Severe neonatal myopathy due to SUCLG1 deficiency with methylmalonic aciduria detected via newborn screening

Methylmalonic aciduria (MMA) is routinely detected by the expanded TMS-newborn screening and has a broad spectrum of differenzial diagnoses.

Here we describe a girl born at term with intrauterine growth retardation who was detected via newborn screening with a constant elevation of MMA (150 mmol/mol creatinine) and propionylcarnitine. In the first two weeks of life the child presented with muscular hypotonia, poor suckling and lactate elevation (5–13 mmol/L). The combination of these findings led us to suspect a defect of the succinyl:CoA ligase (SUCL). Defects in the two subunits of SUCL have been described recently as new causes of mitochondrial DNA (mtDNA) depletion in patients with mild MMA and mitochondrial encephalopathy either with hepatopathy (SUCLG1) or myopathy (SUCLA2). A muscle biopsy performed at three weeks of life revealed a combined respiratory chain deficiency and a mitochondrial DNA content of 5% of normal. Sequence analysis of the SUCLA2 gene was normal. In the SUCLG1 gene, novel compound heterozygous mutations c.677G>A p.Gly227Arg and c.523–1G>A were found. The clinical course of our patient was progressive with lack of growth and psychomotor development, feeding difficulties, muscular hypotonia and early death at the age of 4 months. Remarkably, our patient did not develop hepatomegaly (transaminases were only slightly elevated (GOT90U/l, GPT 100U/l), she had no seizures, no hearing impairment or optic atrophy, which is in contrast to most of the reported patients with SUCLG1 mutations. Our patient is the first described with a predominately myopathic form reflected by the high degree of mtDNA depletion in muscle tissue. In conclusion we recommend in any child with mild MMA to consider mtDNA depletion syndrome, especially in cases with lactate elevation.