Yan_2022_Front.Pediatr_9_816265

BACKGROUND: The serine active site-containing protein 1 (SERAC1) biallelic variant usually causes MEGDEL syndrome, clinically characterized by increased excretion of 3-methylglutaconic in the urine, muscle hypotonia, sensorineural deafness, and Leigh-like lesions on brain MRI scans. In this study, we present a case from a Chinese family with disordered metabolism and dystonia owing to SERAC1 variants; the clinical phenotypes of the proband were different from those of MEGDEL syndrome but were similar to those juvenile-onset complicated hereditary spastic paraplegia. Thus, in this study, we aimed to confirm the relationship between SERAC1 variants and complicated hereditary spastic paraplegia. METHODS: MRI and laboratory tests, including gas chromatography/mass spectrometry (GC/MS), were carried out for the proband. Whole-exome sequencing was used to detect the candidate SERAC1 variants. Variants were verified using Sanger sequencing. Various software programs (PolyPhen-2, MutationTaster, PROVEAN, and SIFT) were used to predict the pathogenicity of novel variants. RESULTS: Brain MRI scans showed a symmetric flake abnormal signal shadow in the bilateral basal ganglia in T2-weighted image (T2WI) and fluid-attenuated inversion recovery (FLAIR) analyses. The excretion of 3-methylglutaconic acid was found to be increased in our GC/MS analysis. Whole-exome sequencing showed novel compound heterozygous variants, including a novel c.1495A>G (p.Met499Val) variant in exon 14 of SERAC1 inherited from the father and a novel c.721_722delAG (p.Leu242fs) variant in exon 8 inherited from the mother. The pathogenicity prediction results showed that these two variants were deleterious. CONCLUSIONS: This study presented a patient with complicated hereditary spastic paraplegia caused by SERAC1 variants. These findings expand the number of known SERAC1 variants and the phenotypic spectrum associated with SERAC1 deficiency. This study may contribute to counseling and prevention of hereditary diseases through prenatal.