Phenotypic continuum of NFU1-related disorders

Area of Science:

• Genetics
• Neurology
• Mitochondrial Biology

Background:

• Bi-allelic variants in the Iron-Sulfur Cluster Scaffold (NFU1) gene are linked to multiple mitochondrial dysfunction syndrome 1 (MMDS1), a severe leukoencephalopathy.
• Previous research identified NFU1 variants primarily associated with early-onset, fatal neurological conditions.

Purpose of the Study:

• To investigate the phenotypic spectrum associated with bi-allelic NFU1 variants.
• To explore the relationship between MMDS1 and hereditary spastic paraplegia (HSP) in the context of NFU1 mutations.

Main Methods:

• Clinical and genetic analysis of 19 individuals from 10 families with bi-allelic NFU1 missense variants.
• Neuroimaging (MRI) to identify white matter abnormalities.
• Phenotypic correlation to determine the range of clinical presentations.

Main Results:

• Identified a spectrum of early-onset neurological disorders, ranging from neurodevelopmental delay with severe hypotonia to hereditary spastic paraplegia with longer survival.
• Observed invariable white matter abnormalities on neuroimaging in all affected individuals.
• Noted frequent neurological decompensation, reversible or irreversible, following febrile illness.

Conclusions:

• Bi-allelic NFU1 variants are associated with a broader phenotypic continuum than previously recognized, encompassing both MMDS1 and HSP.
• MMDS1 and HSP may represent different ends of the phenotypic spectrum caused by NFU1 dysfunction.
• NFU1-related disorders should be considered in early-onset leukoencephalopathies and spastic paraplegias, especially with a history of febrile illness-triggered decompensation.