Neonatal Respiratory Insufficiency Caused by an (Homozygous) ABCA3-Stop Mutation: a Systematic Evaluation of Therapeutic Options

Abstract

Background:

Autosomal recessive ABCA3 (ATP-binding cassette protein A3) gene mutations have been associated with neonatal respiratory distress and pediatric interstitial lung disease. The clinical course of the disease depends on the underlying mutations. Therefore, knowledge of course, symptoms and treatment of the disease is important.

Patient and Methods:

A term newborn suffered from progressive respiratory insufficiency, which led to death at the age of 4.8 months. The girl developed interstitial lung disease. Infections as well as structural and functional disorders of the lung were systematically excluded. A homozygous c.4681C>T (Arg 1561 Stop) mutation of the ABCA3 gene was identified. A literature review of the pathophysiology and treatment options of the disease was done. Therapeutic approaches with corticosteroids, macrolide, and hydroxychloroquine did not improve the clinical course.

Results:

Therapeutic strategies for chronic interstitial lung disease have been used successfully in cases of a mild clinical course in juvenile patients with ABCA3 gene mutation. In our patient with homozygous ABCA3 gene mutation, they were not effective. Lung transplantation remains as a therapeutic option, but because of donor organ shortage and associated morbidity and mortality it is rarely feasible.

Conclusion:

More experience in the treatment of newborns with ABCA3 gene mutations is needed. Randomized, prospective evaluation of the different therapeutic approaches in a specific registry may improve prognosis and treatment of affected individuals.

Zusammenfassung

Hintergrund:

Autosomal rezessiv vererbte ABCA3 (ATP-binding cassette protein A3)-Mu­tationen sind mit schwerem neonatalem Lungenversagen und chronischer interstitieller Lungenerkrankung assoziiert. Der klinische Verlauf der Erkrankung ist stark von den zugrunde liegenden Mutationen abhängig. Aus diesem Grund sind Verlaufsbeschreibungen zu Symptomatik und Therapie wichtig.

Patientin und Methodik:

Ein reifes Neugeborenes litt an einer progredienten respiratorischen Insuffizienz, die im Alter von 4,8 Monaten zum Tod führte. Gleichzeitig entwickelte sich eine interstitielle Lungenerkrankung. Infektionen, funktionelle Störungen und strukturelle Lungenerkrankungen wurden systematisch ausgeschlossen. Ursächlich lag eine homozygote c.4681C>T (Arg 1561 Stop)-Mutation des ABCA3-Gens vor. Eine ausführliche Literaturrecherche zur Pathophysiologie und Therapie der Erkrankung wurde durchgeführt. Therapieversuche mit Corticosteroiden, Makrolid und Hydroxychloroquin erbrachten keine relevante Verbesserung der klinischen Situation.

Ergebnisse:

Die genannten Therapieansätze werden bereits bei Patienten mit ABCA3-Mutationen angewendet und sind bei milden klinischen Verläufen erfolgreich. Bei unserer Patientin mit homozygoter ABCA3-Stopp-Mutation hatten sie keinen Effekt. Die Therapieoption der Lungentransplantation wird im Säuglingsalter wegen Spenderorganmangels und assoziierter Morbidität und Mortalität nur selten realisiert. Nach ausführlicher Evaluation wurde diese Therapiemöglich­keit bei unserer Patientin verworfen.

Schlussfolgerung:

Es besteht Notwendigkeit, mehr Erfahrungen in der Behandlung von Neugeborenen mit ABCA3-Mutationen zu sammeln. Therapieoptionen sollten in einem Patientenregister systematisch erfasst und möglichst randomi­siert prospektiv evaluiert werden, um so Prognose und Betreuung der Patienten zu verbessern.

Key words

ABCA3 gene mutation - neonatal respiratory distress - pediatric interstitial lung disease - medical treatment - lung transplantation

Schlüsselwörter

ABCA3-Mutation - neonatales Lungenversagen - interstitielle Lungenerkrankung bei Kindern - medikamentöse Behandlung - Lungentransplantation

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