Carnitine palmitoyltransferase-2 deficiency in a 4-year-old boy presenting with autism spectrum disorder: continuing to uncover links between autism and carnitine
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
The diagnosis of autism spectrum disorder (ASD) represents a varied grouping of neurodevelopmental disorders whose genetic etiology is multifactorial and implicates hundreds of genes. Subsequent defects fatty acid metabolism have been hypothesized to be among these. Carnitine palmitoyltransferase-2 (CPT-2) is located in the internal mitochondrial membrane and removes carnitine from acyl-CoA for beta-oxidation. Lipid metabolism has been suggested in the pathology of ASD, and ASD patients have previously demonstrated altered acyl-carnitine profiles as well as long chain acyl-CoA dehydrogenase (LCAD) deficiencies. In this case report we present a patient with ASD who was found to have a defect in the CPT-2 gene.
Case Presentation
A 4-year-old male presented for a genetics evaluation with a clinical diagnosis of ASD. He was first noted to have developmental delays around 1 year of age when his lingual development deteriorated; he was diagnosed with ASD at around 18 months of age. At 4 years old, his greatest area of concern continues to be his language development, with a vocabulary of approximately thirty words; he communicates mostly nonverbally. However, he also demonstrates behavioral issues including difficulty with transitions, temper tantrums, repetitive behaviors like hand flapping, and disinterest in age-appropriate play.
His Invitae panel test demonstrated a homozygous pathogenic variant at the CPT-2 gene (c.338C>T ;p.Ser113Leu) consistent with the CPT-2 deficiency in this patient. Heterozygous pathogenic LZTR-1 gene (c.509G>A; p.Arg170Gln) is consistent with a diagnosis of autosomal dominant LZTR-1 related conditions. However, his features were not suggestive of Noonan syndrome. He never diagnosed with schwannomatosis nor was his family history ever significant for either of these disorders.
Diagnostic Workup
The patient’s urine organic acids and complete metabolic panel were within normal limits. The rest of his metabolic work up including his acyl-carnitine profile is currently pending.
Discussion
This report concerns a case of ASD associated with both CPT-2 and LZTR-1 deficiency. The patient does not exhibit classic findings of Noonan syndrome or schwannomatosis, suggesting contribution from his CPT-2 deficiency to his ASD symptomology.
In patients with multiple genetic defects that can present with developmental delay, it can be challenging to determine each defect’s relative contribution to the phenotype. These patients may demonstrate one, both, or neither of the phenotypes depending on the genes involved. Dual diagnoses may involve genes with synergistic or antagonistic properties, and the phenotypes may present accordingly. In light of this diagnostic challenge, whole genome sequencing and panel testing continue to expand our genomic understanding of complex neurodevelopmental disorders such as ASD as well as their potential treatments.
Conclusion
There has been a link suggested between carnitine deficiency and autism spectrum disorder in the literature. However, the exact mechanism remains unclear, especially considering the multifactorial nature of ASD. While further research is needed to fully elucidate this association, this case further supports the growing body of literature on this topic.
The diagnosis of autism spectrum disorder (ASD) represents a varied grouping of neurodevelopmental disorders whose genetic etiology is multifactorial and implicates hundreds of genes. Subsequent defects fatty acid metabolism have been hypothesized to be among these. Carnitine palmitoyltransferase-2 (CPT-2) is located in the internal mitochondrial membrane and removes carnitine from acyl-CoA for beta-oxidation. Lipid metabolism has been suggested in the pathology of ASD, and ASD patients have previously demonstrated altered acyl-carnitine profiles as well as long chain acyl-CoA dehydrogenase (LCAD) deficiencies. In this case report we present a patient with ASD who was found to have a defect in the CPT-2 gene.
Case Presentation
A 4-year-old male presented for a genetics evaluation with a clinical diagnosis of ASD. He was first noted to have developmental delays around 1 year of age when his lingual development deteriorated; he was diagnosed with ASD at around 18 months of age. At 4 years old, his greatest area of concern continues to be his language development, with a vocabulary of approximately thirty words; he communicates mostly nonverbally. However, he also demonstrates behavioral issues including difficulty with transitions, temper tantrums, repetitive behaviors like hand flapping, and disinterest in age-appropriate play.
His Invitae panel test demonstrated a homozygous pathogenic variant at the CPT-2 gene (c.338C>T ;p.Ser113Leu) consistent with the CPT-2 deficiency in this patient. Heterozygous pathogenic LZTR-1 gene (c.509G>A; p.Arg170Gln) is consistent with a diagnosis of autosomal dominant LZTR-1 related conditions. However, his features were not suggestive of Noonan syndrome. He never diagnosed with schwannomatosis nor was his family history ever significant for either of these disorders.
Diagnostic Workup
The patient’s urine organic acids and complete metabolic panel were within normal limits. The rest of his metabolic work up including his acyl-carnitine profile is currently pending.
Discussion
This report concerns a case of ASD associated with both CPT-2 and LZTR-1 deficiency. The patient does not exhibit classic findings of Noonan syndrome or schwannomatosis, suggesting contribution from his CPT-2 deficiency to his ASD symptomology.
In patients with multiple genetic defects that can present with developmental delay, it can be challenging to determine each defect’s relative contribution to the phenotype. These patients may demonstrate one, both, or neither of the phenotypes depending on the genes involved. Dual diagnoses may involve genes with synergistic or antagonistic properties, and the phenotypes may present accordingly. In light of this diagnostic challenge, whole genome sequencing and panel testing continue to expand our genomic understanding of complex neurodevelopmental disorders such as ASD as well as their potential treatments.
Conclusion
There has been a link suggested between carnitine deficiency and autism spectrum disorder in the literature. However, the exact mechanism remains unclear, especially considering the multifactorial nature of ASD. While further research is needed to fully elucidate this association, this case further supports the growing body of literature on this topic.