Factors in the Pathogenesis of the Brain Damage and Anaemia in the Lesch‒Nyhan Syndrome

McKeran, R O

doi:10.1002/9780470720301.ch6

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…Megaloblastic anaemia in Lesch-Nyhan patients is associated with megaloblastic findings in bone marrow and has been considered the result of increased folic acid consumption, due to enhanced de novo purine synthesis [ 52 ]. Nevertheless, this anaemia is not corrected by folate therapy.…”

Section: Aetiologymentioning

confidence: 99%

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Torres

Puig

2007

Orphanet J Rare Dis

251

155

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Section: Aetiologymentioning

confidence: 99%

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Torres

Puig

2007

Orphanet J Rare Dis

251

155

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“…Prior studies have shown dopaminergic neurons to be especially vulnerable to ATP loss due to energy failure, and HPRT-mediated purine recycling is postulated to play a role in maintaining cellular purines, including ATP (McKeran, 1977;McCreanor and Harkness, 1995;Jinnah and Friedmann, 2000). To determine if the loss of HPRT might be associated with reduced ATP, adenine nucleotide levels were measured.…”

Section: Energy Failurementioning

confidence: 99%

“…Alternative intrinsic biochemical mechanisms must be considered. Because ATP is a downstream product of HPRT, HPRT deficiency may result in energy limitation (McKeran, 1977;McCreanor and Harkness, 1995;Jinnah and Friedmann, 2000). HPRT deficiency also causes secondary metabolic changes that may increase oxidative stress (Visser et al, 2002;Smith and Jinnah, 2007).…”

mentioning

confidence: 99%

Consequences of impaired purine recycling in dopaminergic neurons

et al. 2008

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A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction.

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“… 3 – 5 Some reports of LND and its variants occasionally also mentioned another feature of the phenotype, macrocytic anemia. 6 , 7 However, this problem is not widely recognized because it has received very little attention in the literature. There is no information on its frequency, severity, or clinical significance.…”

Section: Introductionmentioning

confidence: 99%

Macrocytic anemia in Lesch–Nyhan disease and its variants

Çakmaklı

Torres

Menendez³

et al. 2019

Genetics in Medicine

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PurposeLesch-Nyhan disease (LND) is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study is to describe macrocytic erythrocytes as another common aspect of the phenotype.MethodsResults of 257 complete blood counts (CBC) from a total of 65 patients over a 23-year period were collected from two reference centers where many patients are seen regularly.ResultsMacrocytic erythrocytes occurred in 81–92% of subjects with LND or its neurological variants. After excluding cases with iron deficiency because it might pseudo-normalize erythrocyte volumes, macrocytosis occurred in 97% of subjects. Macrocytic erythrocytes were sometimes accompanied by mild anemia, and rarely by severe anemia.ConclusionsThese results establish macrocytic erythrocytes as very common aspect of the clinical phenotype of LND and its neurological variants. Macrocytosis is so characteristic that its absence should prompt suspicion for some secondary process, such as iron deficiency. Because macrocytosis is uncommon in normal children, it can also be used as a clue for early diagnosis in children with neurodevelopmental delay. Better recognition of this characteristic feature of the disorder will also help to prevent unnecessary diagnostic testing and unnecessary attempts to treat it with folate or B12 supplements.

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Factors in the Pathogenesis of the Brain Damage and Anaemia in the Lesch‒Nyhan Syndrome

Cited by 8 publications

References 35 publications

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Consequences of impaired purine recycling in dopaminergic neurons

Macrocytic anemia in Lesch–Nyhan disease and its variants

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