Expanding the Spectrum of NUBPL-Related Leukodystrophy

Abstract

Mitochondrial leukodystrophies constitute a group of different conditions presenting with a wide range of clinical presentation but with some shared neuroradiological features. Genetic defects in NUBPL have been recognized as cause of a pediatric onset mitochondrial leukodystrophy characterized by onset at the end of the first year of life with motor delay or regression and cerebellar signs, followed by progressive spasticity. Early magnetic resonance imagings (MRIs) show white matter abnormalities with predominant involvement of frontoparietal regions and corpus callosum. A striking cerebellar involvement is usually observed. Later MRIs show spontaneous improvement of white matter abnormalities but worsening of the cerebellar involvement evolving to global atrophy and progressive involvement of brainstem. After the 7 cases initially described, 11 more subjects were reported. Some of them were similar to patients from the original series while few others broadened the phenotypic spectrum. We performed a literature review and report on a new patient who further expand the spectrum of NUBPL-related leukodystrophy. With our study we confirm that the association of cerebral white matter and cerebellar cortex abnormalities is a feature commonly observed in early stages of the disease but beside the original and so far prevalent presentation, there are also uncommon phenotypes: clinical onset can be earlier and more severe than previously thought and signs of extraneurological involvement can be observed. Brain white matter can be diffusely abnormal without anteroposterior gradient, can progressively worsen, and cystic degeneration can be present. Thalami can be involved. Basal ganglia can also become involved during disease evolution.

Keywords

leukodystrophy - NUBPL - complex I - mitochondrial

^* These authors equally contributed to the study.

Publication History

Received: 19 November 2022

Accepted: 12 January 2023

Article published online:
03 March 2023

• References

• 1 Ghezzi D, Zeviani M. Human diseases associated with defects in assembly of OXPHOS complexes. Essays Biochem 2018; 62 (03) 271-286
• 2 Zhang J, Liu M, Zhang Z. et al. Genotypic spectrum and natural history of cavitating leukoencephalopathies in childhood. Pediatr Neurol 2019; 94: 38-47
• 3 Roosendaal SD, van de Brug T, Alves CAPF. et al. Imaging patterns characterizing mitochondrial leukodystrophies. AJNR Am J Neuroradiol 2021; 42 (07) 1334-1340
• 4 Kevelam SH, Rodenburg RJ, Wolf NI. et al. NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern. Neurology 2013; 80 (17) 1577-1583
• 5 Helman G, Caldovic L, Whitehead MT. et al; SDH Study Group. Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy. Ann Neurol 2016; 79 (03) 379-386
• 6 Hempel M, Kremer LS, Tsiakas K. et al. LYRM7 - associated complex III deficiency: a clinical, molecular genetic, MR tomographic, and biochemical study. Mitochondrion 2017; 37: 55-61
• 7 Dallabona C, Abbink TE, Carrozzo R. et al. LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain 2016; 139 (Pt 3): 782-794
• 8 Sharma S, Singh P, Fernandez-Vizarra E, Zeviani M, Van der Knaap MS, Saran RK. Cavitating leukoencephalopathy with posterior predominance caused by a deletion in the APOPT1 gene in an Indian boy. J Child Neurol 2018; 33 (06) 428-431
• 9 Melchionda L, Haack TB, Hardy S. et al. Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency. Am J Hum Genet 2014; 95 (03) 315-325
• 10 Sheftel AD, Stehling O, Pierik AJ. et al. Human ind1, an iron-sulfur cluster assembly factor for respiratory complex I. Mol Cell Biol 2009; 29 (22) 6059-6073
• 11 Calvo SE, Tucker EJ, Compton AG. et al. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 2010; 42 (10) 851-858
• 12 Balint B, Charlesworth G, Stamelou M. et al. Mitochondrial complex I NUBPL mutations cause combined dystonia with bilateral striatal necrosis and cerebellar atrophy. Eur J Neurol 2019; 26 (09) 1240-1243
• 13 Friederich MW, Perez FA, Knight KM. et al. Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement. Mol Genet Metab 2020; 129 (03) 236-242
• 14 Protasoni M, Bruno C, Donati MA. et al. Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement. Mol Genet Metab 2020; 129 (01) 26-34
• 15 Tenisch EV, Lebre AS, Grévent D. et al. Massive and exclusive pontocerebellar damage in mitochondrial disease and NUBPL mutations. Neurology 2012; 79 (04) 391
• 16 Kimonis V, Al Dubaisi R, Maclean AE. et al. NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum. J Med Genet 2021; 58 (05) 314-325
• 17 Stellingwerff MD, Figuccia S, Bellacchio E. et al. LBSL: case series and DARS2 variant analysis in early severe forms with unexpected presentations. Neurol Genet 2021; 7 (02) e559
• 18 Steenweg ME, Ghezzi D, Haack T. et al. Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain 2012; 135 (Pt 5): 1387-1394
• 19 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424