Leukoencephalopathy with cysts and hyperglycinemia may result from NFU1 deficiency
Introduction
Lipoic acid is a sulfur-containing cofactor covalently attached to and essential for the function of several key enzymatic complexes such as pyruvate dehydrogenase complex (PDHc), α-ketoglutarate dehydrogenase (α-KGDH), branched chain keto acid dehydrogenase (BCKDH) activity and H protein activity from the glycine cleavage system (GCS) (Cameron et al., 2011, Navarro-Sastre et al., 2011).
Lipoic acid is formed in mitochondria by a series of reactions involving the transfer of an octanoyl-ACP derived from fatty acid biosynthesis onto an apoprotein by LIPT2 and the addition of the sulfur component in a reaction catalyzed by lipoic acid synthase (LIAS), an enzyme possessing two [4Fe–4S] clusters (Hiltunen et al., 2010). The [4Fe–4S] cluster, which is a cofactor of LIAS as well as other mitochondrial proteins (see below), is assembled by a complex metabolic pathway involving proteins such as NFU1 (NFU Iron–Sulfur cluster scaffold homolog (S. cerevisiae), ISCU (Iron–Sulfur cluster scaffold homolog), BOLA3 (bolA family member 3 (Escherichia coli)) and IBA57 (IBA57, iron-sulfur cluster assembly homolog (Saccharomyces. cerevisiae)) (Ajit Bolar et al., 2013, Cameron et al., 2011).
In this pathway NFU1 probably acts as a scaffold downstream of ISCU during Fe–S cluster biogenesis (Navarro-Sastre et al., 2011), whereas BOLA3 is related to proteins that bind glutaredoxins, which play an unknown role in Fe–S cluster biogenesis. Mutations in either NFU1 or BOLA3 disrupt the function of LIAS which adds lipoate moiety to key subunits E2 of PDHc and α-KGDH, and to the related enzymes involved in branched chain amino acid metabolism and glycine degradation. IBA57 is part of the iron–sulfur cluster assembly machinery (Ajit Bolar et al., 2013).
Defects in iron–sulfur cluster biosynthesis pathway ([Fe–S] clusters) lead to abnormal function of the enzyme-bound cofactor lipoate but also of many proteins involved in intermediary metabolism and oxidative phosphorylation, as they participate in electron transfer reactions and in complex I, II and III functions (Rouault and Tong, 2008). This explains the multiple mitochondrial dysfunction syndrome associated with NFU1, BOLA3, LIAS, ISCU and IBA57 mutations (Ajit Bolar et al., 2013, Cameron et al., 2011, Haack et al., 2013, Kollberg et al., 2009, Navarro-Sastre et al., 2011).
Up to now, two reports describe patients with NFU1 mutations, all presenting with infantile encephalopathy and neurological regression leading to death before the age of 15 months. Most patients had pulmonary hypertension, and hyperglycinemia and lactic acidosis were common findings. Interestingly, one mutation, p.Gly208Cys, was frequent in European patients. Some patients apparently presented with leukoencephalopathy but no brain MRI were available (Navarro-Sastre et al., 2011).
Here, we report on a new patient of French origin with two NFU1 mutations, one shared with the Spanish patients and the other one not reported as yet. The findings at presentation included neurological regression, leukoencephalopathy with cysts and hyperglycinemia. The association of neurological regression mimicking an energetic disease, even with intermittent hyperlactatemia in the basal state, along with hyperglycinemia suggested the diagnosis. Administration of oral lipoic acid was without effect.
Section snippets
Patient
The patient, a girl, was the first child of non-consanguineous French parents. She was born after an uneventful pregnancy and spontaneous delivery at term with normal birth parameters. Up to 14 months old, psychomotor development was normal. She could support her head at age one month, sit unaided at age 7 months and had an excellent follow with eyes. The course of the disease was marked by two episodes of metabolic acidosis at 5 and 18 months of age. The first episode occurred in a context of
Brain MRI
Brain magnetic resonance imaging (MRI) revealed progressive leukoencephalopathy with extensive signal abnormalities in the periventricular cerebral white matter and in the corpus callosum (Fig. 1). The abnormal white matter and corpus callosum were partially cystic or with cavitation. Basal ganglia, cerebellum and brain stem were normal. The MRS spectroscopy with long TE (144) shows no peak of lactate. There was no argument for a stroke-like episode.
Metabolic investigation
Biochemical analysis revealed a mild
Discussion
Here, we report on a child with neurological regression, leukoencephalopathy with cysts and hyperglycinemia due to NFU1 mutations. Our report raises the possibility that this disease may be underdiagnosed, as biochemical clues of energetic disease such as hyperlactatemia were only intermittently present. The atypical leukoencephalopathy was associated with elevated levels of glycine, and the combined features are suggestive of the diagnosis. Finally one of the detected mutations, p.Gly208Cys,
Acknowledgments
We are grateful to the patient and her family. This work was supported by Association Française contre les Myopathies [grant number 15947], Fondation Bettencourt, Association Noa Luu, Association Nos Anges and Fondation Lejeune [grant 2011 – 2012].
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Severe Pulmonary Hypertension as the Debut of Metabolic Disease
2020, Archivos de BronconeumologiaA genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation
2020, Brain and DevelopmentCitation Excerpt :The most common NFU1 substitution is Gly208Cys, while the second most common our patient’s Gly189Arg substitution [1]. The Gly189Arg substitution presented as compound heterozygous but was not previously been found to be homozygous [1,2,4]. Patients with this substitution were reported to have milder symptoms and a later age of onset when compared with those with the homozygous Gly208Cys substitution or the heterozygous Gly208Cys/c.146delC null mutation, showing a similar, yet less severe impairment of function [4,5].
Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood
2018, American Journal of Human GeneticsCitation Excerpt :Similar to mutations in iron-sulfur-cluster biogenesis defects, such as NFU1, BOLA3, NFS1, IBA57, or ISCU,65–71 mutations in PMPCB impact the function of several iron-sulfur-cluster-containing enzymes particularly in muscle, the most affected tissue included in our analysis. Respiratory chain complex II is sensitive to iron-sulfur cluster dysfunction65–71 and its enzymatic activity was virtually absent in the affected individual muscle biopsy. Assembly of complex I, which contains eight iron-sulfur clusters,72 was hampered in fibroblast mitochondria leading to the accumulation of abnormal subcomplexes.
Steps Toward Understanding Mitochondrial Fe/S Cluster Biogenesis
2018, Methods in EnzymologyCitation Excerpt :Patients of multiple mitochondrial dysfunction syndromes (MMDSs) present with functional defects in many mitochondrial Fe/S centers; recently, causative mutations were identified in the genes coding for Iba57 and Isca2 of the ISA complex (Ajit Bolar et al., 2013; Al-Hassnan et al., 2015; Lossos et al., 2015; Torraco et al., 2017). MMDS patients have also been identified with mutations in the gene for NFU1 (Ahting et al., 2015; Cameron et al., 2011; Invernizzi et al., 2014; Navarro-Sastre et al., 2011; Nizon et al., 2014; Tonduti et al., 2015). Nfu1 has been characterized to bind [4Fe4S] clusters formed on the ISA complex and to transfer them to a host of client proteins present from yeast to human, including aconitase, Sdh2 (the Fe/S subunit SDH), and LIAS (Cai et al., 2016; Melber et al., 2016).
Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients
2017, Molecular Genetics and MetabolismCitation Excerpt :It seems that BOLA3, ISCA2 and IBA57 are not involved in this function either. Six BOLA3 patients [12,16,17] and > 25 patients with NFU1 mutations have been reported to date [12,13,24,49,50]. The clinical and biochemical phenotypes of these two deficiencies are quite similar, with early onset of severe encephalopathy, variable cardiomyopathy, PDHc and mitochondrial RC defects (Tables 2 and 3).
Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy
2017, American Journal of Human GeneticsCitation Excerpt :Low branched-chain amino acid concentrations were also observed in P2 and in previously reported lipoic acid synthesis defects with either LIPT17 or LIAS6 deficiency. On the other hand, it is important to note that a large proportion of individuals with related disorders such as E3 subunit31 and NFU1 deficiency13 have shown only transient or intermittent biochemical abnormalities. Therefore, there is a large heterogeneity of clinical and biochemical spectrum in these diseases.