Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases

• Objective: 3-Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Methods: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Results: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days–33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 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 learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic “putaminal eye” was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. Interpretation: MEGDHEL syndrome is a progressive deafness–dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004–1015. © 2017 American Neurological Association

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

3 methylglutaconic acid

lactic acid

carboxylesterase

SERAC1 protein

human

3 methylglutaconic aciduria dystonia deafness hepatopathy encephalopathy Leigh like syndrome

aciduria

adolescent

adult

Article

basal ganglion

brain disease

child

clinical feature

communication skill

differential diagnosis

disease course

dyskinesia

dystonia

epilepsy

female

gene

gene mutation

genetic variability

hearing impairment

human

human tissue

hypersalivation

hypoglycemia

incidence

infant

intellectual impairment

intelligence

lactate blood level

lactic acidosis

Leigh disease

liver disease

liver dysfunction

liver failure

major clinical study

multicenter study

muscle biopsy

muscle hypotonia

neuroimaging

neuroradiology

newborn

newborn disease

nuclear magnetic resonance imaging

optic nerve atrophy

perception deafness

phenotype

priority journal

prognosis

putamen

serac1 gene

spasticity

speech development

survival

tongue disease

visual impairment

walking

amino acid sequence

clinical trial

cohort analysis

deafblindness

diagnostic imaging

disease exacerbation

genetics

male

mutation

preschool child

young adult

Carboxylic Ester Hydrolases

Child

Preschool

Cohort Studies

Deaf-Blind Disorders

Disease Progression

Humans

Infant

Newborn

Intellectual Disability

Optic Atrophy

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