NFU1-Related Disorders as Key Differential Diagnosis of Cavitating Leukoencephalopathy

Abstract

Genetic leukoencephalopathies represent an expanding group of inherited disorders associated with involvement of brain white matter. Cystic degeneration has been previously described with some acquired or inherited leukoencephalopathies. We describe a 6-month-old Brazilian boy with a 2-month history of severe and rapidly progressive developmental and psychomotor regression and seizures. Neurological examination showed spastic tetraparesis and lethargy. Neuroimaging showed diffuse and symmetric cavitating cystic leukoencephalopathy. Whole-exome sequencing revealed compound heterozygous mutations in the NFU1 gene, providing definite genetic diagnosis of multiple mitochondrial dysfunction syndrome type 1. We report a rare presentation of early-onset cystic leukoencephalopathy in the context of multiple mitochondrial dysfunction syndrome type 1.

Keywords

leukodystrophy mitochondrial disease - leukoencephalopathy - neuroimaging

Note

Full consent was obtained from the patient's parents for the case report. This study was approved by the authors' ethics institution.

• References

• 1 Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72 (08) 750-759
• 2 Vanderver A, Prust M, Tonduti D. , et al; GLIA Consortium. Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab 2015; 114 (04) 494-500
• 3 Invernizzi F, Ardissone A, Lamantea E. , et al. Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations. Front Genet 2014; 5: 412
• 4 Cameron JM, Janer A, Levandovskiy V. , et al. Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am J Hum Genet 2011; 89 (04) 486-495
• 5 Navarro-Sastre A, Tort F, Stehling O. , et al. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am J Hum Genet 2011; 89 (05) 656-667
• 6 Kohlschütter A, Eichler F. Childhood leukodystrophies: a clinical perspective. Expert Rev Neurother 2011; 11 (10) 1485-1496
• 7 Kurt YG, Kurt B, Aydin I, Agilli M, Aydin FN. NFU1 gene mutation and mitochondrial disorders. Neurol India 2016; 64 (04) 630-632
• 8 Ferrer-Cortès X, Font A, Bujan N. , et al. Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease. J Inherit Metab Dis 2013; 36 (05) 841-847
• 9 Ahting U, Mayr JA, Vanlander AV. , et al. Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency. Front Genet 2015; 6: 123