SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome

Abstract

SUCLA2 is a component of mitochondrial succinate-CoA ligase and nucleotide diphosphokinase activities. Its absence results in Krebs cycle failure, mitochondrial DNA depletion, and a childhood-fatal encephalomyopathy. We describe a purely neurologic allelic form of the disease consisting of deafness, putamenal hyperintensity on MRI and a myoclonic-dystonic movement disorder unchanging from childhood into, so far, the late fourth decade. We show that succinate supplementation circumvents the Krebs cycle block, but does not correct the neurologic disease. Our patients' Arg407Trp mutation has been reported in children with (yet) no MRI abnormalities. It remains possible that early succinate supplementation could impact the disease.

Figure 1

SUCLA2 p.Arg407Trp mutationin a sibship with nonprogressive movement disorder and sensorineural hearing loss. (A) Pedigree. Filled symbols, affected patients; beneath each symbol the patient’s microarray result in the indicated region of chromosome 13, with absence of dots depicting homozygosity of SNP genotypes, and his or herSUCLA2c.1219 C> T mutation. (B) MRI brain in patient II:3 shows selective putamenal hyperintensity (arrows). (C) Muscle electron micrographs showing normal mitochondrial structure, and generally no myofiber pathology. (D) Mitochondrial DNA quantities at the D‐Loop and ATP8 mitochondrial genome loci, relative to nuclear DNA at β‐microglobulin (B2M); a value lower than 40% of control is required for a diagnosis of mitochondrial depletion ⁸ , ⁹ . (E) Relative succinyl‐CoA ligase activity in fibroblasts in the presence of GTP (for SUCLG2‐related activity) or ATP (for SUCLA2‐related activity); activity is expressed as a ratio with the activity of another enzyme, short‐chain 3‐ hydroxyacyl‐CoA dehydrogenase (SCHAD).