Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G>A mitochondrial DNA mutation: a case report

Abstract

Background: Leigh Syndrome (LS) is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem. Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors.

Case presentation: Here we report the clinical and molecular features of a 15-month-old female LS patient. Direct sequencing of her muscle-derived mtDNA revealed the presence of two apparently homoplasmic variants: the novel m.14792C>G and the already known m.14459G>A resulting in p.His16Asp change in cytochrome b (MT-CYB) and p.Ala72Val substitution in ND6 subunit, respectively. The m.14459G>A was heteroplasmic in the mother's blood-derived DNA.

Conclusions: The m.14459G>A might lead to LS, complicated LS or Leber Optic Hereditary Neuropathy. A comprehensive re-evaluation of previously described 14459G>A-mutated patients does not explain this large clinical heterogeneity.

Figure 1

Neuroradiological and molecular features in our proband. A. Brain MRI showed bilateral symmetric hyperintense lesions on T2-weighted images in the head of caudate, putamen (top left), thalami (top right) and ventral mesencephalum (bottom left); these lesions were hypointense in T1-weighted images (bottom right). B. PCR-RFLP analysis of m.14459G > A mutation. The transition m.14459G > A creates a restriction site for endonuclease MaeIII in mutated amplicons obtained using a modified primer set previously described (FOR14430*-RC14710) producing two fragments of 251 and 29 base pairs (the latter is not visible on the agarose gel) while wild type molecules remain uncut. C. PCR-RFLP analysis of m.14792C > G variant. The variant m.14792C > G is recognized by restriction endonuclease HinfI which cuts mutated PCR-amplified fragments (encompassing 14400-14963 nucleotides) producing molecules of 392 and 171 base pairs. Control samples are from healthy unrelated independent subjects.