Ornithine carbamoyl transferase deficiency: A neuropathological study

Harding, Brian; Leonard, James V.; Erdohazi, Magda

doi:10.1007/bf00572763

Cited by 62 publications

(21 citation statements)

References 21 publications

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“…This is in line with the growing number of recently described neurological pathologies showing abnormal expression or phosphorylation of neuronal cytoskeleton proteins such as NFs or microtubule-associated proteins (Hirokawa and Takeda, 1998;Julien, 1999;Saez et al, 1999;Sanchez et al, 2000). Our results are consistent with clinical findings in hyperammonemic neonates or infants with brain lesions compatible with neuronal fiber loss or defects of neurite outgrowth, such as cortical atrophy, ventricular enlargement, demyelination, or gray and white matter hypodensities (Harding et al, 1984;Msall et al, 1984;Wakamoto et al, 1999), which can be acquired in utero (Filloux et al, 1986).…”

Section: Ammonium Exposure Impairs Cholinergic Axonal Growth Decreassupporting

confidence: 92%

“…They mainly occur in cases of prolonged hyperammonemic crises, or when blood ammonium reaches levels between 180 and 500 M, or both during the first 2 years of life (Msall et al, 1984;Uchino et al, 1998;Bachmann, 2002Bachmann, , 2003. In the few reported brain autopsies of pediatric patients, Alzheimer's type II astrocytes, perivascular spongiosis, and cystic necrosis at the junction of cortical gray and white matter have been observed (Harding et al, 1984;Filloux et al, 1986;Dolman et al, 1988). The mechanisms leading to irreversible alterations are not understood.…”

mentioning

confidence: 99%

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Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Braissant¹,

Henry²,

Villard³

et al. 2002

J. Neurosci.

100

137

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Hyperammonemia in neonates and infants affects brain development and causes mental retardation. We report that ammonium impaired cholinergic axonal growth and altered localization and phosphorylation of intermediate neurofilament protein in rat reaggregated brain cell primary cultures. This effect was restricted to the phase of early maturation but did not occur after synaptogenesis. Exposure to NH 4 Cl decreased intracellular creatine, phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected axons from ammonium toxic effects, although this did not restore high-energy phosphates. The protection by creatine was glial cell-dependent. Our findings suggest that the means to efficiently sustain CNS creatine concentration in hyperammonemic neonates and infants should be assessed to prevent impairment of axonogenesis and irreversible brain damage.

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Section: Ammonium Exposure Impairs Cholinergic Axonal Growth Decreassupporting

confidence: 92%

mentioning

confidence: 99%

Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Braissant¹,

Henry²,

Villard³

et al. 2002

J. Neurosci.

100

137

View full text Add to dashboard Cite

show abstract

“…Neuroimaging studies performed months later in neonatal coma survivors are consistent with these pathological findings, correlating with hypomyelination of white matter, myelination delay, cystic changes of the white matter and gliosis of the deep grey-matter nuclei (Dolman et al 1988;Harding et al 1984;Kornfeld et al 1985).…”

Section: Pathological Changes In Urea Cycle Disordersmentioning

confidence: 77%

Neurological implications of urea cycle disorders

Gropman

Summar

Leonard³

2007

J of Inher Metab Disea

Self Cite

191

152

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SummaryThe urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1 H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

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“…These findings include ventricular enlargement, cerebral atrophy, cystic degeneration and delayed myelination [2,3]. In addition, astrocytes take on a characteristic appearance known as Alzheimer type II astrocytosis, in which the cells are enlarged (swollen) with a large pale nucleus, prominent nucleolus and margination of the chromatin pattern.…”

Section: Neuropathology Of Congenital Otc Deficiencymentioning

confidence: 99%

“…A follow-up CT scan in this patient showed bilateral ventricular dilatation and severe cerebral atrophy. It has been proposed that much of the neuropathological damage in congenital OTC deficiency is acquired in utero [2,8]. Studies of congenital OTC deficiency are facilitated by the availability of an appropriate animal model, the 'sparse-fur' (spf) mouse.…”

Section: Neuropathology Of Congenital Otc Deficiencymentioning

confidence: 99%

Evidence for a Central Cholinergic Deficit in Congenital Ornithine Transcarbamylase Deficiency

1998

Dev Neurosci

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Congenital ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea cycle enzymes in humans. A large percentage of survivors of neonatal OTC deficiency suffer severe developmental disorders, including seizures, mental retardation and cerebral palsy. Neuropathological studies reveal ventricular enlargement, cerebral atrophy and delayed myelination, as well as Alzheimer type II astrocytosis. Using the sparse-fur (spf) mouse model of congenital OTC deficiency, studies of central cholinergic integrity revealed a developmental delay in choline acetyltransferase activity and of high-affinity [³H]-choline uptake in several brain structures. Subsequent studies of muscarinic cholinergic binding site distribution showed a widespread loss of M₁ sites, consistent with cholinergic cell loss. These alterations are similar to those reported in Alzheimer’s disease, suggesting that the severe cognitive dysfunction in congenital OTC deficiency may at least partly result from a muscarinic cholinergic lesion. Possible mechanisms involved in the pathogenesis of cholinergic cell loss in congenital OTC deficiency include ammonia-induced inhibition of pyruvate and α-oxoglutarate oxidation, resulting in decreased synthesis of acetyl CoA and a cerebral energy deficit, as well as NMDA receptor-mediated excitotoxicity. Treatment of spf mice with acetyl-L-carnitine (ALCAR) results in partial recovery of the developmental choline acetyltransferase deficit, suggesting a potential therapeutic benefit of ALCAR in congenital OTC deficiency. Other therapies currently used include ammonia-lowering strategies (using sodium benzoate or sodium phenylacetate) and, in severe cases, liver transplantation.

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Ornithine carbamoyl transferase deficiency: A neuropathological study

Cited by 62 publications

References 21 publications

Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Ammonium-Induced Impairment of Axonal Growth Is Prevented through Glial Creatine

Neurological implications of urea cycle disorders

Evidence for a Central Cholinergic Deficit in Congenital Ornithine Transcarbamylase Deficiency

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