current
SDHA:c.1664G>A (p.Gly555Glu) AND Mitochondrial complex II deficiency
current
classified by single submitter
Pathogenic
germline
human
not provided
curation
In a patient with mitochondrial complex II deficiency (252011), born of first-cousin parents, Van Coster et al. (2003) identified a homozygous 1664G-A transition in exon 13 of the SDHA gene, resulting in a gly555-to-glu (G555E) substitution. The patient died at 5.5 months of age following a respiratory infection. Crossreacting material (CRM) for flavoprotein as well as iron-containing protein was decreased, and CRM for the entire complex II was reduced even more. The observation prompted speculation of a labile interaction between iron-containing protein and flavoprotein polypeptides and of a key role of the amino acid at position 555 in the interacting domain. The observation pointed to the fragile equilibrium of intermediate metabolism in infants with complex II deficiency. Although the patient's clinical course differed from that in the patients with Leigh syndrome (256000) reported by Bourgeron et al. (1995) and Parfait et al. (2000) (see 600857.0001 and 600857.0002), Van Coster et al. (2003) noted that she had died in infancy before any sign of Leigh syndrome could develop.
12794685
7550341
10746566
Pagnamenta et al. (2006) reported a 10-year-old boy with relatively mild Leigh syndrome and isolated deficiency of mitochondrial complex II, born of consanguineous Palestinian parents, in whom they identified homozygosity for the G555E mutation in the SDHA gene. The unaffected parents were heterozygous for the mutation, which was not found in 60 controls. The authors noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation. Pagnamenta et al. (2006) stated that both patients had comparable activities and stability of mitochondrial respiratory chain enzymes. Biochemical studies of cultured fibroblasts showed that the size of the band corresponding to the partially assembled complex II differed slightly between the 2 patients; however, their phenotypic variability remained unexplained.
12794685
16798039
In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; 613642), including 13 patients from 2 consanguineous families and 2 sporadic patients, Levitas et al. (2010) identified homozygosity for the G555E mutation. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions. Levitas et al. (2010) noted that the unaffected father of 1 of the patients was also homozygous for the G555E mutation, and he had 3 sibs who had died at a young age due to cardiovascular failure. Evaluation of other subunits of complex II (SDHB, 185470; SDHD, 602690) and a candidate modifier gene (SDHAF1; 612848) showed no difference between the father, his affected son, and other Bedouin patients. The enzymatic activity of the father's complex II was decreased by 42% and was more similar to that of the other patients than to the heterozygous mother or controls. Levitas et al. (2010) stated that they did not have an explanation for the normal phenotype of the father.
20551992
SDHA:c.1664G>A (p.Gly555Glu)
NM_004168.2:c.1664G>A
NG_012339.1:g.38098G>A
NC_000005.9:g.251453G>A
NP_004159.2:p.Gly555Glu
missense
G555E
GLY555GLU
5p15.3
succinate dehydrogenase complex, subunit A, flavoprotein (Fp)
SDHA
Mitochondrial complex II deficiency
Complex 2 mitochondrial respiratory chain deficiency
Succinate CoQ reductase deficiency
Mitochondrial respiratory chain complex II deficiency
current
Pathogenic
germline
human
not provided
curation
In a patient with mitochondrial complex II deficiency (252011), born of first-cousin parents, Van Coster et al. (2003) identified a homozygous 1664G-A transition in exon 13 of the SDHA gene, resulting in a gly555-to-glu (G555E) substitution. The patient died at 5.5 months of age following a respiratory infection. Crossreacting material (CRM) for flavoprotein as well as iron-containing protein was decreased, and CRM for the entire complex II was reduced even more. The observation prompted speculation of a labile interaction between iron-containing protein and flavoprotein polypeptides and of a key role of the amino acid at position 555 in the interacting domain. The observation pointed to the fragile equilibrium of intermediate metabolism in infants with complex II deficiency. Although the patient's clinical course differed from that in the patients with Leigh syndrome (256000) reported by Bourgeron et al. (1995) and Parfait et al. (2000) (see 600857.0001 and 600857.0002), Van Coster et al. (2003) noted that she had died in infancy before any sign of Leigh syndrome could develop.
12794685
7550341
10746566
Pagnamenta et al. (2006) reported a 10-year-old boy with relatively mild Leigh syndrome and isolated deficiency of mitochondrial complex II, born of consanguineous Palestinian parents, in whom they identified homozygosity for the G555E mutation in the SDHA gene. The unaffected parents were heterozygous for the mutation, which was not found in 60 controls. The authors noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation. Pagnamenta et al. (2006) stated that both patients had comparable activities and stability of mitochondrial respiratory chain enzymes. Biochemical studies of cultured fibroblasts showed that the size of the band corresponding to the partially assembled complex II differed slightly between the 2 patients; however, their phenotypic variability remained unexplained.
16798039
12794685
In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; 613642), including 13 patients from 2 consanguineous families and 2 sporadic patients, Levitas et al. (2010) identified homozygosity for the G555E mutation. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions. Levitas et al. (2010) noted that the unaffected father of 1 of the patients was also homozygous for the G555E mutation, and he had 3 sibs who had died at a young age due to cardiovascular failure. Evaluation of other subunits of complex II (SDHB, 185470; SDHD, 602690) and a candidate modifier gene (SDHAF1; 612848) showed no difference between the father, his affected son, and other Bedouin patients. The enzymatic activity of the father's complex II was decreased by 42% and was more similar to that of the other patients than to the heterozygous mother or controls. Levitas et al. (2010) stated that they did not have an explanation for the normal phenotype of the father.
20551992
SDHA, GLY555GLU
GLY555GLU
SDHA
MITOCHONDRIAL COMPLEX II DEFICIENCY