Patient with Glutaric Aciduria Type 1 and a Familial ACAN Gene Variant

BACKGROUND: Glutaric aciduria type 1 (MIM#231670) is an autosomal recessive disease caused by biallelic pathogenic variants in the GCDH gene, resulting in the deficiency of glutaryl CoA dehydrogenase. Patients typically present with acute life-threatening encephalopathic crises in the first year of life. Diagnosis is based on the detection of increased quantities of 3-hydroxyglutaric acid, glutaric acid, and glutaconic acids in urine. Elevated glutarylcarnitine is also found in plasma and is used for newborn screening. Prompt recognition of the disease and restriction of lysine and tryptophan with carnitine supplementation may prevent brain lesions. ACAN gene variants can cause short stature and advanced bone age, with or without early-onset osteoarthritis (MIM#165800). It is a highly variable autosomal dominant disease.

CASE STUDY/METHODS: A 16-month-old male patient with Glutaric aciduria type 1 was referred for genetic counselling. His disease was detected by newborn screening, molecularly confirmed and had been on a diet since the first month of life. His mother and maternal grandmother have short stature with early-onset arthritis. He is currently 3 years of age and his height is on the 3rd centile.

RESULTS: GCDH gene sequencing revealed two likely pathogenic variants in compound heterozygosity (confirmed with parental studies). A likely pathogenic variant in the ACAN gene was identified in the mother and this variant was later detected in the patient.

DISCUSSION/CONCLUSION: Genetic testing is now ubiquitous, thus, it is easier for additional conditions to be detected in patients already diagnosed with a genetic disease. This represents an extra challenge to healthcare providers since the patients’ clinical manifestations tend to be attributed to a single cause. Collecting an in-depth family history can help minimise the underdiagnosis of patients and their families.