Novel mutation causing propionic acidemia associated with unexplained autoimmune thyrotoxicosis

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism (IEM) typically presenting with acute decompensation in neonates due to propionyl-CoA carboxylase (PCC) deficiency.
• PA has a higher prevalence in the United Arab Emirates (UAE), necessitating focused research within this population.

Observation:

• A severe case of PA in a newborn Emirati female was linked to a novel homozygous frameshift variant (c.2158_2159insT; p.Glu720Valfs*14) in the PCCA gene's last exon.
• Diagnostic challenges arose from isolated elevation of plasma proprionylcarnitine (C3) on newborn screening, with persistently negative urinary organic acids even during critical illness.
• The patient also exhibited an unexplained diagnosis of neonatal thyrotoxicosis, adding complexity to the clinical presentation.

Findings:

• The novel PCCA gene variant resulted in a severe clinical phenotype of propionic acidemia.
• Atypical biochemical markers, specifically isolated C3 elevation without characteristic urinary organic acid abnormalities, complicated the diagnosis of PA.
• The co-occurrence of neonatal thyrotoxicosis presented a unique clinical scenario in this patient.

Implications:

• This case underscores the importance of considering novel genetic variants and atypical biochemical profiles in diagnosing IEMs like PA.
• The findings may prompt re-evaluation of diagnostic criteria and screening protocols for PA, particularly in populations with higher prevalence.
• Further research is warranted to understand the potential interplay between PCCA gene mutations, metabolic derangements, and conditions like neonatal thyrotoxicosis.