ATAD3 duplications bridge mitochondrial diseases and Aicardi–Goutières syndrome

Sep 29, 2026

Uploaded by Jacob

A recurrent 68-kb heterozygous duplication of the ATAD3 locus is linked to a mitochondrial disorder with prenatal or neonatal onset and rapid fatal progression, featuring cardiomyopathy, hyperlactataemia, cataract, and encephalopathy. Clinical, neuroimaging, and molecular features were characterized in nine patients (median onset 11 days; ages 3 days–3 years). Five showed prenatal signs and neonatal hypotonia with frequent cardiomyopathy, cataract/corneal opacities, and hyperlactataemia. Two had prolonged survival with progressive brain atrophy, epileptic encephalopathy, elevated cerebrospinal fluid neopterin or alpha-interferon activity, and imaging similarities to Aicardi–Goutières syndrome.

LanguageEnglish

CategoryHealthcare

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Pages8

Reading Time20 min

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Abstract

Study overview and patient cohort

Clinical manifestations and prenatal/neonatal findings

Neurological course and prolonged survival

Biomarkers and neuroimaging findings

Proposed mechanism and implications

Introduction

Primary mitochondrial diseases and ATAD3 locus

DOI: 10. 1111/dmcn.16414 C A SE SE R I E S ATAD3 duplications bridge mitochondrial diseases and Aicardi–Goutières syndrome Pauline Planté-Bordeneuve1 | Claire-Marine Bérat2 | Sylvain Hanein3 | Cyril Gitiaux4,5 | ATAD3 Study Group* | Julie Steffann1,2,5 | Isabelle Desguerre2,4,5 | Agnès Rötig2,5 | Nathalie Boddaert2,5,6 | Giulia Barcia1,2,5 1Service de Médecine Génomique des Maladies Rares, APHP Centre, Hôpital Necker-Enfants Malades, Paris, France 2Reference Center for Mitochondrial Disorders, Necker Hospital, APHP, Université Paris Cité, Paris, France 3Bioinformatic Platform, Institute of Genetic Diseases, INSERM UMR1163, Institut Imagine, Université Paris Cité, Paris, France 4Paediatric Neurology Department, Necker Hospital, APHP Centre, Université Paris Cité, Paris, France 5Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France 6Paediatric Radiology Department, APHP, Hôpital Necker-Enfants Malades, Université Paris Cité, Institut Imagine, INSERM U1163 and U1299, Paris, France Correspondence Giulia Barcia, Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, Université Paris Cité, Paris 75015, France. [Email:](Email: giulia.barcia@aphp.fr)[ giulia.barcia@aphp.fr](Email: giulia.barcia@aphp.fr) Abstract A recurrent 68-kb heterozygous duplication ofthe ATAD3 locus has been implicated in a mitochondrial disorder characterized by prenatal or neonatal onset and rapidly fatal course with cardiomyopathy, hyperlactataemia, cataract, and encephalopathy. We analysed the clinical, neuroimaging, and molecular spectrum associated with duplication of the ATAD3 gene cluster in nine patients (four males, five females; age range: 3 days–3 years, median: 11 days, mean: 7.8 months, SD: 1 year 1 month). Five patients presented with prenatal signs (intrauterine growth restriction in four of nine and cardiac abnormalities in three of nine) leading to medical termination of pregnancy in one case. All live-born children presented with neonatal hypotonia, frequently associated with cardiomyopathy (five of eight), cataract or corneal opacities (five of eight), and hyperlactataemia (six of eight). Two patients carrying distinct duplications exhibited a long survival (>2 years) and presented with major progressive brain atrophy with epileptic encephalopathy. We documented elevated cerebrospinal fluid neopterin in one and increased cerebrospinal fluid alphainterferon activity in the other. Brain magnetic resonance imaging showed white matter T2 hyperintensity (seven of seven) and temporal cystic leukoencephalopathy (five of seven). Nuclear magnetic resonance spectroscopy showed a lactate peak in five of five patients; brain computed tomography showed basal ganglia calcificationsin two of three patients. In this study, we expand the clinical spectrum of ATAD3 duplications, including prolonged survival and severe neurological involvement with neuroimaging similarities to Aicardi–Goutières syndrome and more broadly interferonopathy. We suggest a putative common mechanism that involves mitochondrial nucleic acid leakage and interferon response. With a prevalence of 1:2000 to 1:5000 live births, primary mitochondrial diseases (PMDs) caused by pathogenic variants in nuclear or mitochondrial genomes are among the most common inherited metabolic diseases.1 Over 400 disease-causing nuclear and mitochondrial DNA genes are associated with PMDs.2 Among them, ATAD3A is localized in a locus containing three highly homologous tandemly arrayed genes, that is, ATAD3C, ATAD3B, and ATAD3A, on chromosome 1p36.3. ATAD3A is ubiquitously expressed and encodes the ATPase family AAA domain-containing protein 3A, which localizes between the inner and outer mitochondrial membranes. Although its precise molecular functions are not fully understood, ATAD3A has been implicated in Abbreviations: CSF, cerebrospinal fluid; IFN, interferon; PMD, primary mitochondrial disease. *Members ofthe ATAD3 Study Group

FAQs

What genetic change defines the disorder described in the study?

The study focuses on a recurrent 68-kb heterozygous duplication of the ATAD3 locus, affecting the ATAD3 gene cluster.

What were the main clinical features in most patients?

Most live-born children presented with neonatal hypotonia, frequently cardiomyopathy, cataract or corneal opacities, and hyperlactataemia.

How did the findings differ in the two patients with prolonged survival?

Those patients showed longer survival (>2 years) with major progressive brain atrophy, epileptic encephalopathy, elevated cerebrospinal fluid neopterin or increased alpha-interferon activity, and imaging similarities to Aicardi–Goutières syndrome.

Sep 29, 2026

Uploaded by Jacob