\>A | [G14459A\-F7](https://mitofam.com/doc/2119/) | Canada | LHON/spasticity\-dystonia | 2 | 1 | 2004 | [14735584](https://pubmed.ncbi.nlm.nih.gov/14735584/) |  |
| 8 | 14459 | m.14459G\>A | G14459A\-F8 | Canada | LHON | 0 | 0 | 2004 | [14735584](https://pubmed.ncbi.nlm.nih.gov/14735584/) |  |
| 9 | 14459 | m.14459G\>A | [G14459A\-F9](https://mitofam.com/doc/2120/) | Antigua and Barbuda | LHON plus dystonia | 6 | 4 | 2004 | [14735585](https://pubmed.ncbi.nlm.nih.gov/14735585/) |  |
| 10 | 14459 | m.14459G\>A | [G14459A\-F10](https://mitofam.com/doc/2121/) | Mexico | Leigh syndrome | 1 | 0 | 2009 | [19714555](https://pubmed.ncbi.nlm.nih.gov/19714555/) |  |
| 11 | 14459 | m.14459G\>A | G14459A\-F11 | Australia | Leigh syndrome | 0 | 0 | 2011 | [21364701](https://pubmed.ncbi.nlm.nih.gov/21364701/) |  |
| 12 | 14459 | m.14459G\>A | G14459A\-F12 | Australia | Leigh syndrome | 0 | 1 | 2011 | [21364701](https://pubmed.ncbi.nlm.nih.gov/21364701/) |  |
| 13 | 14459 | m.14459G\>A | G14459A\-F13 | Italy | Leigh disease | 1 | 0 | 2011 | [21749722](https://pubmed.ncbi.nlm.nih.gov/21749722/) |  |
| 14 | 14459 | m.14459G\>A | G14459A\-F14 | China | LHON | 0 | 0 | 2012 | [22879922](https://pubmed.ncbi.nlm.nih.gov/22879922/) |  |
| 15 | 14459 | m.14459G\>A | G14459A\-F15 | France | Leigh syndrome | 0 | 0 | 2013 | [23847141](https://pubmed.ncbi.nlm.nih.gov/23847141/) |  |
| 16 | 14459 | m.14459G\>A | G14459A\-F16 | France | Leigh syndrome | 0 | 0 | 2013 | [23847141](https://pubmed.ncbi.nlm.nih.gov/23847141/) |  |
| 17 | 14459 | m.14459G\>A | G14459A\-F17 | Japan | Leigh syndrome | 0 | 0 | 2017 | [28429146](https://pubmed.ncbi.nlm.nih.gov/28429146/) |  |
| 18 | 14459 | m.14459G\>A | G14459A\-F18 | Japan | Leigh syndrome | 0 | 0 | 2017 | [28429146](https://pubmed.ncbi.nlm.nih.gov/28429146/) |  |
| 19 | 14459 | m.14459G\>A | [G14459A\-F19](https://mitofam.com/doc/2122/) | Canada | Dystonia/spasticity/ataxia; LHON spectrum | 3 | 3 | 2018 | [29408632](https://pubmed.ncbi.nlm.nih.gov/29408632/) | Figure 1 |
| 20 | 14459 | m.14459G\>A | G14459A\-F20 | China | Late\-onset Leigh syndrome | 0 | 0 | 2018 | [30128709](https://pubmed.ncbi.nlm.nih.gov/30128709/) |  |
| 21 | 14459 | m.14459G\>A | G14459A\-F21 | Algeria | LHON plus dystonia | 0 | 0 | 2019 | [31221418](https://pubmed.ncbi.nlm.nih.gov/31221418/) |  |
| 22 | 14459 | m.14459G\>A | G14459A\-F22 | China | LHON | 0 | 0 | 2019 | [32045392](https://pubmed.ncbi.nlm.nih.gov/32045392/) |  |
| 23 | 14459 | m.14459G\>A | G14459A\-F23 | China | LHON | 0 | 0 | 2019 | [32045392](https://pubmed.ncbi.nlm.nih.gov/32045392/) |  |
| 24 | 14459 | m.14459G\>A | G14459A\-F24 | China | LHON | 0 | 0 | 2019 | [32045392](https://pubmed.ncbi.nlm.nih.gov/32045392/) |  |
| 25 | 14459 | m.14459G\>A | G14459A\-F25 | China | LHON plus dystonia | 0 | 0 | 2019 | [32045392](https://pubmed.ncbi.nlm.nih.gov/32045392/) |  |
| 26 | 14459 | m.14459G\>A | G14459A\-F26 | Argentina | Leigh syndrome | 0 | 1 | 2021 | [33717984](https://pubmed.ncbi.nlm.nih.gov/33717984/) |  |
| 27 | 14459 | m.14459G\>A | [G14459A\-F27](https://mitofam.com/doc/2123/) | China | LHON plus dystonia overlapping MELAS | 1 | 2 | 2021 | [33779865](https://pubmed.ncbi.nlm.nih.gov/33779865/) |  |
| 28 | 14459 | m.14459G\>A | G14459A\-F28 | Uruguay | Leigh syndrome | 0 | 0 | 2021 | [34536563](https://pubmed.ncbi.nlm.nih.gov/34536563/) |  |
| 29 | 14459 | m.14459G\>A | G14459A\-F29 | Sweden | Leigh syndrome | 0 | 0 | 2009 | [19103152](https://pubmed.ncbi.nlm.nih.gov/19103152/) |  |

# **Carrier Information**

| **No.** | **Position** | **Variant** | **Family ID** | **Carrier ID** | **Type (Fam/De novo/Uninf)** | **Gender (F/M)** | **Proband (Y/N)** | **Affected (Y/N)** | **Die/Alive(D/A)** | **Age** | **Blood Mutant Level** | **Muscle Mutant level** | **Urine Mutant level** | **Other Mutant level** | **Clinical Features** | **Note** |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 1 | 14459 | m.14459G\>A | G14459A\-F1 | G14459A\-F1\-P1 | Fam | F | Y | Y | A | 19 | Homo | Homo | / | Homo (leukocyte); Homo (skeletal muscle) | LHON; basal ganglia lesions on MRI; no extrapyramidal signs |  |
| 2 | 14459 | m.14459G\>A | G14459A\-F1 | G14459A\-F1\-P2 | Fam | F | N | Y | A | 42 | 50% | / | / | 50% (leukocyte mtDNA) | LHON / optic atrophy / peripapillary telangiectasias |  |
| 3 | 14459 | m.14459G\>A | G14459A\-F2 | G14459A\-F2\-P1 | Uninf | F | Y | Y | A | 13 | / | 50% | / | \~50% (skeletal muscle) | Generalized dystonia and athetosis; basal ganglia lesions; no LHON |  |
| 4 | 14459 | m.14459G\>A | G14459A\-F3 | G14459A\-F3\-III6 | Fam | F | N | Y | ND | 32 years | 73% | / | / | / | LHON with bilateral optic atrophy | Original label III\-10 |
| 5 | 14459 | m.14459G\>A | G14459A\-F3 | G14459A\-F3\-III3 | Fam | F | N | ND | ND | ND | \>99% | / | / | / | ND | Original label III\-5 |
| 6 | 14459 | m.14459G\>A | G14459A\-F3 | G14459A\-F3\-IV8 | Fam | ND | N | Y | ND | ND | \>99% | / | / | / | LHON patient | Original label IV\-26 |
| 7 | 14459 | m.14459G\>A | G14459A\-F3 | G14459A\-F3\-IV11 | Fam | ND | N | Y | ND | 13 years | \>99% | / | / | / | Milder dystonia with greater intellectual impairment | Original label IV\-35 |
| 8 | 14459 | m.14459G\>A | G14459A\-F3 | G14459A\-F3\-IV12 | Fam | F | Y | Y | ND | 10 years | \>99% | / | / | / | Early\-onset dystonia with bilateral basal ganglia lesions | Original label IV\-36 |
| 9 | 14459 | m.14459G\>A | G14459A\-F3 | G14459A\-F3\-V1 | Fam | ND | N | Y | ND | 5 years | / | / | / | \>99% (ND) | Mild generalized dystonia with abnormal basal ganglia lucencies | Original label V\-11 |
| 10 | 14459 | m.14459G\>A | G14459A\-F4 | G14459A\-F4\-P1 | Fam | M | ND | Y | D | 9 mo eval | / | / | / | 97% (F) | Leigh disease; motor delay; extreme hypotonia; elevated blood/CSF lactate; basal ganglia lesions; seizures; spasticity; possible dystonic posturing |  |
| 11 | 14459 | m.14459G\>A | G14459A\-F4 | G14459A\-F4\-P2 | Fam | M | ND | Y | D | 3 mo eval | / | 97% | / | 97% (Liver) | Leigh disease; roving eye movements; hypotonia; neurologic and developmental regression; seizures; elevated blood/CSF lactate; metabolic acidosis |  |
| 12 | 14459 | m.14459G\>A | G14459A\-F5 | G14459A\-F5\-P1 | De novo | F | ND | Y | D | 8 mo eval | \>99% | 95% | / | 99% (F); 98% (Liver) | Leigh disease; developmental delay; athetosis; abnormal extraocular movements; hypotonia; regression; elevated blood/CSF lactate; MRI consistent with Leigh disease; hypoventilation | Original label P3 |
| 13 | 14459 | m.14459G\>A | G14459A\-F6 | G14459A\-F6\-P1 | De novo | M | Y | Y | D | 30 | 40% | / | / | / | Bilateral visual failure at age 18; vertigo; bilateral hearing loss; cerebellar ataxia; brisk reflexes; Babinski sign; brainstem/red nucleus lesions; depression and suicide | Original label P2 |
| 14 | 14459 | m.14459G\>A | G14459A\-F7 | G14459A\-F7\-II3 | Fam | F | Y | Y | A | 45 | Positive; load NR | / | / | / | Spasticity/dystonia beginning in childhood; bulbar dystonia; walker required | Original label AII\-1 |
| 15 | 14459 | m.14459G\>A | G14459A\-F7 | G14459A\-F7\-II1 | Fam | M | N | Y | A | 49 | Positive; load NR | / | / | / | LHON with painless visual loss at 19; severe visual impairment; slight hearing loss | Original label AII\-2 |
| 16 | 14459 | m.14459G\>A | G14459A\-F7 | G14459A\-F7\-II2 | Fam | M | N | N | A | 56 | Positive; load NR | / | / | 80% (F) | Healthy | Original label AII\-3 |
| 17 | 14459 | m.14459G\>A | G14459A\-F7 | G14459A\-F7\-I1 | Fam | F | N | N | D | 78 | 4% | / | / | / | No LHON/dystonia; prior stroke; fatal myocardial infarction after sampling | Original label AI\-1 |
| 18 | 14459 | m.14459G\>A | G14459A\-F8 | G14459A\-F8\-P1 | Uninf | M | Y | Y | A | 17 | 72% | / | / | / | Isolated LHON; visual deterioration at 16; central scotomas; optic nerve pallor | Original label BII\-1 |
| 19 | 14459 | m.14459G\>A | G14459A\-F9 | G14459A\-F9\-III6 | Fam | F | N | N | A | 35 | Homo | / | / | / | Healthy |  |
| 20 | 14459 | m.14459G\>A | G14459A\-F9 | G14459A\-F9\-IV10 | Fam | F | Y | Y | A | 3 | / | Homo | / | / | Acute bulbar/corticospinal dysfunction; stroke/dystonia/spasticity; bilateral putaminal lesions; elevated lactate |  |
| 21 | 14459 | m.14459G\>A | G14459A\-F9 | G14459A\-F9\-IV8 | Fam | M | N | Y | A | 7 | Homo | / | / | / | Hemiparesis, dysarthria, spasticity/dystonia, putaminal MRI lesion; NF1/cognitive delay/ADHD |  |
| 22 | 14459 | m.14459G\>A | G14459A\-F9 | G14459A\-F9\-IV9 | Fam | M | N | N | A | ND | Homo | / | / | / | Healthy |  |
| 23 | 14459 | m.14459G\>A | G14459A\-F9 | G14459A\-F9\-IV2 | Fam | F | N | Y | A | 5 | Homo | / | / | / | New onset limp; mild right hemiparesis; bilateral putaminal MRI lesions; lactate doublet on MRS |  |
| 24 | 14459 | m.14459G\>A | G14459A\-F10 | G14459A\-F10\-III1 | Fam | F | Y | Y | A | 10 months | / | \>95% | / | / | Developmental regression seizures MRI compatible with Leigh syndrome | Original label III\-1 |
| 25 | 14459 | m.14459G\>A | G14459A\-F10 | G14459A\-F10\-II2 | Fam | F | N | N | A | ND | \<5% | / | / | / | Healthy | Original label II\-2 |
| 26 | 14459 | m.14459G\>A | G14459A\-F11 | G14459A\-F11\-P1 | Uninf | ND | Y | Y | ND | ND | / | 95% | / | / | Leigh syndrome |  |
| 27 | 14459 | m.14459G\>A | G14459A\-F12 | G14459A\-F12\-P1 | Fam | ND | ND | Y | ND | ND | / | / | / | 97% (F) | Leigh syndrome |  |
| 28 | 14459 | m.14459G\>A | G14459A\-F12 | G14459A\-F12\-P2 | Fam | ND | ND | Y | ND | ND | / | 97% | / | / | Leigh syndrome |  |
| 29 | 14459 | m.14459G\>A | G14459A\-F13 | G14459A\-F13\-P1 | Fam | F | Y | Y | ND | 15 m | \>99% | \>99% | / | / | Leigh disease with dystonia, psychomotor delay/regression, hypotonia, seizures, apneas, retinal involvement, external ophthalmoplegia, basal ganglia/thalami/mesencephalum MRI lesions, lactate/pyruvate elevation |  |
| 30 | 14459 | m.14459G\>A | G14459A\-F13 | G14459A\-F13\-P2 | Fam | F | N | N | ND | ND | \<2% | / | / | / | Healthy |  |
| 31 | 14459 | m.14459G\>A | G14459A\-F14 | G14459A\-F14\-P1 | Fam | ND | Y | Y | ND | ND | Homo/near\-Homo | / | / | / | LHON |  |
| 32 | 14459 | m.14459G\>A | G14459A\-F15 | G14459A\-F15\-P1 | Uninf | F | Y | Y | ND | \<1 onset | / | / | / | Homo (ND) | CNS regression; Leigh; normal blood lactate; RC normal in muscle; decreased CI in liver; decreased CI\+IV in fibroblast |  |
| 33 | 14459 | m.14459G\>A | G14459A\-F16 | G14459A\-F16\-P1 | Uninf | M | Y | Y | ND | \<1 onset | / | / | / | Homo (ND) | CNS PMR dystonia; ptosis; Leigh; increased blood/CSF lactate; decreased CI in muscle/fibroblast |  |
| 34 | 14459 | m.14459G\>A | G14459A\-F17 | G14459A\-F17\-P1 | Uninf | ND | Y | Y | ND | ND | / | / | / | 54% (F) | Leigh syndrome; isolated complex I deficiency | Original label Pt28 |
| 35 | 14459 | m.14459G\>A | G14459A\-F18 | G14459A\-F18\-P1 | Uninf | ND | Y | Y | ND | ND | / | / | / | 96% (F) | Leigh syndrome; isolated complex I deficiency | Original label Pt593 |
| 36 | 14459 | m.14459G\>A | G14459A\-F19 | G14459A\-F19\-III2 | Fam | F | Y | Y | A | 63 | / | 98\.4% | / | 96\.8% (F) | Ataxia, dystonic speech, dystonia, spasticity, migraine variant headaches |  |
| 37 | 14459 | m.14459G\>A | G14459A\-F19 | G14459A\-F19\-IV1 | Fam | F | N | N | A | 39 | 0 | / | / | / | Healthy | Migraine variant headaches |
| 38 | 14459 | m.14459G\>A | G14459A\-F19 | G14459A\-F19\-IV2 | Fam | F | N | N | A | 36 | 0 | / | / | / | Healthy | Migraine variant headaches |
| 39 | 14459 | m.14459G\>A | G14459A\-F19 | G14459A\-F19\-V1 | Fam | F | N | N | A | 20 | 0 | / | / | / | Healthy | Migraine variant headaches |
| 40 | 14459 | m.14459G\>A | G14459A\-F20 | G14459A\-F20\-P1 | Uninf | F | Y | Y | ND | 3 | 93% | / | / | / | Ataxia; pyramidal signs; bulbar palsy; developmental delay | Original label Case6 |
| 41 | 14459 | m.14459G\>A | G14459A\-F21 | G14459A\-F21\-P1 | Uninf | M | Y | Y | A | 18 | / | / | / | Homo (ND) | Bilateral optic atrophy; decreased visual acuity; strabismus; vertical gaze palsy; parkinsonism; generalized dystonia; putaminal necrosis |  |
| 42 | 14459 | m.14459G\>A | G14459A\-F22 | G14459A\-F22\-M14459 | Uninf | M | Y | Y | ND | 16 | Hetero | / | / | / | Worst BCVA 0\.05/0\.05; OA; no dystonia; follow\-up 3y BCVA 0\.05/0\.05 | Original label m14459GAcase1 |
| 43 | 14459 | m.14459G\>A | G14459A\-F23 | G14459A\-F23\-M14459 | Uninf | M | Y | Y | ND | 17 | Hetero | / | / | / | Worst BCVA 0\.1/0\.2; ISON; no dystonia; follow\-up 3y BCVA 0\.1/0\.2 | Original label m14459GAcase2 |
| 44 | 14459 | m.14459G\>A | G14459A\-F24 | G14459A\-F24\-M14459 | Uninf | M | Y | Y | ND | 17 | Homo | / | / | / | Worst BCVA 0\.05/0\.05; OA; no dystonia; follow\-up 2y BCVA 0\.05/0\.05 | Original label m14459GAcase3 |
| 45 | 14459 | m.14459G\>A | G14459A\-F25 | G14459A\-F25\-M14459 | Uninf | M | Y | Y | ND | 3 | Homo | / | / | / | Worst BCVA 0\.01/0\.05; dystonia; OA and T2 high signal in BG; follow\-up 2y BCVA 0\.05/0\.1 | Original label m14459GAcase4 |
| 46 | 14459 | m.14459G\>A | G14459A\-F26 | G14459A\-F26\-P1 | Uninf | ND | ND | Y | ND | ND | / | / | / | Homo (ND) | Leigh syndrome in two siblings |  |
| 47 | 14459 | m.14459G\>A | G14459A\-F27 | G14459A\-F27\-III1 | Fam | F | Y | Y | A | 23 | 39\.1% | 94% | 88\.1% | 80\.8% (BM) | Visual decline at 15; seizures and dystonia at 18; MELAS\-like/LHON\-dystonia; basal ganglia and precentral MRI lesions; elevated CSF lactate | Carrying m.6064A\>T: 97\.7% (B), 96\.6% (U), 100% (BM), 95\.7% (M) |
| 48 | 14459 | m.14459G\>A | G14459A\-F27 | G14459A\-F27\-II5 | Fam | F | N | Y | A | ND | 13\.5% | / | / | / | Optic atrophy and mild visual disturbance | Carrying m.6064A\>T: 93% (B) |
| 49 | 14459 | m.14459G\>A | G14459A\-F27 | G14459A\-F27\-III3 | Fam | M | N | N | A | 8 | 15\.5% | / | / | / | Healthy | Carrying m.6064A\>T: 93% (B) |
| 50 | 14459 | m.14459G\>A | G14459A\-F27 | G14459A\-F27\-III2 | Fam | M | N | Y | D | 4 | / | / | / | / | Respiratory distress and death in childhood |  |
| 51 | 14459 | m.14459G\>A | G14459A\-F28 | G14459A\-F28\-P1 | Uninf | ND | Y | Y | ND | 20 y | 100% | / | / | / | Leigh syndrome; onset 5 y; MDC 7 | Original label P2 |
| 52 | 14459 | m.14459G\>A | G14459A\-F29 | G14459A\-F29\-P1 | Uninf | M | Y | Y | D | 4 mo | / | Positive; load NR | / | 99% (F) | Leigh syndrome; developmental retardation; hypotonia; dystonia/dyskinesia | Original label patient 20 |

For abbreviations and other usage instructions, please see [Mitofam Info](https://mitofam.com/doc/385/).