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Cerebral palsy and pyruvate dehydrogenase deficiency: identification of two new mutations in the E1alpha gene
W Lissens1, P Vreken, P G Barth
1Department of Paediatric Neurology, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium. lgenlsw@az.vub.ac.be
Insights
Pyruvate dehydrogenase (PDH) complex deficiency, a cause of congenital lactic acidosis, was identified in two girls with neurological symptoms. Genetic analysis revealed novel mutations in the E1alpha gene, highlighting the importance of mutation identification for genetic counseling.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Pyruvate dehydrogenase (PDH) complex deficiency is a primary cause of congenital lactic acidosis.
- Mutations in the X-linked E1alpha subunit gene are the most common cause of PDH deficiency.
Observation:
- Two unrelated girls presented with static encephalopathy, spastic quadriplegia, microcephaly, seizures, and one with hypocalcemia.
- Diagnosis of PDH deficiency occurred in adolescence, with low muscle PDH activity but normal subunit levels and lactate/pyruvate ratios.
Findings:
- Mutation analysis identified an R288H substitution in the E1alpha gene in the girl with hypocalcemia.
- A 12 bp insertion causing a four amino acid duplication at the C-terminus was found in the second girl.
- Both patients had skewed X-inactivation patterns, indicating heterozygous mutations.
Implications:
- This study identifies novel mutations in the PDH E1alpha gene.
- Hypocalcemia is a newly recognized clinical finding in PDH complex deficiency.
- Accurate mutation identification is crucial for recurrence risk assessment and genetic counseling in families affected by PDH deficiency.
Unlabelled:
Pyruvate dehydrogenase (PDH) complex deficiency, a common cause of congenital lactic acidosis, is mostly due to mutations in the X-linked gene coding for the E1alpha subunit of the complex. We have studied two unrelated girls presenting a static encephalopathy with spastic quadriplegia, microcephaly and seizures and in one girl, hypocalcaemia, a new finding in PDH complex deficiency. PDH deficiency was diagnosed in adolescence and both girls had low PDH complex activity in muscle but normal amounts of all subunits on Western blotting, and a normal lactate/pyruvate ratio in blood and CSF. Mutation analysis of the E1alpha gene at the cDNA or DNA level revealed an arginine to histidine substitution at amino acid position 288 (R288H) in the girl with hypocalcaemia and a 12 bp insertion, predicting a four amino acid duplication at the c-terminal end of the protein in the second girl. They both carried a normal and a mutated E1alpha gene and X-inactivation studies showed skewed patterns.
Conclusion:
Mutation identification in pyruvate dehydrogenase complex deficiency remains important especially for the determination of the recurrence risk and for reliable genetic counselling in couples with an affected child.