An incidental finding in newborn screening leading to the diagnosis of a patient with ECHS1 mutations

Abstract

Short-chain enoyl-CoA hydratase (ECHS1) is a mitochondrial beta-oxidation enzyme involved in the metabolism of acyl-CoA fatty acid esters, as well as in valine metabolism. ECHS1 deficiency has multiple manifestations, including Leigh syndrome early at birth or in childhood with poor prognosis, to cutis laxa, exercise-induced dystonia and congenital lactic acidosis.Here we describe the case of a newborn with mutations in ECHS1 that caught our attention after the incidental finding of 3-hydroxy-butyryl\3-hydroxy-isobutyryl\malonylcarnitine (C4OH\C3DC) and tiglylcarnitine (C5:1) on blood spot in the newborn screening (NBS) program. Diagnosis was suspected based on the analysis of organic acids on dried urine spot. A moderate increase of 2-methyl-2,3-dihydroxybutyric acid, was detected, which is a known marker of this disease. Exome analysis showed c.404A>G (p.Asn135Ser) mutation in homozygosis in the ECHS1 gene. The child was therefore admitted to the hospital. Initial examination showed little response to auditory stimuli and mild hypertonia of the extremities. Clinical deterioration was evident at 4 months of age, including neurological and cardiac involvement, and the patient died at 5 months of age. This case illustrates how an incidental detection in the NBS Program can lead to the diagnosis ECHS1 deficiency. Although it is a severe disease, with no treatment available, early detection would allow adequate genetic counseling avoiding the odyssey that suffered most of these families.

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene

“…P12 died at 5 months from LS and respiratory infection. 23 The severe clinical deterioration by the time of genetic confirmation precluded any therapeutic intervention in this patient.…”

Metabolic Serendipities of Expanded Newborn Screening

“…Early identification of this condition and initiation of treatment are crucial in order to avoid potentially devastating and irreversible neurological damage [ 7 ]. Even if the disease detected has no treatment available, early detection would allow for adequate genetic counseling [ 8 ].…”

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency

“…In contrast, intermediate and mild cases usually have normal laboratory values. A review of the literature 1‐4,6‐29 revealed 67 patients with most suffering the early onset presentation. Average age at death was 28.0 + 43.8 months (range 16 h to 156 months) for 27 early onset patients (age <12 months) for whom age at death was reported.…”