Case ReportA genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation
Introduction
There is an increasingly recognized subgroup of mitochondrial disorders caused by defective iron-sulfur (Fe-S) cluster biosynthesis. A complex synthesis and distribution mechanism is located in the mitochondria that attaches the various classes of Fe-S clusters to the enzymes as essential cofactors (Fig. 1A-I, II). Mutations of three genes in these pathways—NFU1, BOLA3, and IBA57—are called multiple mitochondrial dysfunction syndromes (MMDSs) because the mutated mitochondrial proteins impair the diverse mitochondrial pathways and ATP production [1]. Key phenotypic features of NFU1 mutations are failure to thrive, pulmonary hypertension, infantile encephalopathy, and neurological regression [2]. Hyperglycinemia, lactic acidosis, and brain magnetic resonance imaging (MRI) changes— signal abnormalities in the periventricular cerebral white matter, such as cysts and cavitations—are all clues to an NFU1 mutation diagnosis [1], [3], [4] with a fatal clinical course [1]. However, in 2015, Tonduti et al. [5] described a new spastic paraplegia phenotype that had not been reported to that point, which was associated with NFU1 in a 30-year-old patient with spastic paraplegia and a relapsing-remitting course.
With the approval of our ethics committee and written consent from her legal guardians, we report on a female patient, now 41 months old, who was diagnosed with a homozygous mutation in NFU1 that had not previously been reported as homozygous. Her sister died at the age of 16 months due to a severe neurological course that is presumed to have been caused by the same disease. Other than a very rare mild presentation and the mutation first reported as homozygous, we also want to draw attention to a marked intrafamilial phenotypic variation.
Section snippets
Case
The patient was born via normal spontaneous delivery, weighing 3200 g, with no adverse perinatal events. Her mother and father were first-degree cousins. She had one healthy brother, as well as an older sister who had died 6 years prior (Fig. 1B). The sister had developed normally until the age of 13 months, but then lost the ability to sit without support, before later losing head control. She also began to have difficulty swallowing. At the age of 16 months, she developed difficulty
Discussion
The fatal mitochondrial disease was first described by Seyda et al. [6] in 2001 in four patients, comprising three siblings and one additional, unrelated patient. Ten years after the first report, Cameron et al. [7] described NFU1 and BOLA3 mutations in the patients from Seyda et al.’s report; a month later, Navarro-Sastre et al. [3] identified disease-causing NFU1 mutations in 10 patients. Table 1 summarizes all the reported NFU1 patients. Here, we report on a child who has neurological
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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