Abstract
Leukodystrophies are genetic disorders of cerebral white matter that almost exclusively have a progressive disease course. We became aware of three members of a family with a disorder characterized by a sudden loss of all previously acquired abilities around 1 year of age followed by almost complete recovery within 2 years. Cerebral MRI and myelin sensitive imaging showed a pronounced demyelination that progressed for several months despite signs of clinical improvement and was followed by remyelination. Exome sequencing did not-identify any mutations in known leukodystrophy genes but revealed a heterozygous variant in the FBP2 gene, c.343G>A, p. Val115Met, shared by the affected family members. Cerebral MRI of other family members demonstrated similar white matter abnormalities in all carriers of the variant in FBP2. The FBP2 gene codes for muscle fructose 1,6-bisphosphatase, an enzyme involved in gluconeogenesis that is highly expressed in brain tissue. Biochemical analysis showed that the variant has a dominant negative effect on enzymatic activity, substrate affinity, cooperativity and thermal stability. Moreover, it also affects the non-canonical functions of muscle fructose 1,6-bisphosphatase involved in mitochondrial protection and regulation of several nuclear processes. In patients' fibroblasts, muscle fructose 1,6-bisphosphatase shows no colocalization with mitochondria and nuclei leading to increased reactive oxygen species production and a disturbed mitochondrial network. In conclusion, the results of this study indicate that the variant in FBP2 disturbs cerebral energy metabolism and is associated with a novel remitting leukodystrophy.