Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy

M. Boyer, M. Sowa, I. Di Meo, S. Eftekharian, M. R. Steenari, V. Tiranti, J. E. Abdenur

Research output: Contribution to journalArticle

Abstract

Ethylmalonic encephalopathy (EE) is a devastating neurodegenerative disease caused by mutations in the ETHE1 gene critical for hydrogen sulfide (H2S) detoxification. Patients present in infancy with hypotonia, developmental delay, diarrhea, orthostatic acrocyanosis and petechiae. Biochemical findings include elevated C4, C5 acylcarnitines and lactic and ethylmalonic acid (EMA) in body fluids. Current treatment modalities include metronidazole and N-acetylcysteine (NAC) to lower the production and promote detoxification of toxic H2S. Patients are typically identified after the onset of clinical symptoms and there is limited information about long term response to treatment. We report the findings of two unrelated patients with EE, identified through newborn screening, who were managed with conventional treatment (NAC, metronidazole alternated with neomycin) and in patient 2, a novel dietary treatment restricting sulfur containing amino acids. Pathogenic mutations were confirmed in the ETHE1 gene (homozygous splice site mutation in patient 1, c.505 + 1G > A; compound heterozygous mutations in patient 2, c.131_132delAG + c.566delG). Both patients were started on metronidazole and NAC by 10 weeks of age and treated for 23 months. Patient 1 did not accept the metabolic formula due to palatability and parental refusal for gastrostomy tube placement. She demonstrated improved biomarkers (EMA, lactic acid and thiosulfate) and an attenuated clinical course. Patient 2 was started on a low methionine and cysteine diet at 8 months of age utilizing SOD Anamix® Early Years, (Nutricia). Baseline EMA levels were (642 mg/g Cr; n = 2) and decreased with medical treatment by 38% to a mean of 399 (n = 4, SD = 71, p 0.0013). With dietary treatment EMA levels were further reduced by 42% to a mean of 233 (n = 8, SD = 52, p 0.0030). Lactic acid, thiosulfates and clinical outcomes were also improved. Our long-term follow-up confirms previous reports of clinical improvement with NAC and metronidazole treatment. Additionally, our studies suggest that a diet restricted in sulfur-containing amino acids results in further improvement in clinical outcomes and biochemical markers.

Original languageEnglish
Pages (from-to)57-63
Number of pages7
JournalMolecular Genetics and Metabolism
Volume124
Issue number1
DOIs
Publication statusPublished - May 1 2018

Fingerprint

Metronidazole
Acetylcysteine
Newborn Infant
Thiosulfates
Lactic Acid
Detoxification
Nutrition
Sulfur
Genes
Neurodegenerative diseases
Amino Acids
Hydrogen Sulfide
Sulfur Amino Acids
Neomycin
Poisons
Body fluids
Mutation
Biomarkers
Therapeutics
Methionine

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy. / Boyer, M.; Sowa, M.; Di Meo, I.; Eftekharian, S.; Steenari, M. R.; Tiranti, V.; Abdenur, J. E.

In: Molecular Genetics and Metabolism, Vol. 124, No. 1, 01.05.2018, p. 57-63.

Research output: Contribution to journalArticle

Boyer, M. ; Sowa, M. ; Di Meo, I. ; Eftekharian, S. ; Steenari, M. R. ; Tiranti, V. ; Abdenur, J. E. / Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy. In: Molecular Genetics and Metabolism. 2018 ; Vol. 124, No. 1. pp. 57-63.
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