Leber plus disease

General Information (adopted from Orphanet):

Synonyms, Signs: [IBIS]
LHON plus syndromes [IBIS]
Leber&#39
s &quot
plus&quot
LHON-plus syndrome [IBIS]
atypical LHON [IBIS]
Leber &#39
plus&#39
disease [IBIS]
Number of Symptoms 79
OrphanetNr: 99718
OMIM Id: 165200
500001
ICD-10: H47.2
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: < 0.1 of 100 000
Inheritance: Mitochondrial
26170609 [IBIS]
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: Mitochondrial disease with dilated cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Mitochondrial disease with eye involvement
 -Rare eye disease
 -Rare genetic disease
Mitochondrial disease with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Mitochondrial oxidative phosphorylation disorder due to a point mutation of mitochondrial DNA
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease
Optic neuropathy
 -Rare eye disease
 -Rare genetic disease

Comment:

While the typical manifestation of LHON is vision loss, there have been other manifestations reported within select pedigrees. Cardiac arrhythmias, peripheral neuropathies, dystonia, and myoclonus can occur in LHON carriers. Some families from Holland, Australia, and North America have particularly severe manifestations, including ataxia, juvenile onset encephalopathy, spastic dystonia, and psychiatric disturbances. These phenotypes have been called “LHON plus syndromes” and have been linked to other mtDNA point mutations that affect OXPHOS complex I activity but differ from the three commonly seen in LHON (PMID:26170609). Other definitions of LHON plus / Leber "plus" are: Leber's "plus" is described as neurological abnormalities in patients with Leber's hereditary optic neuropathy (PMID:7629530). Multiple sclerosis-like illness, spinal cord disease, brain stem and basal ganglia involvement, and Charcot-Marie-Tooth disease, as well as skeletal changes have been considered to be such abnormalities of Leber's "plus". It is noteworthy that patients in Leber's "plus" families may develop only the movement disorder, which suggests that the phenotypes of Leber's "plus" families may vary (PMID:7629530). Involved genes: MT-ND1 (PMID:23091534); MT-ND2 (PMID:7629530); MT-ND3 (Orphanet); MT-ND4 (PMID:23091534); MT-ND5 (PMID:7629530); MT-ND6 (PMID:7654063);

Symptom Information: Sort by abundance 

1
 (HPO:0001098) Abnormality of the fundus 7629530 IBIS 2 / 7739
2
 (HPO:0200057) Marcus Gunn pupil 16170145 IBIS 3 / 7739
3
 (HPO:0000648) Optic atrophy 7629530 IBIS 238 / 7739
4
 (HPO:0000543) Optic disc pallor 7629530 IBIS 67 / 7739
5
 (HPO:0001138) Optic neuropathy 9684025 IBIS 12 / 7739
6
 (HPO:0001085) Papilledema 7629530 IBIS 31 / 7739
7
 (HPO:0000479) Abnormality of the retina 7629530 IBIS 74 / 7739
8
 (HPO:0000640) Gaze-evoked nystagmus 23091534 IBIS 27 / 7739
9
 (HPO:0007979) Gaze-evoked horizontal nystagmus 23091534 IBIS 5 / 7739
10
 (HPO:0010544) Vertical nystagmus 23091534 IBIS 5 / 7739
11
 (HPO:0000602) Ophthalmoplegia 9684025 IBIS 56 / 7739
12
 (HPO:0000577) Exotropia 23091534 IBIS 43 / 7739
13
 (HPO:0007817) Horizontal supranuclear gaze palsy 23091534 IBIS 3 / 7739
14
 (HPO:0000651) Diplopia 23091534 IBIS 37 / 7739
15
 (HPO:0000551) Abnormality of color vision 16170145 IBIS 20 / 7739
16
 (HPO:0000576) Centrocecal scotoma 7629530 IBIS 6 / 7739
17
 (HPO:0000505) Visual impairment 23864591 IBIS 297 / 7739
18
 (HPO:0000618) Blindness 7629530 IBIS 124 / 7739
19
 (HPO:0000529) Progressive visual loss 7629530 IBIS 54 / 7739
20
 (HPO:0003128) Lactic acidosis Frequent [IBIS] 66.7% (n=6) 18216301 IBIS 116 / 7739
21
 (HPO:0011675) Arrhythmia 26170609 IBIS 226 / 7739
22
 (HPO:0008972) Decreased activity of mitochondrial respiratory chain 16170145 IBIS 34 / 7739
23
 (HPO:0011923) Decreased activity of mitochondrial complex I 16170145 IBIS 35 / 7739
24
 (HPO:0003200) Ragged-red muscle fibers Frequent [IBIS] 66.7% (n=6) 18216301 IBIS 37 / 7739
25
 (HPO:0001252) Muscular hypotonia 23091534 IBIS 990 / 7739
26
 (HPO:0001336) Myoclonus Very frequent [IBIS] 100% (n=6) 18216301 IBIS 115 / 7739
27
 (HPO:0011448) Ankle clonus 7629530 IBIS 31 / 7739
28
 (HPO:0003394) Muscle cramps 18216301 IBIS 106 / 7739
29
 (HPO:0008969) Leg muscle stiffness 7629530 IBIS 5 / 7739
30
 (HPO:0001324) Muscle weakness 7629530 IBIS 859 / 7739
31
 (HPO:0001298) Encephalopathy 26170609 IBIS 72 / 7739
32
 (HPO:0003474) Sensory impairment 7629530 IBIS 54 / 7739
33
 (HPO:0002495) Impaired vibratory sensation 7629530 IBIS 26 / 7739
34
 (HPO:0009830) Peripheral neuropathy 26170609 IBIS 206 / 7739
35
 (HPO:0001271) Polyneuropathy Occasional [IBIS] 22.2% (n=36) 7629530 IBIS 56 / 7739
36
 (HPO:0001251) Ataxia 23864591 IBIS 413 / 7739
37
 (HPO:0002321) Vertigo 23091534 IBIS 58 / 7739
38
 (HPO:0001300) Parkinsonism Rare [IBIS] 2.8% (n=36) 7629530 IBIS 75 / 7739
39
 (HPO:0003487) Babinski sign 16170145 IBIS 179 / 7739
40
 (HPO:0001347) Hyperreflexia 7629530 IBIS 363 / 7739
41
 (HPO:0001257) Spasticity 16170145 IBIS 251 / 7739
42
 (HPO:0002313) Spastic paraparesis 7629530 IBIS 33 / 7739
43
 (HPO:0001269) Hemiparesis 16170145 IBIS 51 / 7739
44
 (HPO:0010550) Paraplegia 7629530 IBIS 10 / 7739
45
 (HPO:0000473) Torticollis 7629530 IBIS 42 / 7739
46
 (HPO:0001332) Dystonia Rare [IBIS] 2.8% (n=36) 7629530 IBIS 197 / 7739
47
 (HPO:0000708) Behavioral abnormality 26170609 IBIS 212 / 7739
48
 (HPO:0100034) Motor tics Rare [IBIS] 2.8 (n=36) 7629530 IBIS 5 / 7739
49
 (HPO:0001260) Dysarthria 23864591 IBIS 329 / 7739
50
 (HPO:0000726) Dementia Rare [IBIS] 2.8% (n=36) 7629530 IBIS 131 / 7739
51
 (HPO:0007307) Rapid neurologic deterioration 23864591 IBIS 3 / 7739
52
 (HPO:0001263) Global developmental delay 23864591 IBIS 853 / 7739
53
 (HPO:0000802) Impotence 7629530 IBIS 20 / 7739
54
 (HPO:0001288) Gait disturbance 23091534 IBIS 318 / 7739
55
 (HPO:0001337) Tremor Occasional [IBIS] 25% (n=36) 7629530 IBIS 200 / 7739
56
 (HPO:0002174) Postural tremor Occasional [IBIS] 25% (n=36) 7629530 IBIS 22 / 7739
57
 (HPO:0002076) Migraine Occasional [IBIS] 8.7% (n=6) 7629530 IBIS 41 / 7739
58
 (HPO:0001250) Seizures Rare [IBIS] 5.6% (n=36) 7629530 IBIS 1245 / 7739
59
 (HPO:0001761) Pes cavus Rare [IBIS] 2.8% (n=36) 7629530 IBIS 225 / 7739
60
 (HPO:0002942) Thoracic kyphosis Occasional [IBIS] 19.4% (n=36) 7629530 IBIS 14 / 7739
61
 (HPO:0008445) Cervical spinal canal stenosis 7629530 IBIS 3 / 7739
62
 (HPO:0001009) Telangiectasia 16170145 IBIS 46 / 7739
63
 (HPO:0000020) Urinary incontinence 7629530 IBIS 75 / 7739
64
 (HPO:0000365) Hearing impairment 15026512 IBIS 539 / 7739
65
 (HPO:0002134) Abnormality of the basal ganglia 16170145 IBIS 13 / 7739
66
 (HPO:0002363) Abnormality of brainstem morphology Rare [IBIS] 2.8% (n=36) 7629530 IBIS 14 / 7739
67
 (HPO:0002500) Abnormality of the cerebral white matter 7629530 IBIS 73 / 7739
68
 (HPO:0002143) Abnormality of the spinal cord 7629530 IBIS 4 / 7739
69
 (HPO:0012444) Brain atrophy 23091534 IBIS 24 / 7739
70
 (HPO:0012707) Elevated brain lactate level by MRS Frequent [IBIS] 50% (n=6) 18216301 IBIS 2 / 7739
71
 (HPO:0002542) Olivopontocerebellar atrophy 23091534 IBIS 11 / 7739
72
 (MedDRA:10072198) Auditory neuropathy spectrum disorder 15026512 IBIS 1 / 7739
73
 (MedDRA:10012303) Demyelinating disorders 21685233 IBIS 1 / 7739
74
 (MedDRA:10020565) Hyperaemia 7629530 IBIS 1 / 7739
75
 (MedDRA:10062198) Microangiopathy 7629530 IBIS 4 / 7739
76
 (OMIM) MRI shows white matter lesions 7629530 IBIS 2 / 7739
77
 (OMIM) Mitochondrial proliferation Frequent [IBIS] 66.7% (n=6) 18216301 IBIS 4 / 7739
78
 (OMIM) Multiple sclerosis-like illness (516003.0001) Rare [IBIS] 2.8% (n=36) 7629530 IBIS 3 / 7739
79
 (OMIM) Spastic dystonia 26170609 IBIS 3 / 7739

Associated genes:

MT-ND1; MT-ND2; MT-ND4; MT-ND5; MT-ND6;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information: