Alternative titles; symbols
ORPHA: 17; DO: 0080128;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p11.2 | Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) | 245400 | Autosomal recessive | 3 | SUCLG1 | 611224 |
A number sign (#) is used with this entry because of evidence that mitochondrial DNA depletion syndrome-9 (MTDPS9) is caused by homozygous or compound heterozygous mutation in the alpha subunit of the succinate-CoA ligase gene (SUCLG1; 611224) on chromosome 2p11.
See MTDPS5 (612073) for a description of a similar disorder caused by mutation in the beta subunit of the succinate-CoA ligase gene (SUCLA2; 603921).
Mitochondrial DNA depletion syndrome-9 (MTDPS9) is a severe autosomal recessive disorder characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. Some patients die in early infancy (summary by Rouzier et al., 2010).
For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).
Early Descriptions
Erickson (1965) reported a mentally retarded brother and sister with familial infantile lactic acidosis. They had relatives who died in infancy, perhaps of the same condition. The diagnosis was suggested by discrepancy between total cations and anions in the blood. Treatment consisted of replacing glucose with galactose and administering bicarbonate. Worsley et al. (1965) described 2 brothers who presented in the second year of life with ataxia, muscle twitching, and intermittent hyperpnea at rest. The condition progressed with mental deterioration, loss of scalp hair, and death about 6 months after onset. Widespread necrotizing encephalopathy was found at autopsy. Spontaneous increases in lactic acid in the blood were apparently responsible for the hyperpnea. Renal amino aciduria and lowered serum phosphate were also found. They suggested that this was the first description of familial lactic acidosis in young children.
Haworth et al. (1967) described an American Indian family in which 3 sibs were mentally retarded and had convulsions, other neurologic abnormalities, muscular hypotonia, obesity, and signs and symptoms of metabolic acidosis. Blood lactate and pyruvate levels were elevated. Five other Indians died before 2 years of age with symptoms suggesting the same disorder. Binkiewicz et al. (1972) observed 2 sibs with severe physical and mental retardation and lactate levels about 4 times normal. Pyruvate was essentially normal. Metabolic findings suggested impaired oxidation of NADH2 associated with decreased effectiveness of the mitochondrial respiratory chain.
Brunette et al. (1972) studied a thiamine-responsive case of lactic acidosis. Thiamine-dependent pyruvate dehydrogenase activity was normal in leukocytes and cultured skin fibroblasts. There was partial deficiency of biotin-dependent hepatic pyruvate carboxylase activity.
Goodyer and Lancaster (1984) studied fibroblasts from a female with lactic acidosis that was lethal in the newborn period. A brother had succumbed to the same disorder. Although pyruvate dehydrogenase was not reduced in cell sonicates, flux through the enzyme and other mitochondrial multienzyme dehydrogenases was severely impaired in intact cells. Deficient conversion of lactate to carbon dioxide could be repaired by addition to the incubation medium of electron acceptors such as methylene blue or dichlorophenolindophenol.
Patients with SUCLG1 Mutations
Ostergaard et al. (2007) described patients with fatal infantile lactic acidosis resulting from mutation in the SUCLG1 gene (611224.0001). The patients had an exceedingly severe phenotype with antenatal manifestations and severe lactic acidosis in the first day of life and death within 2 to 4 days. Similar findings, i.e., a combined oxidative phosphorylation deficiency and mtDNA depletion (MTDPS5; 612073), are found in patients with mutation in the SUCLA2 gene (603921). However, the phenotypes of patients with SUCLA2 were milder; they were generally healthy at birth but presented with severe hypotonia and muscle weakness at age 3 to 6 months. Subsequently, they developed a Leigh syndrome-like disorder with hearing impairment and dystonia, and they had a life span of up to 21 years.
Ostergaard et al. (2010) reported a Swedish boy with recessive encephalomyopathic mtDNA depletion syndrome and methylmalonic aciduria due to mutation in the SUCLG1 gene (611224.0002). He was born of unrelated parents from the same small rural area in northern Sweden. Development was normal in the first 3 months, but he presented at age 6 months with failure to thrive and severe hypotonia with inability to balance his head. He also had hyperhidrosis. Laboratory studies showed lactic acidosis. He subsequently showed delayed psychomotor development, poor feeding and growth, and hearing impairment. After a gastrointestinal illness at age 2 years, 3 months, he developed severe lactic acidosis, shock, and respiratory insufficiency, leading to death. Serial brain MRI showed progressive, bilateral, increased attenuation of the putamen, globus pallidus, and caudate together with increasing subarachnoid space and widening of the lateral ventricles. Southern blot analysis of muscle tissue showed moderately decreased mtDNA. There was no evidence of cardiomyopathy. Ostergaard et al. (2010) noted the phenotypic similarities to fumarase deficiency (606812).
Rouzier et al. (2010) reported 2 unrelated affected individuals with this disorder. The first child presented at age 1 day with severe hypotonia, respiratory failure, and hypoglycemia. Laboratory investigations indicated lactic acidosis and excretion of methylmalonic acid. Brain MRI showed symmetric T2-hyperintense lesions of the basal ganglia. At age 7 months, he had severely delayed psychomotor development with no head control and poor spontaneous movements. He presented with recurrent episodes of acidosis and respiratory failure, and died at age 1 year. Skeletal muscle biopsy showed severe mtDNA depletion (11% of controls). The second child presented with severe hypotonia, feeding difficulties, and failure to thrive at age 3 months. He had lactic acidosis and moderate excretion of methylmalonic acid, and later showed lack of head control and severe psychomotor retardation. Although he was alive at age 12 years, he had severe axial hypotonia with no active movements and very atrophic muscles. He needed tube-feeding and permanent respiratory support by tracheotomy. Skeletal muscle biopsy showed markedly reduced activities for respiratory complexes I and IV, and severe mtDNA depletion (18% of controls).
Chinopoulos et al. (2019) reported a female patient who had retardation of gross motor development with generalized hypotonia since 4.5 months of age. She also had a unilateral congenital cataract. Laboratory evaluation showed a mild elevation in transaminases and blood lactate. Brain MRI revealed enlarged subarachnoid spaces and symmetric T2-hyperintense lesions of the basal ganglia. Metabolic testing showed elevated methylmalonic acid and methylcitrate, as well as a slight increase of citric acid cycle intermediates in the urine, and increased 3-hydroxyisovalerylcarnitine and propionylcarnitine in plasma. At 26 months of age she had failure to thrive, psychomotor retardation, progressive severe myopathy, and intermittent dystonic movements. Brain MRI demonstrated bilateral abnormal signal in the putamen and caudate nuclei, severe brain atrophy, and ventriculomegaly. Brainstem auditory evoked potentials showed sensorineural hearing loss. Repeat acylcarnitine profile and urine organic acids showed increased C3 and C4 dicarboxylic carnitines, methylmalonic acid, citric acid cycle intermediates, and 3-OH-isovaleric acid. Quantitation of mtDNA content in muscle demonstrated a mild depletion, and electron transport chain activity in muscle was normal. The patient died at age 3.5 years due to cardiorespiratory failure in the setting of a respiratory tract infection.
In a consanguineous family of Pakistani origin with autosomal recessive fatal infantile lactic acidosis, Ostergaard et al. (2007) found a combined respiratory chain enzyme deficiency associated with mitochondrial DNA depletion. To identify the disease-causing gene, they performed single-nucleotide polymorphism (SNP) homozygosity mapping and found homozygous regions on 4 chromosomes. DNA sequencing revealed a homozygous 2-bp deletion in SUCLG1 (611224.0001), a gene that encodes the alpha subunit of the Krebs cycle enzyme succinate-coenzyme A ligase (SUCL). The mtDNA depletion was thought to be explained by decreased mitochondrial nucleoside diphosphate kinase (NDPK; see 156491) activity resulting from the inability of NDPK to form a complex with SUCL.
In patients with encephalomyopathic mtDNA depletion and methylmalonic aciduria, Ostergaard et al. (2010) and Rouzier et al. (2010) identified mutations in the SUCLG1 gene (611224.0002-611224.0005). One patient with a slightly milder phenotype and survival to age 12 years was heterozygous for a truncating mutation and had some residual enzyme activity.
In a female child with MTDPS9, Chinopoulos et al. (2019) identified a mutation in the SUCLG1 gene (A209E; 611224.0006) that was heterozygous at the genomic DNA level but homozygous at the transcriptional level. The mutation, which was found by Sanger sequencing, was present in heterozygous state in the father; an unknown ovary donor had been used for in vitro fertilization. Testing in patient fibroblasts showed absence of detectable SUCLG1 protein and decreased mitochondrial substrate-level phosphorylation.
Binkiewicz, A., Jungas, R. L., Hochman, H., Senior, B. Familial idiopathic lactic acidosis--petite mutant disease in man? (Abstract) Pediat. Res. 6: 395 only, 1972.
Brunette, M. G., Delvin, E., Hazel, B., Scriver, C. R. Thiamine-responsive lactic acidosis in a patient with deficient low-Km pyruvate carboxylase activity in liver. Pediatrics 50: 702-711, 1972. [PubMed: 4343503]
Chinopoulos, C., Batzios, S., van den Heuvel, L. P., Rodenburg, R., Smeets, R., Waterham, H. R., Turkenburg, M., Ruiter, J. P., Wanders, R. J. A., Doczi, J., Horvath, G., Dobolyi, A., Vargiami, E., Wevers, R. A., Zafeiriou, D. Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. Molec. Genet. Metab. 126: 43-52, 2019. [PubMed: 30470562] [Full Text: https://doi.org/10.1016/j.ymgme.2018.11.009]
Erickson, R. J. Familial infantile lactic acidosis. J. Pediat. 66: 1004-1016, 1965. [PubMed: 14288452] [Full Text: https://doi.org/10.1016/s0022-3476(65)80085-3]
Goodyer, P. R., Lancaster, G. A. Inherited lactic acidosis: correction of the defect in cultured fibroblasts. Pediat. Res. 18: 1144-1148, 1984. [PubMed: 6440113] [Full Text: https://doi.org/10.1203/00006450-198411000-00018]
Haworth, J. C., Ford, J. D., Younoszai, M. K. Familial chronic acidosis due to an error in lactate and pyruvate metabolism. Canad. Med. Assoc. J. 97: 773-779, 1967. [PubMed: 6050895]
Lie, S. O., Loken, A. C., Stromme, J. H., Aagenaes, O. Fatal congenital lactic acidosis in two siblings. I. Clinical and pathological studies. Acta Paediat. Scand. 60: 129-137, 1971. [PubMed: 5548117] [Full Text: https://doi.org/10.1111/j.1651-2227.1971.tb06632.x]
Ostergaard, E., Christensen, E., Kristensen, E., Mogensen, B., Duno, M., Shoubridge, E. A., 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. 81: 383-387, 2007. [PubMed: 17668387] [Full Text: https://doi.org/10.1086/519222]
Ostergaard, E., Schwartz, M., Batbayli, M., Christensen, E., Hjalmarson, O., Kollberg, G., Holme, E. A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria. Europ. J. Pediat. 169: 201-205, 2010. [PubMed: 19526370] [Full Text: https://doi.org/10.1007/s00431-009-1007-z]
Rouzier, C., Le Guedard-Mereuze, S., Fragaki, K., Serre, V., Miro, J., Tuffery-Giraud, S., Chaussenot, A., Bannwarth, S., Caruba, C., Ostergaard, E., Pellissier, J.-F., Richelme, C., Espil, C., Chabrol, B., Paquis-Flucklinger, V. The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein. J. Med. Genet. 47: 670-676, 2010. [PubMed: 20693550] [Full Text: https://doi.org/10.1136/jmg.2009.073445]
Skrede, S., Stromme, J. H., Stokke, O., Lie, S. O., Eldjarn, L. Fatal congenital lactic acidosis in two siblings. II. Biochemical studies in vivo and vitro. Acta Paediat. Scand. 60: 138-145, 1971. [PubMed: 5548118] [Full Text: https://doi.org/10.1111/j.1651-2227.1971.tb06633.x]
Worsley, H. E., Brookfield, R. W., Elwood, J. S., Noble, R. L., Taylor, W. H. Lactic acidosis with necrotizing encephalopathy in two sibs. Arch. Dis. Child. 40: 492-501, 1965. [PubMed: 5829993] [Full Text: https://doi.org/10.1136/adc.40.213.492]