Complicated Hereditary Spastic Paraplegia Caused by SERAC1 Variants in a Chinese Family.

Dandan Yan,Fengying Cai,Dong Li,Shaopei Chen,Chunhua Zhang,Xiufang Zhi,Jie Zheng,Jianbo Shu,Chunquan Cai

doi:10.3389/fped.2021.816265

Abstract

BackgroundThe 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.MethodsMRI 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.ResultsBrain 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.ConclusionsThis 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.

Highlights

An increase in 3-methylglutaconic acid (3-MGA) indicates 3-methylglutaconic aciduria (3-MGA-uria), which was first reported in 2006 by Wortmann and colleagues [1]. 3-MGA-uria is a heterogeneous group of metabolic disorders, biochemically characterized by elevated 3-MGA and 3-methylglutaric acid excretion in urine
– – 0.000 Damaging syndrome is serious, comprising an infantile-onset phenotype characterized by feeding problems, liver failure, spasticity, dystonia, hearing loss, truncal hypotonia, and premature death [16,17,18]
The individual in this study only presented with one of the clinical characteristics of MEGDEL syndrome (3-MGA-uria), along with other symptoms not usually associated with this syndrome, including decreased myodynamia of both lower extremities, enhanced muscular tension and tendon reflexes, pyramidal tract injury, limp, and abnormal spinal and brain MRI; these symptoms were more similar to those of cHSP than MEGDEL syndrome

Summary

Introduction

An increase in 3-methylglutaconic acid (3-MGA) indicates 3-methylglutaconic aciduria (3-MGA-uria), which was first reported in 2006 by Wortmann and colleagues [1]. 3-MGA-uria is a heterogeneous group of metabolic disorders, biochemically characterized by elevated 3-MGA and 3-methylglutaric acid excretion in urine. Type IV represents a confusing and ever-growing subgroup encompassing all “unclassified” symptoms [2, 5], which includes MEDGEL syndrome, characterized by 3-MGA-uria, dystoniadeafness, encephalopathy, and Leigh-like syndrome (MEGDEL, OMIM ID: 614739), known to be caused by serine active site containing 1 (SERAC1) variants. 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. 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. In this study, we aimed to confirm the relationship between SERAC1 variants and complicated hereditary spastic paraplegia

Objectives

Methods

Results

Conclusion