Genotype-phenotype correlations: sudden death in an infant with very-long-chain acyl-CoA dehydrogenase deficiency
Curtis R Coughlin1, Can Ficicioglu
1Section of Biochemical Genetics, The Children's Hospital of Philadelphia, 34th& Civic blvd. 9S23, Philadelphia, PA 19104, USA.
Insights
Very-long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is a fatty acid oxidation disorder. A severe genotype, even with residual enzyme activity, can lead to fatal outcomes, highlighting limitations in predicting disease severity.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Very-long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder impacting fatty acid oxidation.
- Patient phenotypes are diverse, often categorized by symptom onset and clinical presentation.
- Early diagnosis and intervention have led to many VLCADD patients remaining asymptomatic.
Observation:
- A common mutation, c.848T>C (p.V283A), is linked to residual enzyme activity and milder phenotypes, often found in screened asymptomatic individuals.
- A patient presented with fatal hypoglycemia shortly after birth, prior to newborn screening diagnosis.
- This patient possessed a compound heterozygous genotype (c.848T>C, c.342+1G>C) within the ACADVL gene.
Findings:
- The identified genotype, despite including a mutation associated with residual activity, did not prevent a severe, fatal outcome.
- This case challenges the predictive power of genotype alone in determining the clinical trajectory of VLCADD.
Implications:
- Genotype-phenotype correlations in VLCADD require further refinement, especially for severe early-onset cases.
- Relying solely on genotype may underestimate the risk of severe complications in certain VLCADD patients.
- This underscores the need for comprehensive clinical monitoring alongside genetic information for affected individuals.
Abstract:
Very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. The phenotype of VLCADD is heterogeneous, and patients are typically classified into three categories based upon onset of symptoms and clinical findings. As a result of early diagnosis and treatment, many patients with VLCADD have remained asymptomatic. A general genotype-phenotype correlation has been elicited. A genotype that is associated with residual enzyme activity is more likely to present with an attenuated phenotype. One prevailing mutation, the c.848T>C (p.V283A), has been associated with residual enzyme activity and has been identified in many asymptomatic individuals diagnosed through either newborn or family screening. We present a patient who died as a result of fatal hypoglycemia at 38 h of life before diagnosis of VLCADD could be established by newborn screening. Despite the early onset of the disease, the patient was found to have a missense mutation within the ACADVL gene with a c.848T>C, c.342+1G>C genotype. Genotype alone remains limited in its predictive ability to determine which affected individuals are at risk for fatal complications.
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