Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1

Fellman, Vineta; Banerjee, Rishi; Lin, Kai Lan; Pulli, Ilari; Cooper, Helen; Tyynismaa, Henna; Kallijärvi, Jukka

doi:10.1016/j.bbadis.2021.166298

Cited by 5 publications

(5 citation statements)

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“…However, due to the low birth weight of our patient it can be assumed that the initial onset had been intrauterine. Fellman et al and Maas et al also report two cases of infantile MEGDHEL Syndrome who were small for gestational age ( 2 , 10 ). Pediatric acute liver failure (PALF) is a progressive, potentially lethal clinical condition mainly occurring in the first year of life and according to the PALF Study group defined as a rapidly progressive, potentially fatal clinical syndrome with (a) biochemical evidence of hepatocellular injury and (b) a coagulopathy that cannot be corrected with vitamin K alone with an INR ≥ 1.5 with hepatic encephalopathy or an INR ≥ 2.0 regardless of the presence of hepatic encephalopathy ( 11 , 12 ).…”

Section: Discussionmentioning

confidence: 97%

Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome

Kirchberg,

Lainka,

Gangfuß

et al. 2024

Front. Pediatr.

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Background/purposeMEGDHEL syndrome is a rare autosomal recessive metabolic disorder, which is characterized by 3-methylglutaconic aciduria with deafness-dystonia, hepatopathy, encephalopathy and Leigh-like syndrome. It is caused by biallelic pathogenic variants in the SERAC1 gene. Due to the unspecific symptoms and the diverse manifestations of the clinical phenotype, the diagnosis is challenging. Infantile MEGDHEL syndrome often has a severe disease course with acute liver failure. Differentiation from other metabolic disorders is difficult and requires a multidisciplinary approach.Case presentationA two-day-old small for gestational age neonate was admitted to our pediatric intensive care unit (PICU) due to severe liver failure with distinct hyperammonemia and hypoglycemia without elevation of transaminases or cholestasis. Due to high ammonia level, continuous hemodialysis was established immediately after admission. In addition, protein intake was stopped, and the patient anabolized with intravenous glucose. Temporary stabilization could be achieved after four days. In the further course, severe neurological and cardiocirculatory complications occurred, which ultimately led to the infant's death. In the metabolic diagnostics, a pronounced lactate acidosis and in urine an increased excretion of 3-methylglutaconic acid as well as other metabolites of mitochondrial energy metabolism has been the leading findings besides the hyperammonemia. Post-mortem trio whole genome analysis detected a homozygous pathogenic variant in SERAC1 with evidence of SERAC1 deficiency leading to the diagnosis of infantile MEGDHEL syndrome.ConclusionWhen pediatricians are faced with hepatopathy or even acute liver failure without elevation of transaminases or cholestasis in newborns, SERAC1 deficiency should be considered as a potential differential diagnosis. The initial treatment is based on the recommended management of suspected metabolic disorders. Even while no cure is available yet, patients should be offered proper supportive management through a multidisciplinary team. In addition, genetic confirmation of the diagnosis is important for the families, especially regarding further family planning.If a newborn presents with hyperammonemia, hypoglycemia and impaired liver synthesis function without elevation of transaminases or cholestasis, the possible presence of MEGDHEL syndrome due to a SERAC1 mutation should be considered.

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Section: Discussionmentioning

confidence: 97%

Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome

Kirchberg,

Lainka,

Gangfuß

et al. 2024

Front. Pediatr.

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“…A defective remodelling of PG can affect mitochondrial cardiolipin synthesis and lipid metabolism, resulting in metabolic acidosis in our patient. It has been noticed that patients with nonsense SERAC1 mutation have impaired mitochondrial liver function with decreased levels of mitochondrial complexes I, III and IV in their hepathocytes (Fellman et al, 2022). This shows that mitochondrial and hepatic damage are involved in MEGDEHL syndrome, which could explain the hepatic cytolysis in our patient.…”

Section: Discussionmentioning

confidence: 99%

“…However, this protein is important for intracellular cholesterol trafficking and phospholipid remodelling at mitochondrial interfaces and the endoplasmic reticulum (Fellman et al, 2022). According to several studies, the SERAC1 enzyme participates in phosphatidylglycerol (PG) remodelling, which is crucial for mitochondrial function and intracellular cholesterol trafficking (Fellman et al, 2022;Wortmann et al, 2012Wortmann et al, , 2014. In the foetal lung, the PG is the last surfactant to be expressed (after 35 weeks) and the precursor of cardiolipin and glycerol.…”

Section: Discussionmentioning

confidence: 99%

“…It encodes a protein located at the contact sites between the endoplasmic reticulum and mitochondria interface, which is essential for phospholipid exchange (Wortmann et al, 2015). This enzyme is involved in the remodelling of the phospholipid phosphatidylglycerol, the precursor of both cardiolipin, essential for proper mitochondrial function and bis (monoacylglycerol) phosphate, essential for intracellular cholesterol trafficking, respectively (Fellman et al, 2022). Pathogenic variants have been found in the SERAC1 gene in patients with MEGDEL syndrome, most of which are frameshift, nonsense or missense pathogenic variants within or upstream of the Serine‐Lipase domain (Maas et al, 2017; Rodríguez‐García et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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First description of the MEGDEHL syndrome in the Tunisian population via whole‐exome sequencing: Novel nonsense mutation inSERAC1gene

Felhi

Kamel

Hayet

et al. 2022

Intl J of Devlp Neuroscience

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Introduction: MEGDEL syndrome is a rare recessive disorder, with about 100 cases reported worldwide, which is defined by 3-methylglutaconic aciduria (MEG), deafness (D), encephalopathy (E) and Leigh-like syndrome (L). When these manifestations were added to hepatopathy (H), the syndrome was labelled as MEGD(H)EL. Mutations in SERAC1 gene encoding a serine active site containing 1 protein were described in patients affected by this syndrome. Patients and methods: The present study reports the Whole Exome Sequencing (WES) of the first case of MEGDEHL syndrome in Tunisia in a consanguineous family with three affected children. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in the blood of the indexed case, carried out, respectively by Long-Range PCR and qPCR. Results:The WES revealed a novel homozygous nonsense mutation (c.1379G > A; p.W460X) in the SERAC1 gene, which was confirmed by Sanger sequencing. This nonsense mutation was present at a homozygous state in the three affected children and was heterozygous in the parents. In silico analysis using various softwares was performed, and the predictive results supported the pathogenic effect of the identified mutation. Further, long-range PCR and qPCR analyses of the patient's blood excluded any mtDNA deletions or depletions. Conclusion:Sequencing results and bioinformatic tools confirmed that the novel mutation (p.W460X) in the SERAC1 gene causes the severe phenotype in the studied family with MEGDEHL syndrome.

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“…Our patient fits the clinical, laboratory, and neuroimaging phenotypes described for MEGDEL syndrome due to mutations in SERAC1 . The most common onset of MEGDEL is during infancy presenting with hypoglycemia and sepsis-like disease followed by delayed psychomotor development apparent at about 2 years of age with sensorineural deafness, spasticity, and excretion of 3-methylglucoconic acid ( Maas et al, 2017 ; Sequeira et al, 2017 ; Fellman et al, 2022 ). Our patient had early onset neurosensory hearing loss and global developmental delay.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Associated Membrane Scaffolding with Endoplasmic Reticulum: A Dynamic Pathway of Developmental Disease

Saneto

Perez

2022

Front. Mol. Biosci.

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Communication between intracellular organelles is essential for overall cellular function. How this communication occurs and under what circumstances alterations transpire are only the beginning to be elucidated. The pathways of calcium homeostasis, lipid transfer, mitochondrial dynamics, and mitophagy/apoptosis have been linked to the endoplasmic reticulum and tethering sites on the outer and/or inner mitochondrial membrane called mitochondria-associated endoplasmic reticulum membranes (MAM). Sensitive visualization by high-powered microscopy coupled with the advent of massive parallel sequencing has elaborated the structure, while patient’s diseases have uncovered the physiological function of these networks. Using specific patient examples from our pediatric mitochondrial center, we expand how specific genetic pathological variants in certain MAM structures induce disease. Genetic variants in MICU1, PASC-2, CYP2U1, SERAC1, and TANGO2 can induce early development abnormalities in the areas of cognition, motor, and central nervous system structures across multiple MAM pathways and implicate mitochondrial dysregulation.

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Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1

Cited by 5 publications

References 23 publications

Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome

Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome

First description of the MEGDEHL syndrome in the Tunisian population via whole‐exome sequencing: Novel nonsense mutation inSERAC1gene

Mitochondria-Associated Membrane Scaffolding with Endoplasmic Reticulum: A Dynamic Pathway of Developmental Disease

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