Leukoencephalopathy - thalamus and brainstem anomalies - high lactate

General Information (adopted from Orphanet):

Synonyms, Signs: COXPD12
LTBL
Leukoencephalopathy with thalamus and brainstem involvement and high lactate
Number of Symptoms 62
OrphanetNr: 314051
OMIM Id: 614924
ICD-10:
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance:
Age of onset: Neonatal
Infancy
22492562 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Leukodystrophy
 -Rare genetic disease
 -Rare neurologic disease
Mitochondrial disorder due to a defect in mitochondrial protein synthesis
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease

Comment:

A multisystem fatal infantile disease (LTBL) is caused by a homozygous EARS2 (= COXPD12) mutation, the gene encoding mitochondrial glutamyl-tRNA synthetase (PMID:23008233; 22492562). Patients in the ‘mild’ LTBL group partially recovered and regained milestones in the following years with striking magnetic resonance imaging improvement and declining lactate levels, whereas those of the ‘severe’ LTBL group were characterized by clinical stagnation, brain atrophy on magnetic resonance imaging and persistent lactate increases (PMID:22492562).

Symptom Information: Sort by abundance 

1
 (HPO:0000602) Ophthalmoplegia 22492562 IBIS 56 / 7739
2
 (HPO:0000505) Visual impairment 22492562 IBIS 297 / 7739
3
 (HPO:0000508) Ptosis 22492562 IBIS 459 / 7739
4
 (HPO:0001488) Bilateral ptosis 22492562 IBIS 42 / 7739
5
 (HPO:0002151) Increased serum lactate Very frequent [IBIS] 22492562 IBIS 92 / 7739
6
 (HPO:0003128) Lactic acidosis 26893310 IBIS 116 / 7739
7
 (HPO:0001508) Failure to thrive 26893310 IBIS 454 / 7739
8
 (MedDRA:10057576) Cardiac septal hypertrophy 23008233 IBIS 4 / 7739
9
 (HPO:0008972) Decreased activity of mitochondrial respiratory chain 22492562 IBIS 34 / 7739
10
 (HPO:0011923) Decreased activity of mitochondrial complex I 22492562 IBIS 35 / 7739
11
 (HPO:0011924) Decreased activity of mitochondrial complex III 22492562 IBIS 22 / 7739
12
 (HPO:0008347) Decreased activity of mitochondrial complex IV 22492562 IBIS 31 / 7739
13
 (HPO:0001403) Macrovesicular hepatic steatosis rare [HPO:skoehler] 23008233 IBIS 7 / 7739
14
 (HPO:0003200) Ragged-red muscle fibers 23008233 IBIS 37 / 7739
15
 (HPO:0001319) Neonatal hypotonia 22492562 IBIS 101 / 7739
16
 (HPO:0002421) Poor head control 22492562 IBIS 23 / 7739
17
 (HPO:0002490) Increased CSF lactate Very frequent [IBIS] 22492562 IBIS 28 / 7739
18
 (HPO:0002352) Leukoencephalopathy Very frequent [IBIS] 22492562 IBIS 32 / 7739
19
 (HPO:0006789) Mitochondrial encephalopathy Very frequent [IBIS] 22492562 IBIS 5 / 7739
20
 (HPO:0002067) Bradykinesia 22492562 IBIS 62 / 7739
21
 (HPO:0001285) Spastic tetraparesis 22492562 IBIS 29 / 7739
22
 (HPO:0001332) Dystonia 22492562 IBIS 197 / 7739
23
 (HPO:0002376) Developmental regression 22492562 IBIS 74 / 7739
24
 (HPO:0001263) Global developmental delay 22492562 IBIS 853 / 7739
25
 (HPO:0001344) Absent speech 22492562 IBIS 57 / 7739
26
 (HPO:0005216) Chewing difficulties 22492562 IBIS 6 / 7739
27
 (HPO:0001250) Seizures 22492562 IBIS 1245 / 7739
28
 (HPO:0001338) Partial agenesis of the corpus callosum 22492562 IBIS 22 / 7739
29
 (HPO:0002079) Hypoplasia of the corpus callosum 22492562 IBIS 161 / 7739
30
 (HPO:0001396) Cholestasis rare [HPO:skoehler] 23008233 IBIS 136 / 7739
31
 (HPO:0002910) Elevated hepatic transaminases 23008233 IBIS 158 / 7739
32
 (HPO:0001395) Hepatic fibrosis 23008233 IBIS 67 / 7739
33
 (HPO:0002240) Hepatomegaly rare [HPO:skoehler] 23008233 IBIS 467 / 7739
34
 (HPO:0000047) Hypospadias 23008233 IBIS 250 / 7739
35
 (HPO:0000175) Cleft palate rare [HPO:skoehler] 23008233 IBIS 349 / 7739
36
 (HPO:0012751) Abnormal basal ganglia MRI signal intensity 22492562 IBIS 4 / 7739
37
 (HPO:0012747) Abnormal brainstem MRI signal intensity 22492562 IBIS 1 / 7739
38
 (HPO:0012696) Abnormal thalamic MRI signal intensity 22492562 IBIS 2 / 7739
39
 (HPO:0002363) Abnormality of brainstem morphology Very frequent [IBIS] 22492562 IBIS 14 / 7739
40
 (HPO:0002500) Abnormality of the cerebral white matter Very frequent [IBIS] 22492562 IBIS 73 / 7739
41
 (HPO:0010663) Abnormality of thalamus morphology Very frequent [IBIS] 22492562 IBIS 6 / 7739
42
 (HPO:0012444) Brain atrophy 22492562 IBIS 24 / 7739
43
 (HPO:0012762) Cerebral white matter atrophy 22492562 IBIS 3 / 7739
44
 (HPO:0007341) Diffuse swelling of cerebral white matter 22492562 IBIS 5 / 7739
45
 (HPO:0006989) Dysplastic corpus callosum 22492562 IBIS 7 / 7739
46
 (HPO:0007042) Focal white matter lesions 22492562 IBIS 7 / 7739
47
 (HPO:0003676) Progressive disorder Very frequent [IBIS] 100% (n=12) 22492562 IBIS 148 / 7739
48
 (OMIM) Abnormal liver enzymes, intermittent 22492562 IBIS 5 / 7739
49
 (OMIM) Decreased activities of mitochondrial complexes I, III, and IV 22492562 IBIS 1 / 7739
50
 (OMIM) Dysgenesis of the corpus callosum (1 patient) 22492562 IBIS 2 / 7739
51
 (OMIM) Fibrosis, mild (1 patient) 23008233 IBIS 1 / 7739
52
 (OMIM) Impaired mitochondrial respiration 23008233 IBIS 1 / 7739
53
 (OMIM) Increased alpha-fetoprotein 22492562 IBIS 5 / 7739
54
 (OMIM) Increased cerebral lactate 23008233 IBIS 1 / 7739
55
 (OMIM) Interventricular septal hypertrophy (1 patient) 23008233 IBIS 3 / 7739
56
 (OMIM) Lack of head or postural control (in severe cases) 22492562 IBIS 1 / 7739
57
 (OMIM) Lack of speech 22492562 IBIS 17 / 7739
58
 (OMIM) Muscle biopsy shows cytochrome c oxidase-negative fibers 22492562 IBIS 1 / 7739
59
 (OMIM) Swelling of the cerebral white matter 22492562 IBIS 1 / 7739
60
 (OMIM) Swelling of the deep white matter seen on MRI 22492562 IBIS 1 / 7739
61
 (OMIM) T2-weighted hyperintensities in deep cerebral white matter, brainstem, and cerebellar white matter with sparing of the periventricular rim 22492562 IBIS 1 / 7739
62
 (OMIM) Visual defects 22492562 IBIS 4 / 7739

Associated genes:

EARS2;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) COXPD12 is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. ...
Clinical Description OMIM Steenweg et al. (2012) reported a 6-year-old Italian boy with a leukoencephalopathy apparent since early infancy. Hypotonia was noted at 1 month of age, and he did not have head control at 3 months. The patient developed seizures ...
Molecular genetics OMIM In an Italian boy with COXPD12 manifest as leukoencephalopathy with thalamus and brainstem involvement and high lactate, Steenweg et al. (2012) identified compound heterozygosity for 2 mutations in the EARS2 gene (612799.0001 and 612799.0002). The mutations were found ...