New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria
Introduction
Deficiencies in two subunits of the succinyl-coenzyme A synthetase (SCS) have been involved in patients with mitochondrial DNA (mtDNA) depletion, encephalomyopathy and mild methylmalonic aciduria (MMAuria). SCS is the enzyme complex that uses ATP or GTP to catalyze the reversible formation of succinyl-CoA from succinate and coenzyme A. In animals, two different isoforms exist, one specific for ATP (SCS-A) and the other specific for GTP (SCS-G) (Johnson et al., 1998a). The two isoforms SCS-A and G are heterodimeric proteins including the same α-subunit but a different β-subunit (Johnson et al., 1998b). SUCLG1 gene encode for the common α subunit. SUCLA2 and SUCLG2 genes encode for the β subunits of SCS-A and SCS-G, respectively (Johnson et al., 1998b). SCS-G might serve in the synthesis of succinyl-CoA, while SCS-A would serve in the citric acid cycle (Fraser et al., 2006). Tissues with high need for energy, such as heart, show higher activities of SCS-A, while kidney and liver tissues show higher activities of SCS-G. SCS-A is serving both a catabolic and anabolic role, while SCS-G would serve only an anabolic role (Fraser et al., 2006).
To date, 18 patients with SUCLA2 mutations have been reported (Carrozzo et al., 2007, Chinnery, 2007, Elpeleg et al., 2005, Morava et al., 2009, Ostergaard et al., 2007b), whereas mutations in SUCLG1 have been reported in 13 patients (Carrozzo, 2009, Ostergaard et al., 2007a, Ostergaard et al., 2010). The first patient reported with SUCLG1 mutations displayed a very severe antenatal phenotype with early mortality (Ostergaard et al., 2007a). The phenotypes of SUCLA2 patients and of the other SUCLG1 patients were milder with hypotonia, muscle atrophy, dystonia, “Leigh-like” syndrome, mtDNA depletion in muscle and a short life span of up to 21 years (Carrozzo et al., 2007, Carrozzo, 2009, Elpeleg et al., 2005; Ostergaard, 2008; Ostergaard et al., 2007b, Ostergaard et al., 2010). It has been hypothesized that a genetic defect of the SCS disrupts the tight complex with mitochondrial nucleoside diphosphate kinase, thereby impairing mtDNA synthesis, leading to mtDNA depletion in patients (Elpeleg et al., 2005). Here, we describe the clinical, radiologic, biochemical and genetic features of three children presenting with encephalopathy, hypotonia, muscle atrophy and dystonia; we also compared the phenotype of our patients with the other reported SUCLA2 and SUCLG1 patients, in order to identify possible common and differential clinical and metabolic patterns.
Section snippets
Patients
Patient 1, the first boy of French unrelated parents, was born after a normal pregnancy and term delivery (birth weight: 2740 g/−1.5 SD), length: 47 cm/−1 SD, HC: 36 cm). At 2 months of age, he presented with feeding difficulties, delayed motor development, growth retardation, altered eye contact, axial hypotonia and peripheral muscular hypertonia. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) were normal. At 6 months of age, after a febrile episode,
Results
The clinical and biochemical features of the 3 patients are summarized in Table 1, Table 2. All patients presented bilateral T 2 and FLAIR hyperintensities in bilateral caudate nuclei and bilateral putamen. Lactate was observed in basal ganglia (striatum) in 2/3 patients (Fig. 1F). Patients display moderate cortical atrophy, caudate atrophy and ventricular dilatation. Brainstem and cerebellum were normal.
Common biological findings were increased lactate and MMA in plasma and/or urine (Table 1).
Discussion
We studied the clinical, biochemical, radiologic and genetic features of three new SUCLG1 patients and compared them to the phenotype of all other reported patients with SUCLA2 or SUCLG1 mutations (Table 2) (Carrozzo et al., 2007, Carrozzo, 2009, Chinnery, 2007, Elpeleg et al., 2005, Morava et al., 2009, Ostergaard et al., 2007a, Ostergaard et al., 2007b, Ostergaard et al., 2010). Some clinical data was not available for all patients and performing this type of analysis when data for some
Conclusions
In summary, we identified four novel SUCLG1 mutations in three European families with encephalomyopathy and severe combined RC deficiency. This report enlarges the phenotypic spectrum of SUCLG1 mutations and confirms that brain MRI lesions with basal ganglia and a characteristic metabolic profile are the hallmarks of the SCS defects. The absence of mtDNA depletion in the muscle of 2 of our 3 patients, may suggest alternative physiopathological mechanisms such as depletion of succinyl-CoA,
Acknowledgments
We thank Dr. Monique Fontaine (CHRU de Lille, France) for C4-DC identification in patient 1. We are grateful to all patients, doctors, nurses, and other people who were involved with this study. Funding: This research was supported by the Mitocircle contract from the European commission (No. 005260).
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