3-methylglutaconic_Aciduria_With_Deafness_Encephalopathy_And_Leigh-like_Syndrome

Mendelian MONDO:0013875 Pathograph 40 Show in embeddings browser

MEGDEL syndrome, also termed MEGD(H)EL when hepatopathy is included, is an autosomal recessive neurometabolic disorder caused by biallelic pathogenic SERAC1 variants. Classic disease combines infantile feeding and developmental difficulties, hypotonia, progressive dystonia and spasticity, sensorineural hearing loss, secondary 3-methylglutaconic aciduria, and characteristic basal-ganglia MRI abnormalities. Neonatal hypoglycemia and liver dysfunction are frequent but variable. SERAC1 deficiency disrupts phosphatidylglycerol remodeling and is associated with altered cardiolipin composition, cholesterol trafficking, mitochondrial structure, and calcium handling. Experimental work also implicates SFXN1-dependent serine transport, one-carbon metabolism, and mitochondrial DNA maintenance. The spectrum extends to juvenile complicated spastic paraplegia and adult-onset dystonia; variant type alone does not reliably predict severity. Treatment is supportive and individualized.

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Inheritance

Autosomal recessive HP:0000007

Biallelic pathogenic SERAC1 variants cause autosomal recessive disease. Heterozygous carriers are generally asymptomatic; parental testing helps establish phase and recurrence risk.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"SERAC1 deficiency is inherited in an autosomal recessive manner."

GeneReviews states the inheritance pattern.

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.

◆

Subtypes

Severe infantile MEGD(H)EL

The classic presentation may begin with neonatal hypoglycemia, sepsis-like illness or liver dysfunction, followed by infantile hypotonia and developmental delay, and progressive dystonia, spasticity and hearing loss. Severe disability is common, but neonatal involvement and early death are not obligatory.

Show evidence (1 reference)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"MEGD(H)EL syndrome is characterized by neonatal hypoglycemia, a sepsis-like clinical picture for which no infectious agent can be found, feeding problems, poor weight gain, muscular hypotonia, developmental delay, and liver involvement."

Summarizes the classic infantile presentation.

Juvenile-onset complicated hereditary spastic paraplegia

A later-onset presentation with complicated spastic paraplegia and variable cognitive or other neurological involvement. In one large family, three affected siblings remained independently ambulant into adolescence or adulthood; a tested fibroblast line had a milder PG abnormality despite loss of full-length SERAC1. Residual activity was proposed, not demonstrated.

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.

Juvenile- or adult-onset generalized dystonia

Later-onset generalized dystonia, sometimes with parkinsonian or pyramidal signs, occurs at the milder end of the spectrum. Cognitive or developmental difficulties may precede the movement disorder; individual reports vary in the strength of their molecular confirmation.

Show evidence (2 references)

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.

PMID:29686941 SUPPORT Human clinical

"At 24 years old, he had a few episodes of subacute encephalopathy triggered by fever and then developed cervical dystonia. Dystonia gradually worsened to become generalized dystonia."

A longitudinal adult case broadens the age-at-onset spectrum.

◈

Mechanistic Hypotheses

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

serine_transport_mtdna EMERGING

Evidence balance 3 support

SERAC1-dependent SFXN1 serine transport supports mitochondrial one-carbon metabolism, nucleotide supply and mtDNA maintenance in experimental systems. This pathway could coexist with lipid remodeling. Its relative importance in human disease and its relationship to tissue-specific lipid and calcium abnormalities remain unresolved. Nucleoside/nucleotide rescue is preclinical.

Pathograph links

Reduced SERAC1 Function -> Impaired Mitochondrial Serine Import DIRECT Experimental SERAC1 loss impairs SFXN1-mediated transport.

Impaired Mitochondrial Serine Import -> Impaired One-Carbon Metabolism INDIRECT UNKNOWN INTERMEDIATES Reduced mitochondrial serine supply impairs the one-carbon pathway in the experimental model.

Impaired One-Carbon Metabolism -> Nucleotide Pool Imbalance INDIRECT UNKNOWN INTERMEDIATES The study links impaired one-carbon metabolism with insufficient nucleotide supply.

Nucleotide Pool Imbalance -> Mitochondrial DNA Depletion DIRECT Insufficient nucleotide supply limits maintenance of mtDNA in the experimental systems.

Mitochondrial DNA Depletion -> Mitochondrial Bioenergetic Impairment INDIRECT UNKNOWN INTERMEDIATES Rescue of mtDNA and mitochondrial function supports a contribution of nucleotide-limited mtDNA maintenance; intermediate respiratory-subunit effects are not resolved by the abstract.

Show evidence (3 references)

PMID:35235340 SUPPORT In vitro / ex vivo

"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"

The experimental study identifies SERAC1-dependent SFXN1 transport.

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 in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides"

This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.

PMID:35235340 SUPPORT Model organism

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

Preclinical rescue supports nucleotide limitation in the experimental systems.

Discussions and Knowledge Gaps

How do SERAC1-dependent lipid remodeling and serine transport contribute to human disease?

KNOWLEDGE GAP OPEN serac1_pathway_relationship

Attached to

pathophysiology#Impaired Phosphatidylglycerol Remodeling mechanistic_hypotheses#serine_transport_mtdna

Patient fibroblast lipid rescue and experimental serine/nucleotide rescue support complementary roles. ER-mitochondria contact-site and outer-membrane localization are not mutually exclusive. Their relationship and tissue-specific contributions remain uncertain; normal clinical mtDNA or respiratory assays do not exclude disease.

Show evidence (3 references)

PMID:22683713 SUPPORT In vitro / ex vivo

"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"

Wild-type complementation partially rescues the patient-cell lipid ratio.

PMID:35235340 SUPPORT In vitro / ex vivo

"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"

The experimental study identifies SERAC1-dependent SFXN1 transport.

PMID:35235340 SUPPORT Model organism

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

Preclinical rescue supports nucleotide limitation in the experimental systems.

Which auditory, hepatic and biochemical features are reproduced in SERAC1-associated canine degeneration?

HUMAN MODEL MISMATCH OPEN canine_model_organ_coverage

Attached to

phenotypes#Sensorineural hearing loss phenotypes#Infantile hepatopathy phenotypes#3-Methylglutaconic aciduria

The canine paper establishes a movement disorder and neuropathological overlap. Hearing and cognition were unassessed; liver and organic-acid measures were not reported. Direct phenotyping is needed before using this model for those disease manifestations. Normal findings would limit those particular model outcomes, not refute human disease mechanisms.

Show evidence (1 reference)

PMID:39596578 SUPPORT Model organism

"Although cognitive function and hearing loss were not assessed in the affected dogs, the canine disorder appears to closely resemble early-onset MEGDHEL syndrome."

The authors explicitly identify unassessed model features.

⚙

Pathophysiology

Reduced SERAC1 Function

Biallelic pathogenic variants reduce SERAC1 function. Some tested truncating alleles lower protein expression, but absence of protein or mislocalization is not established for every allele.

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

SERAC1 hgnc:21061

SFXN1 serine transporter activation GO:0141109 ↓ DECREASED

Downstream

Impaired Phosphatidylglycerol Remodeling SERAC1 dysfunction alters cellular PG remodeling, supported by complementation.

Bis(monoacylglycerol)phosphate Depletion Reduced BMP is observed in SERAC1-deficient cells; the intervening remodeling steps remain incompletely defined.

Mitochondrial Network Fragmentation Patient cells associate loss of SERAC1 with network fragmentation; mediation by individual lipid changes has not been isolated.

Abnormal Mitochondrial Cristae Patient cells and liver tissue show abnormal cristae.

Deficient Mitochondrial Calcium Handling Patient fibroblasts show impaired cytoplasm-to-mitochondria calcium buffering.

Impaired Mitochondrial Serine Import Experimental SERAC1 loss impairs SFXN1-mediated transport.

Show evidence (3 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 In vitro / ex vivo

"Both mutations were found to lead to decreased or absent expression of SERAC1"

Two hepatopathy-associated alleles were linked to reduced protein expression.

PMID:35235340 SUPPORT In vitro / ex vivo

"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"

The single experimental study behind the emerging serine_transport_mtdna hypothesis identifies SERAC1 as an activator required for SFXN1-mediated serine transport.

Impaired Phosphatidylglycerol Remodeling

Patient fibroblasts show an increased PG-34:1/PG-36:1 ratio, partly corrected by wild-type SERAC1. These data establish involvement in remodeling; direct LPG acyltransferase activity of purified SERAC1 has not been established.

phosphatidylglycerol acyl-chain remodeling GO:0036148 ↓ DECREASED

Experimental models

MEGDEL patient dermal fibroblasts PRIMARY CELL CULTURE Patient-cell PG abnormalities and their partial normalization by wild-type SERAC1 directly connect SERAC1 dysfunction to lipid remodeling.

Animal models

Lpgat1 knockout mouse Mouse partially recapitulates LPGAT1-deficient cells and mice connect PG remodeling and mitochondrial PG transport, with a PG34:1/PG36:1 shift resembling SERAC1 deficiency.

Downstream

Altered Cardiolipin Subspecies Composition Altered PG substrate composition is linked to altered cardiolipin species.

Show evidence (2 references)

PMID:22683713 SUPPORT In vitro / ex vivo

Wild-type complementation partially rescues the patient-cell lipid ratio.

PMID:37917582 SUPPORT BACKGROUND Other

"no LPG acyltransferase activity has been identified from SERAC1 to date"

The 2023 LPGAT1 study distinguishes remodeling involvement from demonstrated catalytic activity.

Altered Cardiolipin Subspecies Composition

Cardiolipin acyl-species composition changes in SERAC1-deficient fibroblasts. This observation does not establish a decrease in the overall rate of cardiolipin remodeling.

mitochondrial inner membrane GO:0005743

Downstream

Respiratory Chain Complex Deficiency Altered cardiolipin is a proposed contributor to respiratory dysfunction; the disease-specific intervening assembly steps are unresolved.

Show evidence (1 reference)

PMID:22683713 SUPPORT In vitro / ex vivo

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

The discovery study links altered PG species with cardiolipin composition.

Bis(monoacylglycerol)phosphate Depletion

Reduced BMP accompanies SERAC1 deficiency in patient fibroblasts.

Downstream

Free Cholesterol Accumulation The discovery study links low BMP to abnormal intracellular cholesterol handling.

Show evidence (1 reference)

PMID:22683713 SUPPORT In vitro / ex vivo

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

Patient fibroblasts showed reduced BMP and cholesterol accumulation.

Free Cholesterol Accumulation

Unesterified cholesterol can accumulate or be distributed abnormally in patient fibroblasts. Filipin staining is variable and can be normal in both mild and classic presentations.

intracellular cholesterol transport GO:0032367 ↓ DECREASED

Show evidence (1 reference)

PMID:22683713 SUPPORT In vitro / ex vivo

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

Patient fibroblasts showed reduced BMP and cholesterol accumulation.

Mitochondrial Network Fragmentation

A severely fragmented mitochondrial network was observed in fibroblasts from a lethal neonatal case; this is a cellular finding rather than proof of a universal intermediate.

mitochondrion organization GO:0007005

Experimental models

MEGDEL patient dermal fibroblasts PRIMARY CELL CULTURE A severe neonatal patient line shows a severely fragmented mitochondrial network and altered cristae morphology as distinct structural findings.

Show evidence (1 reference)

PMID:34751152 SUPPORT In vitro / ex vivo

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

These findings concern fibroblasts from one severe neonatal case.

Abnormal Mitochondrial Cristae

Altered cristae were observed in patient fibroblasts and circular cristae in a separate liver biopsy.

Show evidence (2 references)

PMID:34751152 SUPPORT In vitro / ex vivo

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

These findings concern fibroblasts from one severe neonatal case.

PMID:35781780 SUPPORT Human clinical

"The ultrastructural findings included abnormal circular mitochondrial cristae"

Liver ultrastructure corroborates a mitochondrial structural abnormality.

Deficient Mitochondrial Calcium Handling

Calcium buffering between cytoplasm and mitochondria was deficient in a severe patient fibroblast line. Reduced calcium influx is a proposed contributor to respiratory dysfunction.

intracellular calcium ion homeostasis GO:0006874

Experimental models

MEGDEL patient dermal fibroblasts PRIMARY CELL CULTURE The same severe neonatal patient line shows deficient cytoplasm-to-mitochondria calcium buffering, a functional finding distinct from the structural network and cristae changes.

Downstream

Respiratory Chain Complex Deficiency The authors propose this sequence; a selective calcium-rescue experiment is not established by the available abstract.

Show evidence (1 reference)

PMID:34751152 SUPPORT In vitro / ex vivo

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

Calcium buffering was abnormal in patient fibroblasts.

Impaired Mitochondrial Serine Import

Experimental work places SERAC1 in an outer-membrane complex with SFXN1 that facilitates serine import. Outer-membrane localization is compatible with an ER-mitochondria contact-site role.

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

Downstream

Impaired One-Carbon Metabolism Reduced mitochondrial serine supply impairs the one-carbon pathway in the experimental model.

Show evidence (1 reference)

PMID:35235340 SUPPORT In vitro / ex vivo

"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"

The experimental study identifies SERAC1-dependent SFXN1 transport.

Impaired One-Carbon Metabolism

SERAC1 loss impairs mitochondrial one-carbon metabolism in the experimental serine-transport model.

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

one-carbon metabolic process GO:0006730 ↓ DECREASED

Downstream

Nucleotide Pool Imbalance The study links impaired one-carbon metabolism with insufficient nucleotide supply.

Show evidence (1 reference)

PMID:35235340 SUPPORT Model organism

This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.

Nucleotide Pool Imbalance

Loss of SERAC1 disrupts nucleotide availability in experimental systems; nucleotide or nucleoside supplementation rescues downstream mtDNA and mitochondrial function.

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

Downstream

Mitochondrial DNA Depletion Insufficient nucleotide supply limits maintenance of mtDNA in the experimental systems.

Show evidence (2 references)

PMID:35235340 SUPPORT Model organism

This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.

PMID:35235340 SUPPORT Model organism

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

Preclinical rescue supports nucleotide limitation in the experimental systems.

Mitochondrial DNA Depletion

Depletion occurs in Serac1-deficient mice, HEK293T cells and patient-derived immortalized lymphocytes. Hepatic depletion has also been observed clinically, but normal blood or muscle testing in other cases shows that it is not universal across tissues or patients.

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

mitochondrial DNA metabolic process GO:0032042 ↓ 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 Impairment Rescue of mtDNA and mitochondrial function supports a contribution of nucleotide-limited mtDNA maintenance; intermediate respiratory-subunit effects are not resolved by the abstract.

Show evidence (3 references)

PMID:35235340 SUPPORT Model organism

This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.

PMID:23918762 SUPPORT Human clinical

"including hepatic mitochondrial DNA depletion in one patient"

Human liver depletion is consistent with, but does not prove, the experimental transport mechanism.

PMID:35943861 SUPPORT Human clinical

"long-range PCR and qPCR analyses of the patient's blood excluded any mtDNA deletions or depletions"

Normal blood findings limit generalization across patients and tissues.

Respiratory Chain Complex Deficiency

Respiratory-complex deficiencies vary by tissue and patient. One neonatal liver showed reduced complexes I, III and IV, whereas fresh muscle complexes were normal in another confirmed case.

Downstream

Mitochondrial Bioenergetic Impairment Respiratory-chain abnormalities can impair oxidative phosphorylation.

Show evidence (2 references)

PMID:34751152 SUPPORT Human clinical

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

Respiratory-complex abnormalities were observed in one neonatal liver.

PMID:25051967 SUPPORT Human clinical

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

Normal muscle findings do not exclude SERAC1 disease.

Mitochondrial Bioenergetic Impairment

Impaired oxidative phosphorylation is a variable cellular consequence of SERAC1 deficiency. Lipid, calcium and mtDNA pathways are candidate contributors whose relative roles in human tissues remain unresolved.

oxidative phosphorylation GO:0006119 ↓ DECREASED

Downstream

Basal Ganglia Neurodegeneration Mitochondrial dysfunction is a proposed contributor to selective basal-ganglia injury; the basis of selective vulnerability is unresolved.

Infantile hepatopathy Mitochondrial abnormalities coexist with infantile liver disease; the tissue-injury steps are not fully established.

Sensorineural hearing loss Hearing impairment is a clinical consequence associated with SERAC1 deficiency; its anatomical and molecular basis remains uncertain.

3-Methylglutaconic aciduria MEGDEL belongs to the secondary acidurias associated with mitochondrial phospholipid dysfunction; the exact route to organic-acid accumulation is unresolved.

Lactic acidosis Lactate elevation accompanies some episodes of mitochondrial dysfunction.

Show evidence (1 reference)

PMID:23918762 SUPPORT Human clinical

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

A four-patient hepatopathy series supports mitochondrial dysfunction.

Basal Ganglia Neurodegeneration

MRI shows evolving basal-ganglia abnormalities, with early pallidal signal changes, putaminal and caudate swelling with relative dorsal-putaminal sparing, and later atrophy. The characteristic putaminal eye is stage dependent and is a strong diagnostic clue; molecular testing confirms the diagnosis.

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 Basal-ganglia injury is a plausible contributor to dystonia, but clinical coexistence does not establish the full circuit mechanism.

Leigh-like basal ganglia lesions The structural injury is expressed as the evolving MRI abnormality.

Show evidence (1 reference)

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.

✶

Histopathology

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.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 1

Abnormal coagulation FREQUENT Abnormality of coagulation HP:0001928

Show evidence (2 references)

PMID:29205472 SUPPORT Human clinical

"disturbed coagulation tests were documented in 18 of 55 individuals (33%), but only 1 (1/55) had subsequent bleeding problems."

Retrospective cohort observation; the denominator reflects available data.

PMID:29205472 SUPPORT Human clinical

"disturbed coagulation with international normalized ratio > 2, and encephalopathy"

Elevated INR formed part of the neonatal liver-failure criteria.

Digestive 5

Infantile hepatopathy FREQUENT Decreased liver function HP:0001410

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Severe neonatal liver dysfunction was reported in 30/62 (48%) individuals. Nine of these 30 (30%) individuals fulfilled the criteria of neonatal liver failure"

Primary retrospective cohort; denominator is specific to this feature.

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Failure to thrive and feeding problems were a common and concomitant problem (52/66 individuals = 79%)."

Primary cohort observation; any stated denominator applies to this feature only.

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Typically, individuals presented oropharyngeal dyskinesia with repetitive protrusion of the tongue, dysphagia, and excessive drooling (34/59 [58%])."

Primary cohort observation; any stated denominator applies to this feature only.

Hepatomegaly OCCASIONAL HP:0002240

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Hepatomegaly at any age during their lifetime was reported in 17/64 (27%) individuals"

Primary cohort observation; any stated denominator applies to this feature only.

Cholestasis FREQUENT HP:0001396

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"During the first year of life, 24/50 (48%) individuals were reported with transient cholestasis and jaundice."

Primary cohort observation; any stated denominator applies to this feature only.

Ear 1

Sensorineural hearing loss FREQUENT Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Forty‐eight of 61 individuals (79%) were diagnosed with sensorineural hearing impairment"

Primary retrospective cohort; denominator is specific to this feature.

Eye 2

Optic atrophy OCCASIONAL HP:0000648

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Fourteen of 55 individuals (25%) had signs of optic atrophy documented on fundoscopy or MRI"

Primary retrospective cohort; denominator is specific to this feature.

Visual impairment FREQUENT HP:0000505

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"A total of 26 individuals of 62 (42%) were reported to have impaired vision."

Retrospective cohort observation; the denominator reflects available data.

Genitourinary 2

3-Methylglutaconic aciduria VERY_FREQUENT HP:0003535

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Sixty‐one of 62 (98%) individuals had 3‐MGA‐uria"

Primary retrospective cohort; denominator is specific to this feature.

Renal tubular dysfunction OCCASIONAL HP:0000124

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Eight individuals showed impaired tubular function (8/66 = 12%; eg, P3510) mostly transient and in the neonatal period."

Primary cohort observation; any stated denominator applies to this feature only.

Head and Neck 2

Microcephaly 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.

Drooling HP:0002307

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Typically, individuals presented oropharyngeal dyskinesia with repetitive protrusion of the tongue, dysphagia, and excessive drooling (34/59 [58%])."

Primary cohort observation; any stated denominator applies to this feature only.

Immune 1

Recurrent respiratory infections FREQUENT HP:0002205

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Many individuals suffered recurrent respiratory infections (28/66 = 42%), which were also the main cause of death."

Primary cohort observation; any stated denominator applies to this feature only.

Metabolism 5

Lactic acidosis 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 HP:0001987

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Seven individuals did not meet the full definition of liver failure but presented hyperammonemia"

Hyperammonemia can accompany incomplete or severe hepatic presentations.

Hypoglycemia FREQUENT HP:0001943

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Twenty‐nine individuals had recurrent hypoglycemia (glucose values < 2mmol/l in 29/65 = 44%)"

Primary retrospective cohort; denominator is specific to this feature.

Elevated hepatic transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"During the course of a life ASAT/ALAT were transiently increased on multiple occasions in 42/55 (76%) individuals"

Primary cohort observation; any stated denominator applies to this feature only.

Hyperlactatemia VERY_FREQUENT Increased circulating lactate concentration HP:0002151

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Serum lactate levels were increased in 51 of 61 (84%) individuals"

Retrospective cohort observation; the denominator reflects available data.

Musculoskeletal 3

Progressive spasticity VERY_FREQUENT HP:0001257

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Progressive spasticity of the limbs developed at a median age of 15 months (53/65 = 82%, range of onset = 1–48 months)"

Primary retrospective cohort; denominator is specific to this feature.

Hypotonia VERY_FREQUENT HP:0001252

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"The first signs were delayed motor development (57/66 = 86%) and muscular hypotonia (59/65 = 90%), recognized at a median age of 6 months."

Primary retrospective cohort; denominator is specific to this feature.

Scoliosis FREQUENT HP:0002650

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"With disease progression, 39% (19/49) of individuals developed scoliosis."

Primary retrospective cohort; denominator is specific to this feature.

Nervous System 10

Dystonia VERY_FREQUENT HP:0001332

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"dystonia at a median age of 18 months (53/65 = 82%, range of onset = 1–84 months)"

Primary retrospective cohort; denominator is specific to this feature.

Motor developmental delay VERY_FREQUENT Motor delay HP:0001270

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"The first signs were delayed motor development (57/66 = 86%) and muscular hypotonia (59/65 = 90%), recognized at a median age of 6 months."

Primary retrospective cohort; denominator is specific to this feature.

Developmental regression FREQUENT HP:0002376

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Previously obtained skills were lost, starting from a median of 12 months of age, in the majority of individuals (50/67 = 75%)."

Primary retrospective cohort; denominator is specific to this feature.

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

Show evidence (2 references)

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.

PMID:29205472 SUPPORT Human clinical

"Brain MRI studies were available for 55/67 individuals. In all individuals, alterations of the basal ganglia at different stages were observed."

Primary cohort imaging supports high frequency with an available-MRI denominator.

Seizures FREQUENT HP:0001250

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Epilepsy was reported in 23/66 individuals (35%)."

Primary retrospective cohort; denominator is specific to this feature.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"All 67 individuals had intellectual disability, varying in severity (severe, 37/51 = 73%; moderate, 8/51 = 16%; mild, 6/51 = 12%; data on severity were lacking for 16 individuals)."

Primary retrospective cohort; denominator is specific to this feature.

Autistic behavior 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.

Absent speech FREQUENT HP:0001344

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"In 56% of individuals (34/61), speech was completely absent."

Primary cohort observation; any stated denominator applies to this feature only.

Inability to walk independently FREQUENT HP:0002540

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Seventy‐eight percent (26/38) of the individuals never learned to walk."

Retrospective cohort observation; the denominator reflects available data.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:24997715 SUPPORT Human clinical

"Follow-up MRIs demonstrated progressive basal ganglia and cerebellar volume loss."

Human cerebellar involvement prevents interpreting canine cerebellar pathology as an exclusively nonhuman feature.

Growth 1

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Failure to thrive and feeding problems were a common and concomitant problem (52/66 individuals = 79%)."

Primary retrospective cohort; denominator is specific to this feature.

🧬

Genetic Associations

SERAC1

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

Show evidence (3 references)

PMID:22683713 SUPPORT Human clinical

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.

PMID:40821445 SUPPORT BACKGROUND Other

"No correlation has been recognized between the genotype and clinical phenotype."

The full case discussion summarizes the lack of a general genotype-phenotype correlation, consistent with the full GeneReviews chapter.

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

Predicted loss of function and nonsense-mediated decay; this report did not measure protein abundance.

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

Predicted loss of function through frameshift and premature termination; protein activity was not reported in the available abstract.

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)

Paternal missense variant in trans with maternal c.721_722delAG (p.Leu242fs) in a Chinese child with complicated spastic paraplegia. The authors discuss uncertain clinical significance; functional hypomorphism was not established.

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Predicted damaging by computational tools; no residual enzyme activity was measured.

Show evidence (2 references)

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.

PMID:35223715 SUPPORT Human clinical

"the clinical significance of this variant is not yet clear"

The full discussion explicitly limits the missense interpretation.

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

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

Functional effects

SERAC1 phosphatidylglycerol remodeling activity

Predicted truncation; the family report used sequencing and computational evidence. Blood testing found no mtDNA depletion or deletion.

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

Frameshift confirmed at the transcript level; loss of protein function is predicted rather than directly assayed.

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. Splice disruption was predicted computationally; segregation and functional assays were not performed.

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.

c.91+6T>C

Homozygous noncanonical splice variant segregating in a large Iraqi family with variable complicated spastic paraplegia. Patient-cell RNA analysis showed abnormal splicing and preserved overall transcript levels; full-length protein was absent. Milder PG changes could reflect residual function or compensation, but neither explanation was proven.

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 In vitro / ex vivo

"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 In vitro / ex vivo

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

A milder lipid abnormality in one tested family line is associated with the clinical phenotype; the mechanism remains uncertain.

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

Predicted loss of function from a multiexon deletion; the abstract classifies the allele as pathogenic without measuring protein abundance.

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

Supportive Multidisciplinary Care

Action: Supportive Care NCIT:C15747

Platform: Other

Care is supportive, coordinated across metabolic medicine, neurology, nutrition, rehabilitation, audiology and other specialties according to involvement. No disease-modifying human treatment has been established.

Show evidence (1 reference)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietician, and physical therapist when possible."

GeneReviews recommends coordinated supportive care.

Neonatal Metabolic Crisis Management

Action: Hemodialysis NCIT:C15248

Platform: Other

Urgent specialist management addresses hypoglycemia, hyperammonemia, coagulopathy and other organ dysfunction. In one severe neonatal case initially managed as a suspected urea-cycle disorder, protein was temporarily withheld, intravenous glucose and ammonia-lowering therapies were given, and continuous dialysis controlled ammonia. This empiric crisis regimen is not a disease-specific treatment protocol.

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.

Individualized Hearing Rehabilitation

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

Platform: Surgery

Hearing aids and cochlear implants have been used, but expected benefit should be discussed with audiology and the family. In a 36-person retrospective hearing study, 22 received hearing aids and six subsequently received implants; only one implanted individual acquired spoken language, which became less clear with progression. Improved environmental interaction can still be meaningful. The auditory lesion is not consistently localized.

Mechanism Target:

Sensorineural hearing loss — Auditory augmentation may improve access to sound; clinical language benefit is variable and often limited.

Show evidence (1 reference)

PMID:40714654 SUPPORT Human clinical

"Twenty-two individuals received hearing rehabilitation with conventional hearing aids, followed by cochlear implant (CI) surgery in six. One of these six individuals acquired spoken language, which lessened in clarity as disease progressed."

Primary hearing-rehabilitation cohort defines limited and variable language benefit.

Show evidence (1 reference)

PMID:40714654 SUPPORT Human clinical

Primary hearing-rehabilitation cohort defines limited and variable language benefit.

Reported Dexmedetomidine-based Anaesthesia

Action: Pharmacotherapy NCIT:C15986

Agent: dexmedetomidine CHEBI:4466

Platform: Small molecule

One two-year-old undergoing cochlear implantation tolerated ketamine and dexmedetomidine induction with dexmedetomidine maintenance. This case supports feasibility in that individual; it does not establish an optimal anaesthetic regimen, comparative safety or a specific malignant-hyperthermia susceptibility in MEGDEL.

Show evidence (1 reference)

PMID:39592976 SUPPORT Human clinical

"The ICU period was smooth, and she was released the next day. The anaesthetic plan was tolerated without any complications."

Single-case perioperative outcome; no comparative safety inference.

Nutritional and Feeding Support

Action: gastrostomy Ontology label: Gastrostomy NCIT:C52006

Platform: Surgery

Assess growth, nutritional intake and swallowing safety. Feeding therapy and enteral support, including gastrostomy when needed, address inadequate intake or unsafe feeding.

Show evidence (2 references)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"Management of neonatal hypoglycemia; feeding therapy and gastrostomy tube as needed"

GeneReviews recommends feeding support.

PMID:29205472 SUPPORT Human clinical

"Thirty‐seven of 58 individuals (64%) were given tube feeding."

Tube feeding was common in the primary cohort.

Perioperative Risk Management

Action: Supportive Care NCIT:C15747

Platform: Other

Plan anaesthesia individually with attention to organ involvement, glucose, hydration, temperature and postoperative recovery. The MEGDEL case report discusses limiting fasting, avoiding prolonged propofol infusion and avoiding succinylcholine in patients with myopathy based on wider mitochondrial-disease practice; these are extrapolated precautions, not MEGDEL-specific comparative evidence.

Show evidence (3 references)

PMID:39592976 SUPPORT INDIRECT BACKGROUND Other

"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"

The case report summarizes a wider myopathy precaution; it does not establish a MEGDEL-specific absolute contraindication.

PMID:39592976 SUPPORT INDIRECT BACKGROUND Other

"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 INDIRECT BACKGROUND Other

"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

When both parents carry a pathogenic SERAC1 variant, each pregnancy has a 25% chance of an affected child. Confirm familial variants and phase, offer carrier testing to at-risk relatives, and discuss prenatal or preimplantation testing when appropriate.

Show evidence (2 references)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected"

GeneReviews recurrence risk assumes both parents are known carriers.

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"Once the SERAC1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."

Family testing requires known pathogenic variants.

Baclofen for Spasticity

Action: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972

Platform: Small molecule

Oral or intrathecal baclofen may improve spasticity, sometimes temporarily. In the historical cohort, oral baclofen was reported beneficial in 11 of 15 individuals, ineffective in two and associated with worsening in two; responses require individual assessment.

Show evidence (2 references)

PMID:29205472 SUPPORT Human clinical

"Oral baclofen was given to 15 individuals. It was reported as having a positive effect in 11 individuals, whereas in 2 no change was observed, and in another 2, clinical deterioration of spasticity was seen."

Uncontrolled retrospective response data.

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"some individuals have experienced (temporary) improvement of spasticity with oral or intrathecal baclofen treatment"

GeneReviews summarizes symptomatic use.

Deep Brain Stimulation

Action: Deep Brain Stimulation NCIT:C21024

Platform: Surgery

GPi stimulation may be considered for selected refractory dystonia or parkinsonism. A teenage case improved from BFMDRS 30.5 to seven at two years without correction of scoliosis. A separate adult report describes benefit at six months, but its preceding genetic report classified p.Arg411Cys as a VUS. Both are uncontrolled observations, with limited generalizability to severe infantile disease.

Show evidence (3 references)

PMID:33426169 SUPPORT Human clinical

"Her improvement is highlighted by a 2‐year follow‐up BFMDRS score of 7. Importantly, following DBS, the scoliosis did not change"

Case-level benefit with a persistent structural manifestation.

PMID:40884098 SUPPORT Human clinical

"Clinical response to GPi‐DBS has been quantitatively evaluated with the Movement Disorders Society Unified Dystonia Rating Scale (40 → 19)"

A second uncontrolled adult outcome.

PMID:40145675 SUPPORT Human clinical

"rare (gnomAD AF. 0000031, ACMG‐PM2), and overall classified as a variant of uncertain significance (VUS)."

The adult case has a material molecular-confirmation limitation.

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Other

Physical therapy and positioning or mobility equipment support function and reduce orthopedic complications; tailor the program to progressive motor limitations.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/ SUPPORT REVIEW SYNTHESIS Other

"Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications"

Full GeneReviews motor-management recommendations.

Occupational Therapy

Action: Occupational Therapy NCIT:C121351

Platform: Other

Occupational therapy supports fine-motor activities and adaptive equipment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/ SUPPORT REVIEW SYNTHESIS Other

"Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function"

Full GeneReviews recommends assistance with adaptive tasks.

Developmental and Communication Support

Action: Supportive Care NCIT:C15747

Platform: Other

Provide educational support and speech-language assessment, including augmentative and alternative communication tailored to cognition, hearing and motor abilities.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/ SUPPORT REVIEW SYNTHESIS Other

"An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically takes into account cognitive abilities, sensory impairments, and motor skills to determine the most appropriate form of communication."

Full GeneReviews communication-management recommendation.

Seizure Management

Action: Pharmacotherapy NCIT:C15986

Platform: Other

Manage epilepsy with an experienced neurologist. GeneReviews advises avoiding medications known to impair mitochondrial function, including valproic acid.

Show evidence (2 references)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"Developmental and educational support; management of seizures per experienced neurologist; treatment of liver disease per hepatologist"

Specialist-directed symptomatic treatment.

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"Agents and circumstances to avoid: Medications known to impair mitochondrial function (e.g., valproic acid)."

GeneReviews avoidance guidance; no disease-specific comparative drug trial is implied.

Management of Drooling

Action: Supportive Care NCIT:C15747

Platform: Other

Specialist treatment can include salivary-gland botulinum toxin or surgery when drooling contributes to respiratory problems. Two cohort individuals improved with orally administered atropine drops; this is limited case experience.

Show evidence (2 references)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"respiratory problems resulting from excessive drooling improve with botulinum toxin injection in the salivary glands, extirpation of salivary glands, and/or rerouting of glandular ducts."

GeneReviews summarizes symptomatic options.

PMID:29205472 SUPPORT Human clinical

"P28 and P65 were given atropine 0.5% eye drops orally (1 drop every 6 hours), which reduced drooling to a normal level without any side effects."

Reported atropine response in two individuals; not a controlled efficacy estimate.

Clinical Surveillance

Action: Supportive Care NCIT:C15747

Platform: Other

Monitor glucose in infantile MEGD(H)EL and assess growth, nutrition, swallowing, neurological progression, communication, hearing, musculoskeletal and vision problems, and family needs at visits and at least annually. Monitor liver dysfunction with hepatology input.

Show evidence (1 reference)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

"At each visit and at least annually assess growth, nutrition, safety of oral intake, neurologic manifestations, developmental progress, cognition, educational needs, hearing, musculoskeletal manifestations, ophthalmology evaluation, and family needs; laboratory assessment of liver dysfunction..."

GeneReviews surveillance recommendations.

🔬

Biochemical Markers

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 / ex vivo

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

Show evidence (2 references)

PMID:28916646 SUPPORT In vitro / ex vivo

"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 In vitro / ex vivo

"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 3-Methylglutaconic aciduria Positive

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

Show evidence (1 reference)

PMID:29205472 SUPPORT Human clinical

"Sixty‐one of 62 (98%) individuals had 3‐MGA‐uria"

Quantifies the urinary finding in confirmed SERAC1 disease.

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 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 / ex vivo

"Filipin staining showed uneven localization of unesterified cholesterol"

Reports the filipin assay result directly.

Show evidence (2 references)

PMID:22683713 SUPPORT In vitro / ex vivo

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

Original description of the filipin abnormality in patient cells.

PMID:29205472 SUPPORT Human clinical

"Filipin staining of fibroblasts was abnormal in 6 of 10 (60%) individuals."

Normal staining cannot exclude SERAC1 deficiency.

🔬

Diagnosis

Urine organic acid analysis

Urinary organic-acid analysis can identify 3-methylglutaconic and 3-methylglutaric acid elevations and direct molecular testing. Levels fluctuate and can be initially normal; the biochemical finding alone is not specific for MEGDEL.

urine organic acid analysis NCIT:C25294

Show evidence (2 references)

PMID:29686941 SUPPORT Human clinical

"the 3-methylglutaconic aciduria level may fluctuate and can be transiently undetectable."

The longitudinal case illustrates why a normal result does not exclude disease.

PMID:29205472 SUPPORT Human clinical

"In all these cases, urinary organic acid analysis and appropriate genetic testing for SERAC1 variants should be performed."

Primary cohort recommends combined biochemical and genetic investigation.

Brain MRI pattern recognition

The evolving basal-ganglia pattern, especially relative dorsal-putaminal sparing within affected putamen, is a strong clue. The eye is stage dependent, and MRI does not replace molecular confirmation.

brain magnetic resonance imaging NCIT:C16809

The original imaging series termed the sign pathognomonic; current diagnostic criteria require biallelic pathogenic or likely pathogenic SERAC1 variants.

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:24741715 SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of SERAC1 deficiency is established in a proband with suggestive clinical and metabolic (3-methylglutaconic aciduria) findings and biallelic pathogenic variants in SERAC1 identified by molecular genetic testing."

GeneReviews supplies the current confirmatory framework.

Fibroblast phosphatidylglycerol and filipin profiling

Fibroblast PG profiling and filipin staining can support functional assessment, particularly for uncertain alleles. A mild PG shift in one family is not a general prognostic test; normal filipin staining does not exclude the disorder.

fibroblast lipid profiling NCIT:C25294

Show evidence (2 references)

PMID:28916646 SUPPORT In vitro / ex vivo

"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.

PMID:29205472 SUPPORT Human clinical

"Filipin staining of fibroblasts was abnormal in 6 of 10 (60%) individuals."

Normal staining cannot exclude SERAC1 deficiency.

SERAC1 sequencing with copy-number analysis

Identify biallelic pathogenic or likely pathogenic SERAC1 variants with appropriate phase assessment. Panels, exome or genome sequencing may require additional deletion/duplication analysis when copy-number detection is incomplete. Two variants of uncertain significance do not independently confirm the diagnosis.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:24741715 SUPPORT REVIEW SYNTHESIS Other

GeneReviews supplies the current confirmatory framework.

PMID:35781780 SUPPORT Human clinical

"deletion of (at least) exons 2-4, pathogenic"

A reported multiexon deletion supports attention to copy-number coverage.

📈

Progression

Neonatal metabolic and hepatic crisis

Some infants present in the first days of life with hypoglycemia, sepsis-like illness, hepatic dysfunction and metabolic abnormalities. Severe liver failure or multiorgan failure can be fatal, but neonatal disease is variable and liver abnormalities often improve.

Show evidence (1 reference)

PMID:34751152 SUPPORT Human clinical

"In the diagnostic work-up of a newborn infant with a metabolic crisis, lethal multiorgan failure on day six of life, and increased excretion of 3-methylglutaconic acid, we found using whole genome sequencing a homozygous SERAC1 mutation indicating MEGDHEL syndrome (3-methylglutaconic aciduria..."

Restores the homozygous SERAC1/MEGDHEL diagnosis of the neonate with lethal metabolic crisis. The selected clinical sentence does not supply every biochemical detail or demonstrate an intervention window.

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:24741715 SUPPORT REVIEW SYNTHESIS Other

"By age two years, spasticity, dystonia, epilepsy, and progressive deafness prevent further psychomotor development and/or result in loss of acquired skills."

Summarizes progression in the severe infantile phenotype.

Milder later-onset course

Later-onset complicated spastic paraplegia or dystonia can progress more slowly. Some children improve developmental skills; variant class alone does not establish the trajectory.

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.

Variable survival

Survival cannot be summarized as inevitable early death. In the 67-person historical cohort, 16 individuals died at a median age of nine years; the cohort included survivors into adulthood. These are cohort observations, not a current population survival estimate.

Show evidence (2 references)

PMID:29205472 SUPPORT Human clinical

"Sixteen individuals passed away at a median age of 9 years (range = 5 days–16 years"

Reports deaths with their observed age distribution.

PMID:29205472 SUPPORT Human clinical

"Despite the severity of neurological impairment, most affected individuals survive into adulthood."

The cohort discussion explicitly counters a universal early-lethal description.

📊

Prevalence

Published cases worldwide

Cases/families reported in the literature Unknown

A 2020 review identified at least 102 published patients. This historical case count does not establish population point prevalence.

Show evidence (1 reference)

PMID:32684373 SUPPORT REVIEW SYNTHESIS Other

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

Historical review count.

International clinical cohort

Unknown Unknown

The 67-person cohort supports panethnic occurrence; consanguinity was reported in 38/59 families. Candidate founder variants occur in European families. These observations do not establish ethnicity-specific population rates.

Show evidence (2 references)

PMID:29205472 SUPPORT Human clinical

"In 38 of 59 (64%) families, consanguinity was reported."

Provides the cohort denominator.

PMID:29205472 SUPPORT Human clinical

"showing that MEGDHEL syndrome is a panethnic condition."

Cases arose across geographic ancestries.

Genetic database estimates

Unknown Unknown

GeneReviews quotes 0.09 per 100,000 from Tan et al. The underlying study estimates genetic lifetime risk from allele frequencies under Hardy-Weinberg equilibrium and full penetrance; this is not observed point prevalence. The SERAC1 numerical estimate is not reproduced as a measured population rate here.

Show evidence (2 references)

PMID:32305867 SUPPORT Computational

"The lifetime risk is defined as the proportion of a population that at some point in life will develop the disease."

Defines the modeled measure.

PMID:32305867 SUPPORT Computational

"Biallelic combinations of variants were considered to be fully penetrant."

Identifies a material modeling assumption.

🔀

Differential Diagnoses

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 AUH deficiency causes primary 3-methylglutaconic aciduria through defective leucine catabolism. MEGDEL is classified among secondary acidurias associated with phospholipid remodeling.

Show evidence (1 reference)

PMID:23296368 SUPPORT REVIEW SYNTHESIS Other

""primary 3-methylglutaconic aciduria" formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, 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 Barth syndrome, Costeff syndrome, DNAJC19-related DCMA, and TMEM70-, CLPB- or TIMM50-related disorders can share secondary 3-methylglutaconic aciduria. Clinical patterns and molecular testing distinguish them.

Show evidence (1 reference)

PMID:30114719 SUPPORT BACKGROUND Other

"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 HTRA2-related disease can resemble severe neonatal MEGDEL through movement abnormalities, seizures and 3-methylglutaconic aciduria. Central hypopnea/apnea and neutropenia were prominent in the 11-person HTRA2 series, in which death occurred within the first month. This is one differential, not an established uniquely closest diagnosis.

Show evidence (1 reference)

PMID:30114719 SUPPORT INDIRECT 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

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-cell PG abnormalities and their partial normalization by wild-type SERAC1 directly connect SERAC1 dysfunction to lipid remodeling.

Limitations: Fibroblast findings do not establish tissue-specific neuronal, auditory or hepatic pathology.

Readouts

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

Direction: INCREASED

Interpretation: The ratio is a direct lipidomic readout of altered phosphatidylglycerol remodeling.

Show evidence (1 reference)

PMID:22683713 SUPPORT In vitro / ex vivo

"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 / ex vivo

"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 / ex vivo

"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 recapitulates fidelity: moderate A severe neonatal patient line shows a severely fragmented mitochondrial network and altered cristae morphology as distinct structural findings.

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 morphology is observed in patient cells; it does not itself establish defective ER contact sites.

Show evidence (1 reference)

PMID:34751152 SUPPORT In vitro / ex vivo

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

Reports the structural measurement.

Show evidence (1 reference)

PMID:34751152 SUPPORT In vitro / ex vivo

"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.

Deficient Mitochondrial Calcium Handling recapitulates fidelity: moderate The same severe neonatal patient line shows deficient cytoplasm-to-mitochondria calcium buffering, a functional finding distinct from the structural network and cristae changes.

Limitations: The measurement comes from a single patient line carrying one severe truncating allele, so allelic and interindividual variation in calcium handling is unknown, and fibroblast calcium buffering does not establish the equivalent defect in neurons or hair cells.

Readouts

Cytoplasm-to-mitochondria calcium buffering

Direction: DECREASED

Interpretation: Direct observation of impaired cytoplasm-to-mitochondria calcium buffering.

Show evidence (1 reference)

PMID:34751152 SUPPORT In vitro / ex vivo

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

Reports the calcium measurement.

Show evidence (1 reference)

PMID:34751152 SUPPORT In vitro / ex vivo

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

Establishes the model as informative for the calcium-handling node.

🐁

Animal Models

Serac1 knockout mouse

Serac1-null mice were reported to reproduce major diagnostic clinical and biochemical features and support the serine-transport/mtDNA pathway. Nucleoside or nucleotide supplementation rescued mtDNA content and mitochondrial function experimentally.

Species

Mouse

Genotype

Serac1-/-

Publication

PMID:35235340

Pathograph links

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

Limitations: The accessible source is an abstract. It does not resolve which lipid abnormalities or stage-specific human MRI lesions were reproduced, nor the contribution of each pathway to human disease. Preclinical rescue does not establish clinical efficacy or safety.

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

Naturally occurring SERAC1-associated multiple system degeneration affects Kerry Blue Terriers and Chinese Crested dogs. Breed-specific variant concordance and affected compound-heterozygous crosses support genetic causation. Splice disruption was demonstrated for the Chinese Crested allele; loss of protein activity was not directly measured.

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: Published canine neuropathology includes Purkinje-cell, striatal and nigral neuronal loss with ataxia and tremor. Hearing and cognition were not assessed, and hepatic or urine organic-acid phenotyping was not reported. These are untested features, not established absences. The paper does not demonstrate canine lipid, serine-transport or mtDNA abnormalities.

Readouts

Striatal neuronal abundance

Direction: DECREASED

Interpretation: Reported postmortem striatal neuronal loss provides a neuropathological correlate; the paper summarizes prior pathology rather than a new quantitative neuron-counting assay.

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"

Describes canine neuropathology without asserting absence of these anatomical findings in humans.

Show evidence (2 references)

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.

+ 1 more reference

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"

Strong genotype-phenotype concordance supports the association with the canine disorder.

Lpgat1 knockout mouse

A parallel phospholipid-remodeling model, not a SERAC1 genotype model. Lpgat1 deletion produces altered PG species, mitochondrial defects, aciduria, hearing impairment, hepatopathy and cardiomyopathy. It motivates a candidate pathway but does not establish LPGAT1 as a human MEGDEL gene.

Species

Mouse

Genotype

Lpgat1-/-

Publication

PMID:37917582

Pathograph links

Impaired Phosphatidylglycerol Remodeling partially recapitulates fidelity: moderate LPGAT1-deficient cells and mice connect PG remodeling and mitochondrial PG transport, with a PG34:1/PG36:1 shift resembling SERAC1 deficiency.

Limitations: The perturbed gene is LPGAT1. Cardiomyopathy and mortality in these mice cannot be generalized to human SERAC1 disease. Precise PHB/TIM lipid-transfer activity remains unresolved.

Show evidence (2 references)

PMID:37917582 SUPPORT INDIRECT In vitro / ex vivo

"LPGAT1 deficiency also significantly increased the ratio of PG-34:1/PG-36:1 relative to vector control cells"

Cellular lipid similarity supports a partial pathway analogy.

+ 1 more reference

{ }

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, also termed MEGD(H)EL when hepatopathy is included, is an autosomal recessive neurometabolic disorder caused by biallelic pathogenic SERAC1 variants. Classic disease combines infantile feeding and developmental difficulties, hypotonia, progressive dystonia and spasticity, sensorineural hearing loss, secondary 3-methylglutaconic aciduria, and characteristic basal-ganglia MRI abnormalities. Neonatal hypoglycemia and liver dysfunction are frequent but variable. SERAC1 deficiency disrupts phosphatidylglycerol remodeling and is associated with altered cardiolipin composition, cholesterol trafficking, mitochondrial structure, and calcium handling. Experimental work also implicates SFXN1-dependent serine transport, one-carbon metabolism, and mitochondrial DNA maintenance. The spectrum extends to juvenile complicated spastic paraplegia and adult-onset dystonia; variant type alone does not reliably predict severity. Treatment is supportive and individualized.
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 pathogenic SERAC1 variants cause autosomal recessive disease. Heterozygous carriers are generally asymptomatic; parental testing helps establish phase and recurrence risk.
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SERAC1 deficiency is inherited in an autosomal recessive manner.
    explanation: GeneReviews states the inheritance pattern.
    quote_role: REVIEW_SYNTHESIS
  - 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 presentation may begin with neonatal hypoglycemia, sepsis-like illness or liver dysfunction, followed by infantile hypotonia and developmental delay, and progressive dystonia, spasticity and hearing loss. Severe disability is common, but neonatal involvement and early death are not obligatory.
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: MEGD(H)EL syndrome is characterized by neonatal hypoglycemia, a sepsis-like clinical picture for which no infectious agent can be found, feeding problems, poor weight gain, muscular hypotonia, developmental delay, and liver involvement.
    explanation: Summarizes the classic infantile presentation.
    quote_role: REVIEW_SYNTHESIS
- name: Juvenile cHSP
  display_name: Juvenile-onset complicated hereditary spastic paraplegia
  description: A later-onset presentation with complicated spastic paraplegia and variable cognitive or other neurological involvement. In one large family, three affected siblings remained independently ambulant into adolescence or adulthood; a tested fibroblast line had a milder PG abnormality despite loss of full-length SERAC1. Residual activity was proposed, not demonstrated.
  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: Juvenile- or adult-onset generalized dystonia
  description: Later-onset generalized dystonia, sometimes with parkinsonian or pyramidal signs, occurs at the milder end of the spectrum. Cognitive or developmental difficulties may precede the movement disorder; individual reports vary in the strength of their molecular confirmation.
  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.
  - reference: PMID:29686941
    reference_title: Adult-onset Generalized Dystonia as the Main Manifestation of MEGDEL Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 24 years old, he had a few episodes of subacute encephalopathy triggered by fever and then developed cervical dystonia. Dystonia gradually worsened to become generalized dystonia.
    explanation: A longitudinal adult case broadens the age-at-onset 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.
  - reference: PMID:40821445
    reference_title: 'Expanding the Epidemiological and Phenotypic Spectrum of MEGDEL Syndrome: The First Case Report From Egypt.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: No correlation has been recognized between the genotype and clinical phenotype.
    explanation: The full case discussion summarizes the lack of a general genotype-phenotype correlation, consistent with the full GeneReviews chapter.
    quote_role: BACKGROUND
  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: Predicted loss of function and nonsense-mediated decay; this report did not measure protein abundance.
    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: Predicted loss of function through frameshift and premature termination; protein activity was not reported in the available abstract.
    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: Paternal missense variant in trans with maternal c.721_722delAG (p.Leu242fs) in a Chinese child with complicated spastic paraplegia. The authors discuss uncertain clinical significance; functional hypomorphism was not established.
    functional_effects:
    - function: SERAC1 phosphatidylglycerol remodeling activity
      description: Predicted damaging by computational tools; no residual enzyme activity was measured.
    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.
    - 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 clinical significance of this variant is not yet clear
      explanation: The full discussion explicitly limits the missense interpretation.
  - 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: Predicted truncation; the family report used sequencing and computational evidence. Blood testing found no mtDNA depletion or deletion.
    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: Frameshift confirmed at the transcript level; loss of protein function is predicted rather than directly assayed.
    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. Splice disruption was predicted computationally; segregation and functional assays were not performed.
    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: c.91+6T>C
    description: Homozygous noncanonical splice variant segregating in a large Iraqi family with variable complicated spastic paraplegia. Patient-cell RNA analysis showed abnormal splicing and preserved overall transcript levels; full-length protein was absent. Milder PG changes could reflect residual function or compensation, but neither explanation was proven.
    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: IN_VITRO
      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: IN_VITRO
      snippet: These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype
      explanation: A milder lipid abnormality in one tested family line is associated with the clinical phenotype; the mechanism remains uncertain.
  - 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: Predicted loss of function from a multiexon deletion; the abstract classifies the allele as pathogenic without measuring protein abundance.
    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 encodes a protein involved in phosphatidylglycerol remodeling and mitochondrial physiology. Disease-associated variants include truncating, splice, missense and multiexon deletion alleles. The effect on RNA, protein abundance and cellular function depends on the allele and has not been measured for every reported variant. A general genotype-phenotype correlation has not been established. LPGAT1-deficient mice reproduce several overlapping findings, but this does not establish LPGAT1 as a human MEGDEL gene.
pathophysiology:
- name: Reduced SERAC1 Function
  biological_scale: MOLECULAR
  description: Biallelic pathogenic variants reduce SERAC1 function. Some tested truncating alleles lower protein expression, but absence of protein or mislocalization is not established for every allele.
  molecular_functions:
  - preferred_term: SFXN1 serine transporter activation
    term:
      id: GO:0141109
      label: transporter activator activity
    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: 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: IN_VITRO
    snippet: Both mutations were found to lead to decreased or absent expression of SERAC1
    explanation: Two hepatopathy-associated alleles were linked to reduced protein expression.
  - 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: IN_VITRO
    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: The single experimental study behind the emerging serine_transport_mtdna hypothesis identifies SERAC1 as an activator required for SFXN1-mediated serine transport.
  downstream:
  - target: Impaired Phosphatidylglycerol Remodeling
    causal_link_type: DIRECT
    description: SERAC1 dysfunction alters cellular PG remodeling, supported by complementation.
    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: Wild-type complementation partially rescues the patient-cell lipid ratio.
  - target: Bis(monoacylglycerol)phosphate Depletion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced BMP is observed in SERAC1-deficient cells; the intervening remodeling steps remain incompletely defined.
    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: Patient fibroblasts showed reduced BMP and cholesterol accumulation.
  - target: Mitochondrial Network Fragmentation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Patient cells associate loss of SERAC1 with network fragmentation; mediation by individual lipid changes has not been isolated.
    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: These findings concern fibroblasts from one severe neonatal case.
  - target: Abnormal Mitochondrial Cristae
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Patient cells and liver tissue show abnormal cristae.
    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: These findings concern fibroblasts from one severe neonatal case.
  - target: Deficient Mitochondrial Calcium Handling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Patient fibroblasts show impaired cytoplasm-to-mitochondria calcium buffering.
    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: Calcium buffering was abnormal in patient fibroblasts.
  - target: Impaired Mitochondrial Serine Import
    causal_link_type: DIRECT
    description: Experimental SERAC1 loss impairs SFXN1-mediated transport.
    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: IN_VITRO
      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: The experimental study identifies SERAC1-dependent SFXN1 transport.
    hypothesis_groups:
    - serine_transport_mtdna
  gene:
    preferred_term: SERAC1
    term:
      id: hgnc:21061
      label: SERAC1
- name: Impaired Phosphatidylglycerol Remodeling
  biological_scale: MOLECULAR
  description: Patient fibroblasts show an increased PG-34:1/PG-36:1 ratio, partly corrected by wild-type SERAC1. These data establish involvement in remodeling; direct LPG acyltransferase activity of purified SERAC1 has not been established.
  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: Wild-type complementation partially rescues the patient-cell lipid ratio.
  - reference: PMID:37917582
    reference_title: LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: no LPG acyltransferase activity has been identified from SERAC1 to date
    explanation: The 2023 LPGAT1 study distinguishes remodeling involvement from demonstrated catalytic activity.
    quote_role: BACKGROUND
  biological_processes:
  - preferred_term: phosphatidylglycerol acyl-chain remodeling
    term:
      id: GO:0036148
      label: phosphatidylglycerol acyl-chain remodeling
    modifier: DECREASED
  downstream:
  - target: Altered Cardiolipin Subspecies Composition
    causal_link_type: DIRECT
    description: Altered PG substrate composition is linked to altered 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: The discovery study links altered PG species with cardiolipin composition.
- name: Altered Cardiolipin Subspecies Composition
  biological_scale: MOLECULAR
  description: Cardiolipin acyl-species composition changes in SERAC1-deficient fibroblasts. This observation does not establish a decrease in the overall rate of cardiolipin remodeling.
  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: The discovery study links altered PG species with cardiolipin composition.
  cellular_components:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  downstream:
  - target: Respiratory Chain Complex Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Altered cardiolipin is a proposed contributor to respiratory dysfunction; the disease-specific intervening assembly steps are unresolved.
    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: OTHER
      snippet: The abnormal cardiolipin profile that results from SERAC1 mutations may in part explain the defects in oxidative phosphorylation in these patients
      explanation: The full-text discussion presents this as a partial mechanistic explanation.
      quote_role: BACKGROUND
      directness: INDIRECT
- name: Bis(monoacylglycerol)phosphate Depletion
  biological_scale: MOLECULAR
  description: Reduced BMP accompanies SERAC1 deficiency in patient fibroblasts.
  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: Patient fibroblasts showed reduced BMP and cholesterol accumulation.
  downstream:
  - target: Free Cholesterol Accumulation
    causal_link_type: DIRECT
    description: The discovery study links low BMP to abnormal intracellular cholesterol handling.
    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: Patient fibroblasts showed reduced BMP and cholesterol accumulation.
- name: Free Cholesterol Accumulation
  biological_scale: CELLULAR
  description: Unesterified cholesterol can accumulate or be distributed abnormally in patient fibroblasts. Filipin staining is variable and can be normal in both mild and classic presentations.
  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: Patient fibroblasts showed reduced BMP and cholesterol accumulation.
  biological_processes:
  - preferred_term: intracellular cholesterol transport
    term:
      id: GO:0032367
      label: intracellular cholesterol transport
    modifier: DECREASED
- name: Mitochondrial Network Fragmentation
  biological_scale: CELLULAR
  description: A severely fragmented mitochondrial network was observed in fibroblasts from a lethal neonatal case; this is a cellular finding rather than proof of a universal intermediate.
  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: These findings concern fibroblasts from one severe neonatal case.
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
- name: Abnormal Mitochondrial Cristae
  biological_scale: CELLULAR
  description: Altered cristae were observed in patient fibroblasts and circular cristae in a separate liver biopsy.
  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: These findings concern fibroblasts from one severe neonatal case.
  - 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: Liver ultrastructure corroborates a mitochondrial structural abnormality.
- name: Deficient Mitochondrial Calcium Handling
  biological_scale: CELLULAR
  description: Calcium buffering between cytoplasm and mitochondria was deficient in a severe patient fibroblast line. Reduced calcium influx is a proposed contributor to respiratory dysfunction.
  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: Calcium buffering was abnormal in patient fibroblasts.
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
  downstream:
  - target: Respiratory Chain Complex Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors propose this sequence; a selective calcium-rescue experiment is not established by the available abstract.
    evidence:
    - reference: PMID:34751152
      reference_title: Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: suggest that the crucial disease mechanism is disrupted interplay between the ER and mitochondria leading to decreased influx of calcium to mitochondria and secondary respiratory chain deficiency
      explanation: The authors explicitly frame the mechanistic connection as a suggestion.
      directness: INDIRECT
- name: Impaired Mitochondrial Serine Import
  biological_scale: MOLECULAR
  description: Experimental work places SERAC1 in an outer-membrane complex with SFXN1 that facilitates serine import. Outer-membrane localization is compatible with an ER-mitochondria contact-site role.
  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: IN_VITRO
    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: The experimental study identifies SERAC1-dependent SFXN1 transport.
  downstream:
  - target: Impaired One-Carbon Metabolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced mitochondrial serine supply impairs the one-carbon pathway in the experimental 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: Loss of SERAC1 impaired the one-carbon cycle and disrupted the balance of the nucleotide pool, which led to primary mitochondrial DNA (mtDNA) depletion in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides
      explanation: This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.
    hypothesis_groups:
    - serine_transport_mtdna
- name: Impaired One-Carbon Metabolism
  biological_scale: MOLECULAR
  description: SERAC1 loss impairs mitochondrial one-carbon metabolism in the experimental serine-transport 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: Loss of SERAC1 impaired the one-carbon cycle and disrupted the balance of the nucleotide pool, which led to primary mitochondrial DNA (mtDNA) depletion in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides
    explanation: This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.
  biological_processes:
  - preferred_term: one-carbon metabolic process
    term:
      id: GO:0006730
      label: one-carbon metabolic process
    modifier: DECREASED
  downstream:
  - target: Nucleotide Pool Imbalance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The study links impaired one-carbon metabolism with insufficient nucleotide supply.
    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 in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides
      explanation: This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.
    hypothesis_groups:
    - serine_transport_mtdna
- name: Nucleotide Pool Imbalance
  biological_scale: MOLECULAR
  description: Loss of SERAC1 disrupts nucleotide availability in experimental systems; nucleotide or nucleoside supplementation rescues downstream mtDNA and mitochondrial function.
  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 in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides
    explanation: This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.
  - 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: Preclinical rescue supports nucleotide limitation in the experimental systems.
  downstream:
  - target: Mitochondrial DNA Depletion
    causal_link_type: DIRECT
    description: Insufficient nucleotide supply limits maintenance of mtDNA in the experimental systems.
    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 in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides
      explanation: This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.
    - 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: Preclinical rescue supports nucleotide limitation in the experimental systems.
    hypothesis_groups:
    - serine_transport_mtdna
- name: Mitochondrial DNA Depletion
  biological_scale: MOLECULAR
  description: Depletion occurs in Serac1-deficient mice, HEK293T cells and patient-derived immortalized lymphocytes. Hepatic depletion has also been observed clinically, but normal blood or muscle testing in other cases shows that it is not universal across tissues or patients.
  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 in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides
    explanation: This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.
  - 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: including hepatic mitochondrial DNA depletion in one patient
    explanation: Human liver depletion is consistent with, but does not prove, the experimental transport mechanism.
  - 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: long-range PCR and qPCR analyses of the patient's blood excluded any mtDNA deletions or depletions
    explanation: Normal blood findings limit generalization across patients and tissues.
  biological_processes:
  - preferred_term: mitochondrial DNA metabolic process
    term:
      id: GO:0032042
      label: mitochondrial DNA metabolic process
    modifier: DECREASED
  downstream:
  - target: Mitochondrial Bioenergetic Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Rescue of mtDNA and mitochondrial function supports a contribution of nucleotide-limited mtDNA maintenance; intermediate respiratory-subunit effects are not resolved by the abstract.
    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: Preclinical rescue supports nucleotide limitation in the experimental systems.
    hypothesis_groups:
    - serine_transport_mtdna
- name: Respiratory Chain Complex Deficiency
  biological_scale: CELLULAR
  description: Respiratory-complex deficiencies vary by tissue and patient. One neonatal liver showed reduced complexes I, III and IV, whereas fresh muscle complexes were normal in another confirmed case.
  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: Respiratory-complex abnormalities were observed in one neonatal liver.
  - 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: Plasma and cerebrospinal fluid lactate, plasma alanine, and respiratory chain complexes in fresh muscle were normal
    explanation: Normal muscle findings do not exclude SERAC1 disease.
  downstream:
  - target: Mitochondrial Bioenergetic Impairment
    causal_link_type: DIRECT
    description: Respiratory-chain abnormalities can impair oxidative phosphorylation.
    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: A four-patient hepatopathy series supports mitochondrial dysfunction.
- name: Mitochondrial Bioenergetic Impairment
  biological_scale: CELLULAR
  description: Impaired oxidative phosphorylation is a variable cellular consequence of SERAC1 deficiency. Lipid, calcium and mtDNA pathways are candidate contributors whose relative roles in human tissues remain unresolved.
  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: A four-patient hepatopathy series supports mitochondrial dysfunction.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  downstream:
  - target: Basal Ganglia Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mitochondrial dysfunction is a proposed contributor to selective basal-ganglia injury; the basis of selective vulnerability is unresolved.
    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: The MRI series defines tissue involvement without isolating the biochemical cause.
      directness: INDIRECT
  - target: Infantile hepatopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mitochondrial abnormalities coexist with infantile liver disease; the tissue-injury steps are not fully established.
    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: A four-patient hepatopathy series supports mitochondrial dysfunction.
      directness: INDIRECT
  - target: Sensorineural hearing loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hearing impairment is a clinical consequence associated with SERAC1 deficiency; its anatomical and molecular basis remains uncertain.
    evidence:
    - reference: PMID:40714654
      reference_title: Hearing rehabilitation in SERAC1 related MEGD(H)EL syndrome - implications from a multi-center retrospective cohort study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Detailed audiometric data, available for 23 of 31 patients, did not allow for general statements on site and degree of HL.
      explanation: The hearing cohort prevents assigning a specific cochlear cell or anatomical mechanism.
      directness: INDIRECT
  - target: 3-Methylglutaconic aciduria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: MEGDEL belongs to the secondary acidurias associated with mitochondrial phospholipid dysfunction; the exact route to organic-acid accumulation is unresolved.
    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: defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome)
      explanation: The classification supports a secondary phospholipid-associated aciduria.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lactate elevation accompanies some episodes of mitochondrial dysfunction.
    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: One neonatal crisis illustrates the metabolic association.
      directness: INDIRECT
- name: Basal Ganglia Neurodegeneration
  biological_scale: TISSUE
  description: MRI shows evolving basal-ganglia abnormalities, with early pallidal signal changes, putaminal and caudate swelling with relative dorsal-putaminal sparing, and later atrophy. The characteristic putaminal eye is stage dependent and is a strong diagnostic clue; molecular testing confirms the diagnosis.
  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.
  downstream:
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Basal-ganglia injury is a plausible contributor to dystonia, but clinical coexistence does not establish the full circuit mechanism.
    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: Dystonia and basal-ganglia abnormalities coexist in the sibling report.
      directness: INDIRECT
  - target: Leigh-like basal ganglia lesions
    causal_link_type: DIRECT
    description: The structural injury is expressed as the evolving MRI abnormality.
    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.
phenotypes:
- name: 3-Methylglutaconic aciduria
  category: Laboratory
  description: Urinary 3-methylglutaconic acid was elevated in 61/62 tested individuals (98%) in the 67-person cohort. Concentrations fluctuate, and a normal measurement does not exclude the disorder.
  phenotype_term:
    preferred_term: 3-Methylglutaconic aciduria
    term:
      id: HP:0003535
      label: 3-Methylglutaconic aciduria
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sixty‐one of 62 (98%) individuals had 3‐MGA‐uria
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: VERY_FREQUENT
- name: Sensorineural hearing loss
  category: Neurological
  description: Sensorineural hearing impairment was diagnosed in 48/61 (79%) in the 67-person cohort. It may be congenital or progressive and can follow a normal newborn screen. The later 36-person hearing cohort does not establish a uniform anatomical site.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Forty‐eight of 61 individuals (79%) were diagnosed with sensorineural hearing impairment
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: FREQUENT
- name: Dystonia
  category: Neurological
  description: Dystonia occurred in 53/65 (82%) of the 67-person cohort, with median onset at 18 months. Later-onset presentations also occur.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: dystonia at a median age of 18 months (53/65 = 82%, range of onset = 1–84 months)
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: VERY_FREQUENT
- name: Progressive spasticity
  category: Neurological
  description: Progressive limb spasticity occurred in 53/65 (82%), with median onset at 15 months in the 67-person cohort. Juvenile complicated spastic paraplegia is a recognized milder presentation.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Progressive spasticity of the limbs developed at a median age of 15 months (53/65 = 82%, range of onset = 1–48 months)
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: VERY_FREQUENT
- name: Motor developmental delay
  category: Neurological
  description: Delayed motor development occurred in 57/66 (86%) in the retrospective cohort.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first signs were delayed motor development (57/66 = 86%) and muscular hypotonia (59/65 = 90%), recognized at a median age of 6 months.
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: VERY_FREQUENT
- name: Developmental regression
  category: Neurological
  description: Loss of previously acquired skills was reported in 50/67 (75%), starting at a median of 12 months in the retrospective cohort.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Previously obtained skills were lost, starting from a median of 12 months of age, in the majority of individuals (50/67 = 75%).
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: FREQUENT
- name: Hypotonia
  category: Neurological
  description: Muscular hypotonia occurred in 59/65 in the 67-person cohort. Of 59 hypotonic individuals, 28 had axial and 17 generalized hypotonia; localization was unspecified for 14.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first signs were delayed motor development (57/66 = 86%) and muscular hypotonia (59/65 = 90%), recognized at a median age of 6 months.
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: VERY_FREQUENT
- name: Leigh-like basal ganglia lesions
  category: Imaging
  description: Stage-dependent basal-ganglia MRI changes, including a putaminal eye of relatively spared tissue, were found in the systematic imaging series. The eye is not present at every age; later stages show atrophy. Genetic testing confirms the diagnosis.
  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.
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI studies were available for 55/67 individuals. In all individuals, alterations of the basal ganglia at different stages were observed.
    explanation: Primary cohort imaging supports high frequency with an available-MRI denominator.
  review_notes: MRI findings are ascertainment sensitive. The 67-person cohort lists basal-ganglia involvement as 55/56 in Table 1, while the narrative reports abnormalities in all 55 individuals with available MRI. The eye sign itself is stage dependent.
- name: Infantile hepatopathy
  category: Gastrointestinal
  description: Severe neonatal liver dysfunction occurred in 30/62 (48%) in the cohort. Nine of those 30 fulfilled neonatal liver-failure criteria; that 30% subgroup rate must not be applied to all affected individuals. Hepatic abnormalities often improved after infancy.
  phenotype_term:
    preferred_term: Decreased liver function
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Severe neonatal liver dysfunction was reported in 30/62 (48%) individuals. Nine of these 30 (30%) individuals fulfilled the criteria of neonatal liver failure
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: FREQUENT
  review_notes: 'PMID:29205472 is internally inconsistent: Table 1 lists neonatal liver failure as 15/65, whereas the narrative describes nine of 30 individuals with severe neonatal liver dysfunction. The description retains the explicitly qualified narrative count; no total-cohort failure frequency is assigned.'
- name: Lactic acidosis
  category: Laboratory
  description: Lactic acidosis is reported during metabolic crises, but normal lactate occurs in confirmed cases. The cohort rate for elevated serum lactate should not be interpreted as a rate for acidosis.
  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: Hyperammonemia can accompany neonatal hepatic dysfunction, including severe crises. Seven individuals in the cohort had hyperammonemia without meeting its complete liver-failure definition; a general frequency was not established.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seven individuals did not meet the full definition of liver failure but presented hyperammonemia
    explanation: Hyperammonemia can accompany incomplete or severe hepatic presentations.
- name: Hypoglycemia
  category: Laboratory
  description: Recurrent neonatal hypoglycemia was reported in 29/65 (44%) in the retrospective cohort.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twenty‐nine individuals had recurrent hypoglycemia (glucose values < 2mmol/l in 29/65 = 44%)
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: FREQUENT
- name: Seizures
  category: Neurological
  description: Epilepsy was reported in 23/66 (35%) in the retrospective cohort; seizure types vary.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Epilepsy was reported in 23/66 individuals (35%).
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: FREQUENT
- name: Microcephaly
  category: Neurological
  description: Acquired microcephaly is documented in individual cases; available case reports do not establish a population frequency.
  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: Optic atrophy was documented by fundoscopy or MRI in 14/55 (25%) in the cohort. One separate case developed bilateral optic atrophy by age four.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fourteen of 55 individuals (25%) had signs of optic atrophy documented on fundoscopy or MRI
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: OCCASIONAL
- name: Failure to thrive
  category: Constitutional
  description: Failure to thrive and feeding problems were jointly reported in 52/66 individuals (79%). The grouped count does not establish a separate frequency for failure to thrive.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Failure to thrive and feeding problems were a common and concomitant problem (52/66 individuals = 79%).
    explanation: Primary retrospective cohort; denominator is specific to this feature.
- name: Intellectual disability
  category: Neurological
  description: Intellectual disability was recorded in all 67 members of this mostly severe historical cohort; severity was severe in 37, moderate in eight and mild in six of 51 with severity data. This ascertainment-specific finding does not establish obligate intellectual disability across the expanded SERAC1 spectrum.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 67 individuals had intellectual disability, varying in severity (severe, 37/51 = 73%; moderate, 8/51 = 16%; mild, 6/51 = 12%; data on severity were lacking for 16 individuals).
    explanation: Primary retrospective cohort; denominator is specific to this feature.
- name: Scoliosis
  category: Musculoskeletal
  description: Scoliosis developed with disease progression in 19/49 (39%) with data in the retrospective cohort.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: With disease progression, 39% (19/49) of individuals developed scoliosis.
    explanation: Primary retrospective cohort; denominator is specific to this feature.
  frequency: FREQUENT
- name: Autistic behavior
  category: Behavioral
  description: Autistic behavior was reported in a genetically confirmed adult with progressive dystonia and spastic tetraparesis; its frequency in the disorder is unknown.
  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.
- name: Absent speech
  category: Neurological
  description: Speech was completely absent in 34/61 (56%) in the cohort. Others acquired and later lost words; hearing loss alone does not account for the communication phenotype.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 56% of individuals (34/61), speech was completely absent.
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
  frequency: FREQUENT
  review_notes: PMID:29205472 gives 34/61 in the narrative and 34/59 in Table 1. The description uses the narrative denominator; both fall in the FREQUENT band.
- name: Feeding difficulties
  category: Gastrointestinal
  description: Feeding problems accompanied failure to thrive in a grouped 52/66 cohort observation. Thirty-seven of 58 received tube feeding; the combined rate is not a separate feeding-difficulty estimate.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Failure to thrive and feeding problems were a common and concomitant problem (52/66 individuals = 79%).
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
- name: Dysphagia
  category: Gastrointestinal
  description: Dysphagia occurs with oropharyngeal dyskinesia and drooling. The cohort reports a combined 34/59 group, not a separate dysphagia frequency.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typically, individuals presented oropharyngeal dyskinesia with repetitive protrusion of the tongue, dysphagia, and excessive drooling (34/59 [58%]).
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
- name: Drooling
  category: Gastrointestinal
  description: Excessive drooling accompanies impaired oropharyngeal control. A separate frequency cannot be derived from the grouped dyskinesia/dysphagia/drooling count.
  phenotype_term:
    preferred_term: Drooling
    term:
      id: HP:0002307
      label: Drooling
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typically, individuals presented oropharyngeal dyskinesia with repetitive protrusion of the tongue, dysphagia, and excessive drooling (34/59 [58%]).
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
- name: Elevated hepatic transaminases
  category: Hepatic
  description: Transient AST/ALT elevations were reported in 42/55 (76%) in the cohort, most prominently in the first year. Severe neonatal synthetic dysfunction can also occur without elevated transaminases.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During the course of a life ASAT/ALAT were transiently increased on multiple occasions in 42/55 (76%) individuals
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
  frequency: FREQUENT
- name: Hepatomegaly
  category: Hepatic
  description: Hepatomegaly at any age was recorded in 17/64 (27%) in the cohort.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hepatomegaly at any age during their lifetime was reported in 17/64 (27%) individuals
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
  frequency: OCCASIONAL
- name: Cholestasis
  category: Hepatic
  description: Transient cholestasis and jaundice were recorded together in 24/50 (48%) during the first year of life.
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During the first year of life, 24/50 (48%) individuals were reported with transient cholestasis and jaundice.
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
  frequency: FREQUENT
- name: Renal tubular dysfunction
  category: Renal
  description: Impaired renal tubular function was reported in 8/66 (12%), usually transient and neonatal.
  phenotype_term:
    preferred_term: Renal tubular dysfunction
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eight individuals showed impaired tubular function (8/66 = 12%; eg, P3510) mostly transient and in the neonatal period.
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
  frequency: OCCASIONAL
- name: Recurrent respiratory infections
  category: Respiratory
  description: Recurrent respiratory infections affected 28/66 (42%) and contributed substantially to mortality. The authors proposed aspiration and impaired airway clearance; they did not identify an immune defect.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Many individuals suffered recurrent respiratory infections (28/66 = 42%), which were also the main cause of death.
    explanation: Primary cohort observation; any stated denominator applies to this feature only.
  frequency: FREQUENT
- name: Visual impairment
  category: Ophthalmologic
  description: Impaired vision was reported in 26/62 (42%) in the cohort. Optic atrophy is recorded separately; the broader impairment does not establish a single cause.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A total of 26 individuals of 62 (42%) were reported to have impaired vision.
    explanation: Retrospective cohort observation; the denominator reflects available data.
  frequency: FREQUENT
- name: Hyperlactatemia
  category: Biochemical
  description: Serum lactate was elevated in 51/61 (84%) in the cohort. This biochemical measurement does not necessarily imply acidosis and can be normal in individual confirmed cases.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serum lactate levels were increased in 51 of 61 (84%) individuals
    explanation: Retrospective cohort observation; the denominator reflects available data.
  frequency: VERY_FREQUENT
- name: Abnormal coagulation
  category: Hematologic
  description: Disturbed coagulation tests were reported in 18/55 (33%) in the cohort, but only one individual had bleeding. Elevated INR was included in the neonatal liver-failure definition.
  phenotype_term:
    preferred_term: Abnormality of coagulation
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: disturbed coagulation tests were documented in 18 of 55 individuals (33%), but only 1 (1/55) had subsequent bleeding problems.
    explanation: Retrospective cohort observation; the denominator reflects available data.
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: disturbed coagulation with international normalized ratio > 2, and encephalopathy
    explanation: Elevated INR formed part of the neonatal liver-failure criteria.
  frequency: FREQUENT
- name: Inability to walk independently
  category: Neurological
  description: Twenty-six of 38 cohort individuals never acquired independent walking. The source narrative incorrectly labels this fraction 78%; the count corresponds to approximately 68%. Later mild presentations can preserve ambulation.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seventy‐eight percent (26/38) of the individuals never learned to walk.
    explanation: Retrospective cohort observation; the denominator reflects available data.
  frequency: FREQUENT
  review_notes: 'The source has an arithmetic inconsistency: 26/38 is approximately 68%, as also given in its abstract, rather than 78%. The count is retained and the incorrect narrative percentage is not propagated.'
- name: Cerebellar atrophy
  category: Neurological
  description: Progressive cerebellar volume loss was documented in an individual child, alongside basal-ganglia degeneration. Its frequency is not established.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar 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: Follow-up MRIs demonstrated progressive basal ganglia and cerebellar volume loss.
    explanation: Human cerebellar involvement prevents interpreting canine cerebellar pathology as an exclusively nonhuman feature.
biochemical:
- name: Phosphatidylglycerol 34:1 to 36:1 ratio
  notes: An increased PG34:1/PG36:1 ratio in cultured fibroblasts supports defective remodeling. Partial rescue by wild-type SERAC1 supports causality. A milder ratio in one HSP-family line is not a validated predictor of severity for all variants.
  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: IN_VITRO
    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: IN_VITRO
    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: Urinary 3-methylglutaconic and 3-methylglutaric acid elevations are diagnostic clues. Levels may fluctuate or be initially normal; the aciduria is secondary and not specific to SERAC1.
  presence: INCREASED
  readouts:
  - target: 3-Methylglutaconic aciduria
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Urine organic acid analysis is the standard assay reporting on this node.
    evidence:
    - reference: PMID:29205472
      reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Sixty‐one of 62 (98%) individuals had 3‐MGA‐uria
      explanation: Quantifies the urinary finding in confirmed SERAC1 disease.
  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 filipin staining detects excess or unevenly distributed free cholesterol in some patient fibroblasts. It was abnormal in only 6/10 tested cohort lines and can be negative in classic and mild disease.
  presence: INCREASED
  readouts:
  - target: 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.
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Filipin staining of fibroblasts was abnormal in 6 of 10 (60%) individuals.
    explanation: Normal staining cannot exclude SERAC1 deficiency.
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: Some infants present in the first days of life with hypoglycemia, sepsis-like illness, hepatic dysfunction and metabolic abnormalities. Severe liver failure or multiorgan failure can be fatal, but neonatal disease is variable and liver abnormalities often improve.
  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 the diagnostic work-up of a newborn infant with a metabolic crisis, lethal multiorgan
      failure on day six of life, and increased excretion of 3-methylglutaconic acid, we found using
      whole genome sequencing a homozygous SERAC1 mutation indicating MEGDHEL syndrome
      (3-methylglutaconic aciduria with deafness-dystonia, hepatopathy, encephalopathy, and
      Leigh-like syndrome).
    explanation: >-
      Restores the homozygous SERAC1/MEGDHEL diagnosis of the neonate with lethal metabolic crisis.
      The selected clinical sentence does not supply every biochemical detail or demonstrate an
      intervention window.
- 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:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: By age two years, spasticity, dystonia, epilepsy, and progressive deafness prevent further psychomotor development and/or result in loss of acquired skills.
    explanation: Summarizes progression in the severe infantile phenotype.
    quote_role: REVIEW_SYNTHESIS
- phase: Milder later-onset course
  notes: Later-onset complicated spastic paraplegia or dystonia can progress more slowly. Some children improve developmental skills; variant class alone does not establish the trajectory.
  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.
- phase: Variable survival
  notes: Survival cannot be summarized as inevitable early death. In the 67-person historical cohort, 16 individuals died at a median age of nine years; the cohort included survivors into adulthood. These are cohort observations, not a current population survival estimate.
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sixteen individuals passed away at a median age of 9 years (range = 5 days–16 years
    explanation: Reports deaths with their observed age distribution.
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite the severity of neurological impairment, most affected individuals survive into adulthood.
    explanation: The cohort discussion explicitly counters a universal early-lethal description.
prevalence:
- population: Published cases worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: A 2020 review identified at least 102 published patients. This historical case count does not establish population point prevalence.
  evidence:
  - reference: PMID:32684373
    reference_title: MEGDEL Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Since the first description of MEGDEL syndrome in 2006, at least 102 patients have been reported
    explanation: Historical review count.
    quote_role: REVIEW_SYNTHESIS
- population: International clinical cohort
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: The 67-person cohort supports panethnic occurrence; consanguinity was reported in 38/59 families. Candidate founder variants occur in European families. These observations do not establish ethnicity-specific population rates.
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 38 of 59 (64%) families, consanguinity was reported.
    explanation: Provides the cohort denominator.
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: showing that MEGDHEL syndrome is a panethnic condition.
    explanation: Cases arose across geographic ancestries.
- population: Genetic database estimates
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: GeneReviews quotes 0.09 per 100,000 from Tan et al. The underlying study estimates genetic lifetime risk from allele frequencies under Hardy-Weinberg equilibrium and full penetrance; this is not observed point prevalence. The SERAC1 numerical estimate is not reproduced as a measured population rate here.
  evidence:
  - reference: PMID:32305867
    reference_title: Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The lifetime risk is defined as the proportion of a population that at some point in life will develop the disease.
    explanation: Defines the modeled measure.
  - reference: PMID:32305867
    reference_title: Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Biallelic combinations of variants were considered to be fully penetrant.
    explanation: Identifies a material modeling assumption.
diagnosis:
- name: Urine organic acid analysis
  description: Urinary organic-acid analysis can identify 3-methylglutaconic and 3-methylglutaric acid elevations and direct molecular testing. Levels fluctuate and can be initially normal; the biochemical finding alone is not specific for MEGDEL.
  diagnosis_term:
    preferred_term: urine organic acid analysis
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:29686941
    reference_title: Adult-onset Generalized Dystonia as the Main Manifestation of MEGDEL Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the 3-methylglutaconic aciduria level may fluctuate and can be transiently undetectable.
    explanation: The longitudinal case illustrates why a normal result does not exclude disease.
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In all these cases, urinary organic acid analysis and appropriate genetic testing for SERAC1 variants should be performed.
    explanation: Primary cohort recommends combined biochemical and genetic investigation.
- name: Brain MRI pattern recognition
  description: The evolving basal-ganglia pattern, especially relative dorsal-putaminal sparing within affected putamen, is a strong clue. The eye is stage dependent, and MRI does not replace molecular confirmation.
  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:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The diagnosis of SERAC1 deficiency is established in a proband with suggestive clinical and metabolic (3-methylglutaconic aciduria) findings and biallelic pathogenic variants in SERAC1 identified by molecular genetic testing.
    explanation: GeneReviews supplies the current confirmatory framework.
    quote_role: REVIEW_SYNTHESIS
  notes: The original imaging series termed the sign pathognomonic; current diagnostic criteria require biallelic pathogenic or likely pathogenic SERAC1 variants.
- name: Fibroblast phosphatidylglycerol and filipin profiling
  description: Fibroblast PG profiling and filipin staining can support functional assessment, particularly for uncertain alleles. A mild PG shift in one family is not a general prognostic test; normal filipin staining does not exclude the disorder.
  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: IN_VITRO
    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.
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Filipin staining of fibroblasts was abnormal in 6 of 10 (60%) individuals.
    explanation: Normal staining cannot exclude SERAC1 deficiency.
- name: SERAC1 sequencing with copy-number analysis
  description: Identify biallelic pathogenic or likely pathogenic SERAC1 variants with appropriate phase assessment. Panels, exome or genome sequencing may require additional deletion/duplication analysis when copy-number detection is incomplete. Two variants of uncertain significance do not independently confirm the diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The diagnosis of SERAC1 deficiency is established in a proband with suggestive clinical and metabolic (3-methylglutaconic aciduria) findings and biallelic pathogenic variants in SERAC1 identified by molecular genetic testing.
    explanation: GeneReviews supplies the current confirmatory framework.
    quote_role: REVIEW_SYNTHESIS
  - 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: deletion of (at least) exons 2-4, pathogenic
    explanation: A reported multiexon deletion supports attention to copy-number coverage.
differential_diagnoses:
- name: Primary 3-methylglutaconic aciduria (AUH deficiency)
  description: AUH deficiency causes primary 3-methylglutaconic aciduria through defective leucine catabolism. MEGDEL is classified among secondary acidurias associated with phospholipid remodeling.
  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: '"primary 3-methylglutaconic aciduria" formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, 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.
    quote_role: REVIEW_SYNTHESIS
- name: Other secondary 3-methylglutaconic acidurias
  description: Barth syndrome, Costeff syndrome, DNAJC19-related DCMA, and TMEM70-, CLPB- or TIMM50-related disorders can share secondary 3-methylglutaconic aciduria. Clinical patterns and molecular testing distinguish them.
  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: OTHER
    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.
    quote_role: BACKGROUND
- name: ATAD3A-related Harel-Yoon syndrome
  description: GeneReviews includes ATAD3A-related Harel-Yoon syndrome in the genetic differential. Developmental delay, hypotonia and optic atrophy overlap with MEGDEL; axonal neuropathy and hypertrophic cardiomyopathy are additional features of the ATAD3A-related spectrum.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/
    reference_title: SERAC1 Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Global DD, hypotonia, optic atrophy, axonal neuropathy, hypertrophic cardiomyopathy
    explanation: The ATAD3A/Harel-Yoon row of GeneReviews Table 4 lists these findings in the genetic differential; the quote is the complete features cell.
- name: HTRA2 defect
  description: HTRA2-related disease can resemble severe neonatal MEGDEL through movement abnormalities, seizures and 3-methylglutaconic aciduria. Central hypopnea/apnea and neutropenia were prominent in the 11-person HTRA2 series, in which death occurred within the first month. This is one differential, not an established uniquely closest diagnosis.
  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.
    directness: INDIRECT
environmental: []
treatments:
- name: Supportive Multidisciplinary Care
  description: Care is supportive, coordinated across metabolic medicine, neurology, nutrition, rehabilitation, audiology and other specialties according to involvement. No disease-modifying human treatment has been established.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietician, and physical therapist when possible.
    explanation: GeneReviews recommends coordinated supportive care.
    quote_role: REVIEW_SYNTHESIS
- name: Neonatal Metabolic Crisis Management
  description: Urgent specialist management addresses hypoglycemia, hyperammonemia, coagulopathy and other organ dysfunction. In one severe neonatal case initially managed as a suspected urea-cycle disorder, protein was temporarily withheld, intravenous glucose and ammonia-lowering therapies were given, and continuous dialysis controlled ammonia. This empiric crisis regimen is not a disease-specific treatment protocol.
  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: Individualized Hearing Rehabilitation
  description: Hearing aids and cochlear implants have been used, but expected benefit should be discussed with audiology and the family. In a 36-person retrospective hearing study, 22 received hearing aids and six subsequently received implants; only one implanted individual acquired spoken language, which became less clear with progression. Improved environmental interaction can still be meaningful. The auditory lesion is not consistently localized.
  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: Auditory augmentation may improve access to sound; clinical language benefit is variable and often limited.
    evidence:
    - reference: PMID:40714654
      reference_title: Hearing rehabilitation in SERAC1 related MEGD(H)EL syndrome - implications from a multi-center retrospective cohort study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Twenty-two individuals received hearing rehabilitation with conventional hearing aids, followed by cochlear implant (CI) surgery in six. One of these six individuals acquired spoken language, which lessened in clarity as disease progressed.
      explanation: Primary hearing-rehabilitation cohort defines limited and variable language benefit.
  evidence:
  - reference: PMID:40714654
    reference_title: Hearing rehabilitation in SERAC1 related MEGD(H)EL syndrome - implications from a multi-center retrospective cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twenty-two individuals received hearing rehabilitation with conventional hearing aids, followed by cochlear implant (CI) surgery in six. One of these six individuals acquired spoken language, which lessened in clarity as disease progressed.
    explanation: Primary hearing-rehabilitation cohort defines limited and variable language benefit.
- name: Reported Dexmedetomidine-based Anaesthesia
  description: One two-year-old undergoing cochlear implantation tolerated ketamine and dexmedetomidine induction with dexmedetomidine maintenance. This case supports feasibility in that individual; it does not establish an optimal anaesthetic regimen, comparative safety or a specific malignant-hyperthermia susceptibility in MEGDEL.
  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 ICU period was smooth, and she was released the next day. The anaesthetic plan was tolerated without any complications.
    explanation: Single-case perioperative outcome; no comparative safety inference.
  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: Assess growth, nutritional intake and swallowing safety. Feeding therapy and enteral support, including gastrostomy when needed, address inadequate intake or unsafe feeding.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Management of neonatal hypoglycemia; feeding therapy and gastrostomy tube as needed
    explanation: GeneReviews recommends feeding support.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Thirty‐seven of 58 individuals (64%) were given tube feeding.
    explanation: Tube feeding was common in the primary cohort.
- name: Perioperative Risk Management
  description: Plan anaesthesia individually with attention to organ involvement, glucose, hydration, temperature and postoperative recovery. The MEGDEL case report discusses limiting fasting, avoiding prolonged propofol infusion and avoiding succinylcholine in patients with myopathy based on wider mitochondrial-disease practice; these are extrapolated precautions, not MEGDEL-specific comparative evidence.
  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: OTHER
    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: The case report summarizes a wider myopathy precaution; it does not establish a MEGDEL-specific absolute contraindication.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:39592976
    reference_title: Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:39592976
    reference_title: Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: BACKGROUND
    directness: INDIRECT
  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: When both parents carry a pathogenic SERAC1 variant, each pregnancy has a 25% chance of an affected child. Confirm familial variants and phase, offer carrier testing to at-risk relatives, and discuss prenatal or preimplantation testing when appropriate.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected
    explanation: GeneReviews recurrence risk assumes both parents are known carriers.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Once the SERAC1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
    explanation: Family testing requires known pathogenic variants.
    quote_role: REVIEW_SYNTHESIS
- name: Baclofen for Spasticity
  description: Oral or intrathecal baclofen may improve spasticity, sometimes temporarily. In the historical cohort, oral baclofen was reported beneficial in 11 of 15 individuals, ineffective in two and associated with worsening in two; responses require individual assessment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
  evidence:
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Oral baclofen was given to 15 individuals. It was reported as having a positive effect in 11 individuals, whereas in 2 no change was observed, and in another 2, clinical deterioration of spasticity was seen.
    explanation: Uncontrolled retrospective response data.
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: some individuals have experienced (temporary) improvement of spasticity with oral or intrathecal baclofen treatment
    explanation: GeneReviews summarizes symptomatic use.
    quote_role: REVIEW_SYNTHESIS
- name: Deep Brain Stimulation
  description: GPi stimulation may be considered for selected refractory dystonia or parkinsonism. A teenage case improved from BFMDRS 30.5 to seven at two years without correction of scoliosis. A separate adult report describes benefit at six months, but its preceding genetic report classified p.Arg411Cys as a VUS. Both are uncontrolled observations, with limited generalizability to severe infantile disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Deep Brain Stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  evidence:
  - reference: PMID:33426169
    reference_title: Secondary Dystonia in a Novel Mitochondriopathy Responsive to Deep Brain Stimulation Therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her improvement is highlighted by a 2‐year follow‐up BFMDRS score of 7. Importantly, following DBS, the scoliosis did not change
    explanation: Case-level benefit with a persistent structural manifestation.
  - reference: PMID:40884098
    reference_title: GPi-DBS for SERAC1-Related Dystonia-Parkinsonism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical response to GPi‐DBS has been quantitatively evaluated with the Movement Disorders Society Unified Dystonia Rating Scale (40 → 19)
    explanation: A second uncontrolled adult outcome.
  - reference: PMID:40145675
    reference_title: 'Adult-Onset Dystonia-Parkinsonism: Do Not Forget SERAC1.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: rare (gnomAD AF. 0000031, ACMG‐PM2), and overall classified as a variant of uncertain significance (VUS).
    explanation: The adult case has a material molecular-confirmation limitation.
- name: Physical Therapy
  description: Physical therapy and positioning or mobility equipment support function and reduce orthopedic complications; tailor the program to progressive motor limitations.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/
    reference_title: SERAC1 Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications
    explanation: Full GeneReviews motor-management recommendations.
    quote_role: REVIEW_SYNTHESIS
- name: Occupational Therapy
  description: Occupational therapy supports fine-motor activities and adaptive equipment.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/
    reference_title: SERAC1 Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function
    explanation: Full GeneReviews recommends assistance with adaptive tasks.
    quote_role: REVIEW_SYNTHESIS
- name: Developmental and Communication Support
  description: Provide educational support and speech-language assessment, including augmentative and alternative communication tailored to cognition, hearing and motor abilities.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/
    reference_title: SERAC1 Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically takes into account cognitive abilities, sensory impairments, and motor skills to determine the most appropriate form of communication.
    explanation: Full GeneReviews communication-management recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Seizure Management
  description: Manage epilepsy with an experienced neurologist. GeneReviews advises avoiding medications known to impair mitochondrial function, including valproic acid.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Developmental and educational support; management of seizures per experienced neurologist; treatment of liver disease per hepatologist
    explanation: Specialist-directed symptomatic treatment.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Agents and circumstances to avoid: Medications known to impair mitochondrial function (e.g., valproic acid).'
    explanation: GeneReviews avoidance guidance; no disease-specific comparative drug trial is implied.
    quote_role: REVIEW_SYNTHESIS
- name: Management of Drooling
  description: Specialist treatment can include salivary-gland botulinum toxin or surgery when drooling contributes to respiratory problems. Two cohort individuals improved with orally administered atropine drops; this is limited case experience.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: respiratory problems resulting from excessive drooling improve with botulinum toxin injection in the salivary glands, extirpation of salivary glands, and/or rerouting of glandular ducts.
    explanation: GeneReviews summarizes symptomatic options.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:29205472
    reference_title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: P28 and P65 were given atropine 0.5% eye drops orally (1 drop every 6 hours), which reduced drooling to a normal level without any side effects.
    explanation: Reported atropine response in two individuals; not a controlled efficacy estimate.
- name: Clinical Surveillance
  description: Monitor glucose in infantile MEGD(H)EL and assess growth, nutrition, swallowing, neurological progression, communication, hearing, musculoskeletal and vision problems, and family needs at visits and at least annually. Monitor liver dysfunction with hepatology input.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24741715
    reference_title: SERAC1 Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: At each visit and at least annually assess growth, nutrition, safety of oral intake, neurologic manifestations, developmental progress, cognition, educational needs, hearing, musculoskeletal manifestations, ophthalmology evaluation, and family needs; laboratory assessment of liver dysfunction per hepatologist.
    explanation: GeneReviews surveillance recommendations.
    quote_role: REVIEW_SYNTHESIS
mechanistic_hypotheses:
- hypothesis_group_id: serine_transport_mtdna
  hypothesis_label: SERAC1 as an outer-membrane partner of the serine transporter SFXN1
  status: EMERGING
  description: SERAC1-dependent SFXN1 serine transport supports mitochondrial one-carbon metabolism, nucleotide supply and mtDNA maintenance in experimental systems. This pathway could coexist with lipid remodeling. Its relative importance in human disease and its relationship to tissue-specific lipid and calcium abnormalities remain unresolved. Nucleoside/nucleotide rescue is preclinical.
  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: IN_VITRO
    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: The experimental study identifies SERAC1-dependent SFXN1 transport.
  - 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 in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides
    explanation: This proposed sequence was studied in mice and cellular models; it is not a universal clinical finding.
  - 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: Preclinical rescue supports nucleotide limitation in the experimental systems.
animal_models:
- name: Serac1 knockout mouse
  species: Mouse
  genotype: Serac1-/-
  publication: PMID:35235340
  description: Serac1-null mice were reported to reproduce major diagnostic clinical and biochemical features and support the serine-transport/mtDNA pathway. Nucleoside or nucleotide supplementation rescued mtDNA content and mitochondrial function experimentally.
  modeled_mechanisms:
  - target: Mitochondrial DNA Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The mouse reproduces mtDNA depletion and the biochemical diagnostic phenotype, and nucleoside supplementation restores mtDNA content.
    limitations: The accessible source is an abstract. It does not resolve which lipid abnormalities or stage-specific human MRI lesions were reproduced, nor the contribution of each pathway to human disease. Preclinical rescue does not establish clinical efficacy or safety.
    readouts:
    - name: Mitochondrial DNA content
      target: Mitochondrial DNA 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: Mitochondrial DNA 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: Naturally occurring SERAC1-associated multiple system degeneration affects Kerry Blue Terriers and Chinese Crested dogs. Breed-specific variant concordance and affected compound-heterozygous crosses support genetic causation. Splice disruption was demonstrated for the Chinese Crested allele; loss of protein activity was not directly measured.
  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: Published canine neuropathology includes Purkinje-cell, striatal and nigral neuronal loss with ataxia and tremor. Hearing and cognition were not assessed, and hepatic or urine organic-acid phenotyping was not reported. These are untested features, not established absences. The paper does not demonstrate canine lipid, serine-transport or mtDNA abnormalities.
    readouts:
    - name: Striatal neuronal abundance
      target: Basal Ganglia Neurodegeneration
      direction: DECREASED
      interpretation: Reported postmortem striatal neuronal loss provides a neuropathological correlate; the paper summarizes prior pathology rather than a new quantitative neuron-counting assay.
      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: Describes canine neuropathology without asserting absence of these anatomical findings in humans.
    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.
    - reference: PMID:39596578
      reference_title: Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Although cognitive function and hearing loss were not assessed in the affected dogs, the canine disorder appears to closely resemble early-onset MEGDHEL syndrome.
      explanation: The authors explicitly identify unassessed model features.
  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: Strong genotype-phenotype concordance supports the association with the canine disorder.
- name: Lpgat1 knockout mouse
  species: Mouse
  genotype: Lpgat1-/-
  publication: PMID:37917582
  description: A parallel phospholipid-remodeling model, not a SERAC1 genotype model. Lpgat1 deletion produces altered PG species, mitochondrial defects, aciduria, hearing impairment, hepatopathy and cardiomyopathy. It motivates a candidate pathway but does not establish LPGAT1 as a human MEGDEL gene.
  modeled_mechanisms:
  - target: Impaired Phosphatidylglycerol Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: LPGAT1-deficient cells and mice connect PG remodeling and mitochondrial PG transport, with a PG34:1/PG36:1 shift resembling SERAC1 deficiency.
    limitations: The perturbed gene is LPGAT1. Cardiomyopathy and mortality in these mice cannot be generalized to human SERAC1 disease. Precise PHB/TIM lipid-transfer activity remains unresolved.
    evidence:
    - reference: PMID:37917582
      reference_title: LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: LPGAT1 deficiency also significantly increased the ratio of PG-34:1/PG-36:1 relative to vector control cells
      explanation: Cellular lipid similarity supports a partial pathway analogy.
      directness: INDIRECT
    - reference: PMID:37917582
      reference_title: LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: ablation of LPGAT1 in mice leads to multiple common features of MEGDEL syndrome, including neonatal hypoglycemia, high mortality rate, sudden death, growth delay, 3-MGA aciduria, deafness, hepatopathy, and dilated cardiomyopathy
      explanation: Mouse phenotype overlap supports a related model, not human genetic causation.
      directness: INDIRECT
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-cell PG abnormalities and their partial normalization by wild-type SERAC1 directly connect SERAC1 dysfunction to lipid remodeling.
    limitations: Fibroblast findings do not establish tissue-specific neuronal, auditory or hepatic pathology.
    readouts:
    - name: PG-34:1 to PG-36:1 ratio
      target: Impaired Phosphatidylglycerol Remodeling
      direction: INCREASED
      interpretation: The ratio is a direct lipidomic readout of altered phosphatidylglycerol remodeling.
      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
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: A severe neonatal patient line shows a severely fragmented mitochondrial network and altered cristae morphology as distinct structural findings.
    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
      direction: ALTERED
      interpretation: Network morphology is observed in patient cells; it does not itself establish defective ER contact sites.
      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.
    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.
  - target: Deficient Mitochondrial Calcium Handling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The same severe neonatal patient line shows deficient cytoplasm-to-mitochondria calcium buffering, a functional finding distinct from the structural network and cristae changes.
    limitations: The measurement comes from a single patient line carrying one severe truncating allele, so allelic and interindividual variation in calcium handling is unknown, and fibroblast calcium buffering does not establish the equivalent defect in neurons or hair cells.
    readouts:
    - name: Cytoplasm-to-mitochondria calcium buffering
      target: Deficient Mitochondrial Calcium Handling
      direction: DECREASED
      interpretation: Direct observation of impaired cytoplasm-to-mitochondria calcium buffering.
      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: The calcium buffer function between cytoplasm and mitochondria was deficient
      explanation: Establishes the model as informative for the calcium-handling node.
discussions:
- discussion_id: serac1_pathway_relationship
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How do SERAC1-dependent lipid remodeling and serine transport contribute to human disease?
  attaches_to:
  - pathophysiology#Impaired Phosphatidylglycerol Remodeling
  - mechanistic_hypotheses#serine_transport_mtdna
  rationale: Patient fibroblast lipid rescue and experimental serine/nucleotide rescue support complementary roles. ER-mitochondria contact-site and outer-membrane localization are not mutually exclusive. Their relationship and tissue-specific contributions remain uncertain; normal clinical mtDNA or respiratory assays do not exclude disease.
  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: Wild-type complementation partially rescues the patient-cell lipid ratio.
  - 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: IN_VITRO
    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: The experimental study identifies SERAC1-dependent SFXN1 transport.
  - 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: Preclinical rescue supports nucleotide limitation in the experimental systems.
- discussion_id: canine_model_organ_coverage
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Which auditory, hepatic and biochemical features are reproduced in SERAC1-associated canine degeneration?
  attaches_to:
  - phenotypes#Sensorineural hearing loss
  - phenotypes#Infantile hepatopathy
  - phenotypes#3-Methylglutaconic aciduria
  rationale: The canine paper establishes a movement disorder and neuropathological overlap. Hearing and cognition were unassessed; liver and organic-acid measures were not reported. Direct phenotyping is needed before using this model for those disease manifestations. Normal findings would limit those particular model outcomes, not refute human disease mechanisms.
  evidence:
  - reference: PMID:39596578
    reference_title: Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Although cognitive function and hearing loss were not assessed in the affected dogs, the canine disorder appears to closely resemble early-onset MEGDHEL syndrome.
    explanation: The authors explicitly identify unassessed model features.
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:23296368
  title: 'Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.'
- 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:24741715
  title: SERAC1 Deficiency.
  tags:
  - GeneReviews
- reference: PMID:24997715
  title: 'The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations.'
- reference: PMID:25051967
  title: 'MEGDEL Syndrome in a Child From Palestine: Report of a Novel Mutation in SERAC1 Gene.'
- reference: PMID:25642805
  title: 'Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome.'
- reference: PMID:27186703
  title: Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation.
- reference: PMID:28916646
  title: 'SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.'
- reference: PMID:29205472
  title: 'Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.'
- reference: PMID:29686941
  title: Adult-onset Generalized Dystonia as the Main Manifestation of MEGDEL Syndrome.
- reference: PMID:30114719
  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.'
- reference: PMID:32305867
  title: Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases.
- reference: PMID:32684373
  title: MEGDEL Syndrome.
- reference: PMID:33426169
  title: Secondary Dystonia in a Novel Mitochondriopathy Responsive to Deep Brain Stimulation Therapy.
- reference: PMID:33613893
  title: Identification of the rs797045105 in the SERAC1 Gene by Whole-exome Sequencing in a Patient Suspicious of MEGDEL Syndrome.
- reference: PMID:34751152
  title: Severe neonatal MEGDHEL syndrome with a homozygous truncating mutation in SERAC1.
- reference: PMID:35223715
  title: Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family.
- reference: PMID:35235340
  title: SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA.
- reference: PMID:35781780
  title: Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency.
- reference: PMID:35943861
  title: 'First description of the MEGDEHL syndrome in the Tunisian population via whole-exome sequencing: Novel nonsense mutation in SERAC1 gene.'
- reference: PMID:37711114
  title: SERAC1 Deficiency- A New Phenotype.
- reference: PMID:37917582
  title: LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.
- reference: PMID:38445077
  title: 'Distinct neonatal hyperammonemia and liver synthesis dysfunction: case report of a severe MEGDHEL syndrome.'
- reference: PMID:39592976
  title: Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant.
- reference: PMID:39596578
  title: Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1.
- reference: PMID:40145675
  title: 'Adult-Onset Dystonia-Parkinsonism: Do Not Forget SERAC1.'
- reference: PMID:40714654
  title: Hearing rehabilitation in SERAC1 related MEGD(H)EL syndrome - implications from a multi-center retrospective cohort study.
- reference: PMID:40821445
  title: 'Expanding the Epidemiological and Phenotypic Spectrum of MEGDEL Syndrome: The First Case Report From Egypt.'
- reference: PMID:40884098
  title: GPi-DBS for SERAC1-Related Dystonia-Parkinsonism.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/
  title: SERAC1 Deficiency - GeneReviews® - NCBI Bookshelf
notes: This entry includes the infantile MEGD(H)EL, juvenile complicated spastic paraplegia and adult dystonia presentations within the SERAC1-deficiency spectrum. Their differences cannot be reduced to a proven residual-protein gradient. Frequencies from the 67-person retrospective cohort retain feature-specific denominators and are not population estimates; some newly described mild cases were not part of that cohort. The adult p.Arg411Cys case and its DBS follow-up retain a VUS limitation. No cochlear cell type is assigned because audiometry has not established a uniform anatomical lesion. The frequently quoted 0.09 per 100,000 estimate derives from genetic lifetime-risk modeling, not observed point prevalence; the model assumes Hardy-Weinberg equilibrium and fully penetrant biallelic variants. The full 2026 GeneReviews chapter and available primary full texts informed this review; several mechanistic papers remain accessible here only as abstracts.

📚

References & Deep Research

References

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:23296368

Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.

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:24741715

SERAC1 Deficiency.

No top-level findings curated for this source.

PMID:24997715

The Expanding MEGDEL Phenotype: Optic Nerve Atrophy, Microcephaly, and Myoclonic Epilepsy in a Child with SERAC1 Mutations.

No top-level findings curated for this source.

PMID:25051967

MEGDEL Syndrome in a Child From Palestine: Report of a Novel Mutation in SERAC1 Gene.

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:27186703

Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation.

No top-level findings curated for this source.

PMID:28916646

SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.

No top-level findings curated for this source.

PMID:29205472

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

No top-level findings curated for this source.

PMID:29686941

Adult-onset Generalized Dystonia as the Main Manifestation of MEGDEL Syndrome.

No top-level findings curated for this source.

PMID:30114719

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.

No top-level findings curated for this source.

PMID:32305867

Lifetime risk of autosomal recessive mitochondrial disorders calculated from genetic databases.

No top-level findings curated for this source.

PMID:32684373

MEGDEL Syndrome.

No top-level findings curated for this source.

PMID:33426169

Secondary Dystonia in a Novel Mitochondriopathy Responsive to Deep Brain Stimulation Therapy.

No top-level findings curated for this source.

PMID:33613893

Identification of the rs797045105 in the SERAC1 Gene by Whole-exome Sequencing in a Patient Suspicious of MEGDEL 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:35223715

Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family.

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:35781780

Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency.

No top-level findings curated for this source.

PMID:35943861

First description of the MEGDEHL syndrome in the Tunisian population via whole-exome sequencing: Novel nonsense mutation in SERAC1 gene.

No top-level findings curated for this source.

PMID:37711114

SERAC1 Deficiency- A New Phenotype.

No top-level findings curated for this source.

PMID:37917582

LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.

No top-level findings curated for this source.

PMID:38445077

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

No top-level findings curated for this source.

PMID:39592976

Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant.

No top-level findings curated for this source.

PMID:39596578

Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1.

No top-level findings curated for this source.

PMID:40145675

Adult-Onset Dystonia-Parkinsonism: Do Not Forget SERAC1.

No top-level findings curated for this source.

PMID:40714654

Hearing rehabilitation in SERAC1 related MEGD(H)EL syndrome - implications from a multi-center retrospective cohort study.

No top-level findings curated for this source.

PMID:40821445

Expanding the Epidemiological and Phenotypic Spectrum of MEGDEL Syndrome: The First Case Report From Egypt.

No top-level findings curated for this source.

PMID:40884098

GPi-DBS for SERAC1-Related Dystonia-Parkinsonism.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK195853/

SERAC1 Deficiency - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

Deep Research

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)

Review MEGDEL clinical spectrum, evidence, causal mechanisms, and supportive care · 2026-09-21T02:24:09Z · View source

Reviewed the complete existing disorder entry and its matching OpenScientist deep-research report, then audited every one of its 22 cached references. Read actual article bodies where available, rather than accepting content_type metadata as proof of full text. Nine of the original papers had usable full texts after provider regeneration; the remaining original papers remained abstract-only after bounded retrieval attempts. Added seven further primary full-text papers (PMID:29205472, 29686941, 32305867, 33426169, 37917582, 40145675, 40884098), the complete May 2026 GeneReviews chapter NBK195853 via a generated URL cache, its PMID:24741715 abstract, and the 2025 hearing cohort PMID:40714654 abstract. The canine full text PMID:39596578 received an independent delegated source audit. The full GeneReviews care and genetic sections were read, not only its summary. Corrected deterministic null/hypomorphic genotype predictions, claims of obligatory aciduria or early death, an unsupported cochlear localization, and an asserted contradiction between contact-site and outer-membrane localization. Split bundled lipid, calcium, serine, nucleotide and mtDNA findings into 15 atomic mechanisms. Removed a cholesterol-to-bioenergetic edge supported only by shared SERAC1 dependence and qualified unproven causal connections. Distinguish measured protein/RNA effects from predictions, including the uncertain p.Met499Val allele and the p.Arg411Cys VUS in the adult dystonia/DBS reports. Normal filipin, respiratory-chain and mtDNA findings do not exclude disease. The LPGAT1 model is a parallel experimental pathway model and does not establish an additional human MEGDEL gene. Replaced case-report frequency guesses with feature-specific numerators and denominators from the 67-person retrospective cohort. Kept combined feeding/failure-to-thrive and dyskinesia/dysphagia/drooling counts from becoming separate feature rates. Added feeding, swallowing, salivary, hepatic, renal, respiratory and visual findings, absent speech, hyperlactatemia distinct from acidosis, inability to walk and human cerebellar atrophy. Recorded internal source discrepancies: liver failure is nine of 30 severe hepatic cases in the narrative versus 15/65 in Table 1; absent speech is 34/61 in the narrative versus 34/59 in the table; basal-ganglia involvement is described in 55 available scans versus 55/56 in Table 1; the narrative's 78% for 26/38 unable to walk is an arithmetic error (approximately 68%). Peer review independently checked the clinical frequency and care sections. Frequency bands retain ascertainment and age limitations. Expanded supportive care with baclofen response variability, selected-case DBS outcomes, physical and occupational therapy, communication support, seizure management and valproate avoidance, drooling management and surveillance. The hearing cohort limits expected language benefit from implants; neither anatomy nor improved speech can be assumed. Neonatal dialysis/protein-withholding and dexmedetomidine anaesthesia remain case-specific experience. Wider mitochondrial/myopathy precautions are explicitly background extrapolations. Nucleoside rescue remains preclinical. A bounded current trial search found no directly SERAC1-specific intervention record suitable for inclusion; general mitochondrial/depletion studies were not represented as MEGDEL trials. Corrected animal-model claims: canine hearing and cognition were unassessed, liver/organic-acid phenotyping was not reported, neuronal loss was prior postmortem pathology rather than new counts, and cerebellar involvement is not excluded in humans. The mouse abstract does not establish all human lipid, anatomical or treatment outcomes. Differentiated genetic lifetime-risk modeling from observed point prevalence and removed a geographic over-representation claim inferred from selected case reports. All reference caches were generated with just fetch-reference; none were hand-edited. The previously reviewed tracked modern PMC HTML adapter was cherry-picked as a separate reproducibility commit (0f7e99bac2c, equivalent to 21023a155b7), and affected HTML caches were regenerated after the shared upstream dependency was restored to its pristine implementation. PMID:24997715 used the unmodified OpenAlex fallback to actual NCBI article HTML; PMID:40821445 and 33426169 used canonical PMC URLs through the tracked adapter. Generated cache whitespace was normalized by repository pre-commit hooks; no manual cleanup was performed. No frozen dataset-accession cache was read, changed, or staged. Validation: authoritative just validate-disorders passed schema, live terms and 179/179 exact snippets. Focused PMC adapter/reference-patch tests passed (39 tests). Scoped graph, entity, qualifier, coarse-binding, source-defect, snippet-boundary and GeneReviews checks passed. Repository-wide checks passed for reference-cache frontmatter, term-cache integrity, cache order, case collisions, folded hyphens, snippet length, title-only snippets, reference titles, snippet grading, empty snippets and environmental evidence. History schema validation passed. The final diff passes git diff --check after repository pre-commit formatting.

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