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Antenatal manifestations of mitochondrial respiratory chain deficiency
Jürgen-Christoph von Kleist-Retzow1, Valérie Cormier-Daire, Géraldine Viot
1Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U-393, Hôpital des Enfants-Malades, 149 Rue de Sèvres, 75743 Paris Cedex 15, France.
Insights
Disorders of oxidative phosphorylation, specifically respiratory chain enzyme deficiency, can manifest before birth with low birth weight and multiple fetal anomalies. These antenatal findings suggest early disease expression impacting fetal development.
Area of Science:
- Mitochondrial biology
- Developmental biology
- Genetics
Background:
- Disorders of oxidative phosphorylation are a group of inherited metabolic diseases.
- Respiratory chain enzyme deficiencies can lead to severe clinical manifestations.
- Antenatal diagnosis of these conditions is challenging.
Purpose of the Study:
- To review the antenatal manifestations of disorders of oxidative phosphorylation.
- To identify early signs of respiratory chain enzyme deficiency in fetal development.
- To correlate antenatal findings with the diagnosis of oxidative phosphorylation disorders.
Main Methods:
- Retrospective review of 300 cases with proven respiratory chain enzyme deficiency.
- Analysis of fetal development based on pregnancy course, ultrasonography, and birth parameters.
- Detailed examination of fetal movements, amniotic fluid volume, cardiac findings, and structural anomalies.
Main Results:
- Low birth weight (<3rd percentile) observed in 22.7% of cases.
- Intrauterine growth retardation occurred in 16% of cases, isolated or with anomalies.
- Multiple antenatal anomalies were common, affecting various organs (e.g., cardiac, renal, limb defects).
Conclusions:
- Respiratory chain deficiency can present antenatally, indicating early disease gene expression.
- Antenatal manifestations may include growth restriction and diverse fetal malformations.
- Mechanisms for malformation may involve impaired ATP production or altered apoptosis.
Objective:
To review the antenatal manifestations of disorders of oxidative phosphorylation.
Study Design:
A total of 300 cases of proven respiratory chain enzyme deficiency were retrospectively reviewed for fetal development, based on course and duration of pregnancy, antenatal ultrasonography and birth weight, length, and head circumference. Particular attention was given to fetal movements, oligo/hydramnios, fetal cardiac rhythm, fetal heart ultrasound, and ultrasonography/echo Doppler signs of brain, facial, trunk, limb, and organ anomalies.
Results:
Retrospective analyses detected low birth weight (<3rd percentile for gestational age) in 22.7% of cases (68/300, P<.000001). Intrauterine growth retardation was either isolated (48/300, 16%) or associated with otherwise unexplained anomalies (20/300, 6.7%, P<.0001). Antenatal anomalies were usually multiple and involved several organs sharing no common function or embryologic origin. They included polyhydramnios (6/20), oligoamnios (2/20), arthrogryposis (1/20), decreased fetal movements (1/20), ventricular septal defects (2/20), hypertrophic cardiomyopathy (4/20), cardiac rhythm anomalies (4/20), hydronephrosis (3/20), vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula/atresia, renal agenesis and dysplasia, and limb defects (VACTERL) association (2/20), and a complex gastrointestinal malformation (1/20).
Conclusions:
Although a number of metabolic diseases undergo a symptom-free period, respiratory chain deficiency may have an early antenatal expression, presumably related to the time course of the disease gene expression in the embryofetal period. The mechanism triggering malformations is unknown and may include decreased ATP formation and/or an alteration of apoptotic events controlled by the mitochondria.