Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
General Information (adopted from Orphanet):
Synonyms, Signs: |
MTDPS5 MITOCHONDRIAL DNA DEPLETION SYNDROME, ENCEPHALOMYOPATHIC FORM, WITH OR WITHOUT METHYLMALONIC ACIDURIA, AUTOSOMAL RECESSIVE, SUCLA2-RELATED mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria Booth-Haworth-Dilling syndrome Mitochondrial encephalomyopathy - aminoacidopathy |
Number of Symptoms | 66 |
OrphanetNr: | 1933 |
OMIM Id: |
612073
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ICD-10: |
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UMLs: |
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MeSH: |
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MedDRA: |
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Snomed: |
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Prevalence, inheritance and age of onset:
Prevalence: | 2 cases [Orphanet] |
Inheritance: |
Mitochondrial inheritance [Orphanet] |
Age of onset: |
Neonatal [Orphanet] |
Disease classification (adopted from Orphanet):
Parent Diseases: |
Mitochondrial DNA depletion syndrome, encephalomyopathic form
-Rare developmental defect during embryogenesis -Rare eye disease -Rare gastroenterologic disease -Rare genetic disease -Rare neurologic disease |
Symptom Information:
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(HPO:0003355) | Aminoaciduria | 65 / 7739 | ||||
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(HPO:0012120) | Methylmalonic aciduria | 20 / 7739 | ||||
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(HPO:0000252) | Microcephaly | Very frequent [Orphanet] | 832 / 7739 | |||
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(HPO:0001349) | Facial diplegia | 16 / 7739 | ||||
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(HPO:0000508) | Ptosis | Very frequent [Orphanet] | 459 / 7739 | |||
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(HPO:0000486) | Strabismus | 576 / 7739 | ||||
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(HPO:0000505) | Visual impairment | Very frequent [Orphanet] | 297 / 7739 | |||
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(HPO:0000649) | Abnormality of visual evoked potentials | Very frequent [Orphanet] | 34 / 7739 | |||
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(HPO:0000602) | Ophthalmoplegia | 56 / 7739 | ||||
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(HPO:0000512) | Abnormal electroretinogram | Very frequent [Orphanet] | 61 / 7739 | |||
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(HPO:0000407) | Sensorineural hearing impairment | 524 / 7739 | ||||
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(HPO:0000365) | Hearing impairment | Very frequent [Orphanet] | 539 / 7739 | |||
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(HPO:0001257) | Spasticity | 251 / 7739 | ||||
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(HPO:0002540) | Inability to walk | 19 / 7739 | ||||
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(HPO:0001249) | Intellectual disability | 1089 / 7739 | ||||
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(HPO:0002066) | Gait ataxia | Very frequent [Orphanet] | 327 / 7739 | |||
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(HPO:0002194) | Delayed gross motor development | 37 / 7739 | ||||
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(HPO:0002448) | Progressive encephalopathy | 6 / 7739 | ||||
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(HPO:0003134) | Abnormality of peripheral nerve conduction | Very frequent [Orphanet] | 38 / 7739 | |||
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(HPO:0001332) | Dystonia | 197 / 7739 | ||||
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(HPO:0001315) | Reduced tendon reflexes | Very frequent [Orphanet] | 160 / 7739 | |||
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(HPO:0008945) | Loss of ability to walk in early childhood | 2 / 7739 | ||||
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(HPO:0001250) | Seizures | Very frequent [Orphanet] | 1245 / 7739 | |||
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(HPO:0006887) | Intellectual disability, progressive | 68 / 7739 | ||||
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(HPO:0000708) | Behavioral abnormality | Very frequent [Orphanet] | 212 / 7739 | |||
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(HPO:0001263) | Global developmental delay | 853 / 7739 | ||||
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(HPO:0002305) | Athetosis | 31 / 7739 | ||||
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(HPO:0009830) | Peripheral neuropathy | 206 / 7739 | ||||
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(HPO:0001265) | Hyporeflexia | 208 / 7739 | ||||
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(HPO:0000737) | Irritability | 93 / 7739 | ||||
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(HPO:0002514) | Cerebral calcification | Very frequent [Orphanet] | 89 / 7739 | |||
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(HPO:0011968) | Feeding difficulties | 240 / 7739 | ||||
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(HPO:0008872) | Feeding difficulties in infancy | 153 / 7739 | ||||
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(HPO:0001508) | Failure to thrive | 454 / 7739 | ||||
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(HPO:0004322) | Short stature | Very frequent [Orphanet] | 1232 / 7739 | |||
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(HPO:0004326) | Cachexia | Very frequent [Orphanet] | 71 / 7739 | |||
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(HPO:0011362) | Abnormal hair quantity | Very frequent [Orphanet] | 92 / 7739 | |||
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(HPO:0002912) | Methylmalonic acidemia | 14 / 7739 | ||||
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(HPO:0004337) | Abnormality of amino acid metabolism | Very frequent [Orphanet] | 45 / 7739 | |||
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(HPO:0003128) | Lactic acidosis | 116 / 7739 | ||||
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(HPO:0008972) | Decreased activity of mitochondrial respiratory chain | 34 / 7739 | ||||
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(HPO:0003236) | Elevated serum creatine phosphokinase | 214 / 7739 | ||||
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(HPO:0002747) | Respiratory insufficiency due to muscle weakness | 48 / 7739 | ||||
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(HPO:0003202) | Skeletal muscle atrophy | Very frequent [Orphanet] | 281 / 7739 | |||
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(HPO:0001324) | Muscle weakness | 859 / 7739 | ||||
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(HPO:0001252) | Muscular hypotonia | 990 / 7739 | ||||
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(HPO:0010547) | Muscle flaccidity | 466 / 7739 | ||||
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(HPO:0008947) | Infantile muscular hypotonia | 482 / 7739 | ||||
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(HPO:0000007) | Autosomal recessive inheritance | 2538 / 7739 | ||||
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(OMIM) | Hyperkinetic movements | 4 / 7739 | ||||
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(OMIM) | Increased urinary carnitine esters | 1 / 7739 | ||||
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(OMIM) | Methylglutaconic aciduria, mild | 1 / 7739 | ||||
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(OMIM) | Aminoaciduria, intermittent | 1 / 7739 | ||||
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(HPO:0030089) | Abnormal muscle fiber protein expression | Very frequent [Orphanet] | 64 / 7739 | |||
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(HPO:0012758) | Neurodevelopmental delay | Very frequent [Orphanet] | 949 / 7739 | |||
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(OMIM) | Imaging shows signal abnormalities in basal ganglia | 1 / 7739 | ||||
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(OMIM) | Skeletal muscle tissue shows depletion of mitochondrial DNA (mtDNA) | 1 / 7739 | ||||
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(OMIM) | Methylmalonic aciduria, mild | 2 / 7739 | ||||
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(OMIM) | Crying, inconsolable | 1 / 7739 | ||||
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(OMIM) | Increased serum and CSF lactate | 7 / 7739 | ||||
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(HPO:0003593) | Infantile onset | 249 / 7739 | ||||
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(OMIM) | Psychomotor delay, severe | 3 / 7739 | ||||
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(HPO:0002119) | Ventriculomegaly | Very frequent [Orphanet] | 253 / 7739 | |||
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(HPO:0002134) | Abnormality of the basal ganglia | 13 / 7739 | ||||
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(HPO:0002059) | Cerebral atrophy | 171 / 7739 | ||||
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(OMIM) | Axonal and demyelinating peripheral neuropathy (in some patients) | 2 / 7739 |
Associated genes:
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
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Additional Information:
Description: (OMIM) |
Mitochondrial DNA depletion syndrome-5 is an autosomal recessive disorder characterized by infantile onset of hypotonia, progressive neurologic deterioration, a hyperkinetic-dystonic movement disorder, external ophthalmoplegia, deafness, and variable renal tubular dysfunction. Laboratory studies often show mild methylmalonic aciduria (Carrozzo ... |
Clinical Description OMIM |
Elpeleg et al. (2005) reported a small Muslim pedigree with an autosomal recessive encephalomyopathy associated with mtDNA depletion. The proband showed irritability and inconsolable crying in early infancy. She had severely delayed psychomotor development with marked muscle hypotonia, ... |
Molecular genetics OMIM |
Elpeleg et al. (2005) identified a homozygous mutation in the SUCLA2 gene (603921.0001) in 2 first cousins from a consanguineous Muslim family with encephalomyopathy and mitochondrial DNA depletion syndrome-5. Urinary organic acid profiles were not reported in the ... |
Population genetics OMIM |
Ostergaard et al. (2007) estimated the incidence of the encephalomyopathic form of mtDNA depletion syndrome with methylmalonic aciduria in the Faroe Islands to be 1 in 1,700. Carrozzo et al. (2007) estimated the carrier and disease ... |
Diagnosis GeneReviews | 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]:... Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySUCLA2Sequence analysis | Sequence 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.
Clinical Description GeneReviews | 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. ... |
Differential Diagnosis GeneReviews | 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. ... Gene SymbolPhenotypeFunction of Gene ProductUrinary Methylmalonic AcidDGUOKHepatocerebral | dNTP poolsNormalMPV17HepatocerebralUnknownNormalPOLGHepatocerebralmtDNA replicationNormalRRM2BEncephalomyopathic with renal tubulopathydNTP poolsNormalSUCLA2EncephalomyopathicdNTP pools↑SUCLG1Fatal infantile lactic acidosisdNTP pools↑TK2MyopathicdNTP poolsNormalC10orf2 (PEO1)
Management GeneReviews | 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:... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSUCLA213q14 | Succinyl-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