Clinical features and gene diagnosis of L-2-hydroxyglutaric aciduria in 4 children / 中华实用儿科临床杂志

ABSTRACT

Objective To investigate the clinical features and gene diagnostic bases of childhood L-2 -hydroxyglutaric aciduria (L-2-HGA). Methods The clinical data involving manifestations,laboratory examinations of 4 children with L-2-HGA admitted to Beijing Children′s Hospital Affiliated to Capital Medical University from April 2015 to March 2018 were retrospectively analyzed. Each patient had a follow-up visit ranging from 3 months to 3 years and 2 months after initial examination. Results The 4 patients,of whom 2 were siblings,consisted of 1 male and 3 females,whose age of onset ranged from 8 months old to 3 years old. All of them presented with seizures as their initial symptom. The developmental milestones were all normal before onset,while 3 cases gradually became mentally stagnant. Other symptoms included unsteady gait in 3 cases,slight hand trembling when holding items in 2 cases,and pyramidal impairment in 2 cases. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus were detected by cranial magnetic resonance imaging (MRI)in all patients,and cerebral and cerebellar atrophy was ob-served in 1 case. Organic acid analysis by gas chromatography/ mass spectrometry (GC/ MS)demonstrated notable ele-vation of urinary 2-hydroxyglutaric acid in 3 cases. Pathogenic mutations on L2HGDH gene were detected by target -capture high-throughput sequencing in all 4 patients. The compound heterozygous mutations of c. 845G > A (p. Arg282Gln)and c. 800_801delCA (p. Ser267Ter)were identified in case 1,the homozygous missense mutation of c. 584A > G (p. Tyr195Cys ) in case 2 and case 3,and the homozygous frameshift mutation of c. 407delA (p. Lys136SerfsTer3)in case 4. The variants of c. 800_801delCA and c. 407delA were novel mutations firstly reported in this study. Sanger sequencing verified that parents of the 4 cases were all heterozygous carriers. The follow-up study in 2 cases who were put on high dosage of vitamin B2 and L-carnitine had shown a relatively favorable outcome of mild remission in ataxia and absence of mental degradation and further seizures,while the other 2 cases without specific therapy remained relatively stable. Conclusions The main clinical manifestations of L-2-HGA are mental retarda-tion,seizures and ataxia. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus are specific neuroimaging findings. Significant elevation of urinary 2-hydroxyglutaric acid is the basic feature of the disease,while gene assessment should be the gold standard in the diagnosis of L-2-HGA. Treatment with high dosage of vitamin B2 and L-carnitine might be effective to partial patients.