On the pathophysiology of ADSL deficiency

Konference: 2010 6. sympózium a workshop molekulární patologie a histo-cyto-chemie

Kategorie: Onkologická diagnostika

Téma: Keynote lectures of invited speakers

Číslo abstraktu: 003

Autoři: L. Žídková; J. Krijt; MUDr. Alice Hlobilková, Ph.D.; J. Zeman; Prof. MUDr. Milan Elleder (1938 - 2011), DrSc.; Doc.RNDr. Tomáš Adam, Ph.D.

Purine nucleotides may be formed de novo, from small molecules, or by salvage, from preformed purines. Despite the essential functions of purine de novo synthesis (PDNS), salvage pathways recycle nucleotides to meet daily needs. In man, the main source of purines and the site of highest PDNS activity is considered to be the liver. A first disease described in PDNS -adenylosuccinate lyase (ADSL; EC deficiency is an autosomal-recessive disorder presenting extreme variability -from fatal neonatal type presented as encephalopathy to slight mental delay. Currently, no effective treatment is available for adenylosuccinate lyase deficiency, although several approaches have been tested.

Dephosphorylated substrates 5-amino-4-imidazole-N-succino¬carboxamide (SAICA) riboside and succinyladenosine (SAdo) accumulate in body fluids of patients with ADSL deficiency. The content of succinylpurines in cerebrospinal fluid of patients exceeds 100 µmol/l and is two orders of magnitude higher in CSF compared to blood levels. It makes extracerebellar sources of the high concentration of the compounds in CSF unlikely. However, activity of PDNS in adult brain is considered minimal.

We report here results of studies using cultured oligodendroglia and direct biochemical analysis of white matter obtained at autopsy from a patients with severe form of ADSL deficiency. In vitro incorporation study revealed intracellular concentration of succinylpurines of up 100 µmol/l. The contribution of compounds newly synthesized was very high (up to 25%). The analysis of white mater from autopsy revealed extremely high concentration of SAdo and SAICAR (685 and 3124 µmol/g wet weight, respectively; ratio 0.18) exceeding concentration of sum of adenine nucleotides (49 µmol/g wet weight) by orders of magnitude.

Oligodendroglia is responsible for neurological symptoms of ADSL deficiency and provides useful model for development of treatment.

This work was supported by grant from Iceland, Liechtenstein and Norway through the EEA Financial Mechanism and the Norwegian Financial Mechanism A/CZ0046/2/0011 and MSM 0021620806.

Datum přednesení příspěvku: 23. 4. 2010