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

Abstract

Objective3‐Methylglutaconic aciduria, dystonia–deafness, hepatopathy, encephalopathy, Leigh‐like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1.MethodsThis multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported.ResultsSixty‐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.InterpretationMEGDHEL 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

A novel mutation in the SERAC1 gene correlates with the severe manifestation of the MEGDEL phenotype, as revealed by whole‑exome sequencing

“…A range of pathogenic variants that have been observed in patients with MEGDEL syndrome have been identified and confirmed by exome sequencing and Sanger sequencing (4,5,21). Through these studies, the majority of the SERAC1 gene pathogenic variants have been categorized as frameshift, nonsense or missense pathogenic variants within or upstream of the lipase domain (3,4,8).…”

Mitochondrial disease in children

“…Without aminoglycoside exposure, individuals with this variant may have normal hearing until well into adult life, implying a role for newborn screening for the variant followed by lifelong avoidance of aminoglycosides in at‐risk individuals [74]. Childhood‐onset mitochondrial syndromes in which hearing loss is a prominent feature include MERRF, MELAS, KSS and deficiencies of SUCLA2, BCS1L, RRM2B, SERAC1, RMND1 and TRNT1 [19,22,27,38,47,49,75‐78].…”

“…Presentation may be with acute or chronic liver failure and is typically progressive and fatal. However, severe neonatal hepatic dysfunction that usually resolves with time has been reported in approaching 50% of children with SERAC1 mutations [76]. Hepatic involvement may be part of a multisystem disorder, but in neonatal or early infantile mitochondrial liver disease demise from liver failure may occur before neurological symptoms become apparent.…”

The phenotype of adult versus pediatric patients with inborn errors of metabolism

“…This is especially true for IEM manifesting with two waves, an initial phase in childhood predominantly affecting the liver and reflecting the prominent role of these hepatic pathways early in life, and a subsequent phase in adolescence or adulthood affecting the central nervous system and reflecting long-term consequences of altered homeostasis of cholesterol and/or bile acids. Likewise, patients may present with transient neonatal hepatic manifestations (cholestasis, liver failure) followed many years later by a progressive neurodegenerative disease sometimes after a long free interval (Saudubray and Garcia Cazorla 2016) such as in cerebrotendinous xanthomatosis (cataract, spasticity, ataxia, peripheral neuropathy, psychosis) (Degos et al 2016), spastic paraplegia type 5 (CYP7B1 mutations) (Marelli et al 2018), Niemann-Pick type C disease (cognitive decline, ataxia, movement disorders) (Patterson et al 2013), and MEGDEL syndrome (dystonia with Leigh like encephalopathy) (Maas et al 2017;Giron et al 2018). Other IEM reflect changes in metabolic pathways with age such as ornithine amino transferase (OAT) deficiency.…”