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A high rate (20%-30%) of parental consanguinity in cytochrome-oxidase deficiency
J C von Kleist-Retzow1, V Cormier-Daire, P de Lonlay
1Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U-393, Paris, France.
Insights
Respiratory chain defects in children are often caused by complex I or IV deficiencies. Autosomal recessive inheritance is common, impacting genetic counseling for mitochondrial disorders.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Mitochondrial disorders, specifically respiratory chain (RC) defects, represent a significant cause of childhood illness.
- Understanding the prevalence and genetic basis of these defects is crucial for diagnosis and management.
Purpose of the Study:
- To identify the most common types of respiratory chain defects in a pediatric cohort.
- To correlate specific RC defects with clinical manifestations and inheritance patterns.
- To assess the role of parental consanguinity and its geographical distribution in childhood mitochondrial disorders.
Main Methods:
- Analysis of a cohort of 157 pediatric patients with confirmed respiratory chain defects.
- Detailed clinical phenotyping, including hypotonia, growth retardation, cardiomyopathy, encephalopathy, and liver failure.
- Statistical analysis to determine correlations between RC defect types, clinical features, sex ratio, and parental consanguinity.
Main Results:
- Complex I (33%), complex IV (28%), and combined complex I+IV (28%) deficiencies were the most frequent RC defects.
- Truncal hypotonia, growth retardation, cardiomyopathy, encephalopathy, and liver failure were the predominant clinical features.
- Complex I deficiency showed a male predominance (R=1.68), and high rates of parental consanguinity were noted in complex IV and I+IV deficiencies, particularly in North African families (76%).
Conclusions:
- Respiratory chain defects in childhood are primarily linked to complex I and IV deficiencies.
- The study supports an autosomal recessive mode of inheritance for most childhood mitochondrial disorders.
- Findings have significant implications for genetic counseling, especially in populations with high consanguinity rates.
Abstract:
By studying a large series of 157 patients, we found that complex I (33%), complex IV (28%), and complex I+IV (28%) deficiencies were the most common causes of respiratory chain (RC) defects in childhood. Truncal hypotonia (36%), antenatal (20%) and postnatal (31%) growth retardation, cardiomyopathy (24%), encephalopathy (20%), and liver failure (20%) were the main clinical features in our series. No correlation between the type of RC defect and the clinical presentation was noted, but complex I and complex I+IV deficiencies were significantly more frequent in cases of cardiomyopathy (P<.01) and hepatic failure (P<.05), respectively. The sex ratio (male/female) in our entire series was mostly balanced but was skewed toward males being affected with complex I deficiency (sex ratio R=1.68). Interestingly, a high rate of parental consanguinity was observed in complex IV (20%) and complex I+IV (28%) deficiencies. When parental consanguinity was related to geographic origin, an even higher rate of inbreeding was observed in North African families (76%, P<.01). This study gives strong support to the view that an autosomal recessive mode of inheritance is involved in most cases of mitochondrial disorders in childhood, a feature that is particularly relevant to genetic counseling for this devastating condition.