Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases

Abstract

Background: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database.

Results: Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date.

Conclusion: We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.

Keywords: Basal ganglia; Childhood; Leigh syndrome; Mitochondrial disease.

Fig. 1

Patients' demographics and clinical findings. A Demographics and family history data; B frequency of symptoms at onset; C frequency of symptoms at time of diagnosis

Fig. 2

MRI findings. Graph depicts frequency of brain MRI involved regions in our LS cohort (A). Supratentorial pattern: axial (B) and coronal (C) T2WI sequences show hyperintensities of putamen in a patient with complex I deficiency associated to MT-ND3; supra and subtentorial pattern: coronal (D) and sagittal (E) T2WI sequences show hyperintensities in subthalami (D) and brainstem (E) in a patient with complex IV deficiency associated to SURF1; subtentorial pattern: coronal T2WI (F) and FLAIR (G) show hyperintensities (F) and cavited pattern (G) in dentate nuclei in a patient with complex I deficiency associated to NDUFAF6

Fig. 3

Biochemical and molecular diagnoses. Percentage of biochemical diagnoses (A); number of cases for each molecular diagnosis (B)

Fig. 4

Molecular diagnosis in patients with unfavorable outcome