Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: Sengers syndrome
Congenital cataract - hypertrophic cardiomyopathy - mitochondrial myopathy [IBIS]
Number of Symptoms 49
OrphanetNr: 1369
OMIM Id: 212350
615418
ICD-10: Q87.8
UMLs: C1859317
MeSH: C538280
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: 40 cases
Inheritance: Monogenic
Autosomal recessive
25208612 [IBIS]
Age of onset: Neonatal
Infancy
25208612 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Cardiac disease with cataract
 -Rare eye disease
 -Rare genetic disease
Disorder of phospholipids, sphingolipids and fatty acids biosynthesis with skeletal muscle predominant involvement
 -Rare genetic disease
Mitochondrial disease with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Mitochondrial substrate carrier disorder
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease

Comment:

Sengers syndrome is a rare autosomal recessive condition. It was first described by Sengers and colleagues in 1975 with the clinical features of congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy and lactic acidosis after exercise. Two forms of this syndrome have been described, a severe neonatal form that causes infantile death and a more benign form with a longer survival into the fourth decade. Sengers syndrome is caused by mutations in the acylglycerol kinase (AGK) gene, which is located on chromosome 7q34 and consists of 16 exons. Congenital or early-onset cataract is the common phenotypic finding in all reported patients, suggesting a role for AGK in the homeostasis of the human eye lens. Sequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G > A (splice site), c.409C > T (p.Arg137*) and c.877 + 3G > T (splice site), and compound heterozygous c.871C > T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues (PMID:25208612). Involved genes: AKG (PMID:25208612); SLC25A4 (Orphanet);

Symptom Information: Sort by abundance 

1
 (OMIM) COX-deficient fibers 25208612 IBIS 3 / 7739
2
 (MedDRA:10008118) Cerebral infarction 25208612 IBIS 10 / 7739
3
 (HPO:0012447) Abnormal myelination 25208612 IBIS 7 / 7739
4
 (HPO:0007068) Inferior vermis hypoplasia 25208612 IBIS 6 / 7739
5
 (HPO:0002365) Hypoplasia of the brainstem 25208612 IBIS 41 / 7739
6
 (HPO:0001321) Cerebellar hypoplasia 25208612 IBIS 114 / 7739
7
 (OMIM) Increased echogenicity 25208612 IBIS 2 / 7739
8
 (HPO:0006543) Cardiorespiratory arrest 25208612 IBIS 11 / 7739
9
 (HPO:0002788) Recurrent upper respiratory tract infections 25208612 IBIS 31 / 7739
10
 (HPO:0001873) Thrombocytopenia 25208612 IBIS 224 / 7739
11
 (HPO:0002098) Respiratory distress 25208612 IBIS 75 / 7739
12
 (HPO:0002092) Pulmonary hypertension 25208612 IBIS 109 / 7739
13
 (HPO:0009141) Depletion of mitochondrial DNA in muscle tissue 25208612 IBIS 5 / 7739
14
 (HPO:0008209) Premature ovarian failure 25208612 IBIS 28 / 7739
15
 (HPO:0000938) Osteopenia 25208612 IBIS 138 / 7739
16
 (HPO:0002315) Headache 25208612 IBIS 175 / 7739
17
 (HPO:0001508) Failure to thrive 25208612 IBIS 454 / 7739
18
 (HPO:0012378) Fatigue 25208612 IBIS 50 / 7739
19
 (HPO:0001667) Right ventricular hypertrophy 25208612 IBIS 23 / 7739
20
 (MedDRA:10067282) Right atrial dilatation 25208612 IBIS 8 / 7739
21
 (OMIM) Dilation of ventricle 25208612 IBIS 2 / 7739
22
 (HPO:0001250) Seizures 25208612 IBIS 1245 / 7739
23
 (HPO:0001269) Hemiparesis 25208612 IBIS 51 / 7739
24
 (HPO:0009062) Infantile axial hypotonia 25208612 IBIS 3 / 7739
25
 (HPO:0012548) Fatty replacement of skeletal muscle 25208612 IBIS 8 / 7739
26
 (HPO:0001297) Stroke 25208612 IBIS 44 / 7739
27
 (HPO:0003200) Ragged-red muscle fibers 25208612 IBIS 37 / 7739
28
 (OMIM) Fatty infiltration of heart muscle 25208612 IBIS 3 / 7739
29
 (MedDRA:10007669) Carnitine increased 25208612 IBIS 1 / 7739
30
 (HPO:0008872) Feeding difficulties in infancy 25208612 IBIS 153 / 7739
31
 (HPO:0000565) Esotropia 25208612 IBIS 58 / 7739
32
 (MedDRA:10051004) Floppy infant 25208612 IBIS 5 / 7739
33
 (HPO:0003287) Abnormality of mitochondrial metabolism 25208612 IBIS 12 / 7739
34
 (HPO:0008972) Decreased activity of mitochondrial respiratory chain 25208612 IBIS 34 / 7739
35
 (HPO:0002435) Meningocele 25208612 IBIS 23 / 7739
36
 (HPO:0001880) Eosinophilia 25208612 IBIS 35 / 7739
37
 (HPO:0002789) Tachypnea 25208612 IBIS 48 / 7739
38
 (HPO:0002094) Dyspnea 25208612 IBIS 132 / 7739
39
 (HPO:0003128) Lactic acidosis Very frequent [IBIS] 25208612 IBIS 116 / 7739
40
 (HPO:0003756) Skeletal myopathy Very frequent [IBIS] 25208612 IBIS 8 / 7739
41
 (HPO:0001639) Hypertrophic cardiomyopathy Very frequent [IBIS] 25208612 IBIS 137 / 7739
42
 (HPO:0000519) Congenital cataract Very frequent [IBIS] 25208612 IBIS 73 / 7739
43
 (HPO:0001992) Organic aciduria Very frequent [Orphanet] 25208612 IBIS 28 / 7739
44
 (HPO:0000518) Cataract Very frequent [IBIS] Very frequent [Orphanet] 25208612 IBIS 454 / 7739
45
 (HPO:0000639) Nystagmus Very frequent [Orphanet] 25208612 IBIS 555 / 7739
46
 (HPO:0000486) Strabismus Very frequent [Orphanet] 25208612 IBIS 576 / 7739
47
 (HPO:0001638) Cardiomyopathy Very frequent [Orphanet] 25208612 IBIS 192 / 7739
48
 (HPO:0003198) Myopathy Very frequent [Orphanet] 25208612 IBIS 151 / 7739
49
 (HPO:0030089) Abnormal muscle fiber protein expression Very frequent [Orphanet] 25208612 IBIS 64 / 7739

Associated genes:

AKG;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
AGK rs387907024 pathogenic RCV000023812.3
AGK rs387907025 pathogenic RCV000023814.3
AGK rs746709222 pathogenic RCV000191059.1
AGK rs766413410 pathogenic RCV000191058.1
SLC25A4 rs121912683 pathogenic RCV000019911.28
SLC25A4 rs398122942 pathogenic RCV000056253.28

Additional Information:

Description: (OMIM) Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., ...
Clinical Description OMIM In 7 of 22 children in 3 unrelated sibships, Sengers et al. (1975) described congenital cataract and mitochondrial myopathy of skeletal and heart muscle. Cardiomyopathy of hypertrophic type dominated the clinical picture. Histologically, abnormality of mitochondria and storage ...
Molecular genetics OMIM In 2 unrelated patients with myopathic mtDNA depletion syndrome, Calvo et al. (2012) identified homozygous or compound heterozygous mutations in the AGK gene (610345.0001-610345.0003).

In 10 patients from 9 families with Sengers syndrome, Mayr et al. ...