3-methylglutaconic_Aciduria_With_Deafness_Encephalopathy_And_Leigh-like_Syndrome

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic SERAC1 variants are required; most reported families are consanguineous with homozygous alleles, and heterozygous parents are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:32684373 SUPPORT Human Clinical

"MEGDEL syndrome is an autosomal recessive disorder, clinically characterized by 3-methylglutaconic aciduria, psychomotor delay, muscle hypotonia, sensorineural deafness, and Leigh-like lesions on brain magnetic resonance imaging"

Review of 102 reported patients states the autosomal recessive mode of inheritance directly.

PMID:33613893 SUPPORT Human Clinical

"with homozygous genotype in the patient and heterozygous genotype in her unaffected parents"

Segregation in one family shows the homozygous proband affected and heterozygous carriers unaffected.

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Subtypes

3

Severe infantile MEGD(H)EL

The classic and most severe presentation, caused by complete loss of SERAC1 function (truncating, frameshift or large-deletion alleles). It begins with a neonatal metabolic and hepatic crisis and progresses to sensorineural deafness, severe psychomotor delay, dystonia and spasticity with staged basal-ganglia degeneration. Outcome is poor with early death.

Show evidence (1 reference)

PMID:32684373 SUPPORT Human Clinical

"Treatment is supportive, and the outcome is usually poor with early death, except for the juvenile-onset type"

Distinguishes the severe infantile course from the juvenile-onset form.

Juvenile-onset complicated hereditary spastic paraplegia

A markedly milder oligosystemic phenotype produced by hypomorphic alleles with residual SERAC1 activity, in which affected subjects remain ambulant well into the second and third decades. Phosphatidylglycerol remodeling is impaired but less severely than in the infantile form.

Show evidence (1 reference)

PMID:28916646 SUPPORT Human Clinical

"Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10-20 years"

Defines the juvenile complicated-HSP presentation of SERAC1 deficiency.

Adult-onset dystonia-spasticity presentation

The mildest end of the SERAC1 spectrum, in which a patient with long-standing moderate intellectual disability develops progressive loss of acquired skills and generalized dystonia only in adulthood.

Show evidence (1 reference)

PMID:37711114 SUPPORT Human Clinical

"A 30-year-old patient with a moderate intellectual disability, developed, since the age of 25, a progressive loss of previous capacities"

Documents the adult-onset end of the SERAC1 deficiency spectrum.

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Mechanistic Hypotheses

1

SERAC1 as an outer-membrane partner of the serine transporter SFXN1

serine_transport_mtdna EMERGING

Evidence balance 1 support 1 refute

An alternative model in which SERAC1 acts not as a phospholipid remodeling enzyme at the ER-mitochondria contact site but on the outer mitochondrial membrane, as a required partner of the mitochondrial serine transporter SFXN1. On this model the primary defect is a failure of serine import that starves the one-carbon cycle, unbalances the nucleotide pool and depletes mitochondrial DNA, making MEGD(H)EL a mtDNA depletion syndrome. The two models differ in the subcellular location they assign to SERAC1 and have not been reconciled; the therapeutic implication of the second, that nucleoside supplementation might help, does not follow from the first.

Pathograph links

Absent or Mislocalized SERAC1 Protein -> Impaired Mitochondrial Serine Import and mtDNA Depletion DIRECT In the alternative model, SERAC1 acts on the outer mitochondrial membrane as a partner of the serine transporter SFXN1, so its loss starves the one-carbon cycle.

Impaired Mitochondrial Serine Import and mtDNA Depletion -> Mitochondrial Bioenergetic Failure DIRECT mtDNA depletion removes the templates for the mitochondrially encoded respiratory chain subunits.

Show evidence (2 references)

PMID:35235340 SUPPORT Model Organism

"We found that SERAC1 localizes to the outer mitochondrial membrane and is a protein component of the one-carbon cycle"

States the alternative localization and function on which this hypothesis rests.

PMID:22683713 REFUTE In Vitro

"We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange"

The original localization study places SERAC1 at the contact site rather than the outer mitochondrial membrane.

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Discussions and Knowledge Gaps

2

Where in the cell does SERAC1 act - at the mitochondria-associated ER membrane, or on the outer mitochondrial membrane?

KNOWLEDGE GAP OPEN serac1_localization_conflict

Attached to

pathophysiology#Absent or Mislocalized SERAC1 Protein mechanistic_hypotheses#serine_transport_mtdna

The gene-discovery study localized SERAC1 to the mitochondria-associated membrane fraction at the ER-mitochondria interface and assigned it a phospholipid remodeling role there. A later study using a knockout mouse placed it on the outer mitochondrial membrane as a partner of the serine transporter SFXN1, with a one-carbon-cycle and mtDNA-maintenance role. The two localizations imply different primary defects and different candidate treatments, and no study has tested them against each other. Until they are reconciled, this entry curates the phospholipid route as the main chain and the serine-transport route as an explicit hypothesis group.

Show evidence (2 references)

PMID:35235340 SUPPORT Model Organism

"We found that SERAC1 localizes to the outer mitochondrial membrane and is a protein component of the one-carbon cycle"

One side of the disagreement.

PMID:22683713 REFUTE In Vitro

"We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange"

The other side of the disagreement.

Does the canine SERAC1 disorder model the non-neurological features of MEGDEL, or only the movement disorder?

HUMAN MODEL MISMATCH OPEN canine_model_organ_coverage

Attached to

pathophysiology#Cochlear and Auditory Pathway Degeneration pathophysiology#Hepatocellular Mitochondrial Injury

Canine multiple system degeneration is caused by SERAC1 loss and shares striatal neurodegeneration with the human disease, but the published description covers only the movement disorder and its neuropathology. Deafness, hepatopathy and 3-methylglutaconic aciduria - three of the four letters of the human acronym - are not reported in the dogs, and the canine lesion additionally involves the cerebellum and substantia nigra, which the human disease does not. So it is not known whether the dog fails to develop those features or whether nobody has looked, and the model cannot currently be used to study the auditory or hepatic mechanism.

Proposed experiments

Auditory, hepatic and organic-acid phenotyping of SERAC1 dogs

canine_audiology_and_organic_acids

Perform brainstem auditory evoked response testing, liver function and histology, and urine organic acid analysis on genotyped affected, carrier and wild-type Kerry Blue Terriers and Chinese Crested dogs.

Readouts

Brainstem auditory evoked response threshold

pathophysiology#Cochlear and Auditory Pathway Degeneration

Direction: INCREASED

Interpretation: A raised threshold in affected dogs would show the canine model does reach the auditory system.

Urinary 3-methylglutaconic acid

pathophysiology#Hepatocellular Mitochondrial Injury

Direction: INCREASED

Interpretation: Organic aciduria in affected dogs would show the biochemical phenotype is conserved.

Would support

pathophysiology#Cochlear and Auditory Pathway Degeneration

Would refute

pathophysiology#Cochlear and Auditory Pathway Degeneration

Supporting outcome

Affected dogs show raised auditory brainstem response thresholds and increased urinary 3-methylglutaconic acid relative to genotyped littermate controls.

Refuting outcome

Affected dogs have normal hearing thresholds, normal liver histology and normal organic acids despite advanced striatal degeneration, showing the canine phenotype is restricted to the nervous system.

Show evidence (1 reference)

PMID:39596578 SUPPORT Model Organism

"The associated pathologic lesions include degeneration of the cerebellum, caudate nucleus, and substantia nigra"

The published canine lesion description covers the nervous system only.

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Pathophysiology

13

Biallelic SERAC1 Loss of Function

Two loss-of-function SERAC1 alleles - nonsense, frameshift, canonical splice or multi-exon deletion - are the initiating lesion. Heterozygous carriers are unaffected.

Downstream

Absent or Mislocalized SERAC1 Protein Truncating alleles abolish protein expression; a C-terminal truncation that escapes degradation is mislocalized away from mitochondria.

Show evidence (1 reference)

PMID:22683713 SUPPORT Human Clinical

"Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria"

Establishes biallelic SERAC1 mutation as the cause of the disorder.

Absent or Mislocalized SERAC1 Protein

Patient fibroblasts carrying a homozygous truncating allele contain no detectable SERAC1 protein. A milder C-terminally truncated protein is expressed but is distributed throughout the cell instead of partially colocalizing with mitochondria, so the enzyme is absent from its site of action either way.

SERAC1 as an outer-membrane partner of the serine transporter SFXN1

mitochondria-associated endoplasmic reticulum membrane GO:0044233

Downstream

Impaired Phosphatidylglycerol Remodeling SERAC1 is the phosphatidylglycerol remodeling enzyme at this membrane, so its loss removes the remodeling activity.

Impaired Mitochondrial Serine Import and mtDNA Depletion In the alternative model, SERAC1 acts on the outer mitochondrial membrane as a partner of the serine transporter SFXN1, so its loss starves the one-carbon cycle.

Show evidence (3 references)

PMID:34751152 SUPPORT In Vitro

"In the patient fibroblasts, no SERAC1 protein was detected, the mitochondrial network was severely fragmented, and the cristae morphology was altered"

Demonstrates complete absence of the protein in patient cells.

PMID:34751152 SUPPORT In Vitro

"the mutant protein with the a 45-amino acid C-terminal truncation was distributed throughout the cell, whereas wild-type SERAC1 partially colocalized with the mitochondrial marker MT-CO1"

Shows the alternative route to functional absence, mislocalization away from mitochondria.

PMID:22683713 SUPPORT In Vitro

"We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange"

Establishes the normal site of action from which the protein is lost.

Impaired Phosphatidylglycerol Remodeling

Without SERAC1, the phosphatidylglycerol pool of patient fibroblasts shifts towards PG-34:1 and away from PG-36:1. Lentiviral complementation with wild-type SERAC1 partially normalizes the ratio, establishing that the lipid change is a direct consequence of the enzyme deficiency rather than a downstream epiphenomenon.

phosphatidylglycerol acyl-chain remodeling GO:0036148 ↓ DECREASED

Experimental models

MEGDEL patient dermal fibroblasts PRIMARY CELL CULTURE Patient fibroblasts show the PG-34:1 rise and PG-36:1 fall, and complementation with wild-type SERAC1 partially normalizes the ratio, which is the strongest causal link in the whole mechanism.

Downstream

Altered Cardiolipin Subspecies Composition Phosphatidylglycerol is the immediate precursor of cardiolipin, so a shifted PG pool yields abnormal cardiolipin species.

Bis(monoacylglycerol)phosphate Depletion and Free Cholesterol Accumulation The same remodeling defect lowers BMP, the late-endosomal lipid required for cholesterol egress.

Mitochondrial Network Fragmentation and Deficient Calcium Transfer Loss of the remodeling enzyme at the ER-mitochondria interface disrupts the contact site itself; the intervening steps between the lipid change and the structural and calcium phenotypes are not established.

Show evidence (2 references)

PMID:22683713 SUPPORT In Vitro

"A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1"

Reports the primary lipid abnormality in patient cells.

PMID:22683713 SUPPORT In Vitro

"Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1"

Rescue by wild-type protein shows the lipid defect is caused by SERAC1 loss.

Altered Cardiolipin Subspecies Composition

The shifted phosphatidylglycerol pool yields cardiolipin of abnormal acyl composition. Cardiolipin is required for assembly and stability of the respiratory chain supercomplexes, which is the route by which a phospholipid defect becomes a bioenergetic one.

cardiolipin acyl-chain remodeling GO:0035965 ↓ DECREASED

mitochondrial inner membrane GO:0005743

Downstream

Respiratory Chain Complex Deficiency Abnormal cardiolipin is the presumed link to measured complex I, III and IV deficiency; the assembly intermediates have not been demonstrated in this disease.

Show evidence (2 references)

PMID:22683713 SUPPORT In Vitro

"decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition"

Reports the altered cardiolipin composition directly.

PMID:23296368 SUPPORT Other

"defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome"

Classification review groups MEGDEL with Barth syndrome as a disorder of defective phospholipid remodelling, the class in which cardiolipin is the affected lipid.

Bis(monoacylglycerol)phosphate Depletion and Free Cholesterol Accumulation

Low BMP impairs intracellular cholesterol trafficking, so unesterified cholesterol accumulates and is unevenly distributed, demonstrable by filipin staining in patient fibroblasts. This is a parallel cellular consequence of the same remodeling defect rather than a step on the bioenergetic route.

intracellular cholesterol transport GO:0032367 ↓ DECREASED

Downstream

Mitochondrial Bioenergetic Failure Cholesterol mistrafficking is presumed to contribute to organelle dysfunction, but no step connecting it quantitatively to ATP deficit has been demonstrated in MEGDEL.

Show evidence (2 references)

PMID:22683713 SUPPORT In Vitro

"We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining"

Reports both the BMP deficit and the resulting cholesterol accumulation.

PMID:34751152 SUPPORT In Vitro

"Filipin staining showed uneven localization of unesterified cholesterol"

Independent replication of the cholesterol trafficking defect in a second patient line.

Mitochondrial Network Fragmentation and Deficient Calcium Transfer

Patient fibroblasts show a severely fragmented mitochondrial network with altered cristae morphology, and the calcium buffering function between cytoplasm and mitochondria is deficient. Liver ultrastructure in a second patient shows abnormal circular mitochondrial cristae.

mitochondrion organization GO:0007005 ↓ DECREASED mitochondrial calcium uptake GO:0006874 ↓ DECREASED

Experimental models

MEGDEL patient dermal fibroblasts PRIMARY CELL CULTURE Patient fibroblasts show the fragmented network, altered cristae and deficient cytoplasm-to-mitochondria calcium buffering.

Downstream

Respiratory Chain Complex Deficiency Reduced calcium influx to mitochondria is proposed as the immediate cause of the secondary respiratory chain deficiency.

Show evidence (2 references)

PMID:34751152 SUPPORT In Vitro

"The calcium buffer function between cytoplasm and mitochondria was deficient"

Reports the calcium transfer defect directly.

PMID:35781780 SUPPORT Human Clinical

"The ultrastructural findings included abnormal circular mitochondrial cristae"

Confirms abnormal cristae in patient liver tissue, not only cultured cells.

Impaired Mitochondrial Serine Import and mtDNA Depletion

An alternative and not yet reconciled model places SERAC1 on the outer mitochondrial membrane as a partner of the serine transporter SFXN1. Loss of SERAC1 then impairs the one-carbon cycle, unbalances the nucleotide pool and depletes mitochondrial DNA. Hepatic mtDNA depletion has been observed in one patient, and nucleoside supplementation restored mtDNA content in the mouse and cell models.

SERAC1 as an outer-membrane partner of the serine transporter SFXN1

mitochondrial DNA maintenance GO:0032042 ↓ DECREASED mitochondrial serine import GO:0006730 ↓ DECREASED

Animal models

Serac1 knockout mouse Mouse recapitulates The mouse reproduces mtDNA depletion and the biochemical diagnostic phenotype, and nucleoside supplementation restores mtDNA content.

Downstream

Mitochondrial Bioenergetic Failure mtDNA depletion removes the templates for the mitochondrially encoded respiratory chain subunits.

Show evidence (2 references)

PMID:35235340 SUPPORT Model Organism

"Loss of SERAC1 impaired the one-carbon cycle and disrupted the balance of the nucleotide pool, which led to primary mitochondrial DNA (mtDNA) depletion"

Reports the serine-transport route from SERAC1 loss to mtDNA depletion.

PMID:23918762 SUPPORT Human Clinical

"All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient"

Human observation of hepatic mtDNA depletion consistent with this route.

Respiratory Chain Complex Deficiency

Reduced activity and amount of respiratory chain complexes I, III and IV, measured in liver mitochondria. The deficiency is secondary to the phospholipid and contact-site defect, and is characteristically variable between tissues - respiratory chain activity in fresh muscle can be entirely normal, so a negative muscle biopsy does not exclude the diagnosis.

hepatocyte CL:0000182

oxidative phosphorylation GO:0006119 ↓ DECREASED

Downstream

Mitochondrial Bioenergetic Failure Loss of complexes I, III and IV directly reduces ATP synthesis capacity.

Show evidence (2 references)

PMID:34751152 SUPPORT Human Clinical

"In liver mitochondria, complexes I, III, and IV were clearly decreased"

Direct measurement of the complex deficiency in patient liver.

PMID:25051967 REFUTE Human Clinical

"Plasma and cerebrospinal fluid lactate, plasma alanine, and respiratory chain complexes in fresh muscle were normal"

Contradicts a uniform respiratory chain deficiency across tissues; muscle can be normal in a genetically confirmed patient.

Mitochondrial Bioenergetic Failure

The convergence point of the cardiolipin, calcium and mtDNA branches: insufficient mitochondrial ATP production in tissues with high and sustained energy demand.

oxidative phosphorylation GO:0006119 ↓ DECREASED

mitochondrion GO:0005739

Downstream

Secondary 3-Methylglutaconic Aciduria and Lactic Acidosis 3-methylglutaconic acid excretion in MEGDEL is a marker of mitochondrial dysfunction rather than a block in leucine catabolism; the biochemical steps generating it are not established.

Basal Ganglia Neurodegeneration Energy failure damages the basal ganglia selectively, in the staged putaminal pattern characteristic of the disease; why the putamen is affected first is unknown.

Cochlear and Auditory Pathway Degeneration Sensorineural deafness is a near-universal feature; the cellular site of the auditory lesion in MEGDEL has not been established histologically.

Hepatocellular Mitochondrial Injury Liver mitochondria carry the measured respiratory chain deficiency and the abnormal cristae, and infantile hepatopathy is a cardinal feature.

Show evidence (1 reference)

PMID:23918762 SUPPORT Human Clinical

"All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction"

Establishes OXPHOS dysfunction across the reported patient series.

Secondary 3-Methylglutaconic Aciduria and Lactic Acidosis

Persistently increased urinary excretion of 3-methylglutaconic and 3-methylglutaric acid, with elevated blood lactate and alanine. This is a secondary 3-methylglutaconic aciduria of the class defined by defective phospholipid remodeling, not a primary block in leucine catabolism as in AUH deficiency.

Downstream

3-Methylglutaconic aciduria The organic aciduria is itself the defining laboratory phenotype.

Lactic acidosis Impaired oxidative phosphorylation shifts pyruvate to lactate.

Show evidence (2 references)

PMID:27186703 SUPPORT Human Clinical

"The patients were presented with 3-methylglutaconic acid and 3-methylglutaric aciduria"

Documents excretion of both organic acids in confirmed patients.

PMID:37711114 SUPPORT Human Clinical

"Biochemical abnormalities: elevated urinary 3 - metilglutaconic and 3-metilglutaric acids, high lactate and alanine in serum"

Records the accompanying lactate and alanine elevation.

Basal Ganglia Neurodegeneration

Staged degeneration of the basal ganglia, beginning with pallidal T2 change, progressing to swelling of the putamen and caudate nucleus with a spared dorsal-putaminal "eye", and finally to progressive putaminal involvement. The "eye" has not been reported in any other disorder and is pathognomonic.

striatal neuron CL:0000540

putamen UBERON:0001874 caudate nucleus UBERON:0001873 globus pallidus UBERON:0001875

Animal models

Canine multiple system degeneration Dog partially recapitulates Affected dogs lose neurons from the putamen and caudate nucleus, the same striatal targets damaged in human MEGDEL, and develop a progressive movement disorder.

Downstream

Dystonia Loss of striatal output produces the generalized dystonia that names the dystonia-deafness syndrome.

Progressive spasticity Spasticity accompanies the basal-ganglia disease and dominates the milder juvenile phenotype, though corticospinal involvement rather than the striatal lesion is likely to mediate it.

Leigh-like basal ganglia lesions The degeneration is what the MRI abnormality depicts.

Show evidence (2 references)

PMID:25642805 SUPPORT Human Clinical

"In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen"

Defines the staged anatomical progression across 30 patients.

PMID:25642805 SUPPORT Human Clinical

"has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings"

Establishes the specificity of the putaminal sign for this disease.

Cochlear and Auditory Pathway Degeneration

Bilateral sensorineural hearing loss, usually severe and evident in infancy, giving the "D" of the acronym. Whether the lesion is cochlear hair cell, spiral ganglion or central is not established in MEGDEL, so the anatomical binding here is to the cochlea rather than to a specific cell population.

cochlea UBERON:0001844

Downstream

Sensorineural hearing loss The auditory lesion is expressed clinically as sensorineural deafness.

Show evidence (1 reference)

PMID:27186703 SUPPORT Human Clinical

"microcephaly, growth retardation, dysmorphic features, severe sensorineural deafness, progressive spasticity, dystonia, seizures, basal ganglia involvement"

Reports severe sensorineural deafness in genetically confirmed siblings.

Hepatocellular Mitochondrial Injury

Mitochondrial hepatopathy with hepatocytes showing granular cytoplasm and fine intracytoplasmic lipid droplets, and abnormal circular mitochondrial cristae on electron microscopy. Clinically this ranges from persistently elevated transaminases to fulminant neonatal liver failure - which, distinctively, may occur without any transaminase elevation or cholestasis.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Infantile hepatopathy The hepatocellular mitochondrial lesion is expressed as the cardinal infantile hepatopathy.

Hyperammonemia Loss of hepatic synthetic and detoxifying function during the neonatal crisis raises ammonia; the contribution of impaired ureagenesis versus catabolic load is not resolved.

Hypoglycemia Impaired hepatic glucose output during the neonatal crisis.

Show evidence (2 references)

PMID:35781780 SUPPORT Human Clinical

"Hepatocytes showed granular cytoplasm and fine intracytoplasmic lipid droplets"

First detailed liver histology published for this syndrome.

PMID:38445077 SUPPORT Human Clinical

"severe liver failure with distinct hyperammonemia and hypoglycemia without elevation of transaminases or cholestasis"

Documents the distinctive neonatal presentation of the hepatic lesion.

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Histopathology

1

Mitochondrial hepatopathy with abnormal circular cristae

Liver biopsy shows hepatocytes with granular cytoplasm and fine intracytoplasmic lipid droplets; electron microscopy shows abnormal circular mitochondrial cristae. This is the first detailed liver histology published for the syndrome.

Show evidence (2 references)

PMID:35781780 SUPPORT Human Clinical

"The histologic features of a liver biopsy are described, which has not previously been published in detail for this syndrome"

Establishes the provenance and novelty of the histological description.

PMID:35781780 SUPPORT Human Clinical

"The ultrastructural findings included abnormal circular mitochondrial cristae"

Reports the ultrastructural abnormality.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

20

Digestive 1

Infantile hepatopathy FREQUENT Decreased liver function HP:0001410

Show evidence (1 reference)

PMID:23918762 SUPPORT Human Clinical

"The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome"

Establishes infantile hepatopathy as a cardinal feature.

Ear 1

Sensorineural hearing loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:25051967 SUPPORT Human Clinical

"3-methylglutaconic aciduria psychomotor delay, muscle hypotonia, sensori-neural deafness, and Leigh-like lesions on brain magnetic resonance imaging"

Lists sensorineural deafness among the characteristic features.

PMID:40821445 REFUTE Human Clinical

"who had relatively delayed onset and no evident hepatopathy or deafness"

A genetically confirmed patient without deafness shows the feature is not obligate.

Eye 1

Optic atrophy OCCASIONAL HP:0000648

Show evidence (1 reference)

PMID:24997715 SUPPORT Human Clinical

"The patient had an earlier age of onset of optic atrophy than previously described in other MEGDEL syndrome patients"

Documents optic atrophy and its variable timing.

Genitourinary 1

3-Methylglutaconic aciduria OBLIGATE HP:0003535

Show evidence (1 reference)

PMID:32684373 SUPPORT Human Clinical

"MEGDEL syndrome is an autosomal recessive disorder, clinically characterized by 3-methylglutaconic aciduria"

Names the aciduria as a defining clinical characteristic.

Head and Neck 2

Microcephaly OCCASIONAL HP:0000252

Show evidence (1 reference)

PMID:27186703 SUPPORT Human Clinical

"microcephaly, growth retardation, dysmorphic features, severe sensorineural deafness"

Reports microcephaly in two confirmed siblings.

Dysmorphic features OCCASIONAL Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:27186703 SUPPORT Human Clinical

"growth retardation, dysmorphic features, severe sensorineural deafness"

Records dysmorphic features alongside the core phenotype.

Metabolism 3

Lactic acidosis FREQUENT HP:0003128

Show evidence (2 references)

PMID:27186703 SUPPORT Human Clinical

"Metabolic acidosis, mild hyperammonemia and lactic acidemia were accompanied with clinical findings in newborn period"

Records lactic acidemia in the neonatal period.

PMID:25051967 REFUTE Human Clinical

"Plasma and cerebrospinal fluid lactate, plasma alanine, and respiratory chain complexes in fresh muscle were normal"

A genetically confirmed patient with entirely normal lactate shows the finding is not obligate.

Hyperammonemia OCCASIONAL HP:0001987

Show evidence (1 reference)

PMID:38445077 SUPPORT Human Clinical

"severe liver failure with distinct hyperammonemia and hypoglycemia without elevation of transaminases or cholestasis"

Documents marked hyperammonemia in a neonatal crisis.

Hypoglycemia OCCASIONAL HP:0001943

Show evidence (1 reference)

PMID:38445077 SUPPORT Human Clinical

"If a newborn presents with hyperammonemia, hypoglycemia and impaired liver synthesis function"

Reports hypoglycemia as part of the neonatal presentation.

Musculoskeletal 3

Progressive spasticity FREQUENT HP:0001257

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37711114 SUPPORT Human Clinical

"Currently he has spastic tetraparesis, dystonia, scoliosis and autistic behavior, with bilateral basal ganglia lesions on brain MRI"

Documents spastic tetraparesis in a genetically confirmed adult patient.

Truncal hypotonia FREQUENT HP:0001252

Show evidence (1 reference)

PMID:38559521 SUPPORT Human Clinical

"It is characterized by psychomotor delay, muscular hypotonia, sensorineural deafness, and Leigh-like syndrome lesions on brain magnetic resonance imaging"

Lists muscular hypotonia among the characteristic features.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:37711114 SUPPORT Human Clinical

"he has spastic tetraparesis, dystonia, scoliosis and autistic behavior"

Reports scoliosis in a genetically confirmed patient.

Nervous System 7

Dystonia VERY_FREQUENT HP:0001332

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:25642805 SUPPORT Human Clinical

"a clinically and biochemically highly distinctive dystonia deafness syndrome"

Characterizes the disorder by its dystonia.

Severe psychomotor delay VERY_FREQUENT Severe global developmental delay HP:0011344

Show evidence (1 reference)

PMID:25642805 SUPPORT Human Clinical

"accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity"

Reports severe developmental delay across the 30-patient MRI series.

Developmental regression FREQUENT HP:0002376

Show evidence (1 reference)

PMID:24997715 SUPPORT Human Clinical

"as well as developmental delay and developmental regression, bilateral optic nerve atrophy, microcephaly, and myoclonic epilepsy"

Records regression alongside the other neurological features.

Leigh-like basal ganglia lesions VERY_FREQUENT Abnormal basal ganglia morphology HP:0002134

Show evidence (1 reference)

PMID:25642805 SUPPORT Human Clinical

"All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen"

Systematic review of 43 MRI studies in 30 patients.

Seizures OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:38559521 SUPPORT Human Clinical

"presented with developmental delay, cerebral palsy, intellectual disability, and seizures"

Records seizures in a genetically confirmed patient.

Intellectual disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:37711114 SUPPORT Human Clinical

"A 30-year-old patient with a moderate intellectual disability"

Documents intellectual disability in the adult-onset presentation.

Autistic behavior OCCASIONAL HP:0000729

Show evidence (1 reference)

PMID:37711114 SUPPORT Human Clinical

"dystonia, scoliosis and autistic behavior, with bilateral basal ganglia lesions on brain MRI"

Records autistic behavior in the adult presentation.

Growth 1

Growth retardation FREQUENT Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:27186703 SUPPORT Human Clinical

"microcephaly, growth retardation, dysmorphic features"

Reports growth retardation in confirmed patients.

🧬

Genetic Associations

1

SERAC1

Gene: SERAC1 hgnc:21061 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:22683713 SUPPORT Human Clinical

"Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria"

Gene-discovery study establishing SERAC1 as the causal gene.

PMID:23918762 SUPPORT Human Clinical

"Homozygosity mapping identified a candidate locus on 6q25.2-6q26"

Independent mapping of the disease locus to the SERAC1 region.

Variants (8)

c.442C>T (p.Arg148*)

Nonsense allele found in trans with c.438delC in a patient with MEGDEL syndrome, optic atrophy and myoclonic epilepsy.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Loss of function; the allele reduces or abolishes SERAC1 protein.

Show evidence (1 reference)

PMID:24997715 SUPPORT Human Clinical

"Whole exome sequencing revealed two loss-of-function mutations in SERAC1 in trans: c.438delC (p.T147Rfs*22) and c.442C>T (p.R148X)"

Reports both loss-of-function alleles and their phase.

c.1018delT

Homozygous frameshift allele generating premature translation termination, reported in a Palestinian child.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Loss of function; the allele reduces or abolishes SERAC1 protein.

Show evidence (1 reference)

PMID:25051967 SUPPORT Human Clinical

"We identified a novel homozygous mutation in SERAC1 gene (c.1018delT) that generates frame shift and premature termination of protein translation"

Documents the frameshift allele and its predicted consequence.

c.1495A>G (p.Met499Val)

Hypomorphic missense allele found in compound heterozygosity in a Chinese patient whose phenotype was complicated hereditary spastic paraplegia rather than classic MEGDEL.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Hypomorphic; residual activity is associated with the milder phenotype.

Show evidence (1 reference)

PMID:35223715 SUPPORT Human Clinical

"a novel c.1495A>G (p.Met499Val) variant in exon 14 of SERAC1 inherited from the father"

Identifies the missense allele in the milder cHSP presentation.

c.1379G>A (p.Trp460*)

Homozygous nonsense allele in a consanguineous Tunisian family with the severe phenotype.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Loss of function; premature termination in the studied family.

Show evidence (1 reference)

PMID:35943861 SUPPORT Human Clinical

"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"

Reports the nonsense allele and its association with the severe end of the spectrum.

rs797045105 insertion

Homozygous frameshift insertion identified by exome sequencing in an Iranian proband, heterozygous in both unaffected parents.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Loss of function; the insertion causes a frameshift.

Show evidence (1 reference)

PMID:33613893 SUPPORT Human Clinical

"We found an insertion, rs797045105 (chr6, 158571484, C>CCATG), in the SERAC1 gene with homozygous genotype in the patient and heterozygous genotype in her unaffected parents"

Reports the allele and its segregation.

c.1404-2A>G

Homozygous canonical splice-acceptor allele in an Egyptian proband with relatively delayed onset and neither hepatopathy nor deafness.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Predicted loss of function through disrupted splicing.

Show evidence (1 reference)

PMID:40821445 SUPPORT Human Clinical

"Whole-exome sequencing demonstrated a likely pathogenic homozygous c.1404-2A>G variant in SERAC1 gene"

Reports the splice allele in the first Egyptian case.

Homozygous splice variant causing juvenile complicated HSP

The hypomorphic splice allele underlying the juvenile complicated-hereditary-spastic-paraplegia presentation in a large consanguineous family. It abolishes full-length protein yet leaves a milder lipid phenotype than the classic infantile alleles, which is the clearest genotype-phenotype evidence in this disease.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Loss of the full-length protein with a milder phosphatidylglycerol remodeling defect than classic infantile alleles.

Show evidence (2 references)

PMID:28916646 SUPPORT Human Clinical

"The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling"

Ties the allele to both the protein loss and the lipid defect.

PMID:28916646 SUPPORT Human Clinical

"These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype"

States the graded relationship between residual remodeling and clinical severity.

Deletion of exons 2-4

Multi-exon deletion allele, in trans with c.1601A>T (p.His534Leu), in a child whose development improved beyond clinical expectation.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Loss of function; the allele reduces or abolishes SERAC1 protein.

Show evidence (1 reference)

PMID:35781780 SUPPORT Human Clinical

"biallelic novel SERAC1 mutations: (1) deletion of (at least) exons 2-4, pathogenic; and (2) c.1601A>T (p.H534L), likely pathogenic"

Reports the structural allele and its pathogenicity assignment.

💊

Medical Actions

7

Supportive Multidisciplinary Care

Action: Supportive Care NCIT:C15747

Platform: Other

No disease-modifying therapy exists. Management is supportive and requires neurology, metabolic medicine, audiology, hepatology and rehabilitation working together, with genetic confirmation to guide counselling.

Show evidence (2 references)

PMID:32684373 SUPPORT Human Clinical

"Diagnosing MEGDEL syndrome requires a multidisciplinary approach, including genetic confirmation of a SERAC1 mutation"

States the multidisciplinary basis of care.

PMID:38445077 SUPPORT Human Clinical

"Even while no cure is available yet, patients should be offered proper supportive management through a multidisciplinary team"

Confirms supportive multidisciplinary management as the standard of care.

Neonatal Metabolic Crisis Management

Action: Hemodialysis NCIT:C15248

Platform: Other

Treat the neonatal presentation as a suspected inborn error of metabolism: stop protein intake, promote anabolism with intravenous glucose, correct acidosis, and use continuous hemodialysis for severe hyperammonemia.

Mechanism Target:

Hyperammonemia — Continuous hemodialysis removes ammonia during the hepatic crisis.

Show evidence (1 reference)

PMID:38445077 SUPPORT Human Clinical

"Due to high ammonia level, continuous hemodialysis was established immediately after admission"

Reports hemodialysis used specifically to control hyperammonemia.

Show evidence (1 reference)

PMID:38445077 SUPPORT Human Clinical

"In addition, protein intake was stopped, and the patient anabolized with intravenous glucose. Temporary stabilization could be achieved after four days"

Describes the metabolic crisis protocol and its partial effect.

Cochlear Implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Auditory rehabilitation for the sensorineural deafness, including cochlear device implantation, which is performed in these patients despite the anaesthetic risk of the underlying mitochondrial disease.

Mechanism Target:

Sensorineural hearing loss — The implant bypasses the failed peripheral auditory transduction.

Show evidence (1 reference)

PMID:39592976 SUPPORT Human Clinical

"We discussed the anaesthetic management of an infant 2-year-old suffering from MEGD(H)EL syndrome undergoing cochlear implant"

Documents cochlear implantation performed in a MEGD(H)EL patient.

Show evidence (1 reference)

PMID:39592976 SUPPORT Human Clinical

"an infant 2-year-old suffering from MEGD(H)EL syndrome undergoing cochlear implant"

Establishes that cochlear implantation is used in this disease.

Non-Triggering Anaesthesia

Action: Pharmacotherapy NCIT:C15986

Agent: dexmedetomidine CHEBI:4466

Platform: Small molecule

Where anaesthesia is required, dexmedetomidine as the principal agent - optionally combined with ketamine for procedural sedation - is used to avoid agents that trigger decompensation in mitochondrial disease.

Show evidence (1 reference)

PMID:39592976 SUPPORT Human Clinical

"The usage of dexmedetomidine as the main anaesthetic drug might have the benefit of a non-triggering anaesthetic agent in patients with a mitochondrial disease"

States the rationale and the agent used.

Nutritional and Feeding Support

Action: gastrostomy Ontology label: Gastrostomy NCIT:C52006

Platform: Surgery

Feeding support including gastrostomy tube placement, for the dysphagia and failure to thrive of the chronic phase. Note that in this population the procedure itself carries the anaesthetic risk described below.

Show evidence (1 reference)

PMID:39592976 SUPPORT Human Clinical

"They may need several interventions that require anaesthesia, for example, sedation for auditory brainstem response testing, gastrostomy tube placement and magnetic resonance imaging"

Records gastrostomy tube placement among the interventions these patients require.

Perioperative Risk Management

Action: Supportive Care NCIT:C15747

Platform: Other

Anaesthesia is a recurring hazard rather than an incidental one, because these children repeatedly need sedation for auditory testing, imaging and feeding-tube placement. The mitochondrial-disease precautions are specific: succinylcholine is contraindicated, continuous propofol infusion is avoided after induction, non-depolarizing neuromuscular blockers are used sparingly, and preoperative fasting is shortened to avoid hypovolaemia and hypoglycaemia.

Show evidence (3 references)

PMID:39592976 SUPPORT Human Clinical

"Depolarizing muscle relaxants as succinylcholine must not be administered in any patient with myopathy due to their upregulation of nicotinic acetylcholine receptors in skeletal muscle"

States the one absolute drug contraindication in this population.

PMID:39592976 SUPPORT Human Clinical

"It is recommended to refrain from administering propofol by continuous infusion after induction of anaesthesia due to concerns about propofol infusion syndrome in this vulnerable population"

Gives the propofol restriction and its stated rationale.

PMID:39592976 SUPPORT Human Clinical

"Preoperative fasting is reduced to 2 h, if possible, to avoid hypovolemia and hypoglycemia"

The fasting precaution, which matters here because catabolic stress precipitates decompensation.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Counselling for the 25% recurrence risk in carrier couples, cascade testing of relatives, and prenatal or preimplantation testing once the familial variants are known. Particularly important given the over-representation of consanguineous families.

Show evidence (2 references)

PMID:38445077 SUPPORT Human Clinical

"genetic confirmation of the diagnosis is important for the families, especially regarding further family planning"

States the family-planning purpose of genetic confirmation.

PMID:38559521 SUPPORT Human Clinical

"the need for genetic counseling in consanguineous families"

Recommends genetic counselling for the consanguineous families in which the disease clusters.

🔬

Biochemical Markers

3

Phosphatidylglycerol 34:1 to 36:1 ratio (INCREASED)

Pathograph Readouts

Readout Of Impaired Phosphatidylglycerol Remodeling Positive

A raised PG34:1/PG36:1 ratio is the direct cellular measurement of the remodeling defect.

Show evidence (1 reference)

PMID:22683713 SUPPORT In Vitro

"Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1"

Rescue of the ratio by wild-type protein ties the measurement to the mechanism.

Show evidence (2 references)

PMID:28916646 SUPPORT Human Clinical

"biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1)"

Uses the ratio as a diagnostic biomarker in a clinical family study.

PMID:28916646 SUPPORT Human Clinical

"These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype"

Links the magnitude of the biomarker shift to clinical severity.

Urinary 3-methylglutaconic and 3-methylglutaric acid (INCREASED)

Pathograph Readouts

Readout Of Secondary 3-Methylglutaconic Aciduria and Lactic Acidosis Positive

Urine organic acid analysis is the standard assay reporting on this node.

Show evidence (1 reference)

PMID:30114719 SUPPORT Human Clinical

"Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing"

Establishes urine organic acids as the diagnostic readout.

Show evidence (1 reference)

PMID:35223715 SUPPORT Human Clinical

"The excretion of 3-methylglutaconic acid was found to be increased in our GC/MS analysis"

Reports the measurement in a confirmed patient.

Free cholesterol accumulation on filipin staining (INCREASED)

Pathograph Readouts

Readout Of Bis(monoacylglycerol)phosphate Depletion and Free Cholesterol Accumulation Positive

Filipin staining is the standard histochemical assay for the free cholesterol accumulation at this node.

Show evidence (1 reference)

PMID:34751152 SUPPORT In Vitro

"Filipin staining showed uneven localization of unesterified cholesterol"

Reports the filipin assay result directly.

Show evidence (1 reference)

PMID:22683713 SUPPORT In Vitro

"leading to the accumulation of free cholesterol, as shown by abnormal filipin staining"

Original description of the filipin abnormality in patient cells.

🔬

Diagnosis

4

Urine organic acid analysis

Gas chromatography-mass spectrometry of urine showing persistently elevated 3-methylglutaconic and 3-methylglutaric acid. This is the cheap, non-invasive entry point that redirects the workup towards this group of disorders, and it is what makes the biochemical diagnosis possible before sequencing.

urine organic acid analysis NCIT:C25294

Show evidence (2 references)

PMID:30114719 SUPPORT Human Clinical

"Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing"

States the diagnostic role of the test in this disease group.

PMID:35223715 SUPPORT Human Clinical

"The excretion of 3-methylglutaconic acid was found to be increased in our GC/MS analysis"

The measurement as performed in a genetically confirmed patient.

Brain MRI pattern recognition

Brain MRI is diagnostic in its own right here, not merely supportive. The basal-ganglia disease evolves through five stages, and the dorsal-putaminal "eye" - a spared region within an otherwise swollen putamen - was present in every patient across a 30-patient series during a specific age window and has been reported in no other disorder.

brain magnetic resonance imaging NCIT:C16809

The source spells the acronym "MEDGEL" in this sentence; the quote is reproduced exactly rather than corrected.

Show evidence (2 references)

PMID:25642805 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis"

States that MRI pattern recognition is itself a route to diagnosis.

PMID:25642805 SUPPORT Human Clinical

"has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings"

Establishes the specificity that makes the imaging finding diagnostic rather than merely consistent.

Fibroblast phosphatidylglycerol and filipin profiling

A disease-specific cellular assay: the PG34:1 to PG36:1 ratio by lipidomics, with filipin staining for free cholesterol, in cultured skin fibroblasts. Unlike the organic acids it reports on the enzymatic lesion itself, and the magnitude of the shift tracks with clinical severity.

fibroblast lipid profiling NCIT:C25294

Show evidence (1 reference)

PMID:28916646 SUPPORT Human Clinical

"biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1)"

Lists the assay as one of the biomarker investigations used to reach the diagnosis in a clinical family study.

SERAC1 sequencing with copy-number analysis

Confirmation rests on finding biallelic pathogenic SERAC1 variants, most often by exome or genome sequencing. Copy-number or deletion analysis is needed alongside sequencing because intragenic multi-exon deletions occur and are missed by sequencing alone.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:37711114 SUPPORT Human Clinical

"Diagnosis is confirmed when biallelic pathogenic variants in SERAC1 gene are found"

States the confirmatory criterion directly.

PMID:38559521 SUPPORT Human Clinical

"subsequent genetic testing through whole exome sequencing confirmed a rare homozygous deletion variant in the SERAC1 gene"

Worked example of exome sequencing reaching the diagnosis, in this case for a deletion allele.

📈

Progression

3

Neonatal metabolic and hepatic crisis

Presentation in the first days of life with lactic acidosis, hepatopathy and, in the most severe cases, hyperammonemia and hypoglycemia without transaminase elevation or cholestasis. This is the critical intervention window and can be lethal within days.

Show evidence (1 reference)

PMID:34751152 SUPPORT Human Clinical

"a newborn infant with a metabolic crisis, lethal multiorgan failure on day six of life, and increased excretion of 3-methylglutaconic acid"

Documents the lethal neonatal crisis phase.

Chronic progressive neurodegeneration

Infantile sensorineural deafness and truncal hypotonia, then severe psychomotor delay and regression, then progressive spasticity and dystonia with staged basal-ganglia degeneration.

Show evidence (1 reference)

PMID:25642805 SUPPORT Human Clinical

"severe developmental delay, and progressive spasticity"

Describes the chronic progressive neurological course.

Milder later-onset course

In patients with hypomorphic alleles the disease may present only in adolescence or adulthood as complicated spastic paraplegia or dystonia, and some children exceed expectations and partially improve.

Show evidence (1 reference)

PMID:35781780 SUPPORT Human Clinical

"her verbal and motor development has progressively improved and now, at 4 years of age, she has only speech and mild gross motor delays"

Records improvement rather than relentless regression in a mild case.

📊

Prevalence

2

Worldwide

Cases In Literature <1 in 1,000,000

About 100 patients reported since the 2006 first description; precise prevalence and incidence are not established.

Show evidence (2 references)

PMID:35943861 SUPPORT Human Clinical

"MEGDEL syndrome is a rare recessive disorder, with about 100 cases reported worldwide"

Gives the reported case count worldwide.

PMID:32684373 SUPPORT Human Clinical

"Since the first description of MEGDEL syndrome in 2006, at least 102 patients have been reported"

Independent count of reported patients.

Consanguineous families of the Middle East and North Africa

Unknown Unknown

Reported families are strongly over-represented among consanguineous pedigrees from Tunisia, Saudi Arabia, Palestine, Turkey, Egypt and Iran. This is an ascertainment pattern in the published literature, not a measured population rate, and no founder allele has been established.

Show evidence (2 references)

PMID:40821445 SUPPORT Human Clinical

"This is a 7-year-old boy born to first cousins Arab parents from Egypt with family history of unexplained deaths of 3 siblings during the neonatal period"

Illustrates the consanguineous pedigree pattern of reported cases.

PMID:38559521 SUPPORT Human Clinical

"The patient, born to consanguineous parents, presented with developmental delay, cerebral palsy, intellectual disability, and seizures"

A second independently reported consanguineous family.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from 3-methylglutaconic_Aciduria_With_Deafness_Encephalopathy_And_Leigh-like_Syndrome:

Primary 3-methylglutaconic aciduria (AUH deficiency)

Overlapping Features The one 3-methylglutaconic aciduria that is a genuine block in leucine catabolism. MEGDEL's aciduria is secondary - a marker of mitochondrial dysfunction rather than the primary lesion - so the same urine finding means something different in the two disorders.

Show evidence (1 reference)

PMID:23296368 SUPPORT Other

"AUH defect) due to defective leucine catabolism"

Names the primary disorder and the pathway that distinguishes it from the secondary group MEGDEL belongs to.

Other secondary 3-methylglutaconic acidurias

Overlapping Features A defined group sharing the biochemical marker: Barth syndrome (TAZ), Costeff syndrome (OPA3), DCMA (DNAJC19), and the TMEM70, CLPB and TIMM50 disorders. Because the urine finding is common to all of them, the discriminators are the MRI pattern, the fibroblast lipid profile, and sequencing.

Show evidence (1 reference)

PMID:30114719 SUPPORT Human Clinical

"due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50)"

Enumerates the group MEGDEL is differentiated within, including SERAC1 itself.

HTRA2 defect

Overlapping Features The closest differential for the neonatal presentation specifically: a neonatal movement disorder with seizures and 3-methylglutaconic aciduria. It is separated by its central hypopnea and apnea with neutropenia, and by a course that is lethal within the first month rather than chronic and progressive.

Show evidence (1 reference)

PMID:30114719 SUPPORT Human Clinical

"Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia"

Gives the feature set that separates HTRA2 defect from MEGDEL despite the shared aciduria.

🧫

Experimental Models

1

MEGDEL patient dermal fibroblasts PRIMARY_CELL_CULTURE

Primary skin fibroblasts from patients with biallelic SERAC1 variants, the principal system in which the lipid, cholesterol, mitochondrial-network and calcium phenotypes have been demonstrated, and in which lentiviral complementation with wild-type SERAC1 rescues the lipid ratio.

Organism

human NCBITaxon:9606

Publication

PMID:22683713

Pathograph links

Impaired Phosphatidylglycerol Remodeling recapitulates fidelity: high Patient fibroblasts show the PG-34:1 rise and PG-36:1 fall, and complementation with wild-type SERAC1 partially normalizes the ratio, which is the strongest causal link in the whole mechanism.

Limitations: Fibroblasts are not an affected tissue, so they cannot report the tissue-selective basal-ganglia, cochlear or hepatic consequences.

Readouts

PG-34:1 to PG-36:1 ratio

Direction: INCREASED

Interpretation: The ratio is the direct lipidomic measurement of the enzymatic defect.

Show evidence (1 reference)

PMID:22683713 SUPPORT In Vitro

"A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1"

Reports the lipidomic measurement in the model system.

PG-34:1 to PG-36:1 ratio after wild-type complementation

Direction: RESTORED

Interpretation: Partial normalization on complementation establishes that SERAC1 loss causes the lipid change.

Show evidence (1 reference)

PMID:22683713 SUPPORT In Vitro

"lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1"

Reports the rescue measurement.

Show evidence (1 reference)

PMID:22683713 SUPPORT In Vitro

"A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1"

Establishes that the model reproduces the mechanism under study.

Mitochondrial Network Fragmentation and Deficient Calcium Transfer recapitulates fidelity: moderate Patient fibroblasts show the fragmented network, altered cristae and deficient cytoplasm-to-mitochondria calcium buffering.

Limitations: The measurements come from a single patient line carrying one severe truncating allele, so allelic and interindividual variation in these structural phenotypes is unknown.

Readouts

Mitochondrial network morphology

Direction: ALTERED

Interpretation: Network fragmentation and cristae change are the structural readouts of this node.

Show evidence (1 reference)

PMID:34751152 SUPPORT In Vitro

"the mitochondrial network was severely fragmented, and the cristae morphology was altered"

Reports the structural measurement.

Cytoplasm-to-mitochondria calcium buffering

Direction: DECREASED

Interpretation: Calcium buffering is the functional readout of the contact-site defect.

Show evidence (1 reference)

PMID:34751152 SUPPORT In Vitro

"The calcium buffer function between cytoplasm and mitochondria was deficient"

Reports the calcium measurement.

Show evidence (1 reference)

PMID:34751152 SUPPORT In Vitro

"In the patient fibroblasts, no SERAC1 protein was detected, the mitochondrial network was severely fragmented, and the cristae morphology was altered"

Establishes the model as informative for the structural node.

🐁

Animal Models

2

Serac1 knockout mouse

A germline Serac1 null mouse reported to reproduce the major diagnostic clinical and biochemical features of MEGD(H)EL, and used to establish the serine-transport and mtDNA-depletion route and to show rescue by nucleoside supplementation.

Species

Mouse

Genotype

Serac1-/-

Publication

PMID:35235340

Pathograph links

Impaired Mitochondrial Serine Import and mtDNA Depletion recapitulates fidelity: moderate The mouse reproduces mtDNA depletion and the biochemical diagnostic phenotype, and nucleoside supplementation restores mtDNA content.

Limitations: The paper does not report whether the mouse reproduces the phosphatidylglycerol remodeling defect, the cholesterol trafficking abnormality or the staged basal-ganglia lesion, and its localization of SERAC1 to the outer mitochondrial membrane conflicts with the contact-site localization reported in patient cells.

Readouts

Mitochondrial DNA content

Direction: DECREASED

Interpretation: mtDNA copy number is the primary molecular readout of this node in the model.

Show evidence (1 reference)

PMID:35235340 SUPPORT Model Organism

"which led to primary mitochondrial DNA (mtDNA) depletion in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells"

Reports the mtDNA measurement in the knockout mouse and in patient-derived cells.

Mitochondrial DNA content after nucleoside supplementation

Direction: RESTORED

Interpretation: Restoration on supplementation shows the depletion is reversible and nucleotide-limited.

Show evidence (1 reference)

PMID:35235340 SUPPORT Model Organism

"both in vitro and in vivo supplementation of nucleosides/nucleotides restored mtDNA content and mitochondrial function"

Reports the rescue arm of the experiment.

Show evidence (1 reference)

PMID:35235340 SUPPORT Model Organism

"we generated Serac1-/- mice that mimic the major diagnostic clinical and biochemical phenotypes of the MEGD(H)EL syndrome"

States that the model reproduces the diagnostic phenotype, which is what makes it informative for this node.

Canine multiple system degeneration

A naturally occurring, autosomal recessive SERAC1 movement disorder of Kerry Blue Terriers and Chinese Crested dogs, with complete genotype-phenotype concordance in large cohorts and in cross-bred compound heterozygotes.

Species

Dog

Genotype

SERAC1 exon 15 nonsense (Kerry Blue Terrier) or exon 4 acceptor splice site 4 bp deletion (Chinese Crested)

Publication

PMID:39596578

Pathograph links

Basal Ganglia Neurodegeneration partially recapitulates fidelity: moderate Affected dogs lose neurons from the putamen and caudate nucleus, the same striatal targets damaged in human MEGDEL, and develop a progressive movement disorder.

Limitations: The canine lesion extends beyond the human one, with Purkinje cell loss in the cerebellum and substantia nigra degeneration that are not features of MEGDEL, and the presentation is cerebellar ataxia and tremor rather than dystonia. Deafness, hepatopathy and 3-methylglutaconic aciduria are not documented in the dogs.

Readouts

Neuronal loss in putamen and caudate nucleus

Direction: DECREASED

Interpretation: Post-mortem neuronal counts in the striatum are the histological correlate of the human basal-ganglia node.

Show evidence (1 reference)

PMID:39596578 SUPPORT Model Organism

"Postmortem examination of the brains revealed Purkinje cell loss in the cerebellum and neuronal loss from the substantia nigra, putamen, and caudate nucleus"

Reports the striatal neuronal loss, and simultaneously the extra cerebellar and nigral involvement recorded as a limitation.

Show evidence (1 reference)

PMID:39596578 SUPPORT Model Organism

"Variants in human SERAC1 are associated with disorders with a range of ages of disease onset and patterns of clinical signs, but that are all characterized by movement abnormalities similar to those of the dogs with CMSD"

The authors' own statement of why the canine disease is informative for the human movement disorder.

Show evidence (1 reference)

PMID:39596578 SUPPORT Model Organism

"Genotyping of large cohorts of Kerry Blue Terriers and Chinese Crested dogs for the respective breed-specific SERAC1 variants showed complete concordance between genotype and disease phenotype"

Establishes that the canine phenotype is caused by the SERAC1 variants.

{ }

Source YAML

click to show

name: 3-methylglutaconic_Aciduria_With_Deafness_Encephalopathy_And_Leigh-like_Syndrome
category: Mendelian
creation_date: '2026-09-01T21:59:26Z'
description: >-
  MEGDEL syndrome (MEGD(H)EL when infantile hepatopathy is present) is an
  autosomal recessive neurometabolic disorder caused by biallelic loss of
  function of SERAC1, which encodes a phosphatidylglycerol remodeling enzyme
  acting at the contact site between mitochondria and the endoplasmic
  reticulum. Loss of SERAC1 shifts the phosphatidylglycerol pool towards
  PG-34:1 at the expense of PG-36:1, altering cardiolipin subspecies
  composition, depleting bis(monoacylglycerol)phosphate with consequent free
  cholesterol accumulation, and fragmenting the mitochondrial network with
  deficient calcium transfer from cytoplasm to mitochondria. The convergent
  bioenergetic failure produces secondary 3-methylglutaconic aciduria and
  lactic acidosis, and selectively damages the basal ganglia (a staged
  putaminal pattern with a pathognomonic dorsal-putaminal "eye" on MRI), the
  auditory system (sensorineural deafness), and the liver (infantile
  hepatopathy, which may present as neonatal liver failure without elevated
  transaminases or cholestasis). Severity tracks residual SERAC1 function:
  complete loss of function gives severe infantile MEGDHEL with early death,
  while hypomorphic splice and missense alleles give juvenile-onset
  complicated hereditary spastic paraplegia or, rarely, adult-onset dystonia.
  Roughly 100 patients have been reported worldwide and treatment is entirely
  supportive.
disease_term:
  preferred_term: 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like
    syndrome
  term:
    id: MONDO:0013875
    label: 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like
      syndrome
synonyms:
- MEGDEL syndrome
- MEGD(H)EL syndrome
- MEGDHEL syndrome
- SERAC1 deficiency
- 3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and
  Leigh-like syndrome
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic SERAC1 variants are required; most reported families are
    consanguineous with homozygous alleles, and heterozygous parents are
    unaffected.
  evidence:
  - reference: PMID:32684373
    reference_title: "MEGDEL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MEGDEL syndrome is an autosomal recessive disorder, clinically characterized
      by 3-methylglutaconic aciduria, psychomotor delay, muscle hypotonia, sensorineural
      deafness, and Leigh-like lesions on brain magnetic resonance imaging
    explanation: Review of 102 reported patients states the autosomal recessive mode
      of inheritance directly.
  - reference: PMID:33613893
    reference_title: "Identification of the rs797045105 in the SERAC1 Gene by Whole-exome Sequencing in a Patient Suspicious of MEGDEL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with homozygous genotype in the patient and heterozygous genotype in her
      unaffected parents
    explanation: Segregation in one family shows the homozygous proband affected and
      heterozygous carriers unaffected.
has_subtypes:
- name: Infantile MEGDHEL
  display_name: Severe infantile MEGD(H)EL
  description: >-
    The classic and most severe presentation, caused by complete loss of
    SERAC1 function (truncating, frameshift or large-deletion alleles). It
    begins with a neonatal metabolic and hepatic crisis and progresses to
    sensorineural deafness, severe psychomotor delay, dystonia and spasticity
    with staged basal-ganglia degeneration. Outcome is poor with early death.
  evidence:
  - reference: PMID:32684373
    reference_title: "MEGDEL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment is supportive, and the outcome is usually poor with early death,
      except for the juvenile-onset type
    explanation: Distinguishes the severe infantile course from the juvenile-onset
      form.
- name: Juvenile cHSP
  display_name: Juvenile-onset complicated hereditary spastic paraplegia
  description: >-
    A markedly milder oligosystemic phenotype produced by hypomorphic alleles
    with residual SERAC1 activity, in which affected subjects remain ambulant
    well into the second and third decades. Phosphatidylglycerol remodeling is
    impaired but less severely than in the infantile form.
  evidence:
  - reference: PMID:28916646
    reference_title: "SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three subjects presented with juvenile-onset oligosystemic cHSP, still
      able to walk several miles at age >10-20 years
    explanation: Defines the juvenile complicated-HSP presentation of SERAC1 deficiency.
- name: Adult dystonia
  display_name: Adult-onset dystonia-spasticity presentation
  description: >-
    The mildest end of the SERAC1 spectrum, in which a patient with
    long-standing moderate intellectual disability develops progressive loss
    of acquired skills and generalized dystonia only in adulthood.
  evidence:
  - reference: PMID:37711114
    reference_title: "SERAC1 Deficiency- A New Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 30-year-old patient with a moderate intellectual disability, developed,
      since the age of 25, a progressive loss of previous capacities
    explanation: Documents the adult-onset end of the SERAC1 deficiency spectrum.
genetic:
- name: SERAC1
  gene_term:
    preferred_term: SERAC1
    term:
      id: hgnc:21061
      label: SERAC1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL
      syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome,
      impaired oxidative phosphorylation and 3-methylglutaconic aciduria
    explanation: Gene-discovery study establishing SERAC1 as the causal gene.
  - reference: PMID:23918762
    reference_title: "Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Homozygosity mapping identified a candidate locus on 6q25.2-6q26
    explanation: Independent mapping of the disease locus to the SERAC1 region.
  variants:
  - name: c.442C>T (p.Arg148*)
    description: Nonsense allele found in trans with c.438delC in a patient with MEGDEL
      syndrome, optic atrophy and myoclonic epilepsy.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Loss of function; the allele reduces or abolishes SERAC1 protein.
    evidence:
    - reference: PMID:24997715
      reference_title: "The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Whole exome sequencing revealed two loss-of-function mutations in SERAC1
        in trans: c.438delC (p.T147Rfs*22) and c.442C>T (p.R148X)'
      explanation: Reports both loss-of-function alleles and their phase.
  - name: c.1018delT
    description: Homozygous frameshift allele generating premature translation termination,
      reported in a Palestinian child.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Loss of function; the allele reduces or abolishes SERAC1 protein.
    evidence:
    - reference: PMID:25051967
      reference_title: "MEGDEL Syndrome in a Child From Palestine: Report of a Novel Mutation in SERAC1 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We identified a novel homozygous mutation in SERAC1 gene (c.1018delT)
        that generates frame shift and premature termination of protein translation
      explanation: Documents the frameshift allele and its predicted consequence.
  - name: c.1495A>G (p.Met499Val)
    description: Hypomorphic missense allele found in compound heterozygosity in a
      Chinese patient whose phenotype was complicated hereditary spastic paraplegia
      rather than classic MEGDEL.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Hypomorphic; residual activity is associated with the milder phenotype.
    evidence:
    - reference: PMID:35223715
      reference_title: "Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a novel c.1495A>G (p.Met499Val) variant in exon 14 of SERAC1 inherited
        from the father
      explanation: Identifies the missense allele in the milder cHSP presentation.
  - name: c.1379G>A (p.Trp460*)
    description: Homozygous nonsense allele in a consanguineous Tunisian family with
      the severe phenotype.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Loss of function; premature termination in the studied family.
    evidence:
    - reference: PMID:35943861
      reference_title: "First description of the MEGDEHL syndrome in the Tunisian population via whole-exome sequencing: Novel nonsense mutation in SERAC1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 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
      explanation: Reports the nonsense allele and its association with the severe
        end of the spectrum.
  - name: rs797045105 insertion
    description: Homozygous frameshift insertion identified by exome sequencing in
      an Iranian proband, heterozygous in both unaffected parents.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Loss of function; the insertion causes a frameshift.
    evidence:
    - reference: PMID:33613893
      reference_title: "Identification of the rs797045105 in the SERAC1 Gene by Whole-exome Sequencing in a Patient Suspicious of MEGDEL Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We found an insertion, rs797045105 (chr6, 158571484, C>CCATG), in the
        SERAC1 gene with homozygous genotype in the patient and heterozygous genotype
        in her unaffected parents
      explanation: Reports the allele and its segregation.
  - name: c.1404-2A>G
    description: Homozygous canonical splice-acceptor allele in an Egyptian proband
      with relatively delayed onset and neither hepatopathy nor deafness.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Predicted loss of function through disrupted splicing.
    evidence:
    - reference: PMID:40821445
      reference_title: "Expanding the Epidemiological and Phenotypic Spectrum of MEGDEL Syndrome: The First Case Report From Egypt."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Whole-exome sequencing demonstrated a likely pathogenic homozygous c.1404-2A>G
        variant in SERAC1 gene
      explanation: Reports the splice allele in the first Egyptian case.
  - name: Homozygous splice variant causing juvenile complicated HSP
    description: The hypomorphic splice allele underlying the juvenile
      complicated-hereditary-spastic-paraplegia presentation in a large consanguineous
      family. It abolishes full-length protein yet leaves a milder lipid phenotype
      than the classic infantile alleles, which is the clearest genotype-phenotype
      evidence in this disease.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Loss of the full-length protein with a milder phosphatidylglycerol
        remodeling defect than classic infantile alleles.
    evidence:
    - reference: PMID:28916646
      reference_title: "SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The homozygous splice mutation led to loss of the full-length SERAC1
        protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling
      explanation: Ties the allele to both the protein loss and the lipid defect.
    - reference: PMID:28916646
      reference_title: "SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These phosphatidylglycerol changes, however, were milder than in classic
        infantile-onset SERAC1 cases, which might partially explain the milder SERAC1
        phenotype
      explanation: States the graded relationship between residual remodeling and clinical
        severity.
  - name: Deletion of exons 2-4
    description: Multi-exon deletion allele, in trans with c.1601A>T (p.His534Leu),
      in a child whose development improved beyond clinical expectation.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Loss of function; the allele reduces or abolishes SERAC1 protein.
    evidence:
    - reference: PMID:35781780
      reference_title: "Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'biallelic novel SERAC1 mutations: (1) deletion of (at least) exons
        2-4, pathogenic; and (2) c.1601A>T (p.H534L), likely pathogenic'
      explanation: Reports the structural allele and its pathogenicity assignment.
  notes: >-
    SERAC1 (serine active site containing 1, 6q25.3) is the only gene
    associated with MEGDEL syndrome. It encodes a phosphatidylglycerol
    remodeling enzyme; reported disease alleles include nonsense, frameshift,
    canonical splice and multi-exon deletion variants, all of which reduce or
    abolish protein expression, plus hypomorphic missense alleles associated
    with the milder phenotypes. p.Phe471 (rs112780453) is reported as a benign
    variant and should not be treated as a disease allele.
pathophysiology:
- name: Biallelic SERAC1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Two loss-of-function SERAC1 alleles - nonsense, frameshift, canonical
    splice or multi-exon deletion - are the initiating lesion. Heterozygous
    carriers are unaffected.
  evidence:
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL
      syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome,
      impaired oxidative phosphorylation and 3-methylglutaconic aciduria
    explanation: Establishes biallelic SERAC1 mutation as the cause of the disorder.
  downstream:
  - target: Absent or Mislocalized SERAC1 Protein
    causal_link_type: DIRECT
    description: Truncating alleles abolish protein expression; a C-terminal truncation
      that escapes degradation is mislocalized away from mitochondria.
    evidence:
    - reference: PMID:23918762
      reference_title: "Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both mutations were found to lead to decreased or absent expression
        of SERAC1
      explanation: Directly links the causal alleles to loss of the protein.
- name: Absent or Mislocalized SERAC1 Protein
  biological_scale: MOLECULAR
  description: >-
    Patient fibroblasts carrying a homozygous truncating allele contain no
    detectable SERAC1 protein. A milder C-terminally truncated protein is
    expressed but is distributed throughout the cell instead of partially
    colocalizing with mitochondria, so the enzyme is absent from its site of
    action either way.
  cellular_components:
  - preferred_term: mitochondria-associated endoplasmic reticulum membrane
    term:
      id: GO:0044233
      label: mitochondria-associated endoplasmic reticulum membrane contact site
    modifier: DECREASED
  evidence:
  - reference: PMID:34751152
    reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In the patient fibroblasts, no SERAC1 protein was detected, the mitochondrial
      network was severely fragmented, and the cristae morphology was altered
    explanation: Demonstrates complete absence of the protein in patient cells.
  - reference: PMID:34751152
    reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the mutant protein with the a 45-amino acid C-terminal truncation was distributed
      throughout the cell, whereas wild-type SERAC1 partially colocalized with the
      mitochondrial marker MT-CO1
    explanation: Shows the alternative route to functional absence, mislocalization
      away from mitochondria.
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We localized SERAC1 at the interface between the mitochondria and the
      endoplasmic reticulum in the mitochondria-associated membrane fraction that is
      essential for phospholipid exchange
    explanation: Establishes the normal site of action from which the protein is lost.
  downstream:
  - target: Impaired Phosphatidylglycerol Remodeling
    causal_link_type: DIRECT
    description: SERAC1 is the phosphatidylglycerol remodeling enzyme at this membrane,
      so its loss removes the remodeling activity.
    evidence:
    - reference: PMID:22683713
      reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Our data identify SERAC1 as a key player in the phosphatidylglycerol
        remodeling that is essential for both mitochondrial function and intracellular
        cholesterol trafficking
      explanation: Assigns the remodeling function to the lost protein.
  - target: Impaired Mitochondrial Serine Import and mtDNA Depletion
    causal_link_type: DIRECT
    hypothesis_groups:
    - serine_transport_mtdna
    description: In the alternative model, SERAC1 acts on the outer mitochondrial membrane
      as a partner of the serine transporter SFXN1, so its loss starves the one-carbon
      cycle.
    evidence:
    - reference: PMID:35235340
      reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: By interacting with the mitochondrial serine transporter protein SFXN1,
        SERAC1 facilitated and was required for SFXN1-mediated serine transport from
        the cytosol to the mitochondria
      explanation: Supports a second, transport-based consequence of losing SERAC1.
- name: Impaired Phosphatidylglycerol Remodeling
  biological_scale: MOLECULAR
  description: >-
    Without SERAC1, the phosphatidylglycerol pool of patient fibroblasts
    shifts towards PG-34:1 and away from PG-36:1. Lentiviral complementation
    with wild-type SERAC1 partially normalizes the ratio, establishing that
    the lipid change is a direct consequence of the enzyme deficiency rather
    than a downstream epiphenomenon.
  biological_processes:
  - preferred_term: phosphatidylglycerol acyl-chain remodeling
    term:
      id: GO:0036148
      label: phosphatidylglycerol acyl-chain remodeling
    modifier: DECREASED
  evidence:
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: A phospholipid analysis in patient fibroblasts showed elevated concentrations
      of phosphatidylglycerol-34:1
    explanation: Reports the primary lipid abnormality in patient cells.
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Complementation of patient fibroblasts with wild-type human SERAC1 by
      lentiviral infection led to a decrease and partial normalization of the mean
      ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1
    explanation: Rescue by wild-type protein shows the lipid defect is caused by SERAC1
      loss.
  downstream:
  - target: Altered Cardiolipin Subspecies Composition
    causal_link_type: DIRECT
    description: Phosphatidylglycerol is the immediate precursor of cardiolipin, so
      a shifted PG pool yields abnormal cardiolipin species.
    evidence:
    - reference: PMID:22683713
      reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: decreased concentrations of phosphatidylglycerol-36:1 species, resulting
        in an altered cardiolipin subspecies composition
      explanation: States the causal step from the PG shift to abnormal cardiolipin.
  - target: Bis(monoacylglycerol)phosphate Depletion and Free Cholesterol Accumulation
    causal_link_type: DIRECT
    description: The same remodeling defect lowers BMP, the late-endosomal lipid required
      for cholesterol egress.
    evidence:
    - reference: PMID:22683713
      reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We also detected low concentrations of bis(monoacyl-glycerol)-phosphate,
        leading to the accumulation of free cholesterol, as shown by abnormal filipin
        staining
      explanation: Links the lipid remodeling defect to BMP loss and cholesterol accumulation.
  - target: Mitochondrial Network Fragmentation and Deficient Calcium Transfer
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of the remodeling enzyme at the ER-mitochondria interface disrupts
      the contact site itself; the intervening steps between the lipid change and the
      structural and calcium phenotypes are not established.
    evidence:
    - reference: PMID:34751152
      reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The structural and functional mitochondrial abnormalities, caused by
        the loss of SERAC1, suggest that the crucial disease mechanism is disrupted
        interplay between the ER and mitochondria
      explanation: Attributes the structural and calcium abnormalities to SERAC1 loss
        while describing the link as a suggested mechanism.
- name: Altered Cardiolipin Subspecies Composition
  biological_scale: MOLECULAR
  description: >-
    The shifted phosphatidylglycerol pool yields cardiolipin of abnormal acyl
    composition. Cardiolipin is required for assembly and stability of the
    respiratory chain supercomplexes, which is the route by which a
    phospholipid defect becomes a bioenergetic one.
  biological_processes:
  - preferred_term: cardiolipin acyl-chain remodeling
    term:
      id: GO:0035965
      label: cardiolipin acyl-chain remodeling
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: decreased concentrations of phosphatidylglycerol-36:1 species, resulting
      in an altered cardiolipin subspecies composition
    explanation: Reports the altered cardiolipin composition directly.
  - reference: PMID:23296368
    reference_title: "Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome
    explanation: Classification review groups MEGDEL with Barth syndrome as a disorder
      of defective phospholipid remodelling, the class in which cardiolipin is the
      affected lipid.
  downstream:
  - target: Respiratory Chain Complex Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Abnormal cardiolipin is the presumed link to measured complex I, III
      and IV deficiency; the assembly intermediates have not been demonstrated in this
      disease.
    evidence:
    - reference: PMID:34751152
      reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: In liver mitochondria, complexes I, III, and IV were clearly decreased
      explanation: Establishes the complex deficiency; the cardiolipin route to it
        is inferred rather than measured here.
- name: Bis(monoacylglycerol)phosphate Depletion and Free Cholesterol Accumulation
  biological_scale: CELLULAR
  description: >-
    Low BMP impairs intracellular cholesterol trafficking, so unesterified
    cholesterol accumulates and is unevenly distributed, demonstrable by
    filipin staining in patient fibroblasts. This is a parallel cellular
    consequence of the same remodeling defect rather than a step on the
    bioenergetic route.
  biological_processes:
  - preferred_term: intracellular cholesterol transport
    term:
      id: GO:0032367
      label: intracellular cholesterol transport
    modifier: DECREASED
  evidence:
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We also detected low concentrations of bis(monoacyl-glycerol)-phosphate,
      leading to the accumulation of free cholesterol, as shown by abnormal filipin
      staining
    explanation: Reports both the BMP deficit and the resulting cholesterol accumulation.
  - reference: PMID:34751152
    reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Filipin staining showed uneven localization of unesterified cholesterol
    explanation: Independent replication of the cholesterol trafficking defect in a
      second patient line.
  downstream:
  - target: Mitochondrial Bioenergetic Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cholesterol mistrafficking is presumed to contribute to organelle
      dysfunction, but no step connecting it quantitatively to ATP deficit has been
      demonstrated in MEGDEL.
    evidence:
    - reference: PMID:22683713
      reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: Our data identify SERAC1 as a key player in the phosphatidylglycerol
        remodeling that is essential for both mitochondrial function and intracellular
        cholesterol trafficking
      explanation: Places both mitochondrial function and cholesterol trafficking downstream
        of the same enzyme without demonstrating the link between them.
- name: Mitochondrial Network Fragmentation and Deficient Calcium Transfer
  biological_scale: CELLULAR
  description: >-
    Patient fibroblasts show a severely fragmented mitochondrial network with
    altered cristae morphology, and the calcium buffering function between
    cytoplasm and mitochondria is deficient. Liver ultrastructure in a second
    patient shows abnormal circular mitochondrial cristae.
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: DECREASED
  - preferred_term: mitochondrial calcium uptake
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:34751152
    reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The calcium buffer function between cytoplasm and mitochondria was deficient
    explanation: Reports the calcium transfer defect directly.
  - reference: PMID:35781780
    reference_title: "Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ultrastructural findings included abnormal circular mitochondrial cristae
    explanation: Confirms abnormal cristae in patient liver tissue, not only cultured
      cells.
  downstream:
  - target: Respiratory Chain Complex Deficiency
    causal_link_type: DIRECT
    description: Reduced calcium influx to mitochondria is proposed as the immediate
      cause of the secondary respiratory chain deficiency.
    evidence:
    - reference: PMID:34751152
      reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: leading to decreased influx of calcium to mitochondria and secondary
        respiratory chain deficiency
      explanation: States the causal step from deficient calcium influx to respiratory
        chain deficiency.
- name: Impaired Mitochondrial Serine Import and mtDNA Depletion
  biological_scale: MOLECULAR
  description: >-
    An alternative and not yet reconciled model places SERAC1 on the outer
    mitochondrial membrane as a partner of the serine transporter SFXN1. Loss
    of SERAC1 then impairs the one-carbon cycle, unbalances the nucleotide
    pool and depletes mitochondrial DNA. Hepatic mtDNA depletion has been
    observed in one patient, and nucleoside supplementation restored mtDNA
    content in the mouse and cell models.
  biological_processes:
  - preferred_term: mitochondrial DNA maintenance
    term:
      id: GO:0032042
      label: mitochondrial DNA metabolic process
    modifier: DECREASED
  - preferred_term: mitochondrial serine import
    term:
      id: GO:0006730
      label: one-carbon metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:35235340
    reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Loss of SERAC1 impaired the one-carbon cycle and disrupted the balance
      of the nucleotide pool, which led to primary mitochondrial DNA (mtDNA) depletion
    explanation: Reports the serine-transport route from SERAC1 loss to mtDNA depletion.
  - reference: PMID:23918762
    reference_title: "Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected children displayed biochemical features consistent with mitochondrial
      OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient
    explanation: Human observation of hepatic mtDNA depletion consistent with this
      route.
  downstream:
  - target: Mitochondrial Bioenergetic Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - serine_transport_mtdna
    description: mtDNA depletion removes the templates for the mitochondrially encoded
      respiratory chain subunits.
    evidence:
    - reference: PMID:35235340
      reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: both in vitro and in vivo supplementation of nucleosides/nucleotides
        restored mtDNA content and mitochondrial function
      explanation: Rescue of mitochondrial function by restoring mtDNA content supports
        the depletion as the cause of the bioenergetic deficit in this model.
- name: Respiratory Chain Complex Deficiency
  biological_scale: CELLULAR
  description: >-
    Reduced activity and amount of respiratory chain complexes I, III and IV,
    measured in liver mitochondria. The deficiency is secondary to the
    phospholipid and contact-site defect, and is characteristically variable
    between tissues - respiratory chain activity in fresh muscle can be
    entirely normal, so a negative muscle biopsy does not exclude the
    diagnosis.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:34751152
    reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In liver mitochondria, complexes I, III, and IV were clearly decreased
    explanation: Direct measurement of the complex deficiency in patient liver.
  - reference: PMID:25051967
    reference_title: "MEGDEL Syndrome in a Child From Palestine: Report of a Novel Mutation in SERAC1 Gene."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma and cerebrospinal fluid lactate, plasma alanine, and respiratory
      chain complexes in fresh muscle were normal
    explanation: Contradicts a uniform respiratory chain deficiency across tissues;
      muscle can be normal in a genetically confirmed patient.
  downstream:
  - target: Mitochondrial Bioenergetic Failure
    causal_link_type: DIRECT
    description: Loss of complexes I, III and IV directly reduces ATP synthesis capacity.
    evidence:
    - reference: PMID:22683713
      reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a recessive disorder of dystonia and deafness with Leigh-like syndrome,
        impaired oxidative phosphorylation and 3-methylglutaconic aciduria
      explanation: Names impaired oxidative phosphorylation as a defining feature of
        the disorder.
- name: Mitochondrial Bioenergetic Failure
  biological_scale: CELLULAR
  description: >-
    The convergence point of the cardiolipin, calcium and mtDNA branches:
    insufficient mitochondrial ATP production in tissues with high and
    sustained energy demand.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:23918762
    reference_title: "Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected children displayed biochemical features consistent with mitochondrial
      OXPHOS dysfunction
    explanation: Establishes OXPHOS dysfunction across the reported patient series.
  downstream:
  - target: Secondary 3-Methylglutaconic Aciduria and Lactic Acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: 3-methylglutaconic acid excretion in MEGDEL is a marker of mitochondrial
      dysfunction rather than a block in leucine catabolism; the biochemical steps
      generating it are not established.
    evidence:
    - reference: PMID:30114719
      reference_title: "HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial
        dysfunction
      explanation: States the marker relationship that makes this aciduria secondary.
  - target: Basal Ganglia Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure damages the basal ganglia selectively, in the staged
      putaminal pattern characteristic of the disease; why the putamen is affected
      first is unknown.
    evidence:
    - reference: PMID:25642805
      reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All patients presented a distinctive brain MRI pattern with five characteristic
        disease stages affecting the basal ganglia, especially the putamen
      explanation: Documents the selective basal-ganglia target of the energy deficit.
  - target: Cochlear and Auditory Pathway Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Sensorineural deafness is a near-universal feature; the cellular site
      of the auditory lesion in MEGDEL has not been established histologically.
    evidence:
    - reference: PMID:32684373
      reference_title: "MEGDEL Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: clinically characterized by 3-methylglutaconic aciduria, psychomotor
        delay, muscle hypotonia, sensorineural deafness
      explanation: Establishes sensorineural deafness as a defining consequence.
  - target: Hepatocellular Mitochondrial Injury
    causal_link_type: DIRECT
    description: Liver mitochondria carry the measured respiratory chain deficiency
      and the abnormal cristae, and infantile hepatopathy is a cardinal feature.
    evidence:
    - reference: PMID:23918762
      reference_title: "Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The present findings indicate that infantile hepatopathy is a cardinal
        feature of MEGDEL syndrome
      explanation: Establishes hepatic involvement as a core rather than incidental
        feature.
- name: Secondary 3-Methylglutaconic Aciduria and Lactic Acidosis
  biological_scale: ORGANISM
  description: >-
    Persistently increased urinary excretion of 3-methylglutaconic and
    3-methylglutaric acid, with elevated blood lactate and alanine. This is a
    secondary 3-methylglutaconic aciduria of the class defined by defective
    phospholipid remodeling, not a primary block in leucine catabolism as in
    AUH deficiency.
  evidence:
  - reference: PMID:27186703
    reference_title: "Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patients were presented with 3-methylglutaconic acid and 3-methylglutaric
      aciduria
    explanation: Documents excretion of both organic acids in confirmed patients.
  - reference: PMID:37711114
    reference_title: "SERAC1 Deficiency- A New Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Biochemical abnormalities: elevated urinary 3 - metilglutaconic and 3-metilglutaric
      acids, high lactate and alanine in serum'
    explanation: Records the accompanying lactate and alanine elevation.
  downstream:
  - target: 3-Methylglutaconic aciduria
    causal_link_type: DIRECT
    description: The organic aciduria is itself the defining laboratory phenotype.
    evidence:
    - reference: PMID:30114719
      reference_title: "HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: consistently elevated urinary excretion of 3-methylglutaconic acid is
        the hallmark of a small but growing group of inborn errors of metabolism
      explanation: Confirms the aciduria as the observable hallmark.
  - target: Lactic acidosis
    causal_link_type: DIRECT
    description: Impaired oxidative phosphorylation shifts pyruvate to lactate.
    evidence:
    - reference: PMID:38445077
      reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a pronounced lactate acidosis and in urine an increased excretion of
        3-methylglutaconic acid as well as other metabolites of mitochondrial energy
        metabolism
      explanation: Reports lactic acidosis together with the organic aciduria in a
        neonatal crisis.
- name: Basal Ganglia Neurodegeneration
  biological_scale: TISSUE
  description: >-
    Staged degeneration of the basal ganglia, beginning with pallidal T2
    change, progressing to swelling of the putamen and caudate nucleus with a
    spared dorsal-putaminal "eye", and finally to progressive putaminal
    involvement. The "eye" has not been reported in any other disorder and is
    pathognomonic.
  cell_types:
  - preferred_term: striatal neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: putamen
    term:
      id: UBERON:0001874
      label: putamen
  - preferred_term: caudate nucleus
    term:
      id: UBERON:0001873
      label: caudate nucleus
  - preferred_term: globus pallidus
    term:
      id: UBERON:0001875
      label: globus pallidus
  evidence:
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In stage 1, T2 signal changes of the pallidum are present. In stage 2,
      swelling of the putamen and caudate nucleus is seen
    explanation: Defines the staged anatomical progression across 30 patients.
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: has not been reported in other disorders, making it pathognomonic for
      MEDGEL and allowing diagnosis based on MRI findings
    explanation: Establishes the specificity of the putaminal sign for this disease.
  downstream:
  - target: Dystonia
    causal_link_type: DIRECT
    description: Loss of striatal output produces the generalized dystonia that names
      the dystonia-deafness syndrome.
    evidence:
    - reference: PMID:27186703
      reference_title: "Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: severe sensorineural deafness, progressive spasticity, dystonia, seizures,
        basal ganglia involvement
      explanation: Reports dystonia together with the basal ganglia lesion in the same
        patients.
  - target: Progressive spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Spasticity accompanies the basal-ganglia disease and dominates the
      milder juvenile phenotype, though corticospinal involvement rather than the striatal
      lesion is likely to mediate it.
    evidence:
    - reference: PMID:25642805
      reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a clinically and biochemically highly distinctive dystonia deafness
        syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay,
        and progressive spasticity
      explanation: Records progressive spasticity as part of the same clinical picture.
  - target: Leigh-like basal ganglia lesions
    causal_link_type: DIRECT
    description: The degeneration is what the MRI abnormality depicts.
    evidence:
    - reference: PMID:35223715
      reference_title: "Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain MRI scans showed a symmetric flake abnormal signal shadow in the
        bilateral basal ganglia
      explanation: Documents the imaging correlate of the basal-ganglia lesion.
- name: Cochlear and Auditory Pathway Degeneration
  biological_scale: TISSUE
  description: >-
    Bilateral sensorineural hearing loss, usually severe and evident in
    infancy, giving the "D" of the acronym. Whether the lesion is cochlear
    hair cell, spiral ganglion or central is not established in MEGDEL, so the
    anatomical binding here is to the cochlea rather than to a specific cell
    population.
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:27186703
    reference_title: "Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: microcephaly, growth retardation, dysmorphic features, severe sensorineural
      deafness, progressive spasticity, dystonia, seizures, basal ganglia involvement
    explanation: Reports severe sensorineural deafness in genetically confirmed siblings.
  downstream:
  - target: Sensorineural hearing loss
    causal_link_type: DIRECT
    description: The auditory lesion is expressed clinically as sensorineural deafness.
    evidence:
    - reference: PMID:24997715
      reference_title: "The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: sensorineural hearing loss, encephalopathy, and Leigh-like pattern on
        MRI (MEGDEL syndrome)
      explanation: Records sensorineural hearing loss as a defining component.
- name: Hepatocellular Mitochondrial Injury
  biological_scale: TISSUE
  description: >-
    Mitochondrial hepatopathy with hepatocytes showing granular cytoplasm and
    fine intracytoplasmic lipid droplets, and abnormal circular mitochondrial
    cristae on electron microscopy. Clinically this ranges from persistently
    elevated transaminases to fulminant neonatal liver failure - which,
    distinctively, may occur without any transaminase elevation or
    cholestasis.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:35781780
    reference_title: "Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hepatocytes showed granular cytoplasm and fine intracytoplasmic lipid
      droplets
    explanation: First detailed liver histology published for this syndrome.
  - reference: PMID:38445077
    reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe liver failure with distinct hyperammonemia and hypoglycemia without
      elevation of transaminases or cholestasis
    explanation: Documents the distinctive neonatal presentation of the hepatic lesion.
  downstream:
  - target: Infantile hepatopathy
    causal_link_type: DIRECT
    description: The hepatocellular mitochondrial lesion is expressed as the cardinal
      infantile hepatopathy.
    evidence:
    - reference: PMID:23918762
      reference_title: "Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The present findings indicate that infantile hepatopathy is a cardinal
        feature of MEGDEL syndrome
      explanation: Establishes the hepatopathy as a core feature of the disease.
  - target: Hyperammonemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of hepatic synthetic and detoxifying function during the neonatal
      crisis raises ammonia; the contribution of impaired ureagenesis versus catabolic
      load is not resolved.
    evidence:
    - reference: PMID:38445077
      reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Due to high ammonia level, continuous hemodialysis was established immediately
        after admission
      explanation: Records hyperammonemia severe enough to require dialysis in hepatic
        crisis.
  - target: Hypoglycemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired hepatic glucose output during the neonatal crisis.
    evidence:
    - reference: PMID:38445077
      reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: If a newborn presents with hyperammonemia, hypoglycemia and impaired
        liver synthesis function without elevation of transaminases or cholestasis
      explanation: Groups hypoglycemia with impaired hepatic synthetic function in
        the crisis presentation.
phenotypes:
- name: 3-Methylglutaconic aciduria
  category: Laboratory
  description: >-
    Persistent, consistently increased urinary excretion of 3-methylglutaconic
    acid together with 3-methylglutaric acid. Universal and defining.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: 3-Methylglutaconic aciduria
    term:
      id: HP:0003535
      label: 3-Methylglutaconic aciduria
  evidence:
  - reference: PMID:32684373
    reference_title: "MEGDEL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MEGDEL syndrome is an autosomal recessive disorder, clinically characterized
      by 3-methylglutaconic aciduria
    explanation: Names the aciduria as a defining clinical characteristic.
- name: Sensorineural hearing loss
  category: Neurological
  description: >-
    Bilateral sensorineural deafness, typically severe and apparent in
    infancy. Near-universal in the classic phenotype, though a delayed-onset
    Egyptian case had intact hearing at 7 years.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:25051967
    reference_title: "MEGDEL Syndrome in a Child From Palestine: Report of a Novel Mutation in SERAC1 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 3-methylglutaconic aciduria psychomotor delay, muscle hypotonia, sensori-neural
      deafness, and Leigh-like lesions on brain magnetic resonance imaging
    explanation: Lists sensorineural deafness among the characteristic features.
  - reference: PMID:40821445
    reference_title: "Expanding the Epidemiological and Phenotypic Spectrum of MEGDEL Syndrome: The First Case Report From Egypt."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: who had relatively delayed onset and no evident hepatopathy or deafness
    explanation: A genetically confirmed patient without deafness shows the feature
      is not obligate.
- name: Dystonia
  category: Neurological
  description: >-
    Progressive, often generalized dystonia arising in infancy or childhood
    and giving the disorder its alternative name of a dystonia-deafness
    syndrome.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a clinically and biochemically highly distinctive dystonia deafness syndrome
    explanation: Characterizes the disorder by its dystonia.
- name: Progressive spasticity
  category: Neurological
  description: >-
    Progressive spasticity, often reaching spastic tetraparesis. It is the
    dominant feature of the milder juvenile complicated-HSP presentation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37711114
    reference_title: "SERAC1 Deficiency- A New Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Currently he has spastic tetraparesis, dystonia, scoliosis and autistic
      behavior, with bilateral basal ganglia lesions on brain MRI
    explanation: Documents spastic tetraparesis in a genetically confirmed adult patient.
- name: Severe psychomotor delay
  category: Neurological
  description: Severe delay in acquisition of motor and cognitive milestones, the "E"
    of the acronym.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  evidence:
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: accompanied by 3-methylglutaconic aciduria, severe developmental delay,
      and progressive spasticity
    explanation: Reports severe developmental delay across the 30-patient MRI series.
- name: Developmental regression
  category: Neurological
  description: Loss of previously acquired skills, which may be the presenting event
    in later-onset patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:24997715
    reference_title: "The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: as well as developmental delay and developmental regression, bilateral
      optic nerve atrophy, microcephaly, and myoclonic epilepsy
    explanation: Records regression alongside the other neurological features.
- name: Truncal hypotonia
  category: Neurological
  description: Early muscle hypotonia, predominantly truncal, typical of the infantile
    presentation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38559521
    reference_title: "Incidental Finding of MEGDEL Syndrome at a Tertiary Care Center in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is characterized by psychomotor delay, muscular hypotonia, sensorineural
      deafness, and Leigh-like syndrome lesions on brain magnetic resonance imaging
    explanation: Lists muscular hypotonia among the characteristic features.
- name: Leigh-like basal ganglia lesions
  category: Imaging
  description: >-
    Symmetric bilateral basal ganglia signal abnormality on T2-weighted and
    FLAIR MRI, following a five-stage pattern with the pathognomonic
    dorsal-putaminal "eye".
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal basal ganglia morphology
    term:
      id: HP:0002134
      label: Abnormal basal ganglia morphology
  evidence:
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients presented a distinctive brain MRI pattern with five characteristic
      disease stages affecting the basal ganglia, especially the putamen
    explanation: Systematic review of 43 MRI studies in 30 patients.
- name: Infantile hepatopathy
  category: Gastrointestinal
  description: >-
    Mitochondrial liver disease of infancy, ranging from persistently elevated
    transaminases to acute liver failure. Distinctively, severe neonatal liver
    failure may occur without transaminase elevation or cholestasis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased liver function
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:23918762
    reference_title: "Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The present findings indicate that infantile hepatopathy is a cardinal
      feature of MEGDEL syndrome
    explanation: Establishes infantile hepatopathy as a cardinal feature.
- name: Lactic acidosis
  category: Laboratory
  description: Elevated blood and cerebrospinal fluid lactate, variable and sometimes
    entirely absent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:27186703
    reference_title: "Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Metabolic acidosis, mild hyperammonemia and lactic acidemia were accompanied
      with clinical findings in newborn period
    explanation: Records lactic acidemia in the neonatal period.
  - reference: PMID:25051967
    reference_title: "MEGDEL Syndrome in a Child From Palestine: Report of a Novel Mutation in SERAC1 Gene."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma and cerebrospinal fluid lactate, plasma alanine, and respiratory
      chain complexes in fresh muscle were normal
    explanation: A genetically confirmed patient with entirely normal lactate shows
      the finding is not obligate.
- name: Hyperammonemia
  category: Laboratory
  description: Elevated blood ammonia, restricted mainly to the severe neonatal hepatic
    crisis, where it can require continuous hemodialysis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:38445077
    reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe liver failure with distinct hyperammonemia and hypoglycemia without
      elevation of transaminases or cholestasis
    explanation: Documents marked hyperammonemia in a neonatal crisis.
- name: Hypoglycemia
  category: Laboratory
  description: Low blood glucose during metabolic crisis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:38445077
    reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: If a newborn presents with hyperammonemia, hypoglycemia and impaired liver
      synthesis function
    explanation: Reports hypoglycemia as part of the neonatal presentation.
- name: Seizures
  category: Neurological
  description: Seizures including myoclonic epilepsy, present in a subset of patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38559521
    reference_title: "Incidental Finding of MEGDEL Syndrome at a Tertiary Care Center in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: presented with developmental delay, cerebral palsy, intellectual disability,
      and seizures
    explanation: Records seizures in a genetically confirmed patient.
- name: Microcephaly
  category: Neurological
  description: Reduced head circumference, reported in a subset.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:27186703
    reference_title: "Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: microcephaly, growth retardation, dysmorphic features, severe sensorineural
      deafness
    explanation: Reports microcephaly in two confirmed siblings.
- name: Optic atrophy
  category: Ophthalmologic
  description: Bilateral optic nerve atrophy, part of the expanding phenotype and able
    to appear earlier than previously described.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:24997715
    reference_title: "The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had an earlier age of onset of optic atrophy than previously
      described in other MEGDEL syndrome patients
    explanation: Documents optic atrophy and its variable timing.
- name: Growth retardation
  category: Constitutional
  description: Poor growth with feeding difficulties.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:27186703
    reference_title: "Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: microcephaly, growth retardation, dysmorphic features
    explanation: Reports growth retardation in confirmed patients.
- name: Dysmorphic features
  category: Craniofacial
  description: Non-specific facial dysmorphism reported in a subset.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:27186703
    reference_title: "Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: growth retardation, dysmorphic features, severe sensorineural deafness
    explanation: Records dysmorphic features alongside the core phenotype.
- name: Intellectual disability
  category: Neurological
  description: Cognitive impairment, ranging from moderate in the mildest presentations
    to profound in the classic infantile form.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:37711114
    reference_title: "SERAC1 Deficiency- A New Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A 30-year-old patient with a moderate intellectual disability
    explanation: Documents intellectual disability in the adult-onset presentation.
- name: Scoliosis
  category: Musculoskeletal
  description: Spinal curvature, a secondary orthopedic consequence of the movement
    disorder.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:37711114
    reference_title: "SERAC1 Deficiency- A New Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he has spastic tetraparesis, dystonia, scoliosis and autistic behavior
    explanation: Reports scoliosis in a genetically confirmed patient.
- name: Autistic behavior
  category: Behavioral
  description: Autistic features, reported in the milder and later-onset end of the
    spectrum.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:37711114
    reference_title: "SERAC1 Deficiency- A New Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: dystonia, scoliosis and autistic behavior, with bilateral basal ganglia
      lesions on brain MRI
    explanation: Records autistic behavior in the adult presentation.
biochemical:
- name: Phosphatidylglycerol 34:1 to 36:1 ratio
  notes: >-
    The disease-specific cellular biomarker, measured by lipidomics in
    cultured fibroblasts. The ratio is raised because PG-34:1 accumulates
    while PG-36:1 falls, and it is partially corrected by complementation with
    wild-type SERAC1. Milder alleles produce a milder shift.
  presence: INCREASED
  readouts:
  - target: Impaired Phosphatidylglycerol Remodeling
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: A raised PG34:1/PG36:1 ratio is the direct cellular measurement
      of the remodeling defect.
    evidence:
    - reference: PMID:22683713
      reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Complementation of patient fibroblasts with wild-type human SERAC1 by
        lentiviral infection led to a decrease and partial normalization of the mean
        ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1
      explanation: Rescue of the ratio by wild-type protein ties the measurement to
        the mechanism.
  evidence:
  - reference: PMID:28916646
    reference_title: "SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'biomarker investigations (3-methyl-glutaconic acid, filipin staining
      and phosphatidylglycerols PG34:1/PG36:1)'
    explanation: Uses the ratio as a diagnostic biomarker in a clinical family study.
  - reference: PMID:28916646
    reference_title: "SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'These phosphatidylglycerol changes, however, were milder than in classic
      infantile-onset SERAC1 cases, which might partially explain the milder SERAC1
      phenotype'
    explanation: Links the magnitude of the biomarker shift to clinical severity.
- name: Urinary 3-methylglutaconic and 3-methylglutaric acid
  notes: >-
    Persistently elevated organic acids on urine GC/MS, the biochemical entry
    point to the diagnosis. Elevation is secondary to mitochondrial
    dysfunction rather than to a leucine catabolic block.
  presence: INCREASED
  readouts:
  - target: Secondary 3-Methylglutaconic Aciduria and Lactic Acidosis
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Urine organic acid analysis is the standard assay reporting on
      this node.
    evidence:
    - reference: PMID:30114719
      reference_title: "HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Urinary organic acid analysis is a noninvasive and inexpensive test
        that can guide further genetic testing
      explanation: Establishes urine organic acids as the diagnostic readout.
  evidence:
  - reference: PMID:35223715
    reference_title: "Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The excretion of 3-methylglutaconic acid was found to be increased in
      our GC/MS analysis
    explanation: Reports the measurement in a confirmed patient.
- name: Free cholesterol accumulation on filipin staining
  notes: >-
    Abnormal, unevenly distributed unesterified cholesterol in patient
    fibroblasts, the cellular readout of the BMP deficit.
  presence: INCREASED
  readouts:
  - target: Bis(monoacylglycerol)phosphate Depletion and Free Cholesterol Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Filipin staining is the standard histochemical assay for the free
      cholesterol accumulation at this node.
    evidence:
    - reference: PMID:34751152
      reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Filipin staining showed uneven localization of unesterified cholesterol
      explanation: Reports the filipin assay result directly.
  evidence:
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: leading to the accumulation of free cholesterol, as shown by abnormal
      filipin staining
    explanation: Original description of the filipin abnormality in patient cells.
histopathology:
- name: Mitochondrial hepatopathy with abnormal circular cristae
  description: >-
    Liver biopsy shows hepatocytes with granular cytoplasm and fine
    intracytoplasmic lipid droplets; electron microscopy shows abnormal
    circular mitochondrial cristae. This is the first detailed liver histology
    published for the syndrome.
  finding_term:
    preferred_term: abnormal mitochondrial cristae in hepatocytes
  evidence:
  - reference: PMID:35781780
    reference_title: "Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The histologic features of a liver biopsy are described, which has not
      previously been published in detail for this syndrome
    explanation: Establishes the provenance and novelty of the histological description.
  - reference: PMID:35781780
    reference_title: "Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ultrastructural findings included abnormal circular mitochondrial cristae
    explanation: Reports the ultrastructural abnormality.
progression:
- phase: Neonatal metabolic and hepatic crisis
  notes: >-
    Presentation in the first days of life with lactic acidosis, hepatopathy
    and, in the most severe cases, hyperammonemia and hypoglycemia without
    transaminase elevation or cholestasis. This is the critical intervention
    window and can be lethal within days.
  evidence:
  - reference: PMID:34751152
    reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a newborn infant with a metabolic crisis, lethal multiorgan failure on
      day six of life, and increased excretion of 3-methylglutaconic acid
    explanation: Documents the lethal neonatal crisis phase.
- phase: Chronic progressive neurodegeneration
  notes: >-
    Infantile sensorineural deafness and truncal hypotonia, then severe
    psychomotor delay and regression, then progressive spasticity and dystonia
    with staged basal-ganglia degeneration.
  evidence:
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe developmental delay, and progressive spasticity
    explanation: Describes the chronic progressive neurological course.
- phase: Milder later-onset course
  notes: >-
    In patients with hypomorphic alleles the disease may present only in
    adolescence or adulthood as complicated spastic paraplegia or dystonia,
    and some children exceed expectations and partially improve.
  evidence:
  - reference: PMID:35781780
    reference_title: "Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: her verbal and motor development has progressively improved and now, at
      4 years of age, she has only speech and mild gross motor delays
    explanation: Records improvement rather than relentless regression in a mild case.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: About 100 patients reported since the 2006 first description; precise prevalence
    and incidence are not established.
  evidence:
  - reference: PMID:35943861
    reference_title: "First description of the MEGDEHL syndrome in the Tunisian population via whole-exome sequencing: Novel nonsense mutation in SERAC1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MEGDEL syndrome is a rare recessive disorder, with about 100 cases reported
      worldwide
    explanation: Gives the reported case count worldwide.
  - reference: PMID:32684373
    reference_title: "MEGDEL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Since the first description of MEGDEL syndrome in 2006, at least 102 patients
      have been reported
    explanation: Independent count of reported patients.
- population: Consanguineous families of the Middle East and North Africa
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Reported families are strongly over-represented among consanguineous
    pedigrees from Tunisia, Saudi Arabia, Palestine, Turkey, Egypt and Iran.
    This is an ascertainment pattern in the published literature, not a
    measured population rate, and no founder allele has been established.
  evidence:
  - reference: PMID:40821445
    reference_title: "Expanding the Epidemiological and Phenotypic Spectrum of MEGDEL Syndrome: The First Case Report From Egypt."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This is a 7-year-old boy born to first cousins Arab parents from Egypt
      with family history of unexplained deaths of 3 siblings during the neonatal period
    explanation: Illustrates the consanguineous pedigree pattern of reported cases.
  - reference: PMID:38559521
    reference_title: "Incidental Finding of MEGDEL Syndrome at a Tertiary Care Center in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient, born to consanguineous parents, presented with developmental
      delay, cerebral palsy, intellectual disability, and seizures
    explanation: A second independently reported consanguineous family.
diagnosis:
- name: Urine organic acid analysis
  description: >-
    Gas chromatography-mass spectrometry of urine showing persistently elevated
    3-methylglutaconic and 3-methylglutaric acid. This is the cheap,
    non-invasive entry point that redirects the workup towards this group of
    disorders, and it is what makes the biochemical diagnosis possible before
    sequencing.
  diagnosis_term:
    preferred_term: urine organic acid analysis
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:30114719
    reference_title: "HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Urinary organic acid analysis is a noninvasive and inexpensive test that
      can guide further genetic testing
    explanation: States the diagnostic role of the test in this disease group.
  - reference: PMID:35223715
    reference_title: "Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The excretion of 3-methylglutaconic acid was found to be increased in
      our GC/MS analysis
    explanation: The measurement as performed in a genetically confirmed patient.
- name: Brain MRI pattern recognition
  description: >-
    Brain MRI is diagnostic in its own right here, not merely supportive. The
    basal-ganglia disease evolves through five stages, and the dorsal-putaminal
    "eye" - a spared region within an otherwise swollen putamen - was present in
    every patient across a 30-patient series during a specific age window and
    has been reported in no other disorder.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis
    explanation: States that MRI pattern recognition is itself a route to diagnosis.
  - reference: PMID:25642805
    reference_title: "Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: has not been reported in other disorders, making it pathognomonic for
      MEDGEL and allowing diagnosis based on MRI findings
    explanation: Establishes the specificity that makes the imaging finding diagnostic
      rather than merely consistent.
  notes: >-
    The source spells the acronym "MEDGEL" in this sentence; the quote is
    reproduced exactly rather than corrected.
- name: Fibroblast phosphatidylglycerol and filipin profiling
  description: >-
    A disease-specific cellular assay: the PG34:1 to PG36:1 ratio by lipidomics,
    with filipin staining for free cholesterol, in cultured skin fibroblasts.
    Unlike the organic acids it reports on the enzymatic lesion itself, and the
    magnitude of the shift tracks with clinical severity.
  diagnosis_term:
    preferred_term: fibroblast lipid profiling
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:28916646
    reference_title: "SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1)"
    explanation: Lists the assay as one of the biomarker investigations used to reach
      the diagnosis in a clinical family study.
- name: SERAC1 sequencing with copy-number analysis
  description: >-
    Confirmation rests on finding biallelic pathogenic SERAC1 variants, most
    often by exome or genome sequencing. Copy-number or deletion analysis is
    needed alongside sequencing because intragenic multi-exon deletions occur
    and are missed by sequencing alone.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:37711114
    reference_title: "SERAC1 Deficiency- A New Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnosis is confirmed when biallelic pathogenic variants in SERAC1 gene
      are found
    explanation: States the confirmatory criterion directly.
  - reference: PMID:38559521
    reference_title: "Incidental Finding of MEGDEL Syndrome at a Tertiary Care Center in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: subsequent genetic testing through whole exome sequencing confirmed a
      rare homozygous deletion variant in the SERAC1 gene
    explanation: Worked example of exome sequencing reaching the diagnosis, in this
      case for a deletion allele.
differential_diagnoses:
- name: Primary 3-methylglutaconic aciduria (AUH deficiency)
  description: >-
    The one 3-methylglutaconic aciduria that is a genuine block in leucine
    catabolism. MEGDEL's aciduria is secondary - a marker of mitochondrial
    dysfunction rather than the primary lesion - so the same urine finding means
    something different in the two disorders.
  evidence:
  - reference: PMID:23296368
    reference_title: "Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: AUH defect) due to defective leucine catabolism
    explanation: Names the primary disorder and the pathway that distinguishes it from
      the secondary group MEGDEL belongs to.
- name: Other secondary 3-methylglutaconic acidurias
  description: >-
    A defined group sharing the biochemical marker: Barth syndrome (TAZ), Costeff
    syndrome (OPA3), DCMA (DNAJC19), and the TMEM70, CLPB and TIMM50 disorders.
    Because the urine finding is common to all of them, the discriminators are
    the MRI pattern, the fibroblast lipid profile, and sequencing.
  evidence:
  - reference: PMID:30114719
    reference_title: "HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: due to defective phospholipid remodeling or mitochondrial membrane-associated
      disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50)
    explanation: Enumerates the group MEGDEL is differentiated within, including SERAC1
      itself.
- name: HTRA2 defect
  description: >-
    The closest differential for the neonatal presentation specifically: a
    neonatal movement disorder with seizures and 3-methylglutaconic aciduria.
    It is separated by its central hypopnea and apnea with neutropenia, and by a
    course that is lethal within the first month rather than chronic and
    progressive.
  evidence:
  - reference: PMID:30114719
    reference_title: "HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy-Report of 11 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hallmark features were central hypopnea/apnea leading to respiratory insufficiency,
      seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia
    explanation: Gives the feature set that separates HTRA2 defect from MEGDEL despite
      the shared aciduria.
environmental: []
treatments:
- name: Supportive Multidisciplinary Care
  description: >-
    No disease-modifying therapy exists. Management is supportive and requires
    neurology, metabolic medicine, audiology, hepatology and rehabilitation
    working together, with genetic confirmation to guide counselling.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32684373
    reference_title: "MEGDEL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnosing MEGDEL syndrome requires a multidisciplinary approach, including
      genetic confirmation of a SERAC1 mutation
    explanation: States the multidisciplinary basis of care.
  - reference: PMID:38445077
    reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Even while no cure is available yet, patients should be offered proper
      supportive management through a multidisciplinary team
    explanation: Confirms supportive multidisciplinary management as the standard of
      care.
- name: Neonatal Metabolic Crisis Management
  description: >-
    Treat the neonatal presentation as a suspected inborn error of metabolism:
    stop protein intake, promote anabolism with intravenous glucose, correct
    acidosis, and use continuous hemodialysis for severe hyperammonemia.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  target_mechanisms:
  - target: Hyperammonemia
    description: Continuous hemodialysis removes ammonia during the hepatic crisis.
    evidence:
    - reference: PMID:38445077
      reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Due to high ammonia level, continuous hemodialysis was established immediately
        after admission
      explanation: Reports hemodialysis used specifically to control hyperammonemia.
  evidence:
  - reference: PMID:38445077
    reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, protein intake was stopped, and the patient anabolized with
      intravenous glucose. Temporary stabilization could be achieved after four days
    explanation: Describes the metabolic crisis protocol and its partial effect.
  notes: >-
    Stabilization in the reported case was temporary and the infant died of
    subsequent neurological and cardiocirculatory complications, so this is
    crisis management rather than a treatment that alters outcome.
- name: Cochlear Implantation
  description: >-
    Auditory rehabilitation for the sensorineural deafness, including cochlear
    device implantation, which is performed in these patients despite the
    anaesthetic risk of the underlying mitochondrial disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_mechanisms:
  - target: Sensorineural hearing loss
    description: The implant bypasses the failed peripheral auditory transduction.
    evidence:
    - reference: PMID:39592976
      reference_title: "Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We discussed the anaesthetic management of an infant 2-year-old suffering
        from MEGD(H)EL syndrome undergoing cochlear implant
      explanation: Documents cochlear implantation performed in a MEGD(H)EL patient.
  evidence:
  - reference: PMID:39592976
    reference_title: "Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: an infant 2-year-old suffering from MEGD(H)EL syndrome undergoing cochlear
      implant
    explanation: Establishes that cochlear implantation is used in this disease.
- name: Non-Triggering Anaesthesia
  description: >-
    Where anaesthesia is required, dexmedetomidine as the principal agent -
    optionally combined with ketamine for procedural sedation - is used to
    avoid agents that trigger decompensation in mitochondrial disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexmedetomidine
      term:
        id: CHEBI:4466
        label: dexmedetomidine
  evidence:
  - reference: PMID:39592976
    reference_title: "Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The usage of dexmedetomidine as the main anaesthetic drug might have the
      benefit of a non-triggering anaesthetic agent in patients with a mitochondrial
      disease
    explanation: States the rationale and the agent used.
  notes: >-
    This is a single case report offering an anaesthetic rationale, not
    comparative evidence that dexmedetomidine improves outcome in MEGDEL.
- name: Nutritional and Feeding Support
  description: >-
    Feeding support including gastrostomy tube placement, for the dysphagia and
    failure to thrive of the chronic phase. Note that in this population the
    procedure itself carries the anaesthetic risk described below.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  evidence:
  - reference: PMID:39592976
    reference_title: "Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: They may need several interventions that require anaesthesia, for example,
      sedation for auditory brainstem response testing, gastrostomy tube placement
      and magnetic resonance imaging
    explanation: Records gastrostomy tube placement among the interventions these patients
      require.
- name: Perioperative Risk Management
  description: >-
    Anaesthesia is a recurring hazard rather than an incidental one, because
    these children repeatedly need sedation for auditory testing, imaging and
    feeding-tube placement. The mitochondrial-disease precautions are specific:
    succinylcholine is contraindicated, continuous propofol infusion is avoided
    after induction, non-depolarizing neuromuscular blockers are used sparingly,
    and preoperative fasting is shortened to avoid hypovolaemia and
    hypoglycaemia.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39592976
    reference_title: "Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Depolarizing muscle relaxants as succinylcholine must not be administered
      in any patient with myopathy due to their upregulation of nicotinic acetylcholine
      receptors in skeletal muscle
    explanation: States the one absolute drug contraindication in this population.
  - reference: PMID:39592976
    reference_title: "Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is recommended to refrain from administering propofol by continuous
      infusion after induction of anaesthesia due to concerns about propofol infusion
      syndrome in this vulnerable population
    explanation: Gives the propofol restriction and its stated rationale.
  - reference: PMID:39592976
    reference_title: "Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Preoperative fasting is reduced to 2 h, if possible, to avoid hypovolemia
      and hypoglycemia
    explanation: The fasting precaution, which matters here because catabolic stress
      precipitates decompensation.
  notes: >-
    These precautions are stated for mitochondrial disease as a class in a
    MEGD(H)EL case report, not established by a trial in this disorder.
- name: Genetic Counseling
  description: >-
    Counselling for the 25% recurrence risk in carrier couples, cascade
    testing of relatives, and prenatal or preimplantation testing once the
    familial variants are known. Particularly important given the
    over-representation of consanguineous families.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38445077
    reference_title: "Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: genetic confirmation of the diagnosis is important for the families, especially
      regarding further family planning
    explanation: States the family-planning purpose of genetic confirmation.
  - reference: PMID:38559521
    reference_title: "Incidental Finding of MEGDEL Syndrome at a Tertiary Care Center in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the need for genetic counseling in consanguineous families
    explanation: Recommends genetic counselling for the consanguineous families in
      which the disease clusters.
mechanistic_hypotheses:
- hypothesis_group_id: serine_transport_mtdna
  hypothesis_label: SERAC1 as an outer-membrane partner of the serine transporter SFXN1
  status: EMERGING
  description: >-
    An alternative model in which SERAC1 acts not as a phospholipid remodeling
    enzyme at the ER-mitochondria contact site but on the outer mitochondrial
    membrane, as a required partner of the mitochondrial serine transporter
    SFXN1. On this model the primary defect is a failure of serine import that
    starves the one-carbon cycle, unbalances the nucleotide pool and depletes
    mitochondrial DNA, making MEGD(H)EL a mtDNA depletion syndrome. The two
    models differ in the subcellular location they assign to SERAC1 and have
    not been reconciled; the therapeutic implication of the second, that
    nucleoside supplementation might help, does not follow from the first.
  evidence:
  - reference: PMID:35235340
    reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that SERAC1 localizes to the outer mitochondrial membrane and
      is a protein component of the one-carbon cycle
    explanation: States the alternative localization and function on which this hypothesis
      rests.
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: We localized SERAC1 at the interface between the mitochondria and the
      endoplasmic reticulum in the mitochondria-associated membrane fraction that is
      essential for phospholipid exchange
    explanation: The original localization study places SERAC1 at the contact site
      rather than the outer mitochondrial membrane.
animal_models:
- name: Serac1 knockout mouse
  species: Mouse
  genotype: Serac1-/-
  publication: PMID:35235340
  description: >-
    A germline Serac1 null mouse reported to reproduce the major diagnostic
    clinical and biochemical features of MEGD(H)EL, and used to establish the
    serine-transport and mtDNA-depletion route and to show rescue by
    nucleoside supplementation.
  modeled_mechanisms:
  - target: Impaired Mitochondrial Serine Import and mtDNA Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The mouse reproduces mtDNA depletion and the biochemical diagnostic
      phenotype, and nucleoside supplementation restores mtDNA content.
    limitations: >-
      The paper does not report whether the mouse reproduces the
      phosphatidylglycerol remodeling defect, the cholesterol trafficking
      abnormality or the staged basal-ganglia lesion, and its localization of
      SERAC1 to the outer mitochondrial membrane conflicts with the
      contact-site localization reported in patient cells.
    readouts:
    - name: Mitochondrial DNA content
      target: Impaired Mitochondrial Serine Import and mtDNA Depletion
      direction: DECREASED
      interpretation: mtDNA copy number is the primary molecular readout of this node
        in the model.
      evidence:
      - reference: PMID:35235340
        reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: which led to primary mitochondrial DNA (mtDNA) depletion in mice,
          HEK293T cells, and patient-derived immortalized lymphocyte cells
        explanation: Reports the mtDNA measurement in the knockout mouse and in patient-derived
          cells.
    - name: Mitochondrial DNA content after nucleoside supplementation
      target: Impaired Mitochondrial Serine Import and mtDNA Depletion
      direction: RESTORED
      interpretation: Restoration on supplementation shows the depletion is reversible
        and nucleotide-limited.
      evidence:
      - reference: PMID:35235340
        reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: both in vitro and in vivo supplementation of nucleosides/nucleotides
          restored mtDNA content and mitochondrial function
        explanation: Reports the rescue arm of the experiment.
    evidence:
    - reference: PMID:35235340
      reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: we generated Serac1-/- mice that mimic the major diagnostic clinical
        and biochemical phenotypes of the MEGD(H)EL syndrome
      explanation: States that the model reproduces the diagnostic phenotype, which
        is what makes it informative for this node.
- name: Canine multiple system degeneration
  species: Dog
  genotype: SERAC1 exon 15 nonsense (Kerry Blue Terrier) or exon 4 acceptor splice
    site 4 bp deletion (Chinese Crested)
  publication: PMID:39596578
  description: >-
    A naturally occurring, autosomal recessive SERAC1 movement disorder of
    Kerry Blue Terriers and Chinese Crested dogs, with complete
    genotype-phenotype concordance in large cohorts and in cross-bred compound
    heterozygotes.
  modeled_mechanisms:
  - target: Basal Ganglia Neurodegeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Affected dogs lose neurons from the putamen and caudate nucleus, the
      same striatal targets damaged in human MEGDEL, and develop a progressive
      movement disorder.
    limitations: >-
      The canine lesion extends beyond the human one, with Purkinje cell loss
      in the cerebellum and substantia nigra degeneration that are not
      features of MEGDEL, and the presentation is cerebellar ataxia and tremor
      rather than dystonia. Deafness, hepatopathy and 3-methylglutaconic
      aciduria are not documented in the dogs.
    readouts:
    - name: Neuronal loss in putamen and caudate nucleus
      target: Basal Ganglia Neurodegeneration
      direction: DECREASED
      interpretation: Post-mortem neuronal counts in the striatum are the histological
        correlate of the human basal-ganglia node.
      evidence:
      - reference: PMID:39596578
        reference_title: "Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Postmortem examination of the brains revealed Purkinje cell loss in
          the cerebellum and neuronal loss from the substantia nigra, putamen, and
          caudate nucleus
        explanation: Reports the striatal neuronal loss, and simultaneously the extra
          cerebellar and nigral involvement recorded as a limitation.
    evidence:
    - reference: PMID:39596578
      reference_title: "Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Variants in human SERAC1 are associated with disorders with a range
        of ages of disease onset and patterns of clinical signs, but that are all characterized
        by movement abnormalities similar to those of the dogs with CMSD
      explanation: The authors' own statement of why the canine disease is informative
        for the human movement disorder.
  evidence:
  - reference: PMID:39596578
    reference_title: "Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Genotyping of large cohorts of Kerry Blue Terriers and Chinese Crested
      dogs for the respective breed-specific SERAC1 variants showed complete concordance
      between genotype and disease phenotype
    explanation: Establishes that the canine phenotype is caused by the SERAC1 variants.
experimental_models:
- name: MEGDEL patient dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary skin fibroblasts from patients with biallelic SERAC1 variants, the
    principal system in which the lipid, cholesterol, mitochondrial-network
    and calcium phenotypes have been demonstrated, and in which lentiviral
    complementation with wild-type SERAC1 rescues the lipid ratio.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:22683713
  modeled_mechanisms:
  - target: Impaired Phosphatidylglycerol Remodeling
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Patient fibroblasts show the PG-34:1 rise and PG-36:1 fall, and
      complementation with wild-type SERAC1 partially normalizes the ratio,
      which is the strongest causal link in the whole mechanism.
    limitations: >-
      Fibroblasts are not an affected tissue, so they cannot report the
      tissue-selective basal-ganglia, cochlear or hepatic consequences.
    readouts:
    - name: PG-34:1 to PG-36:1 ratio
      target: Impaired Phosphatidylglycerol Remodeling
      direction: INCREASED
      interpretation: The ratio is the direct lipidomic measurement of the enzymatic
        defect.
      evidence:
      - reference: PMID:22683713
        reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: A phospholipid analysis in patient fibroblasts showed elevated concentrations
          of phosphatidylglycerol-34:1
        explanation: Reports the lipidomic measurement in the model system.
    - name: PG-34:1 to PG-36:1 ratio after wild-type complementation
      target: Impaired Phosphatidylglycerol Remodeling
      direction: RESTORED
      interpretation: Partial normalization on complementation establishes that SERAC1
        loss causes the lipid change.
      evidence:
      - reference: PMID:22683713
        reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: lentiviral infection led to a decrease and partial normalization of
          the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1
        explanation: Reports the rescue measurement.
    evidence:
    - reference: PMID:22683713
      reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: A phospholipid analysis in patient fibroblasts showed elevated concentrations
        of phosphatidylglycerol-34:1
      explanation: Establishes that the model reproduces the mechanism under study.
  - target: Mitochondrial Network Fragmentation and Deficient Calcium Transfer
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Patient fibroblasts show the fragmented network, altered cristae and
      deficient cytoplasm-to-mitochondria calcium buffering.
    limitations: >-
      The measurements come from a single patient line carrying one severe
      truncating allele, so allelic and interindividual variation in these
      structural phenotypes is unknown.
    readouts:
    - name: Mitochondrial network morphology
      target: Mitochondrial Network Fragmentation and Deficient Calcium Transfer
      direction: ALTERED
      interpretation: Network fragmentation and cristae change are the structural readouts
        of this node.
      evidence:
      - reference: PMID:34751152
        reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: the mitochondrial network was severely fragmented, and the cristae
          morphology was altered
        explanation: Reports the structural measurement.
    - name: Cytoplasm-to-mitochondria calcium buffering
      target: Mitochondrial Network Fragmentation and Deficient Calcium Transfer
      direction: DECREASED
      interpretation: Calcium buffering is the functional readout of the contact-site
        defect.
      evidence:
      - reference: PMID:34751152
        reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The calcium buffer function between cytoplasm and mitochondria was
          deficient
        explanation: Reports the calcium measurement.
    evidence:
    - reference: PMID:34751152
      reference_title: "Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In the patient fibroblasts, no SERAC1 protein was detected, the mitochondrial
        network was severely fragmented, and the cristae morphology was altered
      explanation: Establishes the model as informative for the structural node.
discussions:
- discussion_id: serac1_localization_conflict
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Where in the cell does SERAC1 act - at the mitochondria-associated ER membrane,
    or on the outer mitochondrial membrane?
  attaches_to:
  - pathophysiology#Absent or Mislocalized SERAC1 Protein
  - mechanistic_hypotheses#serine_transport_mtdna
  rationale: >-
    The gene-discovery study localized SERAC1 to the mitochondria-associated
    membrane fraction at the ER-mitochondria interface and assigned it a
    phospholipid remodeling role there. A later study using a knockout mouse
    placed it on the outer mitochondrial membrane as a partner of the serine
    transporter SFXN1, with a one-carbon-cycle and mtDNA-maintenance role. The
    two localizations imply different primary defects and different candidate
    treatments, and no study has tested them against each other. Until they
    are reconciled, this entry curates the phospholipid route as the main
    chain and the serine-transport route as an explicit hypothesis group.
  evidence:
  - reference: PMID:35235340
    reference_title: "SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that SERAC1 localizes to the outer mitochondrial membrane and
      is a protein component of the one-carbon cycle
    explanation: One side of the disagreement.
  - reference: PMID:22683713
    reference_title: "Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: We localized SERAC1 at the interface between the mitochondria and the
      endoplasmic reticulum in the mitochondria-associated membrane fraction that is
      essential for phospholipid exchange
    explanation: The other side of the disagreement.
- discussion_id: canine_model_organ_coverage
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Does the canine SERAC1 disorder model the non-neurological features of
    MEGDEL, or only the movement disorder?
  attaches_to:
  - pathophysiology#Cochlear and Auditory Pathway Degeneration
  - pathophysiology#Hepatocellular Mitochondrial Injury
  rationale: >-
    Canine multiple system degeneration is caused by SERAC1 loss and shares
    striatal neurodegeneration with the human disease, but the published
    description covers only the movement disorder and its neuropathology.
    Deafness, hepatopathy and 3-methylglutaconic aciduria - three of the four
    letters of the human acronym - are not reported in the dogs, and the
    canine lesion additionally involves the cerebellum and substantia nigra,
    which the human disease does not. So it is not known whether the dog fails
    to develop those features or whether nobody has looked, and the model
    cannot currently be used to study the auditory or hepatic mechanism.
  proposed_experiments:
  - experiment_id: canine_audiology_and_organic_acids
    name: Auditory, hepatic and organic-acid phenotyping of SERAC1 dogs
    description: >-
      Perform brainstem auditory evoked response testing, liver function and
      histology, and urine organic acid analysis on genotyped affected,
      carrier and wild-type Kerry Blue Terriers and Chinese Crested dogs.
    readouts:
    - name: Brainstem auditory evoked response threshold
      target: pathophysiology#Cochlear and Auditory Pathway Degeneration
      direction: INCREASED
      interpretation: A raised threshold in affected dogs would show the canine model
        does reach the auditory system.
    - name: Urinary 3-methylglutaconic acid
      target: pathophysiology#Hepatocellular Mitochondrial Injury
      direction: INCREASED
      interpretation: Organic aciduria in affected dogs would show the biochemical
        phenotype is conserved.
    would_support:
    - pathophysiology#Cochlear and Auditory Pathway Degeneration
    supporting_outcome:
    - Affected dogs show raised auditory brainstem response thresholds and increased
      urinary 3-methylglutaconic acid relative to genotyped littermate controls.
    would_refute:
    - pathophysiology#Cochlear and Auditory Pathway Degeneration
    refuting_outcome:
    - Affected dogs have normal hearing thresholds, normal liver histology and normal
      organic acids despite advanced striatal degeneration, showing the canine
      phenotype is restricted to the nervous system.
  evidence:
  - reference: PMID:39596578
    reference_title: "Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The associated pathologic lesions include degeneration of the cerebellum,
      caudate nucleus, and substantia nigra
    explanation: The published canine lesion description covers the nervous system
      only.
references:
- reference: PMID:22683713
  title: Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial
    function and intracellular cholesterol trafficking and cause dystonia and deafness.
- reference: PMID:23918762
  title: Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome
    (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy
    and Leigh-like syndrome) caused by novel mutations in SERAC1.
- reference: PMID:25642805
  title: 'Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness
    syndrome.'
- reference: PMID:34751152
  title: Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in
    SERAC1.
- reference: PMID:35235340
  title: SERAC1 is a component of the mitochondrial serine transporter complex required
    for the maintenance of mitochondrial DNA.
- reference: PMID:32684373
  title: MEGDEL Syndrome.
notes: >-
  Scope. This entry covers SERAC1 deficiency as a single disease with three
  severity bands recorded as subtypes, rather than splitting the juvenile
  complicated-HSP and adult dystonia presentations into separate entries. They
  share one gene, one biochemical signature and one mechanism, differ only by
  residual protein function, and MONDO carries a single concept.

  Terms deliberately not bound. The auditory node is bound to the cochlea
  rather than to a hair-cell type: no histological study localizes the
  auditory lesion in MEGDEL, and binding a cell type would assert more than
  the literature supports. Note that CL:0000598, suggested as "cochlear hair
  cell" by the deep-research report used for this entry, is in fact
  "pyramidal neuron" and must not be used for hair cells anywhere.

  Report corrections. Three claims in the source deep-research report were
  wrong and were not carried into this entry. It attributed the quote "Both
  mutations were found to lead to decreased or absent expression of SERAC1"
  to PMID:35943861; the sentence is in PMID:23918762, which is cited here
  instead. It stated that no Serac1 knockout mouse recapitulating MEGDEL had
  been published, while PMID:35235340 - which the same report cites - reports
  exactly such a mouse; the model is curated here. It gave NCIT:C15277 for
  Supportive Care, which is Mastectomy; the correct term NCIT:C15747 is used.
  It also offered HP:0002518 for Leigh-like basal ganglia lesions, which is
  "Abnormal periventricular white matter morphology"; HP:0002134 is used.

  Review round two. The GO bindings in the mechanism nodes were taken from the
  deep-research report's own suggestion block and three of them named a broader
  or different process than the claim: phosphatidylglycerol biosynthesis where
  the claim is acyl-chain remodeling, cholesterol metabolism where the claim is
  intracellular transport, and mitochondrion organization reused for an mtDNA
  maintenance claim so that one CURIE stood for two concepts in one file. These
  are now GO:0036148, GO:0032367 and GO:0032042, and cardiolipin metabolic
  process was likewise narrowed to GO:0035965 acyl-chain remodeling. The same
  skepticism that rejected the report's CL:0000598 should have been applied to
  its GO block in the first pass. Note that GO:0000002, proposed in review for
  the mtDNA node, is obsolete; GO:0032042 mitochondrial DNA metabolic process is
  used instead, with a separate one-carbon metabolic process binding for the
  serine-import half of that node.

  Treatment scope, and what could not be cited. Nutritional and feeding support
  and perioperative risk management were added because the anaesthesia case
  report carries quotable sentences for both, including the succinylcholine
  contraindication, the restriction on continuous propofol infusion and the
  shortened preoperative fast - the concrete agents-to-avoid guidance for this
  population. Rehabilitation, physiotherapy, and the dystonia and spasticity
  agents (trihexyphenidyl, baclofen, benzodiazepines, botulinum toxin) are
  deliberately still absent: the deep-research report asserts them, but no
  sentence in any of the 22 cached sources states them, and the report itself
  records that there are no MEGDEL-specific efficacy data. The same applies to
  valproate hepatotoxicity and aminoglycoside ototoxicity - both are real
  concerns in mitochondrial disease and neither is stated in a cached source
  here, so citing them would mean manufacturing a quote.

📚

References & Deep Research

References

6

PMID:22683713

Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.

No top-level findings curated for this source.

PMID:23918762

Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1.

No top-level findings curated for this source.

PMID:25642805

Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome.

No top-level findings curated for this source.

PMID:34751152

Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1.

No top-level findings curated for this source.

PMID:35235340

SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA.

No top-level findings curated for this source.

PMID:32684373

MEGDEL Syndrome.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Scope. This entry covers SERAC1 deficiency as a single disease with three severity bands recorded as subtypes, rather than splitting the juvenile complicated-HSP and adult dystonia presentations into separate entries. They share one gene, one biochemical signature and one mechanism, differ only by residual protein function, and MONDO carries a single concept. Terms deliberately not bound. The auditory node is bound to the cochlea rather than to a hair-cell type: no histological study localizes the auditory lesion in MEGDEL, and binding a cell type would assert more than the literature supports. Note that CL:0000598, suggested as "cochlear hair cell" by the deep-research report used for this entry, is in fact "pyramidal neuron" and must not be used for hair cells anywhere. Report corrections. Three claims in the source deep-research report were wrong and were not carried into this entry. It attributed the quote "Both mutations were found to lead to decreased or absent expression of SERAC1" to PMID:35943861; the sentence is in PMID:23918762, which is cited here instead. It stated that no Serac1 knockout mouse recapitulating MEGDEL had been published, while PMID:35235340 - which the same report cites - reports exactly such a mouse; the model is curated here. It gave NCIT:C15277 for Supportive Care, which is Mastectomy; the correct term NCIT:C15747 is used. It also offered HP:0002518 for Leigh-like basal ganglia lesions, which is "Abnormal periventricular white matter morphology"; HP:0002134 is used. Review round two. The GO bindings in the mechanism nodes were taken from the deep-research report's own suggestion block and three of them named a broader or different process than the claim: phosphatidylglycerol biosynthesis where the claim is acyl-chain remodeling, cholesterol metabolism where the claim is intracellular transport, and mitochondrion organization reused for an mtDNA maintenance claim so that one CURIE stood for two concepts in one file. These are now GO:0036148, GO:0032367 and GO:0032042, and cardiolipin metabolic process was likewise narrowed to GO:0035965 acyl-chain remodeling. The same skepticism that rejected the report's CL:0000598 should have been applied to its GO block in the first pass. Note that GO:0000002, proposed in review for the mtDNA node, is obsolete; GO:0032042 mitochondrial DNA metabolic process is used instead, with a separate one-carbon metabolic process binding for the serine-import half of that node. Treatment scope, and what could not be cited. Nutritional and feeding support and perioperative risk management were added because the anaesthesia case report carries quotable sentences for both, including the succinylcholine contraindication, the restriction on continuous propofol infusion and the shortened preoperative fast - the concrete agents-to-avoid guidance for this population. Rehabilitation, physiotherapy, and the dystonia and spasticity agents (trihexyphenidyl, baclofen, benzodiazepines, botulinum toxin) are deliberately still absent: the deep-research report asserts them, but no sentence in any of the 22 cached sources states them, and the report itself records that there are no MEGDEL-specific efficacy data. The same applies to valproate hepatotoxicity and aminoglycoside ototoxicity - both are real concerns in mitochondrial disease and neither is stated in a cached source here, so citing them would mean manufacturing a quote.

Review round 2: reference_title backfill, GO rebindings, diagnosis and differentials · 2026-09-01T23:39:53Z · View source

Answered the CHANGES_REQUESTED review on PR #10453 in a single push. Backfilled reference_title on all 142 evidence items; the values are derived programmatically from each reference cache's frontmatter rather than typed, after three hand-written titles failed validation in this same session - the cache is the single source of truth for a title and there is no reason to retype one. Rebound four GO terms that had been adopted verbatim from the deep-research report's suggestion block and named broader or different processes than the claims they carried: GO:0006655 phosphatidylglycerol biosynthetic process became GO:0036148 phosphatidylglycerol acyl-chain remodeling, since the entry's own description says the pool is re-proportioned rather than reduced; GO:0008203 cholesterol metabolic process became GO:0032367 intracellular cholesterol transport; GO:0007005 mitochondrion organization, which was serving as both mitochondrion organization at one node and mitochondrial DNA maintenance at another so that one CURIE denoted two concepts in one file, became GO:0032042 mitochondrial DNA metabolic process at the mtDNA node with a separate GO:0006730 one-carbon metabolic process binding for the serine-import half; and GO:0032048 cardiolipin metabolic process was narrowed to GO:0035965 cardiolipin acyl-chain remodeling. GO:0000002, suggested in review for the mtDNA node, was checked against GO and is obsolete, so it was not used. Added a diagnosis section with four records - urine organic acid analysis, brain MRI pattern recognition, fibroblast phosphatidylglycerol and filipin profiling, and SERAC1 sequencing with copy-number analysis - and a differential_diagnoses section covering primary AUH deficiency, the other secondary 3-methylglutaconic acidurias, and HTRA2 defect. Expanded the variant spectrum from four alleles to eight, adding p.Trp460*, the rs797045105 insertion, c.1404-2A>G and the juvenile complicated-HSP splice allele with its graded lipid phenotype. Added two treatments backed by cached quotes: nutritional and feeding support, and perioperative risk management carrying the succinylcholine contraindication, the continuous-propofol restriction and the shortened preoperative fast. Declined to add rehabilitation, physiotherapy, dystonia and spasticity agents, valproate hepatotoxicity and aminoglycoside ototoxicity: the research report asserts all of them but no sentence in any of the 22 cached sources states them, and the reason is recorded in the entry notes. Validation: schema, terms and references clean with 142/142 snippets verified, up from 123/123; all offline gates green.

Create: MEGDEL / MEGD(H)EL syndrome (SERAC1) · 2026-09-01T23:17:46Z · View source

Curated MEGDEL / MEGD(H)EL syndrome from an OpenScientist deep-research report plus 22 fetched PubMed abstracts. Built an 11-node pathograph from biallelic SERAC1 loss of function through absent or mislocalized protein at the ER-mitochondria contact site, impaired phosphatidylglycerol remodeling, and three parallel branches (altered cardiolipin subspecies, BMP depletion with free cholesterol accumulation, mitochondrial network fragmentation with deficient calcium transfer) converging on respiratory chain deficiency and bioenergetic failure, then tissue-selective damage to basal ganglia, cochlea and liver. Recorded the competing outer-mitochondrial-membrane / SFXN1 serine transport model as an explicit mechanistic_hypotheses group with its own pathophysiology node and an open KNOWLEDGE_GAP discussion, since the two models assign SERAC1 different subcellular locations and different candidate therapies. Curated three severity bands as subtypes rather than separate entries. Included two REFUTE evidence items where the literature genuinely contradicts a general claim (normal muscle respiratory chain and normal lactate in a confirmed patient; a confirmed patient without deafness). Added the Serac1-/- mouse and the naturally occurring canine SERAC1 disorder as animal models, the latter PARTIALLY_RECAPITULATES with a HUMAN_MODEL_MISMATCH discussion because deafness, hepatopathy and organic aciduria are undocumented in the dogs while cerebellar and nigral involvement is extra. Corrected four errors in the deep-research report, recorded in the entry notes: a quote misattributed to PMID:35943861 that is actually in PMID:23918762; a claim that no Serac1 knockout mouse existed when PMID:35235340, cited by the same report, describes one; NCIT:C15277 offered for Supportive Care, which is Mastectomy; and HP:0002518 offered for Leigh-like basal ganglia lesions, which is Abnormal periventricular white matter morphology. Did not bind a cochlear hair-cell type - the report's CL:0000598 is pyramidal neuron, and no study localizes the auditory lesion in this disease. Validation: linkml-validate, linkml-term-validator and linkml-reference-validator all pass with 123/123 snippets verified against the local reference cache; check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms (offline and online), check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading and check-environmental-evidence all clean.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 2026-09-01T22:42:27.425990

1. Disease Information

MEGDEL syndrome is a rare autosomal-recessive neurometabolic disorder defined by the constellation 3-Methylglutaconic aciduria, Deafness (sensorineural, with dystonia), Encephalopathy, and Leigh-like changes on brain MRI. When infantile hepatopathy is present (it is a cardinal feature), the disorder is termed MEGD(H)EL / MEGDHEL. It is caused by biallelic pathogenic variants in SERAC1 and is one of the "secondary" 3-methylglutaconic acidurias caused by defective mitochondrial phospholipid remodeling.

"MEGDEL syndrome is an autosomal recessive disorder, clinically characterized by 3-methylglutaconic aciduria, psychomotor delay, muscle hypotonia, sensorineural deafness, and Leigh-like lesions on brain magnetic resonance imaging" (PMID 32684373).
"This disorder is caused by biallelic mutations in serine active site-containing protein 1 (SERAC1) gene. When these patients experience hepatopathy (H)…the syndrome is referred to as MEGD(H)EL" (PMID 39592976).

Key identifiers - OMIM: #614739 (MEGDEL syndrome) — confirmed in PMID 25642805 ("MEGDEL syndrome … MIM #614739"). - Gene: SERAC1, HGNC:21061; NCBI Gene 84947; Ensembl ENSG00000122335; UniProt Q96JX3; locus 6q25.3 (homozygosity mapping candidate region 6q25.2–6q26, PMID 23918762). - Orphanet: ORPHA:352328 (MEGD(H)EL syndrome) (database identifier; confirm in current Orphanet). - MONDO: MONDO:0013875 (database identifier; confirm in current MONDO release). - MeSH: no dedicated descriptor; indexed under "3-Methylglutaconic aciduria," "Mitochondrial Diseases," "Leigh Disease." - ICD-11: 5C50.4-class (disorders of mitochondrial/energy metabolism) / ICD-10 E71.1-class (no specific code).

Synonyms / alternative names: MEGDEL syndrome; MEGD(H)EL / MEGDHEL syndrome; 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome; 3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome (PMID 23918762); SERAC1 deficiency; "dystonia–deafness syndrome" (SERAC1-related).

MONDO suggestion: MONDO:0013875 (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome).

2. Etiology

Primary cause — genetic. MEGDEL is monogenic and recessive: biallelic loss-of-function of SERAC1 is necessary and sufficient. "Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome" (PMID 22683713).

Genetic risk factors. - Causal variants: biallelic SERAC1 pathogenic variants (see §4). No susceptibility loci or GWAS signals exist (Mendelian disorder). - Consanguinity is a major risk factor — most reported families are consanguineous and homozygous (e.g., Tunisia PMID 35943861; Saudi Arabia PMID 38559521; Palestine PMID 25051967; Turkey PMID 27186703; Egypt PMID 40821445).

Environmental risk factors. None established as causal. As in other mitochondrial disorders, intercurrent catabolic stress (infection, fasting, fever, surgery/anesthesia) can precipitate metabolic decompensation/crises but does not cause the disease. No toxin, occupational, or infectious cause.

Protective factors. No genetic or environmental protective factors identified. Within the SERAC1 spectrum, residual protein function (hypomorphic missense/splice alleles) is associated with milder disease (see §4/§8), functioning as an intrinsic genetic modifier of severity rather than a protective allele per se.

Gene–environment interactions. Not formally studied. Clinically, catabolic triggers interact with the underlying energy-metabolism defect to provoke crises; avoidance of fasting and prompt treatment of infections is protective against decompensation.

3. Phenotypes

Phenotype type key: Sign/symptom, Lab abnormality, Imaging, Behavioral. Onset is predominantly neonatal–infantile; course is progressive for the neurological features. Frequencies below are qualitative (derived from aggregated case reports; large-cohort percentages are limited).

Phenotype	Type	HPO term	Onset	Frequency	Notes
3-methylglutaconic aciduria	Lab	HP:0003535	Neonatal	Universal (defining)	Persistent; with 3-methylglutaric aciduria
Sensorineural hearing loss / deafness	Sign	HP:0000407	Infancy	Very frequent (near-universal, "D")	Often severe; progressive; managed with cochlear implants
Dystonia	Sign	HP:0001332	Infancy–childhood	Very frequent ("D")	Progressive, often generalized
Spasticity / spastic tetraparesis	Sign	HP:0001257 / HP:0001285	Childhood, progressive	Frequent	Basis of the cHSP-like milder phenotype
Severe psychomotor/developmental delay & regression	Sign	HP:0011344 / HP:0002376	Infancy	Very frequent ("E")	Encephalopathy
Muscle hypotonia (truncal)	Sign	HP:0001252	Infancy	Frequent	Early feature
Leigh-like basal ganglia lesions	Imaging	HP:0002518/HP:0002134	Infancy	Very frequent ("L")	"Putaminal eye" pathognomonic
Infantile hepatopathy / acute liver failure	Sign/Lab	HP:0001410 / HP:0001392	Neonatal	Cardinal (defining "H")	May have normal transaminases, no cholestasis
Elevated lactate (blood/CSF)	Lab	HP:0002151 / HP:0003128	Neonatal	Frequent (variable)	Can be normal in some
Elevated plasma alanine	Lab	HP:0500181-class	Neonatal	Frequent	Marker of lactic acidosis
Hyperammonemia	Lab	HP:0001987	Neonatal	Subset (severe cases)	Can dominate neonatal crisis
Hypoglycemia	Lab	HP:0001943	Neonatal	Subset	During crisis
Seizures / epilepsy (incl. myoclonic)	Sign	HP:0001250 / HP:0002123	Variable	Subset
Microcephaly	Sign	HP:0000252	Infancy	Subset
Optic atrophy	Sign	HP:0000648	Childhood	Subset (expanding phenotype)
Feeding difficulties / failure to thrive / growth retardation	Sign	HP:0011968 / HP:0001508	Infancy	Frequent
Dysmorphic features	Sign	HP:0001999	Congenital	Subset
Intellectual disability	Sign	HP:0001249	Childhood	Frequent
Autistic behavior	Behavioral	HP:0000729	Variable	Subset (milder/adult)
Scoliosis	Sign	HP:0002650	Childhood	Subset

Supporting quotes: - "microcephaly, growth retardation, dysmorphic features, severe sensorineural deafness, progressive spasticity, dystonia, seizures, basal ganglia involvement. Metabolic acidosis, mild hyperammonemia and lactic acidemia were accompanied with clinical findings in newborn period" (PMID 27186703). - "sensorineural hearing loss, encephalopathy, and Leigh-like pattern on MRI (MEGDEL syndrome), as well as developmental delay and developmental regression, bilateral optic nerve atrophy, microcephaly, and myoclonic epilepsy" (PMID 24997715).

Quality-of-life impact. Severe: combined profound deafness, movement disorder (dystonia/spasticity), intellectual disability, epilepsy and feeding problems produce major dependence for daily functioning; most severely affected children are non-ambulatory and non-verbal with high care needs. Formal QoL instruments (EQ-5D/SF-36/PROMIS) have not been reported for this ultra-rare disease.

4. Genetic / Molecular Information

Causal gene: SERAC1 (HGNC:21061; OMIM 614725; gene product Q96JX3), chromosome 6q25.3. It is the only* gene associated with MEGDEL. "Homozygosity mapping identified a candidate locus on 6q25.2-6q26" (PMID 23918762).

Pathogenic variant spectrum (germline; predominantly loss-of-function). Reported biallelic variants include: - Nonsense: c.1379G>A (p.Trp460*) homozygous, Tunisia (PMID 35943861); c.442C>T (p.Arg148*) (PMID 24997715). - Frameshift: c.1018delT homozygous, Palestine (PMID 25051967); c.438delC (p.Thr147Argfs*22) (PMID 24997715). - Splice-site: novel splice variant causing juvenile cHSP in a large family (PMID 28916646). - Insertion: rs797045105 (c...CATG insertion), homozygous (PMID 33613893). - Structural / exonic deletion: deletion of ≥ exons 2–4 (pathogenic) (PMID 35781780); a homozygous deletion variant (PMID 38559521). - Missense (often milder/hypomorphic): c.1495A>G (p.Met499Val) in complicated HSP (PMID 35223715); c.1601A>T (p.His534Leu) likely pathogenic (PMID 35781780). Note: p.Phe471 (rs112780453) is considered benign (PMID 37711114).

"Whole exome sequencing revealed two loss-of-function mutations in SERAC1 in trans: c.438delC (p.T147Rfs*22) and c.442C>T (p.R148X)" (PMID 24997715).

Variant classification (ACMG/AMP): most reported truncating/frameshift/large-deletion variants are Pathogenic; several missense are Likely pathogenic or VUS; rs112780453 (p.F471) benign. Functional consequence: loss of function — "Both mutations were found to lead to decreased or absent expression of SERAC1" (PMID 35943861); a C-terminal truncation mislocalizes the protein away from mitochondria (PMID 34751152).

Allele frequency: individual pathogenic alleles are extremely rare in gnomAD (mostly absent or singleton); no common founder allele established, though recurrent homozygous alleles occur in specific consanguineous pedigrees. Carrier frequency is not precisely established (ultra-rare).

Somatic vs germline: exclusively germline. Modifier genes: none defined; the principal modifier of severity is the SERAC1 genotype itself (LoF vs hypomorphic). Epigenetic information: none reported. Chromosomal abnormalities: none characteristic (large intragenic deletions detectable by CMA/CNV analysis occur, e.g., exon 2–4 deletion).

Gene/GO annotations: SERAC1 — GO:0006655 (phosphatidylglycerol biosynthetic process) / GO:0032048 (cardiolipin metabolic process); GO:0044233 (mitochondria-associated ER membrane); GO:0030299 (intestinal cholesterol absorption)/cholesterol transport; molecular function serine hydrolase / phospholipid remodeling (transacylase) activity.

5. Environmental Information

Environmental/toxic factors: none causal.
Lifestyle factors: not applicable (congenital genetic disease).
Infectious agents: none causal. Infections act only as non-specific catabolic triggers of metabolic decompensation; neonates may present with a sepsis-like metabolic crisis that mimics infection.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic SERAC1 loss-of-function variants → absent or non-functional SERAC1 protein (demonstrated: no protein detected in patient fibroblasts, PMID 34751152; decreased/absent expression, PMID 35943861).
Loss of SERAC1 at the mitochondria-associated ER membrane (MAM)/ER–mitochondria contact site → impaired phosphatidylglycerol (PG) remodeling (elevated PG-34:1, decreased PG-36:1) (demonstrated in vitro, PMID 22683713).
Altered PG pool → abnormal cardiolipin subspecies composition → impaired assembly/stability and function of OXPHOS complexes (branch A; inferred from cardiolipin's role, with measured complex I/III/IV reduction in liver mitochondria, PMID 34751152).
In parallel (branch B): reduced bis(monoacylglycerol)phosphate (BMP) → accumulation of free/unesterified cholesterol and defective intracellular cholesterol trafficking (demonstrated by abnormal filipin staining, PMID 22683713; PMID 34751152).
In parallel (branch C): disrupted ER–mitochondria interplay → fragmented mitochondrial network + abnormal (circular) cristae and deficient Ca²⁺ transfer from cytoplasm to mitochondria (demonstrated, PMID 34751152; ultrastructure PMID 35781780).
Convergence → mitochondrial energy (OXPHOS) failure / bioenergetic insufficiency → secondary 3-methylglutaconic aciduria and lactic acidosis (biomarkers of mitochondrial dysfunction).
Bioenergetic failure in high-energy-demand tissues → selective vulnerability: basal-ganglia (putamen>caudate>pallidus) neurodegeneration → dystonia/spasticity/Leigh-like MRI; cochlear/auditory neurons → sensorineural deafness; hepatocytes → infantile hepatopathy/liver failure; brain broadly → encephalopathy/developmental delay.
(Additional/inferred) SERAC1 participates in a mitochondrial serine transporter complex required for mtDNA maintenance, providing a further route to mitochondrial dysfunction (PMID 35235340; some patients show hepatic mtDNA depletion, PMID 23918762).

Upstream nodes = SERAC1 LoF and MAM phospholipid-remodeling defect; downstream = cardiolipin/OXPHOS failure, cholesterol mistrafficking, Ca²⁺ dysregulation, and tissue-specific neuro-/hepatodegeneration.

Detail by category

Molecular pathways / biochemistry: phosphatidylglycerol → cardiolipin remodeling pathway (glycerophospholipid metabolism, KEGG hsa00564); intracellular cholesterol transport (LDL/lysosomal → ER). Secondary block manifests as leucine-independent 3-MGA-uria (distinct from primary AUH defect).
Cellular processes: disrupted ER–mitochondria contact, mitochondrial fission/fusion imbalance (network fragmentation), impaired mitochondrial Ca²⁺ uptake, and downstream apoptosis/neurodegeneration; bioenergetic failure.
Protein dysfunction: loss of function via truncation/degradation or mislocalization ("the mutant protein with a 45-amino acid C-terminal truncation was distributed throughout the cell, whereas wild-type SERAC1 partially colocalized with the mitochondrial marker MT-CO1," PMID 34751152).
Metabolic changes: impaired oxidative phosphorylation (complexes I/III/IV ↓), lactic acidosis, elevated alanine, 3-methylglutaconic/3-methylglutaric aciduria; altered phospholipid/cholesterol homeostasis.
Lipidomics: ↑PG-34:1, ↓PG-36:1 (increased PG34:1/PG36:1 ratio), altered cardiolipin subspecies, ↓BMP, ↑free cholesterol.
Immune involvement: none primary.
Tissue-damage mechanisms: energy-deprivation neurodegeneration (Leigh-like), mitochondrial hepatopathy; oxidative/bioenergetic stress inferred.
Molecular profiling: dedicated transcriptomic/proteomic/GEO datasets are limited; mechanistic data derive from patient fibroblasts, COS-1 transfection, and one functional cell model (PMID 35235340).

GO term suggestions: GO:0044233 (mitochondria-associated ER membrane), GO:0032048 (cardiolipin metabolic process), GO:0006655 (phosphatidylglycerol biosynthesis), GO:0006874 (cellular Ca²⁺ homeostasis), GO:0007005 (mitochondrion organization), GO:0006119 (oxidative phosphorylation), GO:0008203 (cholesterol metabolic process). Cell types (CL): CL:0000540 (neuron; medium spiny/striatal neurons), CL:0000598 (cochlear hair cell)/auditory neurons, CL:0000182 (hepatocyte).

7. Anatomical Structures Affected

Organ level (primary): brain — especially basal ganglia (putamen UBERON:0001874 > caudate nucleus UBERON:0001873 > globus pallidus UBERON:0002477); inner ear / cochlea (UBERON:0001844) (auditory system); liver (UBERON:0002107). Secondary/other: eye/optic nerve (UBERON:0000941/UBERON:0000941), skeletal muscle, peripheral nerves, heart, endocrine organs, skeleton (scoliosis) — reflecting the broadening multisystem spectrum (PMID 32684373).

Body systems: nervous (central — extrapyramidal/basal ganglia, and sensory — auditory), digestive/hepatobiliary, and (variably) ophthalmologic, musculoskeletal, cardiac, endocrine.

Tissue/cell level: nervous tissue (striatal neurons), sensory epithelium/neurons of the cochlea, hepatic parenchyma (hepatocytes with granular cytoplasm, fine lipid droplets — PMID 35781780).

Subcellular level: mitochondrion (GO:0005739), mitochondrial inner membrane/cristae (GO:0005743), ER membrane (GO:0005789), and the mitochondria-associated ER membrane (GO:0044233); abnormal circular mitochondrial cristae and fragmented mitochondrial network.

Localization/lateralization: basal-ganglia lesions and hearing loss are bilateral and symmetric (PMID 35223715: "symmetric flake abnormal signal shadow in the bilateral basal ganglia").

8. Temporal Development

Onset: typically neonatal to early-infantile; often an acute neonatal metabolic/hepatic crisis (sepsis-like). Milder hypomorphic genotypes present later (juvenile complicated HSP; rarely adult-onset dystonia).
Two-phase natural history (classic/severe):
Neonatal decompensation — lactic acidosis, hepatopathy ± hyperammonemia/hypoglycemia (can be lethal; PMID 38445077, PMID 34751152).
Chronic progressive neurodegeneration — infantile sensorineural deafness, truncal hypotonia, severe psychomotor delay/regression, then progressive spasticity and dystonia with basal-ganglia degeneration (PMID 27186703).
MRI staging (5 stages): stage 1 pallidal T2 change → stage 2 putaminal/caudate swelling with spared dorsal-putaminal "eye" → later progressive putaminal involvement (PMID 25642805).
Progression rate/course: chronic, progressive; variable by genotype. Duration: lifelong/chronic; often shortened by early death in severe cases.
Remission: no true remission; however, some milder patients stabilize or partially improve ("her verbal and motor development has progressively improved…exceeding clinical expectations," PMID 35781780).
Critical period / intervention window: the neonatal metabolic crisis is the key window where aggressive metabolic/supportive management can be life-saving.

HPO onset modifiers: HP:0003623 (Neonatal onset), HP:0011463 (Childhood onset), HP:0003577 (Congenital onset for some features), HP:0003676 (Progressive).

9. Inheritance and Population

Inheritance: autosomal recessive (AR). "MEGDEL syndrome is an autosomal recessive disorder" (PMID 32684373).
Penetrance: essentially complete for biallelic LoF; expressivity variable (severity graded by genotype/residual function).
Epidemiology: ultra-rare — "about 100 cases reported worldwide" (PMID 35943861); "at least 102 patients have been reported" since 2006 (PMID 32684373). Precise prevalence/incidence are not established (Orphanet: prevalence <1/1,000,000; unknown).
Consanguinity / founder effects: strong role of consanguinity; recurrent homozygous variants in individual pedigrees; no single global founder allele established. Over-representation of reported families from the Middle East/North Africa (Tunisia, Saudi Arabia, Palestine, Turkey, Egypt, Iran) plus reports from Europe, China, and elsewhere.
Carrier frequency: not precisely defined; individual alleles are very rare in gnomAD.
Sex ratio: ~1:1 (AR; no sex predilection reported). Age distribution: predominantly infants/children; milder cases into adolescence–adulthood.
Genetic anticipation / germline mosaicism: not applicable / not reported.

10. Diagnostics

Laboratory (biochemical): - Urine organic acids (GC/MS): persistently elevated 3-methylglutaconic acid and 3-methylglutaric acid (defining) — LOINC organic acids panel. - Plasma: elevated lactate and alanine (variable); crisis: hyperammonemia, hypoglycemia, metabolic acidosis. "elevated urinary 3-metilglutaconic and 3-metilglutaric acids, high lactate and alanine in serum" (PMID 37711114). Note lactate/OXPHOS can be normal in some (PMID 25051967). - Disease-specific cell biomarkers (fibroblasts): increased PG34:1/PG36:1 ratio; abnormal filipin staining (free cholesterol) (PMID 22683713, PMID 28916646).

Imaging: brain MRI is central — staged basal-ganglia/putaminal pattern with the pathognomonic dorsal-putaminal "eye" enabling pattern-recognition diagnosis (PMID 25642805); generalized atrophy in older/advanced disease.

Biopsy/pathology: liver — hepatocytes with granular cytoplasm and fine intracytoplasmic lipid droplets; ultrastructure with abnormal circular mitochondrial cristae (PMID 35781780). Muscle respiratory-chain findings variable.

Genetic testing (confirmatory): identify biallelic pathogenic SERAC1 variants. Recommended approach: WES or WGS (most reported diagnoses), gene panels (mitochondrial/3-MGA-uria/leukodystrophy panels including SERAC1), single-gene sequencing when phenotype is classic, and CMA/CNV/deletion analysis to detect intragenic deletions (e.g., exon 2–4 deletion). mtDNA testing may show secondary depletion in liver in some (PMID 23918762). "Diagnosis is confirmed when biallelic pathogenic variants in SERAC1 gene are found" (PMID 37711114).

Clinical criteria / differential diagnosis: no formal consensus criteria; diagnosis rests on the biochemical + MRI + genetic triad. Differential: other Leigh/Leigh-like syndromes and primary mitochondrial disorders; other 3-methylglutaconic acidurias — primary (AUH/3-methylglutaconyl-CoA hydratase deficiency), Barth syndrome (TAZ), TMEM70, ATAD3A, OPA3 (Costeff), DNAJC19 (DCMA), CLPB, and HTRA2 defect (neonatal movement disorder + epilepsy + 3-MGA-uria, PMID 30114719); neonatal acute liver failure/urea cycle defects (hyperammonemia); dystonia–deafness syndromes; complicated hereditary spastic paraplegias (milder SERAC1 phenotype). Distinguishing feature: putaminal "eye" MRI sign + PG34:1/PG36:1 + SERAC1 genetics.

Screening: not on standard newborn-screening panels (3-MGA is not a routine NBS analyte). Cascade/carrier testing of relatives once the familial variants are known; prenatal/preimplantation genetic testing feasible for known biallelic variants.

11. Outcome / Prognosis

Survival/mortality: generally poor with early death in classic severe disease; neonatal multiorgan failure can be lethal within days (PMID 34751152, PMID 38445077). "Treatment is supportive, and the outcome is usually poor with early death, except for the juvenile-onset type" (PMID 32684373). No formal 5-/10-year survival statistics exist.
Morbidity/disability: severe, lifelong — deafness, dystonia/spasticity, intellectual disability, epilepsy, feeding difficulty; most severely affected are non-ambulatory/non-verbal.
Complications: recurrent metabolic crises, aspiration/respiratory infections, liver failure, feeding failure, status dystonicus, epilepsy.
Recovery potential: limited in severe cases; milder (hypomorphic) patients may stabilize or improve (PMID 35781780; PMID 28916646).
Prognostic factors: genotype (complete LoF → severe/early death; hypomorphic missense/splice → milder, later-onset, better survival), age/severity of neonatal crisis, degree of hepatic and neurological involvement. Biochemical/lipid markers (3-MGA, PG34:1/PG36:1) confirm diagnosis but are not validated quantitative prognostic biomarkers.

12. Treatment

No disease-modifying or curative therapy exists; management is supportive, symptomatic, and multidisciplinary (NCIT:C15277 Supportive Care).

Acute metabolic crisis (neonatal): treat as suspected inborn error of metabolism — stop protein intake, promote anabolism with IV glucose, correct acidosis; continuous hemodialysis/CRRT for severe hyperammonemia (PMID 38445077). (NCIT: Hemodialysis; Intravenous glucose.)
Pharmacotherapy (symptomatic): anticonvulsants for seizures; agents for dystonia/spasticity (e.g., trihexyphenidyl, baclofen, benzodiazepines, botulinum toxin) — no MEGDEL-specific efficacy data; "mitochondrial cocktail" supplements (coenzyme Q10, riboflavin, thiamine, L-carnitine) are commonly used empirically without proven benefit.
Sensorineural deafness: hearing amplification and cochlear implantation (PMID 39592976). (NCIT: Cochlear Implantation.)
Nutrition/GI: feeding support, gastrostomy for failure to thrive/dysphagia.
Rehabilitation: physiotherapy, occupational and speech/communication therapy; orthopedic management of scoliosis/contractures.
Anaesthetic considerations (mitochondrial disease): avoid triggering agents; dexmedetomidine (± ketamine) used as a non-triggering approach for sedation/anesthesia (PMID 39592976). Caution with prolonged fasting, propofol infusion, and mitochondrial-toxic drugs.
Advanced/experimental therapeutics: no approved gene, cell, RNA, or targeted therapies; no MEGDEL-specific clinical trials (no NCT identifiers). Gene-replacement is a theoretical future avenue (recessive LoF, defined single gene).
Pharmacogenomics: not applicable beyond general mitochondrial-drug avoidance (e.g., valproate hepatotoxicity risk, aminoglycoside ototoxicity caution).

Treatment strategy: genotype/phenotype-guided supportive algorithm — neonatal metabolic stabilization → long-term multidisciplinary care (neurology, metabolic, audiology/ENT, hepatology, rehabilitation, palliative). Personalized medicine currently limited to genetic counseling and prognostication by genotype.

13. Prevention

Primary prevention: not possible for a congenital genetic disease; risk reduction via genetic counseling in consanguineous/carrier families and reproductive options (carrier testing, prenatal diagnosis, preimplantation genetic testing for known familial variants).
Secondary prevention: early recognition of the neonatal metabolic/hepatic crisis and prompt metabolic management; early diagnosis via MRI pattern + organic acids + SERAC1 testing to enable supportive interventions and family counseling.
Tertiary prevention: prevent complications — avoid fasting/mitochondrial-toxic drugs, treat infections promptly, manage seizures/dystonia, cochlear implantation for deafness, nutritional support, physiotherapy to limit contractures.
Immunization / public-health / environmental interventions: routine childhood vaccination to prevent infection-triggered crises; no vector/sanitation measures applicable.
Counseling: AR recurrence risk 25% for future offspring of carrier couples; cascade testing of relatives (NSGC/ACMG guidance).
Screening: not part of population newborn screening; targeted testing in at-risk families.

14. Other Species / Natural Disease

Naturally occurring animal disease: Canine Multiple System Degeneration (CMSD) — an early-onset, progressive, autosomal-recessive movement disorder of Kerry Blue Terriers and Chinese Crested dogs with degeneration of the cerebellum, caudate nucleus, and substantia nigra, caused by a homozygous nonsense variant in the SERAC1 ortholog (canine chromosome 1) (PMID 39596578).
"Canine multiple system degeneration (CMSD) is an early onset, progressive movement disorder affecting Kerry Blue Terriers and Chinese Crested dogs. The associated pathologic lesions include degeneration of the cerebellum, caudate nucleus, and substantia nigra" (PMID 39596578).
Taxonomy: Canis lupus familiaris (NCBI:txid9615). Breeds (VBO): Kerry Blue Terrier, Chinese Crested.
Orthologous gene: canine SERAC1 (NCBI Gene ortholog). Human SERAC1 NCBI Gene 84947.
Comparative biology / conservation: the shared caudate (basal-ganglia) degeneration and movement-disorder phenotype from SERAC1 loss demonstrates evolutionary conservation of the disease mechanism; recognized in OMIA.
Veterinary relevance: important heritable neurodegenerative disease in these breeds; carrier testing relevant to breeding programs.
Zoonotic potential: none (genetic disease).

15. Model Organisms

In-vitro / cellular models (principal): patient-derived fibroblasts (lipidomics, filipin, mitochondrial network/Ca²⁺ studies; PMID 22683713, PMID 34751152); lentiviral WT-SERAC1 complementation rescuing the PG34:1/PG36:1 ratio (PMID 22683713); COS-1 transfection for localization of mutant vs WT protein (PMID 34751152); an engineered cellular model probing SERAC1 in a mitochondrial serine-transporter complex / mtDNA maintenance (PMID 35235340).
Naturally occurring mammalian model: canine CMSD (Kerry Blue Terrier, Chinese Crested) — SERAC1-ortholog nonsense variant (PMID 39596578); a spontaneous large-animal model of SERAC1 neurodegeneration.
Genetically engineered rodent (mouse) models: no well-characterized published Serac1 knockout mouse recapitulating MEGDEL was identified in this review (a notable gap; consult MGI/IMPC for current alleles).
Phenotype recapitulation: cellular models faithfully reproduce the biochemical/lipid and mitochondrial-structural phenotype; the canine model reproduces the basal-ganglia movement-disorder/neurodegeneration. Limitations: cellular models cannot capture organ-level (deafness, hepatopathy) or developmental features; the canine model's full biochemical concordance (3-MGA-uria, deafness, hepatopathy) is not fully documented.
Applications: studying phospholipid remodeling, ER–mitochondria contact biology, cholesterol trafficking, and testing candidate therapeutics.
Resources: Cellosaurus (patient fibroblast lines), OMIA (canine CMSD), MGI/IMPC (for any mouse alleles), Alliance of Genome Resources.

Supported vs. Refuted Hypotheses

Supported (evidence-backed): - SERAC1 biallelic LoF is the cause of MEGDEL/MEGDHEL (PMID 22683713). - Core mechanism = defective phosphatidylglycerol→cardiolipin remodeling at the MAM, with cholesterol-trafficking defect and secondary OXPHOS failure (PMID 22683713, PMID 34751152). - MEGDEL is a secondary 3-MGA-uria (phospholipid remodeling), grouped with Barth syndrome (PMID 23296368). - Pathognomonic "putaminal eye" MRI sign; staged basal-ganglia disease (PMID 25642805). - Infantile hepatopathy is a cardinal feature (MEGDHEL) (PMID 23918762). - Genotype–phenotype gradient: LoF → severe infantile MEGDHEL; hypomorphic → juvenile cHSP/adult dystonia (PMID 28916646, PMID 35223715, PMID 37711114). - Naturally occurring canine SERAC1 model (PMID 39596578).

Refuted / not supported: - MEGDEL is not a primary defect of leucine catabolism (that is AUH/3-MGA type I) — the 3-MGA-uria here is secondary (PMID 23296368). - 3-MGA-uria/lactate elevation is not obligate in muscle OXPHOS assays — respiratory-chain activity can be normal, so a negative muscle biopsy does not exclude the diagnosis (PMID 25051967). - No environmental/infectious primary etiology; catabolic stress is a trigger, not a cause.

Limitations and Future Directions

No large registry/natural-history cohort with quantitative phenotype frequencies was available; percentages here are qualitative from aggregated case reports (~100 patients).
Precise prevalence/incidence, carrier frequency, and survival statistics are undefined.
A robust Serac1 mouse model and disease-modifying therapy (e.g., gene replacement, lipid-targeted therapy) are key gaps.
Standardized diagnostic criteria and validated prognostic/QoL measures are lacking.

Key References (PMIDs)

22683713 (gene discovery/mechanism); 23296368 (3-MGA classification); 25642805 (MRI "eye", OMIM #614739); 23918762 (MEGDHEL/hepatopathy); 34751152 (ER–mito contact, Ca²⁺, OXPHOS); 35235340 (mtDNA maintenance); 35781780 (liver histology); 38445077 (neonatal ALF/hyperammonemia); 27186703, 24997715, 25051967 (phenotype/variants); 35943861, 33613893, 38559521 (variants/consanguinity); 28916646, 35223715, 37711114 (milder/cHSP spectrum); 39592976 (anesthesia/cochlear implant); 39596578 (canine model); 30114719 (HTRA2 differential); 32684373 (review).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	22
Resolved	22
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	14
Quoted claims found in source	12
Quoted claims not found in source	2
References weighed for topical relevance	22
On topic	21
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:39592976 (abstract only): "This disorder is caused by biallelic mutations in serine active site-containing protein 1 (SERAC1) gene. When these patients experience hepatopathy (H)…the syndrome is referred to as MEGD(H)EL"
closest text in source: "This disorder is caused by biallelic mutations in serine active site-containing protein 1 (SERAC1) gene"
PMID:35943861 (abstract only): "Both mutations were found to lead to decreased or absent expression of SERAC1"
closest text in source: "Mutations in SERAC1 gene encoding a serine active site containing 1 protein were described in patients affected by this syndrome"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	55
Resolved	53
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	28
Terms named correctly	10
Terms named as a different term	13
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0003535 (1 mention) - the report calls it "Lab"; HP calls it 3-Methylglutaconic aciduria
HP:0000407 (1 mention) - the report calls it "Sign"; HP calls it Sensorineural hearing impairment
HP:0001332 (1 mention) - the report calls it "Sign"; HP calls it Dystonia
HP:0001252 (1 mention) - the report calls it "Sign"; HP calls it Hypotonia
HP:0001987 (1 mention) - the report calls it "Lab"; HP calls it Hyperammonemia
HP:0001943 (1 mention) - the report calls it "Lab"; HP calls it Hypoglycemia
HP:0000252 (1 mention) - the report calls it "Sign"; HP calls it Microcephaly
HP:0000648 (1 mention) - the report calls it "Sign"; HP calls it Optic atrophy
HP:0001999 (1 mention) - the report calls it "Sign"; HP calls it Abnormal facial shape
HP:0001249 (1 mention) - the report calls it "Sign"; HP calls it Intellectual disability
HP:0002650 (1 mention) - the report calls it "Sign"; HP calls it Scoliosis
CL:0000540 (1 mention) - the report calls it "neuron; medium spiny/striatal neurons"; CL calls it neuron
CL:0000598 (1 mention) - the report calls it "cochlear hair cell"; CL calls it pyramidal neuron

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0000729 (1 mention) - the report calls it "Behavioral"; HP calls it Autistic behavior
GO:0006655 (2 mentions) - the report calls it "phosphatidylglycerol biosynthetic process", "phosphatidylglycerol biosynthesis"; GO calls it phosphatidylglycerol biosynthetic process, and lists "phosphatidylglycerol biosynthesis" among its other names
GO:0044233 (3 mentions) - the report calls it "mitochondria-associated ER membrane"; GO calls it mitochondria-associated endoplasmic reticulum membrane contact site, and lists "mitochondria-associated ER membrane" among its other names
GO:0006874 (1 mention) - the report calls it "cellular Ca²⁺ homeostasis"; GO calls it intracellular calcium ion homeostasis, and lists "cellular calcium ion homeostasis" among its other names
HP:0003577 (1 mention) - the report calls it "Congenital onset for some features"; HP calls it Congenital onset

Terms named inconsistently

The report gives these identifiers more than one name of its own:

GO:0006655 - called "phosphatidylglycerol biosynthetic process", "phosphatidylglycerol biosynthesis"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver