DiagnosisClinical 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 atrophyScoliosis or kyphosisDystonia (in most individuals) and/or hyperkinesias (in many) manifest as athetoid or choreiform movements. Sensorineural hearing impairment EpilepsyPostnatal growth retardation, with weight below the 3^rd centilePtosis 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 atrophyBilateral basal ganglia involvement (putamen and caudate nuclei, mainly)Delayed myelinationTestingUrine 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 profilingPlasma 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 biopsyAnalysis 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 testingSequence 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 AciduriaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilitySUCLA2Sequence analysisSequence variants 2>95%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy Confirming/establishing the diagnosis in a probandMetabolic investigations may show some or all of the following:Urinary excretion of MMAElevated plasma MMA concentrationElevated 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. Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in SUCLA2.}

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 3rd 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.

Differential DiagnosisMitochondrial 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 SyndromesView in own windowGene SymbolPhenotypeFunction of Gene ProductUrinary Methylmalonic AcidDGUOKHepatocerebraldNTP poolsNormalMPV17HepatocerebralUnknownNormalPOLGHepatocerebralmtDNA replicationNormalRRM2BEncephalomyopathic with renal tubulopathydNTP poolsNormalSUCLA2EncephalomyopathicdNTP pools↑SUCLG1Fatal infantile lactic acidosisdNTP pools↑TK2MyopathicdNTP poolsNormalC10orf2 (PEO1)
(previously known as Twinkle)HepatocerebralmtDNA replicationNormal

ManagementEvaluations 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 ManifestationsAppropriate 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 contracturesMechanical assistance such as wheelchairs to help mobilityRespiratory aids such as nasal intermittent positive pressure ventilator when indicatedBracing to treat scoliosis or kyphosisBaclofen 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 intakeCochlear implantation for sensorineural hearing loss Surveillance The following are appropriate:Monitoring of growth (height and weight) and respiratory functionMonitoring for development of orthopedic complications such as scoliosis and movement disorders such as dystonia/hyperkinesiasEvaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSUCLA213q14​.2Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrialSUCLA2 homepage - Mendelian genesSUCLA2Data 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) View in own window 603921SUCCINATE-CoA LIGASE, ADP-FORMING, BETA SUBUNIT; SUCLA2 612073MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC WITH METHYLMALONIC ACIDURIA); MTDPS5Pathologic allelic variantsTable 3. Selected SUCLA2 Pathologic Allelic Variants View in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.534+1G>A ^{1--NM_003850​.2
NP_003841​.1 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 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.}