Maternally-inherited Leigh syndrome
General Information (adopted from Orphanet):
| Synonyms, Signs: |
MILS Maternally-inherited Leigh disease Maternally-inherited infantile subacute necrotizing encephalopathy |
| Number of Symptoms | 42 |
| OrphanetNr: | 255210 |
| OMIM Id: |
161700
256000 |
| ICD-10: |
G31.8 |
| UMLs: |
|
| MeSH: |
|
| MedDRA: |
|
| Snomed: |
|
Prevalence, inheritance and age of onset:
| Prevalence: | No data available. |
| Inheritance: |
Mitochondrial 20301352 [IBIS] |
| Age of onset: |
|
Disease classification (adopted from Orphanet):
| Parent Diseases: |
Mitochondrial oxidative phosphorylation disorder due to a point mutation of mitochondrial DNA
-Rare developmental defect during embryogenesis -Rare genetic disease -Rare neurologic disease Neurometabolic disease -Rare genetic disease -Rare neurologic disease |
Comment:
| Among maternally-inherited forms of LS, the most common causative mtDNA defects have been found at positions 8993 and 9176 in the mt-ATP6 gene. This gene encodes one of the two coplex V subunits synthesized by the mitochondrial genome. The m.9176T>C variant has been shown to produce the LS or Leigh-like (LLS) phenotype, which includes ataxic syndrome and bilateral striatal necrosis with lesions in the caudate and putamen. The m.9176T>G substitution affects the same codon within the mt-ATP6 gene, but results in early onset LS and ataxia, with cerebellar atrophy and lesions in the basal ganglia (PMID:21819970). A 24-year-old woman was diagnosed with NARP caused by a heteroplasmic m.T8993G mutation in the MT-ATP6 encoding subunit 6 of mitochondrial ATP synthase. Her son was diagnosed with Leigh syndrome due to a maternally inherited homoplasmic MT-ATP6-m.T8993G mutation (PMID:25240982). In Leigh syndrome the mutant load exceeds 90%; milder symptoms of neuropathy, ataxia, and retinitis pigmentosa (NARP) tend to occur at lower mutant loads (60-90%). Although many reports have emphasized the relationship between the T8993G mutant load and the clinical phenotype, several other reports indicate that this relationship is not always valid. For example, Leigh syndrome has been observed in individuals with a T8993G mutant load in blood or muscle of less than 60% and, conversely, family members with a relatively high T8993G mutant load in blood (78-98%) might be asymptomatic or have only mild symptoms (PMID:19433277). The estimated incidence of Leigh syndrome in children less than 6 years of age was one in 32,000 (PMID:11261513). MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and MT-CO3 are the mitochondrial genes in which pathogenic variants are known to cause mtDNA-associated Leigh syndrome. MT-ATP6 is the only gene in which pathogenic variants are known to cause NARP. Approximately 10% of individuals with Leigh syndrome have either the m.8993T>G or m.8993T>C MT-ATP6 pathogenic variant; approximately 10%-20% have pathogenic variants in other mitochondrial genes. The proportion of individuals with NARP who have a detectable pathogenic variant at MT-ATP6 nucleotide 8993 is unknown but likely greater than 50%; a T-to-G transversion (m.8993T>G) is most common; a T-to-C transition (m.8993T>C) has also been described (PMID:20301352). Involved genes: MT-ATP6 (PMID:20301352); MT-TL1(PMID:20301352); MT-TK (PMID:20301352); MT-TW (PMID:20301352); MT-TV (PMID:20301352); MT-ND1 (PMID:20301352); MT-ND2 (PMID:20301352); MT-ND3 (PMID:20301352); MT-ND4 (PMID:20301352); MT-ND5 (PMID:20301352); MT-ND6 (PMID:20301352); MT-CO3 (PMID:20301352); |
Symptom Information:
|
|
(HPO:0000252) | Microcephaly | 23206802 | IBIS | 832 / 7739 | ||
|
|
(HPO:0001350) | Slurred speech | 19433277 | IBIS | 16 / 7739 | ||
|
|
(HPO:0001315) | Reduced tendon reflexes | 22819295 | IBIS | 160 / 7739 | ||
|
|
(HPO:0002445) | Tetraplegia | 19433277 | IBIS | 26 / 7739 | ||
|
|
(HPO:0001298) | Encephalopathy | 20472868; 9221962 | IBIS | 72 / 7739 | ||
|
|
(HPO:0001251) | Ataxia | 19433277 | IBIS | 413 / 7739 | ||
|
|
(HPO:0012469) | Infantile spasms | 25240982 | IBIS | 18 / 7739 | ||
|
|
(HPO:0001250) | Seizures | 25240982 | IBIS | 1245 / 7739 | ||
|
|
(HPO:0002490) | Increased CSF lactate | 19669818 | IBIS | 28 / 7739 | ||
|
|
(HPO:0002376) | Developmental regression | 8095070 | IBIS | 74 / 7739 | ||
|
|
(HPO:0001265) | Hyporeflexia | 22819295 | IBIS | 208 / 7739 | ||
|
|
(HPO:0000817) | Poor eye contact | 22819295 | IBIS | 26 / 7739 | ||
|
|
(HPO:0008872) | Feeding difficulties in infancy | 25240982 | IBIS | 153 / 7739 | ||
|
|
(HPO:0002013) | Vomiting | 19433277 | IBIS | 191 / 7739 | ||
|
|
(HPO:0001508) | Failure to thrive | 25240982 | IBIS | 454 / 7739 | ||
|
|
(HPO:0001635) | Congestive heart failure | 19669818 | IBIS | 232 / 7739 | ||
|
|
(HPO:0001639) | Hypertrophic cardiomyopathy | 19669818 | IBIS | 137 / 7739 | ||
|
|
(HPO:0003128) | Lactic acidosis | 20472868 | IBIS | 116 / 7739 | ||
|
|
(HPO:0003572) | Low plasma citrulline | 25240982 | IBIS | 7 / 7739 | ||
|
|
(HPO:0002151) | Increased serum lactate | 19669818 | IBIS | 92 / 7739 | ||
|
|
(HPO:0008322) | Abnormal mitochondrial morphology | 19669818 | IBIS | 8 / 7739 | ||
|
|
(HPO:0003236) | Elevated serum creatine phosphokinase | 19669818 | IBIS | 214 / 7739 | ||
|
|
(HPO:0001954) | Episodic fever | 22819295 | IBIS | 27 / 7739 | ||
|
|
(HPO:0002181) | Cerebral edema | 22819295 | IBIS | 19 / 7739 | ||
|
|
(HPO:0001601) | Laryngomalacia | 19669818 | IBIS | 61 / 7739 | ||
|
|
(HPO:0002104) | Apnea | 25240982 | IBIS | 106 / 7739 | ||
|
|
(HPO:0002791) | Hypoventilation | 19669818 | IBIS | 10 / 7739 | ||
|
|
(HPO:0011950) | Bronchiolitis | 19433277 | IBIS | 8 / 7739 | ||
|
|
(HPO:0002883) | Hyperventilation | 19669818 | IBIS | 10 / 7739 | ||
|
|
(HPO:0011947) | Respiratory tract infection | 22819295 | IBIS | 28 / 7739 | ||
|
|
(HPO:0010307) | Stridor | 19669818 | IBIS | 19 / 7739 | ||
|
|
(HPO:0001324) | Muscle weakness | 22819295 | IBIS | 859 / 7739 | ||
|
|
(HPO:0002421) | Poor head control | 19669818 | IBIS | 23 / 7739 | ||
|
|
(HPO:0001290) | Generalized hypotonia | 22819295 | IBIS | 51 / 7739 | ||
|
|
(HPO:0009062) | Infantile axial hypotonia | 19433277 | IBIS | 3 / 7739 | ||
|
|
(HPO:0002339) | Abnormality of the caudate nucleus | 19669818 | IBIS | 1 / 7739 | ||
|
|
(MedDRA:10058267) | Troponin increased | 19669818 | IBIS | 1 / 7739 | ||
|
|
(HPO:0002418) | Abnormality of midbrain morphology | 19669818 | IBIS | 2 / 7739 | ||
|
|
(HPO:0012502) | Abnormality of the internal capsule | 19669818 | IBIS | 1 / 7739 | ||
|
|
(HPO:0002134) | Abnormality of the basal ganglia | 19669818 | IBIS | 13 / 7739 | ||
|
|
(HPO:0010663) | Abnormality of thalamus morphology | 19669818 | IBIS | 6 / 7739 | ||
|
|
(MedDRA:10007548) | Cardiac enzymes increased | 19669818 | IBIS | 4 / 7739 |
Associated genes:
| MT-ATP6; MT-TL1; MT-TK; MT-TW; MT-TV; MT-ND1; MT-ND2; MT-ND3; MT-ND4; MT-ND5; MT-ND6; MT-CO3; |
ClinVar (via SNiPA)
| Gene symbol | Variation | Clinical significance | Reference |
|---|