Monogenic hearing loss

Gene: SERAC1

Green List (high evidence)

Comment on publications: added publications form expert review to support phenotype

Created: 19 Dec 2017, 11:20 a.m.

Comment on list classification: changed Red to Green from expert review and new evidence in the literature

Created: 19 Dec 2017, 11:19 a.m.

Wortmann et al (2017) PMID: 29205472 reclassified MEGDEL syndrome to MEGDHEL syndrome, 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome (MEGDHEL) as they found that liver involvement was an additional clinical feature, so Hepatopathy was incorporated into the acronym. From a study of 67 individuals (39 previously unreported) from 59 families were included (age range 5 days - 33.4 years, median age 9 years) Wortmann et al idenitified 41 different SERAC1 biallelic variants, including 20 that have not been reported before. With exception of two families with a milder phenotype, all affected individuals show a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia was seen in more than 40% of all cases. Starting at a median age of six months muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learnt to walk (68%). 79% suffered hearing loss, 58% never learnt to speak, nearly all had significant intellectual disability (88%).

Created: 19 Dec 2017, 11:18 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 614739; MEGDEL syndrome; 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome; MEGDHEL syndrome

Publications

• 29205472
• 22683713
• 16527507
• 28482397
• 28778788
• 27186703
• 27604308

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
#614739:3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome[Failure to thrive; Hearing loss, sensorineural; Feeding problems; HypotoniaDegrading mitochondria; Psychomotor retardationPsychomotor regressionMental retardationSpasticityDystoniaExtrapyramidal symptomsSeizures (less common)Leigh syndromeLesions in the basal gangliaBrain atrophyCerebellar atrophy; Lactic acidosisHypoglycemia; Recurrent infectionsNeonatal sepsis; Increased serum lactateDefects in mitochondrial oxidative phosphorylation3-methylglutaconic aciduriaAbnormal phospholipid profileAbnormal phosphatidylglycerol profile (increased 34-to-1 and decreased 36-to-1 ratio)Abnormal cardiolipin subspecies compositionIntracellular accumulation of unesterified cholesterolDecreased serum cholesterol (in some)Elevated serum transaminase levelsHyperammonemiaElevated serum alpha-fetoproteinCoagulopathy (INR = 2.2 - 3.5)]

Publications

• PMID:16527507
• 22683713
• 23707711