Abstract
Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the ALDH1L2 (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to ÎČ-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease.
Highlights
Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis.[1]
In 95% of patients it is caused by mutations of the ALDH3A2 gene which encodes for the fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that oxidizes long-chain aldehydes to fatty acids.[2,5,6]
Since this patient does not have mutations in the ALDH3A2 gene, the cause of the disease remained unclear until exome sequencing revealed inherited mutations in the ALDH1L2 gene
Summary
Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis.[1]. SjögrenâLarsson syndrome (SLS: MIM#270200) is one of the most recognized neuro-ichthyotic syndromes characterized by congenital ichthyosis, leukoencephalopathy, intellectual disability, and spastic di- or tetraplegia.[2,3,4] In 95% of patients it is caused by mutations of the ALDH3A2 gene which encodes for the fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that oxidizes long-chain aldehydes to fatty acids.[2,5,6]. SLS patients without mutations in the ALDH3A2 gene have been identified, leaving the cause of the symptoms unknown.[7] Here, we report a patient with a congenital neuro-ichthyotic syndrome but atypical phenotype displaying dysmorphic features, and abnormalities on MRI and MR (1H-MRS) spectroscopy in the absence of ALDH3A2 gene mutations and no spastic paraplegia to suggest classic SLS. We provide evidence that the neuro-ichthyotic syndrome in this case is associated with the loss of expression of the ALDH1L2 gene, which encodes a mitochondrial folate enzyme
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