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SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria

Synonym: SUCLA2 Deficiency
, MD, PhD
Department of Clinical Genetics
National University Hospital Rigshospitalet
Copenhagen, Denmark

Initial Posting: .

Summary

Disease characteristics. SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome is characterized by onset of severe hypotonia in early infancy (birth to five months); severe muscular atrophy with failure to achieve independent ambulation; progressive scoliosis or kyphosis; dystonia and/or hyperkinesias (i.e., athetoid or choreiform movements); epilepsy (infantile spasms or generalized convulsions with onset from birth to three years) in a few children; postnatal growth retardation; and severe sensorineural hearing impairment. The outcome is poor with early lethality.

Diagnosis/testing. Metabolic findings usually include urinary excretion of methylmalonic acid (MMA), elevated plasma methylmalonic acid concentration, and elevated plasma lactate concentration. Plasma carnitine ester profiling shows increased C3-carnitine and C4-dicarboxylic-carnitine. Urinary excretion of C4-dicarboxylic-carnitine is usually approximately 20 times normal. CT/MRI may show central and cortical atrophy, bilateral basal ganglia involvement (mainly the putamen and caudate nuclei), and delayed myelination. SUCLA2 is the only gene known to be associated with this disorder.

Management. Treatment of manifestations: Physical therapy and stretching exercises to promote mobility and prevent contractures; mechanical assistance such as wheelchairs to help mobility; respiratory aids such as nasal intermittent positive pressure ventilator when indicated; bracing to treat scoliosis or kyphosis; baclofen therapy alone or in combination with other medications to treat dystonia/hyperkinesias; antiepileptic drugs for seizures; gastrostomy as needed to assure adequate caloric intake; and cochlear implantation for sensorineural hearing loss.

Surveillance: Monitoring of growth and respiratory function; monitoring for development of scoliosis and dystonia/hyperkinesias.

Genetic counseling. SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria 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 disease-causing mutations in the family have been identified.

Diagnosis

Clinical Diagnosis

SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome is suspected in children with the following clinical findings [Elpeleg et al 2005, Carrozzo et al 2007, Ostergaard et al 2007b]:

  • Hypotonia: onset with lack of head and trunk control usually between birth and age five months
  • Psychomotor delay and severe muscular atrophy
  • Scoliosis or kyphosis
  • Dystonia (in most individuals) and/or hyperkinesias (in many) manifest as athetoid or choreiform movements.
  • Sensorineural hearing impairment
  • Epilepsy
  • Postnatal growth retardation, with weight below the third centile
  • Ptosis and ophthalmoparesis (occasionally)

Electromyography (EMG) may show prolonged mean duration and increased mean amplitude of motor unit potentials suggesting involvement of motor neurons of the medulla spinalis.

Neuroimaging. CT/MRI may show some or all of the following:

  • Central and cortical atrophy
  • Bilateral basal ganglia involvement (putamen and caudate nuclei, mainly)
  • Delayed myelination
  • Testing

Urine organic acids. Urinary excretion of MMA is consistently elevated to 51-212 μmol/mmol creatinine (ref. <3.6 μmol/mmol creatinine) [Ostergaard et al 2007b]. However, the increase of MMA is considerably less pronounced than in classic methylmalonic aciduria (see Disorders of Intracellular Cobalamin Metabolism). Note: As in classic methylmalonic aciduria, MMA excretion is accompanied by increased methylcitrate excretion in periods of stress. Excretion of beta-hydroxypropionic acid, lactate, and Krebs cycle intermediates (such as succinic acid, citric acid, alpha-ketoglutaric acid, and fumaric acid) is variable.

Plasma methylmalonic acid. Plasma MMA concentration is elevated to 0.8-33.0 μmol/L (ref. <0.28 μmol/L), but the concentrations are not as high as in methylmalonic aciduria caused by defects in MUT, the gene encoding methylmalonyl-CoA mutase.

Plasma and CSF lactate. Most affected individuals have the following:

  • Elevated plasma lactate concentration (ref. <2.0 mmol/L)
  • Elevated CSF lactate concentration (ref. 0.8-1.2 mmol/L)

Carnitine ester profiling

  • Plasma concentrations of C3-carnitine and C4-dicarboxylic carnitine are increased.
  • Urinary excretion of C4-dicarboxylic carnitine is increased about 20 times.

    Note: In both plasma and urine, the C4-dicarboxylic carnitine ester is likely to be a mixture of the succinyl and the methylmalonyl carnitine ester.

Muscle biopsy

  • Analysis of respiratory chain enzyme activity shows a combined deficiency of respiratory complex I, III, and IV, with normal complex II activity.
  • Quantitation of mtDNA shows a decreased amount of mtDNA (i.e., mtDNA depletion).
  • Pathologic features include increased variability of fiber diameter with scattered hypertrophic, spherical fibers with an increased number of mitochondria; marked type I fiber predominance; and extensive intracellular fat accumulation in type I fibers.

Molecular Genetic Testing

Gene. SUCLA2 is the only gene known to be associated with SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria.

Clinical testing

  • Sequence analysis. Detection rates by direct sequencing are estimated to be at least 95%.

Table 1. Summary of Molecular Genetic Testing Used in SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SUCLA2Sequence analysis 4Sequence variants>95%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/establishing the diagnosis in a proband

  • Metabolic investigations may show some or all of the following:
    • Urinary excretion of MMA
    • Elevated plasma MMA concentration
    • Elevated plasma lactate concentration
    • Combined respiratory chain complex I, III, and IV deficiency on muscle biopsy*
    • Mitochondrial DNA depletion on muscle biopsy*
  • The diagnosis is confirmed by molecular genetic testing.

* Note: Although muscle biopsy is often done as part of the initial investigations, it is not necessary to confirm the diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Pregnancy and birth are mostly unremarkable. Dysmaturity (relative absence of subcutaneous fat; wrinkling of the skin; prominent fingernails and toenails; and meconium staining of the skin and placental membranes, often associated with postmaturity or placental insufficiency) was reported in a few infants. With a few exceptions, birth weight and birth length were within the normal range.

Muscle hypotonia is the presenting finding in most infants, with onset from birth to age five months. Some infants have fatigue, reduced muscle mass, or motor retardation. All affected children developed severe hypotonia with lack of head and trunk control and none of them achieved ambulation. The muscles are severely atrophic. Progressive scoliosis or kyphosis, found in most affected individuals, required treatment.

Dystonia and hyperkinesias, as athetoid or choreiform movements, were frequent.

Severe sensorineural hearing impairment occurred in nearly all children, most often diagnosed by brain stem audiometry. The age at diagnosis of hearing impairment ranged from eight months to four years. Cochlear implantation improved communication skills.

One child who had intensive communication training was considered to be of normal intellectual ability.

Severe postnatal growth retardation with postnatal weight at or below the third centile is found in nearly all individuals. Feeding problems and gastroesophageal reflux, observed from the neonatal period, lead to failure to thrive. Most children are fed through a percutaneous endoscopic gastrostomy tube. Recurrent airway infections are common. In some individuals, hyperhidrosis was reported.

Respiratory insufficiency was seen in all affected individuals, resulting in frequent pulmonary infections.

Ophthalmologic investigations were normal in most children, but strabismus and ptosis have been reported.

Epilepsy, either infantile spasms or generalized convulsions, with onset from birth to three years was found in a few children.

Life span is shortened, with most children dying in childhood, most commonly from an intercurrent infection.

Genotype-Phenotype Correlations

No phenotypic correlation has been recognized with the splice-site, missense, and insertion-deletion mutations reported to date.

Prevalence

SUCLA2-related mitochondrial DNA depletion syndrome is rare; the exact prevalence is unknown. To date, 17 individuals of different ethnic origins have been reported. A founder mutation in families of Faroese origin has been identified (Table 3).

Allele frequency for the mutation in the Faroese population was calculated by testing 200 Faroese controls for the mutation. Of these, six were heterozygous for the mutation, corresponding to a carrier frequency of 1 in 33 (95% confidence interval 1:23 to 1:55) [Ostergaard et al 2007b].

Differential Diagnosis

Mitochondrial DNA depletion syndrome, characterized by a reduction in mtDNA copy number, has been associated with mutations in eight nuclear genes: POLG, TK2, DGUOK, SUCLA2, SUCLG1, PEO1, MPV17, and RRM2B. The gene products are either involved in mtDNA replication or in regulation of the mitochondrial deoxyribonucleoside triphosphate (dNTP) pools needed for mtDNA replication. Inheritance for all the mtDNA depletion syndromes is autosomal recessive.

Table 2 summarizes the clinical phenotypes associated with mutations in these genes. Note: For some of the genes (POLG and PEO1), other phenotypes not associated with mtDNA depletion with autosomal dominant or recessive inheritance have been reported.

Mutations have recently been reported in SUCLG1, which encodes the α subunit of succinate-CoA ligase [Ostergaard et al 2007a]. Affected individuals show urinary excretion of MMA, combined respiratory chain enzyme deficiency, and mtDNA depletion. The phenotype may be indistinguishable from SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria [Ostergaard et al 2009, personal communication/submitted].

Table 2. Mitochondrial DNA Depletion Syndromes

Gene PhenotypeFunction of Gene ProductUrinary Methylmalonic Acid
DGUOKHepatocerebraldNTP poolsNormal
MPV17HepatocerebralUnknownNormal
POLGHepatocerebralmtDNA replicationNormal
RRM2BEncephalomyopathic with renal tubulopathydNTP poolsNormal
SUCLA2EncephalomyopathicdNTP pools
SUCLG1Fatal infantile lactic acidosisdNTP pools
TK2MyopathicdNTP poolsNormal
C10orf2 (PEO1)
(previously known as Twinkle)
HepatocerebralmtDNA replicationNormal

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria, the following evaluations may be performed:

  • Neurologic evaluation, including brain MRI
  • Hearing evaluation
  • Feeding and swallowing assessment in children with lack of head control or inability to sit without support
  • Developmental assessment including assessment of motor skills, cognition, and speech
  • Physical therapy evaluation of joint range of motion

Treatment of Manifestations

Appropriate management can prolong survival and improve quality of life for affected children. Treatments include the following:

  • Physical therapy and stretching exercises to promote mobility and prevent contractures
  • Mechanical assistance such as wheelchairs to help mobility
  • Respiratory aids such as nasal intermittent positive pressure ventilator when indicated
  • Bracing to treat scoliosis or kyphosis
  • Baclofen therapy alone or in combination with other medications had the best and longest-lasting effect in the treatment of dystonia/hyperkinesias.
  • Antiepileptic drugs to control seizures
  • Gastrostomy when indicated to assure adequate caloric intake
  • Cochlear implantation for sensorineural hearing loss

Surveillance

The following are appropriate:

  • Monitoring of growth (height and weight) and respiratory function
  • Monitoring for development of orthopedic complications such as scoliosis and movement disorders such as dystonia/hyperkinesias

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

SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria 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 mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

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.

Offspring of a proband. Individuals with SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria do not reproduce.

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 family members is possible once the disease-causing mutations in the family are known.

In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.

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

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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.

  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

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. SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria (View All in OMIM)

603921SUCCINATE-CoA LIGASE, ADP-FORMING, BETA SUBUNIT; SUCLA2
612073MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC WITH OR WITHOUT METHYLMALONIC ACIDURIA); MTDPS5

Pathogenic allelic variants

Table 3. Selected SUCLA2 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.534+1G>A 1--NM_003850​.2
NP_003841​.1

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Founder mutation in the Faroe Islands [Carrozzo et al 2007, Ostergaard et al 2007b]

Normal gene product. SUCLA2 encodes the 463 amino acids of the β subunit of the ADP-forming succinate-CoA ligase (A-SUCL). SUCL is a mitochondrial enzyme that catalyses the reversible conversion of succinyl-CoA and ADP or GDP to succinate and ATP or GTP [Lambeth et al 2004]. SUCL is composed of an α subunit, encoded by SUCLG1 and of a β subunit, encoded by either SUCLA2 or SUCLG2. The α subunit forms a heterodimer with either of its β subunits, resulting in an ADP-forming SUCL (A-SUCL) and a GDP-forming SUCL, respectively. The β subunits thus determine the substrate specificity of the enzymes. Both enzymes, located in the mitochondrial matrix, are probably part of the Krebs cycle; however, this has not been established for certain for G-SUCL. Several studies have shown that SUCL forms a complex with mitochondrial nucleoside diphosphate kinase, which is involved in mitochondrial nucleotide homeostasis [Kowluru et al 2002].

Abnormal gene product. The mutations lead to absence of functional SUCL protein. Mitochondrial DNA depletion and the resulting combined deficiency of respiratory chain complexes I, III, and IV are assumed to be caused by the failure to form a complex with mitochondrial nucleoside diphosphate kinase.

References

Literature Cited

  1. Carrozzo R, Dionisi-Vici C, Steuerwald U, Lucioli S, Deodato F, Di Giandomenico S, Bertini E, Franke B, Kluijtmans LA, Meschini MC, Rizzo C, Piemonte F, Rodenburg R, Santer R, Santorelli FM, van Rooij A, Vermunt-de Koning D, Morava E, Wevers RA. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain. 2007;130:862–74. [PubMed: 17301081]
  2. Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, Pagnamenta A, Eshhar S, Saada A. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet. 2005;76:1081–6. [PMC free article: PMC1196446] [PubMed: 15877282]
  3. Kowluru A, Tannous M, Chen HQ. Localization and characterization of the mitochondrial isoform of the nucleoside diphosphate kinase in the pancreatic beta cell: evidence for its complexation with mitochondrial succinyl-CoA synthetase. Arch Biochem Biophys. 2002;398:160–9. [PubMed: 11831846]
  4. Lambeth DO, Tews KN, Adkins S, Frohlich D, Milavetz BI. Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues. J Biol Chem. 2004;279:36621–4. [PubMed: 15234968]
  5. Ostergaard E, Christensen E, Kristensen E, Mogensen B, Duno M, Shoubridge EA, Wibrand F. Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am J Hum Genet. 2007a;81:383–7. [PMC free article: PMC1950792] [PubMed: 17668387]
  6. Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M. Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain. 2007b;130:853–61. [PubMed: 17287286]

Suggested Reading

  1. Copeland WC. Inherited mitochondrial diseases of DNA replication. Annu Rev Med. 2008;59:131–46. [PMC free article: PMC2271032] [PubMed: 17892433]
  2. Fowler B, Leonard JV, Baumgartner MR. Causes of and diagnostic approach to methylmalonic acidurias. J Inherit Metab Dis. 2008;31:350–60. [PubMed: 18563633]
  3. Spinazzola A, Invernizzi F, Carrara F, Lamantea E, Donati A, Dirocco M, Giordano I, Meznaric-Petrusa M, Baruffini E, Ferrero I, Zeviani M. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis. 2009;32:143–58. [PubMed: 19125351]

Chapter Notes

Revision History

  • 26 May 2009 (et) Review posted live
  • 16 January 2009 (eo) Original submission
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