POLG1 mutations associated with progressive encephalopathy in childhood.

• We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.

Nyckelord

Adolescent

Age of Onset

Brain

metabolism

pathology

physiopathology

Child

Preschool

Conserved Sequence

genetics

DNA Mutational Analysis

DNA

Mitochondrial

biosynthesis

genetics

DNA-Directed DNA Polymerase

genetics

Diffuse Cerebral Sclerosis of Schilder

genetics

metabolism

physiopathology

Electron Transport Complex IV

genetics

metabolism

Fatal Outcome

Female

Genetic Predisposition to Disease

genetics

Genetic Screening

Humans

Infant

Liver Diseases

genetics

pathology

physiopathology

Male

Mitochondria

genetics

metabolism

pathology

Mitochondrial Diseases

genetics

metabolism

physiopathology

Mitochondrial Myopathies

genetics

metabolism

physiopathology

Muscle

Skeletal

metabolism

pathology

physiopathology

Mutation

Missense

genetics

Pedigree

Syndrome

Alpers-Huttenlocher syndrome

MEDICINE

Publikations- och innehållstyp

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art (ämneskategori)