A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency

Autor: Shulin Zhang, George Grahame, Stacey Tarrant, Charles L. Hoppel, Ann M. Bergin, Douglas S. Kerr, Jirair K. Bedoyan, Suzanne D. DeBrosse, Ha Kyung Shin, Leah Hecht, Didem Demirbas, Edward Yang, Gerard T. Berry
Rok vydání: 2019
Předmět:
lcsh:QH426-470
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Case Report
Dehydrogenase
Case Reports
macromolecular substances
Pyruvate dehydrogenase phosphatase
Congenital lactic acidosis
lcsh:Diseases of the endocrine glands. Clinical endocrinology
Biochemistry
Genetics and Molecular Biology (miscellaneous)
Frameshift mutation
03 medical and health sciences
0302 clinical medicine
Internal Medicine
medicine
branched‐chain 2‐ketoacid dehydrogenase
030304 developmental biology
Alanine
0303 health sciences
lcsh:RC648-665
Chemistry
pyruvate dehydrogenase phosphatase deficiency
PDP1
hemic and immune systems
pyruvate dehydrogenase complex deficiency
Pyruvate dehydrogenase complex
medicine.disease
Molecular biology
3. Good health
developmental delay
lcsh:Genetics
lactic acidosis
Lactic acidosis
030217 neurology & neurosurgery
Ketogenic diet
Zdroj: JIMD Reports
JIMD Reports, Vol 48, Iss 1, Pp 26-35 (2019)
ISSN: 2192-8312
Popis: Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched‐chain 2‐ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched‐chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary‐specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1. Synopsis Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis.
Databáze: OpenAIRE
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