Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

Abstract

Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations.

Keywords: Leigh syndrome; NDUFV1; OxPhos deficiency; leukodystrophy; leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation.

Figure 1

Neuroimaging findings at three years of age. (A–C) Axial T2-weighted images of brain MRI showing signal abnormalities in the periventricular white matter, putamen, caudate nucleus, splenium of the corpus callosum, and anterior and posterior limb of the internal capsule. (D) Symmetrical bilateral areas of increased signal intensity in the medial thalamic nucleus (black arrow). (E,F) Axial T2-weighted images of the midbrain: (E) interpeduncular cistern (yellow arrow), cerebral peduncle (red arrow), substantia nigra (black arrow); (F) substantia nigra (black arrow) and periaqueductal region (red arrow). (G–I) T2-weighted images of the pons: (G) pyramidal tract (red arrow), pontine tegmentum (black arrow); (H) superior cerebellar peduncle (black arrow), pyramidal tract (red arrow), pontine tegmentum (yellow arrow); (I) diffuse hyper-intensive lesions in the medial lemniscus (yellow arrow). (J,K) T2-weighted images of the medulla oblongata shows abnormal intensities in the medullary tegmentum, spinocerebellar tracts, and pyramids: (J) medullary tegmentum (red arrow), spinocerebellar tract (black arrow); (K) pyramids (yellow arrow). (L) T2-weighted images of the upper cervical spinal cord revealed abnormal intensity within the lateral corticospinal tracts (yellow arrows) and the dorsal columns (black arrows).

Figure 2

Neuroimaging findings at 13 years of age. (A) CT scan of the brain showing cerebral atrophy and ventricular enlargement. (B) Sagittal T1-weighted image of the brain showing ventricular enlargement, thinning of the corpus callosum with foci in the posterior body of the corpus callosum (arrow). (C–E) Axial T2-weighted images of the brain showing signal changes in the periventricular and frontal white matter, the putamen, caudate nucleus, corpus callosum, and anterior limb of the internal capsule. (F–I) Within the brainstem: (F) no signal abnormality was observed in the midbrain; (G) superior cerebellar peduncle (yellow arrow); (H) inferior cerebellar peduncle (black arrow); (I) T2-axial images of the medulla showing spotty high signal in the medulla (arrows), however pyramids and medial lemniscus decussation were preserved. (J,K) T2-axial image of upper cervical spinal cord showing high intensity area in the central part of the spinal cord (arrow).

Figure 3

NDUFV1 mutations detected in a subject. (A) Segregation of the family showing the inheritance pattern of the variants. (B) A graphical representation of NDUFV1 with domains illustrating the position of mutations (red dotted lines) (not to scale). Mutalyzer 2.0.32 (https://mutalyzer.nl/name-checker) for truncated protein prediction, InterPro database (https://www.ebi.ac.uk/interpro/protein) for protein domain prediction, and ClustalW (http://www.ebi.ac.uk/clustalw2) for amino acid (aa) alignment were used. Asterisks (*) indicates conserved aa; IPR011538, NADH: ubiquinone oxidoreductase 51kDa subunit, FMN-binding domain; IPR019554, Soluble ligand binding domain; IPR019575, NADH: ubiquinone oxidoreductase 51kDa subunit, iron-sulfur binding domain. (C) SDS-PAGE immunoblotting of mitochondrial (MT) and total cell lysate (TCL) showing loss of NDUFV1 protein in the subject (S) compared with controls (C1, fHDF; C2, NHDF). HSP60 and ACTB were used as loading controls. (D) BN-PAGE immunoblotting showing destabilization of CI assembly in S. Complex II was used as loading control. (E) OxPhos enzymology revealed CI enzyme deficiency in S compared to C2. Values are expressed as the mean ± SEM. Three independent experiments, two tailed student’s t test done and *** p <0.001 considered statistically significant. (F–H) Lentivirus-mediated complementation assays showing: F, restoration of the NDUFV1 protein in S; G, stabilization of CI assembly; H, restoration of CI enzyme activity. Values are expressed as the mean ± SEM. Three independent experiments, ** p <0.01 considered statistically significant RFP, mtTurbo-RFP; Vector, pCS-CA-MCS.