Leigh syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: Infantile subacute necrotizing encephalopathy
Leigh disease
Number of Symptoms 127
OrphanetNr: 506
OMIM Id: 220111
256000
308930
ICD-10: G31.8
UMLs: C0023264
C0751267
MeSH: D007888
MedDRA: 10062950
Snomed: 29570005

Prevalence, inheritance and age of onset:

Prevalence: 2.75
Inheritance:
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: Mitochondrial disease with eye involvement
 -Rare eye disease
 -Rare genetic disease
Mitochondrial disease with peripheral neuropathy
 -Rare genetic disease
 -Rare neurologic disease
Mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease
Neurometabolic disease
 -Rare genetic disease
 -Rare neurologic disease
Supranuclear oculomotor palsy
 -Rare eye disease
 -Rare genetic disease
Syndrome with a symptomatic strabismus
 -Rare eye disease
 -Rare genetic disease
Unclassified primitive or secondary maculopathy
 -Rare eye disease
 -Rare genetic disease

Comment:

The inheritance of LS is complex, because patients may present mutations in (i) mtDNA-encoded genes, including NADH dehydrogenase subunits 1–6 (ND1–6), Cytochrome c Oxidase 3 (COX3), ATPase6, which affect mitochondrial complexes IV and V and various mitochondrial tRNAs (maternal transmission); or (ii) nuclear genes, which predominantly encode proteins involved in RC assembly, including NADH dehydrogenase (ubiquinone) Fe–S protein 1 (NDUFS1), 2, 4, 7, 8, and NADH dehydrogenase (ubiquinone) flavoprotein (NDUFV) 1 and 2, which affect the RC Complex I; succinate dehydrogenase complex, subunit A (SDHA), which affects Complex II; and COX10 and 15, SCO cytochrome oxidase deficient homolog 1 and 2 (SCO1 and SCO2), and the COX assembly protein, SURF1, which affect Complex IV (PMID:21819970). Leigh syndrome can be inherited as a mitochondrial trait, as an autosomal recessive trait due to mutations in nuclear genes encoding mitochondrial respiratory chain complex subunits or complex assembly proteins, and X-linked related to defects in pyruvate dehydrogenase complex (PDHc) due to mutations in the PDHA1 gene (MIM# 300502) (PMID:24731534). Leigh syndrome is an extremely genetically heterogeneous mitochondrial disorder. Newly identified nuclear genetic causes are increasing (PMID:25419155). Typical onset is usually within the first 2 years of life with heterogeneous involvement of the basal ganglia, brainstem, or white matter on MRI. Whether environmental factors alter phenotypic variability is unknown. The variability of MRI findings may be related to the genetic mutation location (PMID:205469). Patients with mutations in core subunits have a significantly poorer prognosis than patients with mutations in noncore subunits; the variability in prognosis is extremely high. Abnormal motor findings occur in 99.2% (129/130), abnormal ocular findings in 60.8% (79/130) (PMID:25419155). Involved genes: MT-ND1 (PMID:21819970); MT-ND2 (PMID:21819970); MT-ND3 (PMID:21819970); MT-ND4 (PMID:21819970); MT-ND5 (PMID:21819970); MT-ND6 (PMID:21819970); MT-CO3 (PMID:21819970); MT-ATP6 (PMID:21819970); various mitochondrial tRNAs (PMID:21819970); NDUFS1 (PMID:21819970); NDUFS2 (PMID:21819970); NDUFS4 (PMID:21819970); NDUFS7 (PMID:21819970); NDUFS8 (PMID:21819970); NDUFV1 (PMID:21819970); NDUFV2 (PMID:21819970); SDHA (PMID:21819970); COX10 (PMID:21819970); COX15 (PMID:21819970); SCO1 (PMID:21819970); SCO2 (PMID:21819970); SURF1 (PMID:21819970);

Symptom Information: Sort by abundance 

1
 (HPO:0001992) Organic aciduria Very frequent [Orphanet] 20546952 IBIS 28 / 7739
2
 (HPO:0001994) Renal Fanconi syndrome 25419155 IBIS 12 / 7739
3
 (HPO:0012211) Abnormal renal physiology Occasional [IBIS] 5.4% (n=130) 24731534 IBIS 23 / 7739
4
 (HPO:0000100) Nephrotic syndrome 25419155 IBIS 83 / 7739
5
 (HPO:0000091) Abnormality of the renal tubule 20301352 IBIS 15 / 7739
6
 (HPO:0000252) Microcephaly Occasional [IBIS] 11.5% (n=130) 24731534 IBIS 832 / 7739
7
 (HPO:0000639) Nystagmus Very frequent [Orphanet] Occasional [IBIS] 13.6% (n=44) 25351680 IBIS 555 / 7739
8
 (HPO:0000648) Optic atrophy Frequent [Orphanet] Occasional [IBIS] 22.5% (n=44) 25351680 IBIS 238 / 7739
9
 (HPO:0000602) Ophthalmoplegia Frequent [Orphanet] typical [HPO] Frequent [IBIS] 54% (n=13) 20301352 IBIS 56 / 7739
10
 (HPO:0000618) Blindness 10208283 IBIS 124 / 7739
11
 (HPO:0000510) Rod-cone dystrophy 20301352 IBIS 266 / 7739
12
 (HPO:0000496) Abnormality of eye movement 20301352 IBIS 79 / 7739
13
 (HPO:0000508) Ptosis Occasional [IBIS] 15.9% (n=44) 25351680 IBIS 459 / 7739
14
 (HPO:0000486) Strabismus Very frequent [Orphanet] Frequent [IBIS] 40.9% (n=44) 25351680 IBIS 576 / 7739
15
 (HPO:0000580) Pigmentary retinopathy Occasional [IBIS] 22.5% (n=44) 25351680 IBIS 49 / 7739
16
 (HPO:0000597) Ophthalmoparesis Frequent [Orphanet] Frequent [IBIS] 25351680 IBIS 71 / 7739
17
 (HPO:0000405) Conductive hearing impairment Occasional [IBIS] 1.5% (n=130) 24731534 IBIS 164 / 7739
18
 (HPO:0000407) Sensorineural hearing impairment Occasional [IBIS] 16.9% (n=130) 24731534 IBIS 524 / 7739
19
 (HPO:0000365) Hearing impairment Occasional [IBIS] 19.2% (n=130) 24731534 IBIS 539 / 7739
20
 (HPO:0002321) Vertigo Very frequent [Orphanet] 10208283 IBIS 58 / 7739
21
 (HPO:0010864) Intellectual disability, severe Occasional [IBIS] 11.5% (n=130) 24731534 IBIS 120 / 7739
22
 (HPO:0000750) Delayed speech and language development Occasional [IBIS] 6.1% (n=130) 24731534 IBIS 197 / 7739
23
 (HPO:0001332) Dystonia Frequent [IBIS] 44.6% (n=130) 24731534 IBIS 197 / 7739
24
 (HPO:0007359) Focal seizures Occasional [IBIS] 14.6% (n=130) 24731534 IBIS 27 / 7739
25
 (HPO:0001251) Ataxia Very frequent [Orphanet] hallmark [HPO] Frequent [IBIS] 34.6% (n=130) 24731534 IBIS 413 / 7739
26
 (HPO:0000733) Stereotypy Occasional [IBIS] 2.3% (n=130) 24731534 IBIS 58 / 7739
27
 (HPO:0001250) Seizures Frequent [Orphanet] Frequent [IBIS] 39.2% (n=130) 24731534 IBIS 1245 / 7739
28
 (HPO:0003487) Babinski sign Frequent [IBIS] 42.3% (n=130) 24731534 IBIS 179 / 7739
29
 (HPO:0002187) Intellectual disability, profound Occasional [IBIS] 2.3% (n=130) 24731534 IBIS 44 / 7739
30
 (HPO:0001347) Hyperreflexia Frequent [IBIS] 69% (n=13) 20301352 IBIS 363 / 7739
31
 (HPO:0002311) Incoordination Very frequent [Orphanet] 20843336 IBIS 84 / 7739
32
 (HPO:0006801) Hyperactive deep tendon reflexes Occasional [IBIS] 32.3% (n=130) 24731534 IBIS 21 / 7739
33
 (HPO:0002133) Status epilepticus Frequent [Orphanet] 20843336 IBIS 59 / 7739
34
 (HPO:0002141) Gait imbalance Very frequent [Orphanet] 25351680 IBIS 55 / 7739
35
 (HPO:0012469) Infantile spasms 12767455 IBIS 18 / 7739
36
 (HPO:0002375) Hypokinesia Occasional [IBIS] 3.8% (n=130) 24731534 IBIS 25 / 7739
37
 (HPO:0011097) Epileptic spasms Frequent [Orphanet] 6.1% (n=130) 24731534 IBIS 45 / 7739
38
 (HPO:0002487) Hyperkinesis Occasional [IBIS] 1.5% (n=130) 24731534 IBIS 7 / 7739
39
 (HPO:0001260) Dysarthria Occasional [IBIS] 11.5% (n=130) 24731534 IBIS 329 / 7739
40
 (HPO:0002360) Sleep disturbance Occasional [IBIS] 2.3% (n=130) 24731534 IBIS 113 / 7739
41
 (HPO:0006824) Cranial nerve paralysis Occasional [IBIS] 15% (n=13) 20301352 IBIS 81 / 7739
42
 (HPO:0002305) Athetosis Occasional [IBIS] 19.2% (n=130) 24731534 IBIS 31 / 7739
43
 (HPO:0002490) Increased CSF lactate 20301352 IBIS 28 / 7739
44
 (HPO:0002072) Chorea Occasional [IBIS] 19.2% (n=130) 24731534 IBIS 53 / 7739
45
 (HPO:0002067) Bradykinesia Occasional [IBIS] 3.8% (n=130) 24731534 IBIS 62 / 7739
46
 (HPO:0002066) Gait ataxia Very frequent [Orphanet] hallmark [HPO] 20546952 IBIS 327 / 7739
47
 (HPO:0001336) Myoclonus 7715756 IBIS 115 / 7739
48
 (HPO:0009830) Peripheral neuropathy Occasional [IBIS] 6.9% (n=130) 24731534 IBIS 206 / 7739
49
 (HPO:0002015) Dysphagia 25419155 IBIS 301 / 7739
50
 (HPO:0001269) Hemiparesis 24731534 IBIS 51 / 7739
51
 (HPO:0001265) Hyporeflexia Occasional [IBIS] 8% (n=13) 20301352 IBIS 208 / 7739
52
 (HPO:0001257) Spasticity Frequent [IBIS] 36.2% (n=130) 24731534 IBIS 251 / 7739
53
 (HPO:0002179) Opisthotonus Occasional [IBIS] 1.5% (n=130) 24731534 IBIS 35 / 7739
54
 (HPO:0001276) Hypertonia Frequent [IBIS] 33.1% (n=130) 24731534 IBIS 317 / 7739
55
 (HPO:0001315) Reduced tendon reflexes Occasional [IBIS] 15.4% (n=130) 24731534 IBIS 160 / 7739
56
 (HPO:0100543) Cognitive impairment Very frequent [Orphanet] 20546952 IBIS 230 / 7739
57
 (HPO:0100022) Abnormality of movement Very frequent [Orphanet] Occasional [IBIS] 15% (n=13) 20843336 IBIS 129 / 7739
58
 (HPO:0002197) Generalized seizures Occasional [IBIS] 22.3% (n=130) 24731534 IBIS 30 / 7739
59
 (HPO:0002342) Intellectual disability, moderate Occasional [IBIS] 13.1% (n=130) 24731534 IBIS 37 / 7739
60
 (HPO:0001337) Tremor Occasional [IBIS] 5.4% (n=130) 24731534 IBIS 200 / 7739
61
 (HPO:0001249) Intellectual disability Very frequent [Orphanet] Frequent [IBIS] 36.9% (n=130) 24731534 IBIS 1089 / 7739
62
 (HPO:0001263) Global developmental delay Very frequent [Orphanet] Very frequent [IBIS] 100% (n=13) 20301352 IBIS 853 / 7739
63
 (HPO:0001298) Encephalopathy 24731534 IBIS 72 / 7739
64
 (HPO:0001256) Intellectual disability, mild Occasional [IBIS] 8.5% (n=130) 24731534 IBIS 141 / 7739
65
 (HPO:0001270) Motor delay Very frequent [Orphanet] Occasional [IBIS] 9.2% (n=130) 24731534 IBIS 322 / 7739
66
 (HPO:0000819) Diabetes mellitus 25419155 IBIS 131 / 7739
67
 (HPO:0002926) Abnormality of thyroid physiology 25419155 IBIS 1 / 7739
68
 (HPO:0002650) Scoliosis Occasional [IBIS] 6.9% (n=130) 24731534 IBIS 705 / 7739
69
 (HPO:0001761) Pes cavus Occasional [IBIS] 7.7% (n=130) 24731534 IBIS 225 / 7739
70
 (HPO:0001397) Hepatic steatosis Occasional [IBIS] 3.1% (n=130) 24731534 IBIS 75 / 7739
71
 (HPO:0002020) Gastroesophageal reflux 25419155 IBIS 101 / 7739
72
 (HPO:0002017) Nausea and vomiting 10208283 IBIS 134 / 7739
73
 (HPO:0002033) Poor suck Occasional [IBIS] 24.6% (n=130) 24731534 IBIS 37 / 7739
74
 (HPO:0002039) Anorexia 25419155 IBIS 62 / 7739
75
 (HPO:0008872) Feeding difficulties in infancy Frequent [IBIS] 45.4% (n=130) 24731534 IBIS 153 / 7739
76
 (HPO:0011471) Gastrostomy tube feeding in infancy Frequent [IBIS] 33% (n=130) 24731534 IBIS 3 / 7739
77
 (HPO:0002019) Constipation 25419155 IBIS 194 / 7739
78
 (HPO:0002240) Hepatomegaly Occasional [IBIS] 1.5% (n=130) 24731534 IBIS 467 / 7739
79
 (HPO:0001399) Hepatic failure Occasional [IBIS] 12.3% (n=130) 24731534 IBIS 80 / 7739
80
 (HPO:0002910) Elevated hepatic transaminases Occasional [IBIS] 9.2% (n=130) 24731534 IBIS 158 / 7739
81
 (HPO:0001395) Hepatic fibrosis Occasional [IBIS] 3.1% (n=130) 24731534 IBIS 67 / 7739
82
 (HPO:0001508) Failure to thrive Occasional [IBIS] 16.2% (n=130) 24731534 IBIS 454 / 7739
83
 (HPO:0000975) Hyperhidrosis Occasional [IBIS] 9.2% (n=130) 24731534 IBIS 64 / 7739
84
 (HPO:0001034) Hypermelanotic macule 25419155 IBIS 22 / 7739
85
 (HPO:0000998) Hypertrichosis 25419155 IBIS 52 / 7739
86
 (HPO:0001297) Stroke 25419155 IBIS 44 / 7739
87
 (HPO:0001629) Ventricular septal defect 25419155 IBIS 316 / 7739
88
 (HPO:0001670) Asymmetric septal hypertrophy 25419155 IBIS 19 / 7739
89
 (HPO:0011675) Arrhythmia Occasional [IBIS] 3.8% (n=130) 24731534 IBIS 226 / 7739
90
 (HPO:0001639) Hypertrophic cardiomyopathy Occasional [IBIS] 9.2% (n=130) 24731534 IBIS 137 / 7739
91
 (HPO:0001644) Dilated cardiomyopathy Occasional [IBIS] 1.5% (n=130) 24731534 IBIS 141 / 7739
92
 (HPO:0001903) Anemia 10208283 IBIS 289 / 7739
93
 (HPO:0004370) Abnormality of temperature regulation 20301352 IBIS 58 / 7739
94
 (HPO:0002151) Increased serum lactate 20301352 IBIS 92 / 7739
95
 (HPO:0003128) Lactic acidosis 20301352 IBIS 116 / 7739
96
 (HPO:0002928) Decreased activity of the pyruvate dehydrogenase complex 20301352 IBIS 10 / 7739
97
 (HPO:0003348) Hyperalaninemia 20546952 IBIS 19 / 7739
98
 (HPO:0007110) Central hypoventilation Occasional [IBIS] 10% (n=130) 24731534 IBIS 6 / 7739
99
 (HPO:0002883) Hyperventilation Occasional [IBIS] 20% (n=130) 24731534 IBIS 10 / 7739
100
 (HPO:0002111) Restrictive deficit on pulmonary function testing Occasional [IBIS] 13.8% (n=130) 24731534 IBIS 25 / 7739
101
 (HPO:0002880) Respiratory difficulties Frequent [IBIS] 85% (n=13) 20301352 IBIS 15 / 7739
102
 (HPO:0002104) Apnea Occasional [IBIS] 16.1% (n=130) 24731534 IBIS 106 / 7739
103
 (HPO:0002793) Abnormal pattern of respiration 25419155 IBIS 26 / 7739
104
 (HPO:0005957) Breathing dysregulation 20546952 IBIS 6 / 7739
105
 (HPO:0012418) Hypoxemia 25419155 IBIS 18 / 7739
106
 (HPO:0012195) Irregular respiration 8505474 IBIS 3 / 7739
107
 (HPO:0002093) Respiratory insufficiency Very frequent [Orphanet] Frequent [IBIS] 37.7% (n=130) 24731534 IBIS 410 / 7739
108
 (HPO:0002721) Immunodeficiency 25419155 IBIS 97 / 7739
109
 (HPO:0001290) Generalized hypotonia Very frequent [IBIS] 92% (n=13) 20301352 IBIS 51 / 7739
110
 (HPO:0001324) Muscle weakness Very frequent [Orphanet] hallmark [HPO] Occasional [IBIS] 26.2% (n=130) 24731534 IBIS 859 / 7739
111
 (HPO:0001252) Muscular hypotonia Very frequent [Orphanet] Frequent [IBIS] 74.6% (n=130) 24731534 IBIS 990 / 7739
112
 (MedDRA:10013976) Dyspraxia Occasional [IBIS] 1% (n=130) 24731534 IBIS 3 / 7739
113
 (HPO:0002171) Gliosis 20301352 IBIS 48 / 7739
114
 (OMIM) Dysmotility 25419155 IBIS 3 / 7739
115
 (OMIM) Brain MRI shows basal ganglia lesions 20301352 IBIS 3 / 7739
116
 (HPO:0012128) Basal ganglia necrosis 20301352 IBIS 3 / 7739
117
 (OMIM) Lesions show signal increase on T2- and signal decrease on T1-weighted images 24731534 IBIS 2 / 7739
118
 (OMIM) Infantile swallowing difficulty 8505474 IBIS 2 / 7739
119
 (OMIM) Auditory neuropathy 25419155 IBIS 2 / 7739
120
 (HPO:0007146) Bilateral basal ganglia lesions 20301352 IBIS 2 / 7739
121
 (MedDRA:10050012) Bradyphrenia 24731534 IBIS 1 / 7739
122
 (OMIM) Renal tubulopathy 20301352 IBIS 4 / 7739
123
 (OMIM) Brainstem lesions, hyperintense on T2-weighted imaging 20301352 IBIS 2 / 7739
124
 (OMIM) Lesions in basal ganglia, brainstem, cerebellum, thalamus, spinal cord characterized by demyelination, necrosis, gliosis, spongiosis, and capillary proliferation 20301352 IBIS 2 / 7739
125
 (OMIM) Increased urinary lactate 20546952 IBIS 4 / 7739
126
 (OMIM) Cardiac dysfunction Occasional [IBIS] 17.7% (n=130) 24731534 IBIS 3 / 7739
127
 (MedDRA:10063259) Amino acid level increased 20546952 IBIS 1 / 7739

Associated genes:

MT-ND1; MT-ND2; MT-ND3; MT-ND4; MT-ND5; MT-ND6; MT-CO3; MT-ATP6; NDUFS1; NDUFS2; NDUFS4; NDUFS7; NDUFS8; NDUFV1; NDUFV2; SDHA; COX10; COX15; SCO1; SCO2; SURF1;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information: