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MEGDEL Syndrome

Synonyms: 3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Like Syndrome; MEGDHEL Syndrome; SERAC1 Defect

, MD, PhD, , PhD, , PhD, and , MD, PhD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like) syndrome is characterized in neonates by hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. During the first year of life feeding problems, failure to thrive, and/or truncal hypotonia become evident; many infants experience (transient) liver involvement ranging from undulating transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. By age two years progressive deafness, dystonia, and spasticity prevent further psychomotor development and/or result in loss of acquired skills. Affected children are completely dependent on care for all activities of daily living; speech is absent.

Diagnosis/testing.

The diagnosis of MEGDEL syndrome is suspected in a proband with characteristic clinical findings and bilateral basal ganglia involvement on brain MRI. The diagnosis is confirmed by elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) or, ultimately, identification of biallelic SERAC1 pathogenic variants on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is supportive. Care is best provided by a multidisciplinary team including a metabolic pediatrician, pediatric neurologist, dietician, and physical therapist when possible. Some patients have experienced (temporary) improvement of spasticity with treatment with oral or intrathecal baclofen. Respiratory problems resulting from excessive drooling improve with botulinum toxin injection in the salivary glands, extirpation of salivary glands, and/or re-routing of glandular ducts. An age-appropriate diet given via nasogastric tube or gastrostomy can greatly improve overall clinical condition.

Surveillance: Neurologic and orthopedic evaluations as needed based on individual findings are appropriate.

Genetic counseling.

MEGDEL syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.

Diagnosis

Diagnosis of MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like) syndrome should be suspected in a child presenting with psychomotor retardation in combination with:

  • (Progressive) deafness
  • (Progressive) dystonia
  • (Progressive) spasticity
  • Bilateral basal ganglia involvement on brain MRI (comparable to Leigh syndrome)

Note: Most affected children also show neonatal hypoglycemia, neonatal sepsis-like episode without detected infectious agent and (transient) liver involvement ranging from undulating elevation of transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. Serum lactate concentration and serum alanine concentration can be elevated; serum cholesterol concentration may be decreased [Wortmann et al 2006, Wortmann et al 2012b, Sarig et al 2013, Tort et al 2013].

The diagnosis of MEGDEL syndrome is established in a proband with the following:

  • Elevated urinary concentration of 3-methylglutaconic acid (3-MGA) and 3-methylglutaric acid (3-MGC) (see Table 1);
  • Biallelic SERAC1 pathogenic variants (see Table 2).

Table 1.

Urinary Concentration of 3-MGA in MEGDEL Syndrome

Urinary Concentration of 3-MGA (mmol/mol creatinine)
MEGDEL syndrome16-196
Normal controls<10 1
1.

Reference range as used at the Laboratory for Genetic Endocrine and Metabolic Diseases (LGEM), Department of Laboratory Medicine, Radboud UMC Nijmegen, Nijmegen, The Netherlands

If clinical findings point to MEGDEL syndrome and urinary excretion of 3-MGA and 3-MGC is elevated, the diagnosis can be confirmed by molecular genetic testing of SERAC1 (see Table 2). As some laboratories are unable to quantify the urinary excretion of 3-MGA and 3-MGC, the authors also suggest molecular genetic testing if the clinical picture is suggestive of MEGDEL syndrome.

Table 2.

Summary of Molecular Genetic Testing Used in MEGDEL Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method 2
SERAC1Sequence analysis 320/20
Deletion/duplication analysis 4Unknown; none reported 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.
3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

No deletions or duplications involving SERAC1 as causative of MEGDEL syndrome have been reported.

Clinical Characteristics

Clinical Description

The following clinical findings of MEGDEL syndrome are based on the combined personal experience of the authors caring for 40 patients with a molecularly confirmed diagnosis. Of these, 20 have been published: 15 by Wortmann et al [2006] and Wortmann et al [2012b], four by Sarig et al [2013], and one by Tort et al [2013].

Most children with MEGDEL syndrome present in the neonatal period with hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. Several neonates with prolonged jaundice were reported.

During the first year of life affected infants often come to the attention of a physician because of feeding problems, failure to thrive, and/or truncal hypotonia. Liver involvement (ranging from cholestasis, hepatitis of unknown origin to fulminant liver failure) is also frequently seen but mostly transient.

By age two years the neurologic findings become more apparent. Progressive spasticity (as defined by increasing resistance to speed or angle with passive flexion as well as hypertonia and hyperreflexia) and dystonia either prevent further development or lead to loss of acquired skills. Speech is often completely absent, leading to investigation and detection of progressive deafness.

The further clinical course is slowly progressive. Affected children are completely dependent on care for all activities of daily living: they are unable to sit independently and are wheelchair bound and non-ambulatory. Scoliosis and/or contractures may require bracing.

Communication is limited to the expression of comfort and discomfort; speech is absent.

Feeding is complicated by the movement disorder and often also by excessive drooling, often requiring tube feeding.

Some affected individuals have epilepsy which either occurs in the neonatal period or later in the disease course.

The length of survival varies. Some do not survive the neonatal period due to multi-organ failure, some succumb to liver failure in infancy and others to (pulmonary) infections later in life. The oldest living affected individual is age 19 years.

Genotype-Phenotype Correlations

Currently, no clear relationship exists between the type and position of the SERAC1 pathogenic variants and phenotype.

The level of 3-MGA-uria does not correlate with the clinical course.

Prevalence

The prevalence of MEGDEL syndrome is unknown. About 45 affected individuals are known to the authors, 40 from their personal experience [Wortmann et al 2006; Wortmann et al 2012b; Author, unpublished data] and five reported in the literature [Sarig et al 2013, Tort et al 2013].

Differential Diagnosis

Disorders with Increased Urinary Excretion of 3-Methylglutaconic Acid

Increased urinary excretion of the branched-chain organic acid 3-MGA, 3-methylglutaconic aciduria (3-MGA-uria) is a relatively common finding in children investigated for suspected inborn errors of metabolism [Wortmann et al 2013b]. 3-MGA is an intermediate of leucine degradation (Figure 1).

Figure 1.

Figure 1.

Leucine catabolism and possible shunts to cholesterol biosynthesis From Wortmann et al [2012a]

The classification of inborn errors of metabolism with 3-MGA-uria as a discriminative feature has recently been updated [Wortmann et al 2013a, Wortmann et al 2013b] (Table 3). Five forms of inborn errors of metabolism with 3-MGA-uria as a discriminative feature have been recognized (Table 3). They all show a characteristic “syndromal” pattern of signs and symptoms [Wortmann et al 2013a, Wortmann et al 2013b]. The exact source of 3-MGA is known only in 3-methylglutaconyl-CoA hydratase deficiency (or AUH defect), the rarest of the five types, caused by primary deficiency of the mitochondrial enzyme 3-methylglutaconyl-CoA hydratase (3-MGH) resulting in blockage of leucine catabolism. The origin of the increased 3-MGA excretion in all other types is unknown, but mitochondrial dysfunction is thought to be the common denominator [Wortmann et al 2009].

Table 3.

New Classification for Inborn Errors of Metabolism with 3-Methylglutaconic Aciduria as Discriminative Feature

Patho-MechanismDisease NameFormer DesignationAdditional Hallmarks 1 of PhenotypeMode of Inheritance
Primary 3-MGA-uria
Organic aciduria3-methylglutaconyl-CoA hydratase deficiency (AUH defect)3-MGCA type I (3-MGCA-1)Adult onset leukoencephalopathy, dementia, progressive spasticityAR
Secondary 3-MGA-uria
Defective phospholipid remodelingTAZ defect (Barth syndrome)3-MGCA type II (3-MGCA-2)(Cardio)myopathy, short stature, neutropenia, hypocholesterolemia, cognitive phenotype, mild dysmorphic features, OXPHOS dysfunctionXL
SERAC1 defect (MEGDEL syndrome)3-MGCA type IV (3-MGCA-4)Progressive spasticity, dystonia, deafness, Leigh syndrome-like MRI, severe psychomotor retardation, hypocholesterolemia, OXPHOS dysfunctionAR
Mitochondrial membrane disorderOPA3 defect (Costeff syndrome)3-MGCA type III (3-MGCA-3)Ataxia/extrapyramidal dysfunction, optic atrophyAR
TMEM70 defect3-MGCA type IV (3-MGCA-4)Broad phenotype, hypertrophic cardiomyopathy, myopathy, dysmorphic features, cataracts, psychomotor retardation, ATPase deficiency, lactic acidosis, hyperammonemiaAR
DNAJC19 defect (DCMA syndrome)3-MGCA type V (3-MGCA-5)Dilated cardiomyopathy, ECG abnormalities, non-progressive cerebellar ataxia, Small atrophic testes, cryptorchidism, growth failure, anemia, steatosis hepatitisAR
UnknownNOS 3-MGA-uria3-MGCA type IV (3-MGCA-4)Variable, mostly progressive neurologic diseaseUnknown

From Wortmann et al [2013a]. Click here (pdf) for an expanded version of the table with information on protein subcellular localization and function.

OXPHOS = oxidative phosphorylation

DCMA = dilated cardiomyopathy with ataxia

NOS= not otherwise specified

1.

In addition to 3-MGA-uria

3-methylglutaconyl-CoA hydratase deficiency (AUH defect) (OMIM 250950). Affected individuals have adult-onset progressive spasticity and dementia with a characteristic slowly developing radiologic picture of extensive leukoencephalopathy [Wortmann et al 2010]. This is the only one of the five inborn errors of metabolism with 3-MGA-uria (Table 3) with a distinct biochemical finding: elevated urinary excretion of 3-hydroxyisovaleric acid (3-HIVA).

TAZ defect (Barth syndrome). In this X-linked disorder, affected males have 3-MGA-uria, (left ventricular non-compaction) cardiomyopathy, neutropenia, myopathy, typical facial features, hypocholesterolemia, and a cognitive phenotype.

OPA3 defect (Costeff syndrome). Affected infants have a classic triad of 3-MGA-uria, optic atrophy, and movement disorder (ataxia or extrapyramidal disorder).

TMEM70 defect (OMIM 614052). Affected individuals typically present in the neonatal period with muscular hypotonia, hypertrophic cardiomyopathy, psychomotor retardation, 3-MGA-uria, hyperammonemia, and lactic acidosis. Children surviving the neonatal period later show developmental delay. The phenotypic spectrum, however, is variable and becoming broader as more affected individuals are reported. At this time no specific syndromic presentation is evident.

DNAJC19 defect (DCMA syndrome) (OMIM 610198). Affected individuals have a characteristic combination of childhood-onset dilated cardiomyopathy, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure, and 3-MGA-uria.

Not otherwise specified 3-MGA-uria type includes all other individuals with significant and consistent 3-MGA-uria with normal 3-methylglutaconyl-CoA hydratase enzyme activity, and no pathogenic variants identified in TAZ, SERAC1, OPA3, TMEM70, or DNAJC19.

Differential Diagnosis of the Clinical Findings of MEGDEL Syndrome

Dystonia-deafness syndromes

  • Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria). Caused by mutation of SUCLA2, this disorder shares with MEGDEL syndrome the clinical features of early-onset dystonia and deafness as well as severe failure to thrive. In some affected individuals basal ganglia involvement visible on brain MRI is reported. 3-MGA-uria and elevated serum lactate are also common; however, the specific metabolite profile of this disorder (i.e., a mild increase in urinary methylmalonic acid and serum acyl-carnitine ester abnormalities [increased C3- and C4-dicarboxyli-carnitine esters]) is not found in MEGDEL syndrome.
  • Mohr-Tranebjaerg syndrome (MTS), caused by mutation of TIMM8A. Affected individuals have progressive deafness in infancy; dystonia develops later in life, and in some it only develops in adulthood. Basal ganglia lesions can be found on brain MRI. These features are also characteristic for MEGDEL syndrome; however, in MTS 3-MGA is not excreted [Wortmann et al 2012a].

Mitochondrial disorders. Caused by mutation of mitochondrial DNA (mtDNA) or nuclear DNA, mitochondrial disorders can present with any sign or symptom. Tissues with higher requirements for oxidative metabolism, such as the central nervous system and cardiac and skeletal muscle, are predominantly affected. Although 3-MGA-uria is often seen in mitochondrial disorders, the excretion is lower than in MEGDEL syndrome [Wortmann et al 2012a]. The different signs and symptoms of MEGDEL syndrome can be found frequently in mitochondrial disorders. For example, progressive deafness is often reported with the mitochondrial DNA m.3243A>G pathogenic variant. Leigh syndrome and dystonia are a typical neuro(radio)logic finding in mitochondrial disorders in relation to deficiency of complex I or IV of the respiratory chain. The combination of the clinical findings deafness, spasticity, dystonia, and Leigh syndrome is distinctive for MEGDEL syndrome. See also Mitochondrial Disorders Overview.

Cerebral palsy. Slowly progressive spasticity and dystonia as seen in MEGDEL syndrome may be misdiagnosed as cerebral palsy when deafness or abnormalities on brain MRI are not recognized. Therefore, the authors recommend that urinary organic acid analysis be performed on individuals with atypical cerebral palsy.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MEGDEL syndrome, the following evaluations are recommended:

  • Complete audiologic examination including hearing test, brain stem auditory evoked potentials (BAEP)
  • Complete neurologic examination, including brain MRI
  • Complete orthopedic examination for evidence of contractures and/or scoliosis needing treatment
  • Developmental assessment, IQ testing
  • Complete pulmonary examination for evidence of respiratory problems due to excessive drooling and/or scoliosis needing treatment
  • Complete investigation of liver function including ASAT, ALAT, gamma-GT, serum concentration of bilirubin (total and direct), serum concentration of ammonia, clotting tests
  • Complete evaluation of feeding and diet to determine if tube feeding is necessary
  • Evaluation of excessive drooling (if present) for evidence of aspiration and/or dehydration
  • ECG
  • Clinical genetics consultation

Treatment of Manifestations

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

Applicable supportive treatment [SB Wortmann, personal communication] includes:

  • For (progressive) spasticity. Some patients experienced (temporary) improvement of spasticity with treatment with oral or intrathecal baclofen.
  • For excessive drooling. Patients experienced great improvement (e.g., of respiratory problems) with botulinum toxin injection in the salivary glands, extirpation of salivary glands, and/or re-routing of glandular ducts.
  • For failure to thrive. An age-appropriate diet given via nasogastric tube or gastrostomy can greatly improve overall clinical condition.

Surveillance

Surveillance includes neurologic and orthopedic evaluations as needed based on individual findings.

Agents/Circumstances to Avoid

Medications known to impair mitochondrial function (e.g., valproic acid) should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MEGDEL syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele). However, although not reported, it is possible that one of the pathogenic variants identified in the child is de novo. Thus, confirmation of carrier status of both parents may be warranted.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with MEGDEL syndrome have not been reported to reproduce. If they were to reproduce, their offspring would be obligate heterozygotes (i.e., carriers of one mutated allele).

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MEGDEL syndrome are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

MEGDEL Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
SERAC16q25​.3Protein SERAC1SERAC1SERAC1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MEGDEL Syndrome (View All in OMIM)

614725SERINE ACTIVE SITE-CONTAINING PROTEIN 1; SERAC1
6147393-METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME; MEGDEL

Molecular Genetic Pathogenesis

SERAC1 is involved in remodeling phosphatidylglycerol-34:1 (PG-34:1; where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) to phosphatidylglycerol-36:1 species, of which the latter is the precursor for bis(monoacylglycerol)phosphate (BMP) and the long cardiolipin species above cardiolipin-68:5. Consequently, mutation of SERAC1 results in less PG-36:1 and lower concentrations of BMP, leading to the accumulation of intracellular free cholesterol. In addition, the altered cardiolipin species distribution in the mitochondrial membranes likely causes the mitochondrial dysfunction.

Gene structure. SERAC1 comprises 16 exons resulting in an mRNA transcript of 58,777 base pairs (NM_032861.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 4 (pdf).

Normal gene product. SERAC1 (serine active site containing 1) encodes SERAC1, a protein of 654 amino acids with a conserved serine-lipase domain (consensus lipase motif GxSxG), which is member of the PGAP-like protein domain family (PFAM PF07819).

Abnormal gene product. Mutation of SERAC1 impairs the function of SERAC1 in phospholipid remodeling, which has consequences for mitochondrial function and intracellular cholesterol trafficking.

References

Literature Cited

  • Sarig O, Goldsher D, Nousbeck J, Fuchs-Telem D, Cohen-Katsenelson K, Iancu TC, Manov I, Saada A, Sprecher E, Mandel H. 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. Am J Med Genet A. 2013;161:2204–15. [PubMed: 23918762]
  • Tort F, García-Silva MT, Ferrer-Cortès X, Navarro-Sastre A, Garcia-Villoria J, Coll MJ, Vidal E, Jiménez-Almazán J, Dopazo J, Briones P, Elpeleg O, Ribes A. Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. Mol Genet Metab. 2013;110:73–7. [PubMed: 23707711]
  • Wortmann S, Rodenburg RJ, Huizing M, Loupatty FJ, de Koning T, Kluijtmans LA, Engelke U, Wevers R, Smeitink JA, Morava E. Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation. Mol Genet Metab. 2006;88:47–52. [PubMed: 16527507]
  • Wortmann SB, Rodenburg RJ, Jonckheere A, de Vries MC, Huizing M, Heldt K, van den Heuvel LP, Wendel U, Kluijtmans LA, Engelke UF, Wevers RA, Smeitink JA, Morava E. Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain. 2009;132:136–46. [PubMed: 19015156]
  • Wortmann SB, Kremer BH, Graham A, Willemsen MA, Loupatty FJ, Hogg SL, Engelke UF, Kluijtmans LA, Wanders RJ, Illsinger S, Wilcken B, Cruysberg JR, Das AM, Morava E, Wevers RA. 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. Neurology. 2010;75:1079–83. [PubMed: 20855850]
  • Wortmann SB, Kluijtmans LA, Engelke UF, Wevers RA, Morava E. The 3-methylglutaconic acidurias: what's new? J Inherit Metab Dis. 2012a;35:13–22. [PMC free article: PMC3249181] [PubMed: 20882351]
  • Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH, Schuurs-Hoeijmakers JH, Kulik W, Lammens M, Christin C, Kluijtmans LA, Rodenburg RJ, Nijtmans LG, Grünewald A, Klein C, Gerhold JM, Kozicz T, van Hasselt PM, Harakalova M, Kloosterman W, Barić I, Pronicka E, Ucar SK, Naess K, Singhal KK, Krumina Z, Gilissen C, van Bokhoven H, Veltman JA, Smeitink JA, Lefeber DJ, Spelbrink JN, Wevers RA, Morava E, de Brouwer AP. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet. 2012b;44:797–802. [PubMed: 22683713]
  • Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J Inherit Metab Dis. 2013a;36:923–8. [PubMed: 23296368]
  • Wortmann SB, Kluijtmans LA, Rodenburg RJ, Sass JO, Nouws J, van Kaauwen EP, Kleefstra T, Tranebjaerg L, de Vries MC, Isohanni P, Walter K, Alkuraya FS, Smuts I, Reinecke CJ, van der Westhuizen FH, Thorburn D, Smeitink JA, Morava E, Wevers RA. 3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients. J Inherit Metab Dis. 2013b;36:913–21. [PubMed: 23355087]

Chapter Notes

Author Notes

Authors’ websites:

Dr. SB Wortmann and Prof. RA Wevers are interested in patients with elevated urinary excretion of 3-methylglutaconic acid. Combining the clinical, biochemical, and neuroradiologic findings of these patients they are able to define homogeneous subgroups in which they perform next generation sequencing to unravel the underlying genetic disorders. This is followed by biochemical investigations to characterize the function of the affected protein.

Revision History

  • 17 April 2014 (me) Review posted live
  • 17 January 2014 (adb) Original submission
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