Abstract
Background: Krabbe disease is caused by biallelic mutations of GALC gene. NDUFAF1 gene mutations are related to mitochondrial encephalopathy. To date, there has been no report on the co-pathogenesis of these two gene mutations. There were three children in a family who presented with global developmental retardation. MRI showed lesions in the white matter and dentate nucleus of the cerebellum.Methods: Clinical data of the proband and her family members were gathered in a retrospective manner. Karyotype, FISH, whole exome sequencing was performed using genomic DNAs extracted from peripheral blood samples. Enzyme activities of galactosylceramidase (GALC) and mitochondria were determined to verify gene functions.Results: This study reported a pedigree of leukoencephalopathy, in which 3 of the 4 children showed phenotypes of developmental delay, hearing/visual impairment, and peripheral neuropathy. Mutations of NDUFAF1 (c.278A>G; p. His93Arg, c.247G> A; p. Asp83Asn) and GALC (c.599C>A; p.Ser200*) were identified in all three cases. The proband's parents carried these mutations as a heterozygous state. Clinical features, MRI changes, enzyme activity of GALC, and mitochondrial function analysis demonstrated that this pedigree was caused by GALC and NDUFAF1 gene mutations working together.Conclusion: We first report a pedigree of Krabbe disease with biallelic mitochondrial gene NDUFAF1 mutations. For multiple gene mutations found in genetic testing, clinical phenotypes, gene functions, and family history should be comprehensively analyzed. Gene panel examination may miss pathogenic mutations, and prenatal diagnosis of patients with polygenic inheritance needs careful consideration.
Highlights
Krabbe disease is caused by biallelic mutations of GALC gene
She tragically died early in 3 months. Two probands of this family had similar symptoms, and it was strange that genetic testing revealed mutations in NDUFAF1 and GALC, respectively. Sanger sequencing of these two genes was performed for this patient, and the results showed a homozygous mutation in the GALC gene (c.[599C>A]; [599C>A]; p.Ser200∗) and the two mutations
Gene sequencing analysis was further performed on the healthy 5-year-old child in the pedigree, and the results showed heterozygous mutation in the GALC gene (c.599C>A (p.Ser200∗) and compound heterozygous NDUFAF1 mutations
Summary
Krabbe disease is caused by biallelic mutations of GALC gene. There has been no report on the co-pathogenesis of these two gene mutations. MRI showed lesions in the white matter and dentate nucleus of the cerebellum. It has been clinically experienced that we may miss some pathogenic mutations because of monitoring and technology errors, or simultaneously detect mutations in several pathogenic genes in a patient, which makes it difficult to determine whether a disease is caused by a single gene or multiple genes and further complicates prenatal diagnosis. MRI changes in white matter were more extensive in the cases described in this study compared to those in patients with KD. Few cases of leukoencephalopathy caused by the gene mutation of NDUFAF1 have been reported. Our study extends the clinical and molecular phenotypes of KD and further contributes to identify the common pathogenicity of double gene mutations in this family
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