MEGDEL syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: MEGDEL
3-methylglutaconic aciduria with deafness - encephalopathy - Leigh-like syndrome
Number of Symptoms 47
OrphanetNr: 352328
OMIM Id: 614739
ICD-10: E71.1
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: < 0.1 of 100 000
Inheritance: Monogenic
Autosomal recessive
24741715 [IBIS]
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: 3-methylglutaconic aciduria
 -Rare genetic disease
Disorder of phospholipids, sphingolipids and fatty acids biosynthesis with central nervous system predominant involvement
 -Rare genetic disease
Mitochondrial disorder due to a defect in assembly or maturation of the respiratory chain complexes
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease
Neurometabolic disease
 -Rare genetic disease
 -Rare neurologic disease
Syndromic genetic deafness
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare otorhinolaryngologic disease

Comment:

MEGDEL is also called 3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome (PMID:23918762) or MEGDHEL or former 3-MGCA type IV or 3-MGCA-4 (PMID:24741715). The syndrome refers to a SERAC1 defect. MEGDEL syndrome is inherited in an autosomal recessive manner (PMID:24741715). The term "Leigh-like syndrome" is often used for individuals with clinical and other features that are strongly suggestive of Leigh syndrome but who do not fulfill the stringent diagnostic criteria because of atypical neuropathology (variation in the distribution or character of lesions or with the additional presence of unusual features such as extensive cortical destruction), atypical or normal neuroimaging, normal blood and CSF lactate levels, or incomplete evaluation (PMID:20301352). MEGDEL syndrome was recently found to be caused by mutations in SERAC1, encoding a protein essential for mitochondrial function, phospholipid remodeling, and intracellular cholesterol trafficking (PMID:25051967). Some patients have experienced (temporary) improvement of spasticity with treatment with oral or intrathecal baclofen. Respiratory problems resulting from excessive drooling improve with botulinum toxin injection in the salivary glands, extirpation of salivary glands, and/or re-routing of glandular ducts. An age-appropriate diet given via nasogastric tube or gastrostomy can greatly improve overall clinical condition (PMID:24741715).

Symptom Information: Sort by abundance 

1
 (HPO:0003535) 3-Methylglutaconic aciduria Frequent [IBIS] 25051967 IBIS 10 / 7739
2
 (HPO:0003344) 3-Methylglutaric aciduria Frequent [IBIS] 24741715 IBIS 6 / 7739
3
 (HPO:0000252) Microcephaly 24997715 IBIS 832 / 7739
4
 (HPO:0000648) Optic atrophy 24997715 IBIS 238 / 7739
5
 (HPO:0008527) Congenital sensorineural hearing impairment 25051967 IBIS 165 / 7739
6
 (HPO:0000407) Sensorineural hearing impairment Frequent [IBIS] 25051967 IBIS 524 / 7739
7
 (HPO:0000750) Delayed speech and language development 25051967 IBIS 197 / 7739
8
 (HPO:0001298) Encephalopathy 24997715 IBIS 72 / 7739
9
 (HPO:0001250) Seizures 24741715 IBIS 1245 / 7739
10
 (HPO:0001263) Global developmental delay Frequent [IBIS] 25051967 IBIS 853 / 7739
11
 (HPO:0001257) Spasticity Frequent [IBIS] 25051967 IBIS 251 / 7739
12
 (HPO:0001344) Absent speech 24741715 IBIS 57 / 7739
13
 (HPO:0002376) Developmental regression 24997715 IBIS 74 / 7739
14
 (HPO:0001254) Lethargy 25051967 IBIS 104 / 7739
15
 (HPO:0001270) Motor delay 25051967 IBIS 322 / 7739
16
 (HPO:0001332) Dystonia Frequent [IBIS] 25051967 IBIS 197 / 7739
17
 (HPO:0011968) Feeding difficulties 24997715 IBIS 240 / 7739
18
 (HPO:0002033) Poor suck 25051967 IBIS 37 / 7739
19
 (HPO:0006583) Fatal liver failure in infancy 24741715 IBIS 3 / 7739
20
 (HPO:0001511) Intrauterine growth retardation 25051967 IBIS 358 / 7739
21
 (HPO:0001510) Growth delay 25051967 IBIS 295 / 7739
22
 (HPO:0001508) Failure to thrive Frequent [IBIS] 24741715 IBIS 454 / 7739
23
 (HPO:0003128) Lactic acidosis 25051967 IBIS 116 / 7739
24
 (HPO:0001943) Hypoglycemia 25051967 IBIS 131 / 7739
25
 (HPO:0002151) Increased serum lactate 24741715 IBIS 92 / 7739
26
 (HPO:0002904) Hyperbilirubinemia Frequent [IBIS] 24741715 IBIS 32 / 7739
27
 (HPO:0003348) Hyperalaninemia 24741715 IBIS 19 / 7739
28
 (HPO:0002090) Pneumonia 25051967 IBIS 59 / 7739
29
 (HPO:0008936) Muscular hypotonia of the trunk Frequent [IBIS] 24741715 IBIS 77 / 7739
30
 (HPO:0001290) Generalized hypotonia 25051967 IBIS 51 / 7739
31
 (HPO:0001252) Muscular hypotonia Frequent [IBIS] 40% (n=5) 25051967 IBIS 990 / 7739
32
 (OMIM) Lesions in the basal ganglia 25051967 IBIS 1 / 7739
33
 (OMIM) Abnormal phospholipid profile 24741715 IBIS 1 / 7739
34
 (OMIM) Leigh syndrome 24741715 IBIS 7 / 7739
35
 (OMIM) Abnormal cardiolipin subspecies composition 24997715 IBIS 1 / 7739
36
 (OMIM) Intracellular accumulation of unesterified cholesterol 22683713 IBIS 1 / 7739
37
 (OMIM) Degrading mitochondria 22683713 IBIS 1 / 7739
38
 (MedDRA:10062938) Mitochondrial hepatopathy Frequent [IBIS] 23918762 IBIS 2 / 7739
39
 (HPO:0012444) Brain atrophy 24997715 IBIS 24 / 7739
40
 (IBIS) Leigh-like lesions on brain magnetic resonance imaging (MRI) Frequent [IBIS] 25051967 IBIS 3 / 7739
41
 (MedDRA:10054859) Myoclonic epilepsy 24997715 IBIS 7 / 7739
42
 (OMIM) Defects in mitochondrial oxidative phosphorylation 24741715 IBIS 1 / 7739
43
 (HPO:0001272) Cerebellar atrophy 24997715 IBIS 197 / 7739
44
 (MedDRA:10061308) Neonatal infection 25051967 IBIS 2 / 7739
45
 (OMIM) Abnormal phosphatidylglycerol profile (increased 34-to-1 and decreased 36-to-1 ratio) 24741715 IBIS 1 / 7739
46
 (OMIM) Decreased serum cholesterol 24741715 IBIS 6 / 7739
47
 (HPO:0001320) Cerebellar vermis hypoplasia 25051967 IBIS 57 / 7739

Associated genes:

SERAC1;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) MEGDEL is an autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia, and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellar atrophy as well as ...
Clinical Description OMIM Wortmann et al. (2006, 2009) reported 4 unrelated girls with an encephalomyopathy associated with mildly and intermittently increased urinary 3-methylglutaconic aciduria. Three children were born of 3 unrelated sets of consanguineous Turkish parents, and the fourth child was ...
Molecular genetics OMIM In 15 individuals from 13 families with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, Wortmann et al. (2012) identified 14 different homozygous or compound heterozygous mutations in the SERAC1 gene (see, e.g., 614725.0001-614725.0006). The first 2 mutations ...