Rare Clinical Gene Variant of GBE2: Glycogen Storage Disease IV

Document Type

Conference Proceeding

Publication Date

2024

Publication Title

Genetics in Medicine Open

Abstract

Background: Glycogen storage diseases (GSDs) are inherited inborn errors of carbohydrate metabolism. Specifically, GSD-IV is an autosomal recessive disorder due to GBE1 gene mutations with estimated prevalence of 1:6000,000-1:800,0000. It is characterized by a mutation in GBE1, which is located on chromosome 3 and encodes 1,4 alpha-glucan branching enzyme1 and catalyzes glycogen. GBE1 mutations cause intracellular polyglucosan accumulation in the nervous system, liver and heart. GBE1 mutations with childhood and adult-onset subtypes have progressive liver cirrhosis, cardiomyopathy and varying neuronal dysfunction. Prenatal diagnostic testing for GSD-IV is offered to patients with a positive family history or previously affected pregnancy. Perinatal demise, fetal akinesia, thickened nuchal fold, neonatal hypotonia, multiple joint contractures, and fetal hydrops are common, but nonspecific findings of GSD-IV perinatal subtype. As a result, several cases of GBE1 mutation are discovered prenatally via exome sequencing (ES) when performed due to abnormal ultrasound findings. Certain subtypes, however, reveal missense GBEI1 mutations and retain residual enzyme activity. Therefore, prenatal GSD IV diagnosis requires extensive genetic testing to identify gene mutations as well as a detailed family investigation. Case presentation: A 31-year-old primigravida with a negative family history was referred for abnormal ultrasound findings of multiple joint contractures, thickened nuchal fold, and prominent paraspinal muscles identified at 22 weeks gestation. After extensive genetic counseling, amniocentesis was performed and revealed normal karyotype (46, XY) and negative spinal muscular atrophy analysis and microarray. However, ES showed compound heterozygous variants of GBE1 with a diagnosis of autosomal recessive GSD-IV. ES identified a paternal pathogenic variant (c.691+2 T>C), a splice site variant known to have absent enzyme activity, and a maternal likely pathogenic variant (c.708 G>C), a missense mutation with unknown residual enzyme activity previously reported in a perinatally affected child that did not result in lethality. Antenatal surveillance included monthly growth ultrasound and weekly fluid assessments. Growth remained within normal limits without evidence of hydrops, however, primary cesarean delivery at 36 weeks gestation was performed for oligohydramnios and breech presentation. A male infant delivered with Apgar scores 7/8 and spontaneous respiratory effort. Birth weight 2440g at 1st percentile, length 44cm at <1st percentile and head circumference 34cm at 36th percentile. Physical exam confirmed limb deformities of flexed hips with extended knee joints and flexed elbows and bilateral clenched fists. Initial survey was notable for webbed neck, bell-shaped chest, poor sucking reflexes and hypotonia. The infant was discharged on day 3 of life with twice weekly physical and occupational therapy and orthopedic splinting. Ultrasound imaging of hip and abdomen and echocardiogram at 6 months were unremarkable with no evidence of cardiac or hepatic disease. At 15 months the child exhibits delayed gross and fine motor skills secondary to hypotonia. He is meeting age-appropriate language and cognitive milestones. He follows closely with pediatrics, orthopedics, nutrition, genetics, hepatology and cardiology to continue biannual assessments of organs function known to be impaired by GSD-IV. Conclusion: Prenatal counseling for rare genetic disorders with phenotypic heterogeneity remains difficult and further characterization of genotype-phenotype correlation in GBE1 gene mutation variants is needed to counsel affected families. Current literature reports a spectrum of neonatal outcomes, ranging from progressive myopathies to lethal abnormalities. This infant with GSD-IV exhibits motor developmental delay without cardiac or hepatic impairment, suggesting residual GBE1 enzyme activity. While ultrasound is often the initial fetal assessment and identifies structural abnormalities, it remains a poor predictor of neonatal prognosis. Further classifying gene variants for rare diagnoses that phenotypically represent a continuum of disease is essential in stratifying risk, considering goals of care and determining prenatal and postnatal testing

Volume

2

Issue

Suppl 1

Comments

2024 ACMG (American College of Medical Genetics and Genomics) Annual Clinical Genetics Meeting, March 12-16,2024, Toronto, Canada

DOI

10.1016/j.gimo.2024.101713

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