Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.
A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded.
Fillano
James J
JJ
Department of Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
Goldenthal
Michael J
MJ
Rhodes
C Harker
CH
Marín-García
José
J
D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000201:enzymology* / Q000235:genetics*; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D002658:Developmental Disabilities / Q000201:enzymology* / Q000235:genetics*; D042967:Electron Transport Complex I; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000378:metabolism; D004827:Epilepsy / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008931:Mitochondria, Muscle / Q000201:enzymology* / Q000235:genetics*; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics; D009097:Multienzyme Complexes / Q000378:metabolism; D009123:Muscle Hypotonia / Q000201:enzymology* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
D004272:DNA, Mitochondrial; D009097:Multienzyme Complexes; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III