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Neurotossicità iperammoniemia martinelli
1. 1
Disordini del ciclo dell’urea:
la neurotossicità dell'iperammoniemia
Diego Martinelli
Unità Operativa Complessa Patologia Metabolica
diego.martinelli@opbg.net
Napoli 26 - 28 Novembre 2013
2. Pathogenetic Mechanisms of Hyperammonemia
…in general the age of onset, duration and degree of hyperammonemia may predict
prognosis….
……….the underlying mechanisms of hyperammonemic encephalopathy are not
completely understood………
Gropman A, Summar M, Leonard JV
JIMD 2007;30:865-79
...although several theories exist, it is
not well understood how
hyperammonemia
disrupts brain function…..
Gropman A
MGM 2010;100:S20-S30
6. PROGNOSIS DEPENDS ON COMA DURATION
Msall et al. NEJM 1984;310:1500-5
Picca et al. Pediatr Nephrol 2001;16:862-7
Good 2y
22.210.1
2210*
pre-treatment
Bad 2y
4711*
*p<0.02
48.811.2
4911
7813
7. • PERI-INSULAR
• FRONTAL
• PARIETAL
• OCCIPITAL
ADC map
ADC map
• THALAMIC RESTRICTED DIFFUSION (unusual in UCDs)
…suggesting that brain MRI may assist in determining prognosis & helping
clinicians with subsequent treatment decisions
12. The concentration changes of the nitrogen scavenger
glutamine have to be interpreted in the light of NH4 levels.
In contrast to other hyperammonemic syndromes, in PA
plasma glutamine do not increase in hyperammonemia,
whereas CSF glutamine concentrations are elevated.
2010
13. depletion of oxaloacetate (>methylcitrate production)
reduced supply of succinyl-CoA
alfa-ketoglutarate
glutamate > glutamine
14. Glutamine synthesis the principal means of NH4 detoxification?
The osmotic action of glutamine
CEREBRAL EDEMA
NEURON
ASTROCYTE
SWELLING
ASTROCYTE
SWELLING
NH4
NH4
Glutamate
Glutamine
GS
Alzheimer type II
astrocytosis
Glutamine
Alzheimer type II
astrocytosis
Glutamate
25. The role of energy failure
NH4+ exposure
generates
secondary Cr
deficiency in
brain cell
cultures
Braissant 2010
• altered oxidative
phosphorylation
• cessation of ATP
synthesis
• production of
ROS and cell
death
26. Pathogenesis of brain damage in HA: others
Astrocyte swelling can cause a secondary release of Glu into the intercellular space
KGM neurotoxic ?
**
*
↑↑
«Trojan horse» hypothesis
SNAT5
Modified from Braissant; J Inherit Metab Dis (2013) 36:595–612
*KMG : α-ketoglutaramate; AKGM are increased in UCDs
ROS ↑↑
MPT open
↓↓ SNAT5. Trapping GLn
Altered Neurotrasnsmitter
system
**Imp:, brain NO metabolism is affected in a number of ways by NH4 + exposure. Effects vary
depending on whether the exposure is acute or chronic, on brain cell type, and whether Arg
supply is normal or decreased
Braissant; J Inherit Metab Dis (2013) 36:595–612;Albrecht; Hepatolgoy . 2006 Oct;44(4):788-94; Halámková; Talanta. 2012 Oct 15;100:7-11;
Vergara F et al; Science 1974;183:81-83; P. Desjardins et al. / Neurochemistry International 60 (2012) 690–696
27. Pathogenesis underlying brain dysfunction. Acute and chronic
hyperammonemia
Conclusions
•
How HA can lead to severe consequences in the central nervous system (CNS) remains unclear.
•
The rise in ammonia levels, the elevations of glutamine, and the effect of glutamine on the brain are
proposed to account for the different effects of acute (vs chronic) hyperammonemia on the brain.
•
In acute hyperammonemia the excessive NMDA receptors activation could be inducing neuronal death
•
In chronic hyperammonemia the impaired function of the glutamate-nitric oxide-cGMP pathway,
associated to NMDA receptors could be inducing cognitive impairment.
•
N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors are fundamental for
learning because they are the major modulators of the long-term potentiation, the electrophysiologic
mechanism for learning.
Braissant; J Inherit Metab Dis (2013) 36:595–612;Albrecht; Hepatolgoy . 2006 Oct;44(4):788-94; Halámková; Talanta. 2012 Oct 15;100:7-11;
Vergara F et al; Science 1974;183:81-83; P. Desjardins et al. / Neurochemistry International 60 (2012) 690–696;
Cauli O et al Metab Brain Disease ; 2009 Mar;24(1):69-80; Alison S. Et al ; Chest Chest 2007;132;1368-1378