G8363A

# **General Information**

| **Position** | **8363** | **Variant** | **m.8363G\>A** | **Locus** | **MT\-TK** | **RNA** | **tRNA Lys** |
| --- | --- | --- | --- | --- | --- | --- | --- |
| **Homoplasmy** | \- | **Heteroplasmy** | \+ | **mitoTIP** | Pathogenic | **Pathogenicity** | Cfrm \[LP] |

"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.8363G\>A** variant in MT\-TK has been reported in 11 pedigrees. To date, 35 carriers have been reported. Reported mutation loads ranged from 2% to 98%, with a median of 67% overall; affected carriers showed mutation loads from 6\.6% to 98%, with a median of 79\.5%; unaffected carriers showed mutation loads from 2% to 67%, with a median of 34%. In one affected carrier, a marked tissue\-specific difference was observed, with higher mutation loads in blood (60\.6%), muscle (65\.2%), other tissue (88\.4%), and other tissue (65\.1%) than in cox\-negative single fibers (6\.6%). In one unaffected carrier, a marked tissue\-specific difference was observed, with higher mutation loads in urine (33%) than in blood (10%). Similar tissue\-specific differences were observed in 2 additional carriers. The main clinical manifestations among affected carriers included leigh syndrome, seizures, MERRF, ataxia, developmental delay, short stature, mental retardation, oligosymptomatic, and other features.

| **No.** | **Position** | **Variant** | **Family ID** | **Nationality** | **Diseases** | **Unaffected Maternal Relatives** | **Affected Maternal Relatives** | **Publication Year** | **PMID/Ref** | **Note** |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 1 | 8363 | m.8363G\>A | [G8363A\-F1](https://mitofam.com/doc/2206/) | Japanese | MERRF | 0 | 1 | 1997 | [9052804](https://pubmed.ncbi.nlm.nih.gov/9052804/) | Family A |
| 2 | 8363 | m.8363G\>A | [G8363A\-F2](https://mitofam.com/doc/2207/) | Japanese | MERRF | 0 | 1 | 1997 | [9052804](https://pubmed.ncbi.nlm.nih.gov/9052804/) | Family B |
| 3 | 8363 | m.8363G\>A | [G8363A\-F3](https://mitofam.com/doc/2208/) | USA | Autism / Leigh syndrome / neurologic disorders | 1 | 3 | 2000 | [10868777](https://pubmed.ncbi.nlm.nih.gov/10868777/) | Table 1 family (I\-1, II\-1\-II\-4\). |
| 4 | 8363 | m.8363G\>A | [G8363A\-F4](https://mitofam.com/doc/2209/) | USA | Leigh syndrome / MERRF | 1 | 5 | 2000 | [11108511](https://pubmed.ncbi.nlm.nih.gov/11108511/) | Figure 1 pedigree. |
| 5 | 8363 | m.8363G\>A | G8363A\-F5 | Czech Republic | Leigh syndrome; COX deficiency | 0 | 0 | 2006 | [16326995](https://pubmed.ncbi.nlm.nih.gov/16326995/) | / |
| 6 | 8363 | m.8363G\>A | G8363A\-F6 | Czech Republic | Leigh syndrome; COX deficiency | 0 | 0 | 2006 | [16326995](https://pubmed.ncbi.nlm.nih.gov/16326995/) | / |
| 7 | 8363 | m.8363G\>A | G8363A\-F7 | Poland | Leigh syndrome | 0 | 0 | 2007 | [18176892](https://pubmed.ncbi.nlm.nih.gov/18176892/) | / |
| 8 | 8363 | m.8363G\>A | G8363A\-F8 | Czech Republic | Leigh syndrome; myopathy; cardiomyopathy; encephalopathy | 0 | 0 | 2008 | [18319067](https://pubmed.ncbi.nlm.nih.gov/18319067/) | / |
| 9 | 8363 | m.8363G\>A | [G8363A\-F9](https://mitofam.com/doc/2210/) | Italy | MERRF\-like syndrome; deafness; myopathy; ataxia; lipomatosis | 7 | 3 | 2009 | [19278689](https://pubmed.ncbi.nlm.nih.gov/19278689/) | Fig. 1 |
| 10 | 8363 | m.8363G\>A | [G8363A\-F10 ](https://mitofam.com/doc/2211/)| China | Fluctuating ataxia / mitochondrial disease | 1 | 0 | 2022 | [35821181](https://pubmed.ncbi.nlm.nih.gov/35821181/) | / |
| 11 | 8363 | m.8363G\>A | G8363A\-F11 | France | Mitochondrial disease; lipomatosis | 0 | 0 | 2025 | [39600123](https://pubmed.ncbi.nlm.nih.gov/39600123/) | / |

# **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 | 8363 | m.8363G\>A | G8363A\-F1 | G8363A\-F1\-II1 | Fam | F | N | Y | A | ND | 50\.0% | / | / | / | Convulsions at age 33 years | Original label: Family A I\-2; Figure 1 blood 50\.0% (B). |
| 2 | 8363 | m.8363G\>A | G8363A\-F1 | G8363A\-F1\-II2 | Fam | M | Y | Y | A | 8 | / | / | / | / | MERRF; myoclonus epilepsy; generalized seizures; cerebellar ataxia at age 7; mild muscle weakness with hypotonia; elevated lactate and pyruvate; cardiac insufficiency | Original label: Family A II\-1; proband. |
| 3 | 8363 | m.8363G\>A | G8363A\-F2 | G8363A\-F2\-II1 | Fam | F | N | Y | A | 52 | 60\.6% | 65\.2% | / | 88\.4\+/\-6\.6% (COX\-negative single fibers); 65\.1\+/\-8\.0% (COX\-positive single fibers) | Dysarthria beginning in her 40s; elevated lactate and pyruvate after aerobic exercise | Original label: Family B I\-2; Figure 1 blood 60\.6% (B), muscle 65\.2% (M). |
| 4 | 8363 | m.8363G\>A | G8363A\-F2 | G8363A\-F2\-II2 | Fam | F | Y | Y | A | 15 | / | / | / | / | MERRF; myoclonus epilepsy; cerebellar ataxia since age 9; marked generalized muscle weakness and atrophy; moderate mental deterioration | Original label: Family B II\-2; proband. |
| 5 | 8363 | m.8363G\>A | G8363A\-F3 | G8363A\-F3\-I1 | uninf | F | N | Y | A | 30 | 28% | / | / | / | Tachycardia; frequent headaches; irritable bowel symptoms | I\-1; mother. |
| 6 | 8363 | m.8363G\>A | G8363A\-F3 | G8363A\-F3\-II1 | Fam | F | N | Y | A | 10 | Detected | / | / | / | Generalized seizures; learning disability; oppositional behavior; tremor; mild motor dyspraxia | II\-1; blood PCR positive, percent ND. |
| 7 | 8363 | m.8363G\>A | G8363A\-F3 | G8363A\-F3\-II2 | Fam | F | N | N | A | 9 | Detected | / | / | / | Healthy | II\-2; blood PCR positive, percent ND. |
| 8 | 8363 | m.8363G\>A | G8363A\-F3 | G8363A\-F3\-II3 | Fam | F | N | Y | A | 6 | 82% | 86% | / | / | Leigh syndrome; ataxia; myoclonus; seizures; cognitive regression; high lactate; COX\-negative muscle | II\-3\. |
| 9 | 8363 | m.8363G\>A | G8363A\-F3 | G8363A\-F3\-II4 | Fam | M | Y | Y | A | 4\.3 | 60% | 61% | / | / | Autism; language/play regression; hyperactivity; toe\-walking; stereotypies; self\-injurious behavior; seizures | II\-4; proband. |
| 10 | 8363 | m.8363G\>A | G8363A\-F4 | G8363A\-F4\-I1 | uninf | F | N | Y | A | 51 | 59% | / | / | / | Oligosymptomatic; leg pain and numbness; sensory deficits in stocking distribution | Figure 1/2 I1\. |
| 11 | 8363 | m.8363G\>A | G8363A\-F4 | G8363A\-F4\-II1 | Fam | F | N | Y | A | 32 | 72% | 84% | / | / | MERRF; myoclonus; seizures; progressive hearing loss; migraine\-like headaches; sensory symptoms; ragged red/COX\-negative fibers | Figure 1/2 II1; symptom onset in late 20s. |
| 12 | 8363 | m.8363G\>A | G8363A\-F4 | G8363A\-F4\-II2 | Fam | F | N | Y | A | ND | 61% | / | / | / | Oligosymptomatic | Figure 1/2 II3\. |
| 13 | 8363 | m.8363G\>A | G8363A\-F4 | G8363A\-F4\-III1 | Fam | M | N | Y | A | 14 | / | / | / | / | Leg control problems | Figure 1 III1; no molecular testing in child; included because mother II1 has confirmed target mutation and phenotype is reported. |
| 14 | 8363 | m.8363G\>A | G8363A\-F4 | G8363A\-F4\-III2 | Fam | M | N | N | A | 9 | / | / | / | / | Healthy | Figure 1 III2; no molecular testing in child; included because mother II1 has confirmed target mutation and phenotype is reported. |
| 15 | 8363 | m.8363G\>A | G8363A\-F4 | G8363A\-F4\-III3 | Fam | F | N | Y | D | 2\.5 | / | / | / | / | Neuropathologically confirmed Leigh syndrome; developmental delay; respiratory problems; optic atrophy; died at 2\.5 years | Figure 1 III3; no molecular testing in child; included because mother II1 has confirmed target mutation and phenotype is reported. |
| 16 | 8363 | m.8363G\>A | G8363A\-F4 | G8363A\-F4\-III4 | Fam | F | Y | Y | D | 13 mo; died 27 mo | \>98% | \>98% | / | / | Leigh syndrome; failure to thrive; developmental delay/regression; abnormal respiration; seizures; lactic acidosis; ragged red fibers; cardiorespiratory failure | Figure 1/2 III4; RFLP load quantified in blood and muscle. |
| 17 | 8363 | m.8363G\>A | G8363A\-F5 | G8363A\-F5\-P1 | Uninf | ND | Y | Y | ND | ND | / | / | / | Detected (ND) | Leigh syndrome; combined COX deficiency | One of two unrelated children with mtDNA 8363G\>A; no individual label, sex, age, tissue or load reported. |
| 18 | 8363 | m.8363G\>A | G8363A\-F6 | G8363A\-F6\-P1 | Uninf | ND | Y | Y | ND | ND | / | / | / | Detected (ND) | Leigh syndrome; combined COX deficiency | Second unrelated child with mtDNA 8363G\>A; no individual label, sex, age, tissue or load reported. |
| 19 | 8363 | m.8363G\>A | G8363A\-F7 | G8363A\-F7\-P1 | Uninf | M | Y | Y | D | 28 mo | / | / | / | Very high heteroplasmy (ND) | Leigh syndrome; COX deficiency; hyperlactataemia; respiratory alkalosis; developmental delay; left ventricular hypertrophy | Sequencing chromatogram suggested very high heteroplasmy; exact numeric load and sample source not explicitly stated. |
| 20 | 8363 | m.8363G\>A | G8363A\-F8 | G8363A\-F8\-P1 | Uninf | M | Y | Y | D | 12 | / | 80% | / | 89% (Heart); 87% (Frontal cortex); 97% (Liver) | Leigh syndrome; failure to thrive; hypotony; epilepsy; respiratory failure; hypertrophic cardiomyopathy; encephalopathy | Patient 1; autopsy/biopsy tissue study; Table 1 gives tissue heteroplasmy. |
| 21 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-III2 | Fam | F | N | Y | A | 51 | 62% | / | 87% | / | Neurosensorial hypoacusia; slurred speech; mild ptosis; short stature | III\-4 |
| 22 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-III3 | Fam | F | N | Y | A | 65 | 58% | / | 70% | / | Diabetes; cervico\-lipomas; mild cognitive deficit; logorrhoea; short stature | III\-5 |
| 23 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-IV5 | Fam | F | N | Y | A | 35 | 46% | / | 85% | / | Behavioural and psychiatric abnormalities with bipolar\-disorder features | IV\-6 |
| 24 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-IV6 | Fam | F | Y | Y | D | 29 | 90% | 92% | 95% | 95% (F); 79% (Myoblasts) | Mental retardation; sensorineural hearing loss; myopathy; myoclonic epilepsy; ataxia; lipomas; short stature; cerebellar atrophy | IV\-7; died at age 30 from respiratory infection, sepsis and respiratory failure |
| 25 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-IV7 | Fam | F | Y | Y | A | 29 | 85% | 93% | 96% | 86% (Myoblasts) | Mental retardation; sensorineural hearing loss; myopathy; myoclonic epilepsy; ataxia; lipomas; migraine\-like cephalalgia | IV\-8 |
| 26 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-III1 | Fam | F | N | N | A | ND | 10% | / | 33% | / | Healthy | Original label III\-2\. |
| 27 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-IV1 | Fam | M | N | N | A | ND | 45% | / | / | / | Healthy | Original label IV\-1\. |
| 28 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-IV2 | Fam | F | N | N | A | ND | 2% | / | 10% | / | Healthy | Original label IV\-2\. |
| 29 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-IV3 | Fam | F | N | N | A | 34 | 35% | / | 52% | / | Healthy | Original label IV\-4\. |
| 30 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-IV4 | Fam | F | N | N | A | 33 | 45% | / | 67% | / | Healthy | Original label IV\-5\. |
| 31 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-V1 | Fam | M | N | N | A | ND | / | / | / | / | Healthy | Original label V\-1; untested child of target\-positive mother IV\-4\. |
| 32 | 8363 | m.8363G\>A | G8363A\-F9 | G8363A\-F9\-V2 | Fam | F | N | N | A | ND | / | / | / | / | Healthy | Original label V\-2; untested child of target\-positive mother IV\-4\. |
| 33 | 8363 | m.8363G\>A | G8363A\-F10 | G8363A\-F10\-II1 | Fam | M | Y | Y | A | 20 | 39% | 96% | 67% | 78% (BM) | Fluctuating ataxia; dysarthria; mild muscle weakness; exercise intolerance; sensory axonal peripheral neuropathy; RRF/RBF/COX\-deficient fibers; elevated lactate | Oral mucosa 78% recorded in Other Mutant level as BM. |
| 34 | 8363 | m.8363G\>A | G8363A\-F10 | G8363A\-F10\-I1 | uninf | F | N | N | A | ND | 20% | / | / | / | Healthy | Asymptomatic mother had 20% heteroplasmy in blood cells. |
| 35 | 8363 | m.8363G\>A | G8363A\-F11 | G8363A\-F11\-P1 | Uninf | F | Y | Y | A | 42 | 45% | / | / | / | Exercise intolerance with walking range 200 m; muscle pain and dyspnea on exertion; postexercise muscle pain; mild lower\-limb amyotrophy; symmetrical proximal upper\-limb lipomatosis; hypokinetic dilated cardiomyopathy; chronic kidney disease; elevated CK and lactate | No lipoma biopsy; stable after 2 years; no family carrier testing reported. |

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