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Case Reports
. 2010 Aug;68(2):159-64.
doi: 10.1203/PDR.0b013e3181e5c3a4.

Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy

Johan L K Van Hove  1 , Margarita S Saenz, Janet A Thomas, Renata C Gallagher, Mark A Lovell, Laura Z Fenton, Sarah Shanske, Sommer M Myers, Ronald J A Wanders, Jos Ruiter, Marjolein Turkenburg, Hans R Waterham
Affiliations
Case Reports

Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy

Johan L K Van Hove et al. Pediatr Res. 2010 Aug.

Abstract

This patient presented on the first day of life with pronounced lactic acidosis with an elevated lactate/pyruvate ratio. Urine organic acids showed Krebs cycle metabolites and mildly elevated methylmalonate and methylcitrate. The acylcarnitine profile showed elevated propionylcarnitine and succinylcarnitine. Amino acids showed elevated glutamic acid, glutamine, proline, and alanine. From the age 2 of mo on, she had elevated transaminases and intermittent episodes of liver failure. Liver biopsy showed steatosis and a decrease of mitochondrial DNA to 50% of control. She had bilateral sensorineural hearing loss. Over the course of the first 2 y of life, she developed a progressively severe myopathy with pronounced muscle weakness eventually leading to respiratory failure, Leigh disease, and recurrent hepatic failure. The hepatic symptoms and the metabolic parameters temporarily improved on treatment with aspartate, but neither muscle symptoms nor brain lesions improved. Laboratory testing revealed a deficiency of succinyl-CoA ligase enzyme activity and protein in fibroblasts because of a novel homozygous mutation in the SUCLG1 gene: c.40A>T (p.M14L). Functional analysis suggests that this methionine is more likely to function as the translation initiator methionine, explaining the pathogenic nature of the mutation. Succinyl-CoA ligase deficiency due to an SUCLG1 mutation is a new cause for mitochondrial hepatoencephalomyopathy.

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Figures

Figure 1
Figure 1
Biochemical pathway Legend: This biochemical pathway shows the interrelationship of the Krebs cycle and the methylmalonate pathway as it relates to the metabolic block in this condition.
Figure 2
Figure 2
Brain imaging Legend: A. Normal brain MRI at age two months. Axial T2 image at the level of the foramen of Monroe shows normal signal intensity and volume of bilateral basal ganglia, normal ventricular size and normal cerebral volume. B. Abnormal brain MRI at age 14 months. Axial T2 image at the level of the foramen of Monroe shows symmetric abnormal increased signal and volume loss in bilateral basal ganglia. There is cortical and subcortical volume loss with enlargement of the lateral and third ventricles and enlarged cerebral sulci. Myelination is normal.
Figure 3
Figure 3
Pathology of the liver biopsy Legend: A liver needle biopsy taken at age 3 months showed marked macro- and microvesicular steatosis, more marked around the portal areas, without inflammation, cholestasis or fibrosis. Hematoxylin and eosin staining, original magnification 400X, scale bar is 100 μm.
Figure 4
Figure 4
Molecular analyses Legend: A. Sequencing of the SUCLG1 gene. The patient shows homozygosity for the c.40A>T mutation, whereas each parent shows heterozygosity for this mutation. B. Analysis of the enzyme activity in fibroblasts. C. SUCLG1 mRNA in fibroblasts of patient and control with and without incubation with emetine. D. Western blot of SUCLG1 protein shows decreased amount of normal sized peptide compared to controls. (Pat = patient, Ctr = control)
Figure 5
Figure 5
Comparison of the amino terminus of SUCLG1 proteins Legend: Alignment of the predicted amino-terminal coding sequences of the SUCLG1 proteins from human, chimpanzee, rat and mouse. * denotes M14, which is mutated in the patient. ↓ indicates the predicted mitochondrial targeting sequence cleavage site.
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