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X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the
H H Dahl1, L L Hansen, R M Brown
1Murdoch Institute for Research into Birth Defects, Royal Children's Hospital, Melbourne, Australia.
Insights
Pyruvate dehydrogenase (PDH) deficiency, caused by an E1 alpha gene mutation, presents with varied neurological symptoms. This study details a specific mutation and its mother-to-daughter transmission, expanding the condition's known spectrum.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Pyruvate dehydrogenase (PDH) deficiency is a rare genetic disorder affecting cellular metabolism.
- Mutations in the X-linked gene for the E1 alpha subunit are a known cause of PDH deficiency.
Observation:
- Three female patients with PDH E1 alpha deficiency due to the same specific mutation (R302C) were studied.
- Two patients exhibited severe neurological dysfunction and brain abnormalities, while the third presented with milder intellectual disability and seizures in adulthood.
- The adult patient was the mother of one of the severely affected individuals, indicating mother-to-daughter transmission.
Findings:
- A recurrent C-to-T substitution (R302C) in the PDH E1 alpha gene was identified in all three patients.
- This mutation leads to arginine-to-cysteine replacement at amino acid position 302.
- The study highlights the variable clinical expressivity of X-linked PDH E1 alpha deficiency in heterozygous females.
Implications:
- This research expands the recognized clinical spectrum of PDH E1 alpha deficiency, including adult-onset and milder forms.
- It establishes the first documented case of mother-to-daughter transmission of this specific PDH E1 alpha mutation.
- Understanding the genetic basis of variable expression is crucial for accurate diagnosis and genetic counseling in affected families.
Abstract:
Three female patients are described with pyruvate dehydrogenase (PDH) deficiency as a result of mutation in the X-linked gene for the E1 alpha subunit of the complex. Two of these patients illustrate typical presentations of PDH E1 alpha deficiency, with severe neurological dysfunction, degenerative changes and developmental anomalies in the brain, together with variable lactic acidosis. The third patient extends the known spectrum of the condition to include mild to moderate mental retardation and seizures in an adult. All three patients have the same mutation in the PDH E1 alpha gene. This mutation, a C-to-T substitution in a CpG dinucleotide in amino acid codon 302 (designated R302C), results in the replacement of arginine by cysteine at this position. The mildly affected adult was the mother of one of the other patient, making this the first described instance of mother-to-daughter transmission of a mutation causing PDH E1 alpha deficiency. The genetic basis of the variable expression of X-linked PDH E1 alpha deficiency in heterozygous females is discussed.