Two patients with clinically distinct manifestation of pyruvate dehydrogenase deficiency due to mutations in PDHA1
M Magner1, K Vinšová, M Tesařová
1Department of Pediatrics and Adolescent Medicine, Charles University, Prague, Czech Republic.
Insights
Pyruvate dehydrogenase complex (PDHc) deficiency, often due to PDHA1 gene mutations, shows varied clinical symptoms and diagnostic challenges. Normal PDHc activity may not always rule out this condition.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Pyruvate dehydrogenase complex (PDHc) deficiency is primarily caused by E1α-subunit deficits.
- Mutations in the PDHA1 gene are a common genetic cause of PDHc deficiency.
- Understanding the clinical and diagnostic spectrum is crucial for patient management.
Observation:
- Two boys with PDHA1 gene mutations presented with distinct clinical courses and neurological symptoms.
- Patient 1 exhibited early hypotonia and psychomotor retardation, progressing to spasticity.
- Patient 2 showed seizures and hyporeflexia in toddlerhood, later diagnosed with dystonia and myopathy despite normal mental development.
Findings:
- Brain MRI revealed Leigh syndrome lesions in both patients.
- Enzymatic assays showed PDHc deficiency in patient 1's lymphocytes, but not patient 2's.
- Direct measurement confirmed E1-subunit deficiency in patient 2, highlighting diagnostic complexities.
- Novel mutations (c.857C>T and c.367C>T) in the PDHA1 gene were identified in the patients.
Implications:
- This study highlights the broad clinical variability of PDHc deficiency.
- Diagnostic challenges exist, as normal PDHc activity measurements may not exclude the disease.
- Accurate genetic analysis of the PDHA1 gene is essential for definitive diagnosis.
Abstract:
The most common cause of pyruvate dehydrogenase complex (PDHc) deficiency is the deficit of the E1α-subunit. The aim of this study was to describe distinct course of the disease in two boys with mutations in PDHA1 gene and illustrate the possible obstacles in measurement of PDHc activity. Clinical data and metabolic profiles were collected and evaluated. PDHc and E1α-subunit activities were measured using radiometric assay. Subunits of PDHc were detected by Western blot. PDHA1 gene was analysed by direct sequencing. In patient 1, the initial hypotonia with psychomotor retardation was observed since early infancy. The child gradually showed symptoms of spasticity and arrest of psychomotor development. In patient 2, the disease manifested by seizures and hyporeflexia in the toddler age. The diagnosis was confirmed at the age of seven years after attacks of dystonia and clinical manifestation of myopathy with normal mental development. Brain MRI of both patients revealed lesions typical of Leigh syndrome. Enzymatic analyses revealed PDHc deficiency in isolated lymphocytes in the first but not in the second patient. The direct measurement of PDH E1-subunit revealed deficiency in this individual. In patient 1, a novel hemizigous mutation c.857C>T (Pro250Leu) was detected in the X-linked PDHA1 gene. Mutation c.367C>T (Arg88Cys) was found in patient 2. We present first two patients with PDHc deficit due to mutations in PDHA1 gene in the Czech Republic. We document the broad variability of clinical symptoms of this disease. We proved that normal PDHc activity may not exclude the disease.
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