Megaloblastic Anæmia in the Lesch-Nyhan Syndrome

Zee, S. P. M. Van Der; Schretlen, E. D. A. M.; Monnens, L.A.H.

doi:10.1016/s0140-6736(68)92002-3

Cited by 45 publications

(17 citation statements)

References 6 publications

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“…Thus, the hematological problems in this patient were a mild anemia (a low RBC count), macrocytosis, and megaloblastic bone marrow changes. All these are occasionally found in the LeschNyhan syndrome [1,6,7]. Some authors have postulated that macrocytosis and megaloblastic changes in the bone marrow probably differ in the series because of different variables, such as nutritional status of the population studied or spontaneous disappearance of the megaloblastosis [7].…”

Section: Discussionmentioning

confidence: 99%

“…Self-mutilation is an important neurological characteristic, which is observed in patients with severe neurological manifestations [5]. Macrocytic anemia has been reported in association with megaloblastic bone marrow changes in HPRT-deficient patients [1,6]. Macrocytosis and megaloblastic bone marrow changes have been reported without anemia [7].…”

Section: Introductionmentioning

confidence: 99%

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A new point mutation in a hypoxanthine phosphoribosyltransferase-deficient patient

Hidalgo-Laos

Kedar

Williams

et al. 1997

Pediatric Nephrology

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A 12-year-old boy was referred because of abdominal pain, gross hematuria, and passage of stones. Further evaluation showed growth delay, low average range of intellectual functioning, and a speech articulation disorder. No signs of self-mutilation or self-injurious behavior were present. He had hyperuricemia, hyperuricosuria, uric acid crystalluria, uric acid calculi, macrocytosis, megaloblastic bone marrow changes, and mild anemia. Hypoxanthine phosphoribosyltransferase (HPRT) enzyme activity was reduced to approximately 26% of normal. Polymerase chain reaction-single strand conformational polymorphism analysis of the HPRT gene in DNA isolated from the patient's blood lymphocytes revealed a single nucleotide substitution at codon 200 in exon 8. The base change was a guanine to cytosine transversion, resulting in the conservative amino acid substitution of threonine in place of arginine. To our knowledge, this mutation has not previously been reported.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A new point mutation in a hypoxanthine phosphoribosyltransferase-deficient patient

Hidalgo-Laos

Kedar

Williams

et al. 1997

Pediatric Nephrology

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“…Older patients with the L-N syndrome occasionally develop megaloblastic anemia [49] associated with low erythrocyte adenine nucleotide levels [27]. The anemia and lowered adenine nucleotides improve with oral adenine therapy [27].…”

Section: Discussionmentioning

confidence: 99%

Adenine and Folic Acid in the Lesch-Nyhan Syndrome

Benke¹,

Herrick²,

Smitten³

et al. 1973

Pediatr Res

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Therapy of identical twin males with the enzyme defect of the Lesch-Nyhan (L-N) syndrome was instituted at 12 hr of age with adenine, 10 mg/kg/24 hr, administered to one twin and folic acid, 15 mg/24 hr, to both. At 4 years of age both twins demonstrate delayed neurologic development and spasticity but are less severely affected than most other patients with this disorder. Administered in subsequent studies to two maternal cousins of the twins who had clinical features of the L-N syndrome and absence of erythrocyte hypoxanthine-guanine phosphoribosyltransferase activity were adenine, 10 mg/kg/24 hr, adenine, 40 mg/kg/24 hr, folic acid, and monosodium glutamate. Low dose adenine had a slight suppressive effect on glycine-1-14 C incorporation into uric acid; high dose adenine had a strong suppressive effect in the second patient. We conclude that the adenine dose chosen for therapy was too low. 2,8-Dihydroxyadenine, a toxic breakdown product of adenine, was detected in the urine at both adenine dose levels. Folic acid and monosodium glutamate in these patients further stimulate accelerated glycine-ll4 C incorporation into uric acid. In vitro transport studies, performed with inverted hamster jejunal preparations, suggest that adenine is largely converted to adenine monophosphate when exposed to the mucosal surface. This may limit the passage of orally administered adenine to the central nervous system in patients. Adenine and purine precursors affect the biochemical pathology of the L-N syndrome, in vivo and in vitro, but therapeutic use of adenine, 10 mg/kg/24 hr, and folic acid started on the 1st day of life did not prevent central nervous system dysfunction. Speculation

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“…Homologous recombination has been demonstrated for the hypoxanthine phosphoribosyltransferase (HPRT) gene. 52,95 Although HPRT defects are primarily associated with Lesch-Nyhan syndrome 96 and gout, megaloblastic anemia has been noted in both patients with Lesch-Nyhan syndrome 97 as well as Hprt Ϫ/Ϫ mice 98 and likely results from the impaired purine metabolism inherent to this defect of nucleotide salvage. As previously noted, RNAi has been used in hES cells 44,[53][54][55] and is highly efficient, approximating a true gene knock-out effect.…”

Section: Sources and Utility Of Disease-specific Hes Cell Linesmentioning

confidence: 99%

Scientific and clinical opportunities for modeling blood disorders with embryonic stem cells

Lensch

Daley

2006

Blood

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Our considerable wealth of data concerning hematologic processes has come despite difficulties working with stem and progenitor cells in vitro and their propensity to differentiate. Key methodologies that have sought to overcome such limitations include transgenic/knock-out animals and in vitro studies using murine embryonic stem cells, because both permit investigation of the formation of hematopoietic tissue from nonhematopoietic precursors. Although there have been many successful studies in model animals for understanding hematopoieticcell development, differences between lower vertebrates and humans have left gaps in our understanding. Clearly, human-specific strategies to study the onset of hematopoiesis, particularly the earliest events leading to the specification of both normal and abnormal hematopoietic tissue, could bring an investigational re- Fifty years of pluripotent stem-cell studiesDefined by their capacity to generate progeny of all 3 embryonic germ layers (ectoderm, endoderm, and mesoderm), pluripotent stem cells were first studied by Stevens and Little 1 in experiments that involved isolation of the undifferentiated component of spontaneous testicular teratomas in the 129 inbred mouse strain. These embryonal carcinoma cells (ECCs) differentiated in vitro following aggregation into cystic "embryoid bodies" (EBs) where they again demonstrated the elaboration of all 3 germ layers. 2 Although surprising considering their tumor origins, some lines of ECCs were further shown to contribute multiple tissues to chimeric mice following introduction into the murine blastocyst. 3 An extension of these studies naturally sought to isolate the stem-cell component of "normal," nontumor tissues including the early embryo. It would be another 27 years after Stevens and Little began the isolation of the ECCs before murine embryonic stem (mES) cells were first derived from the day 2.5 postfertilization murine blastocyst. 4,5 This was followed by the description of yolk sac-like blood islands containing embryonic globin-expressing, nucleated megaloblasts in murine ES cell-derived EBs, 6 thereby setting the stage for an entirely new area of investigation, namely, the in vitro formation of hematopoietic tissue from nonhematopoietic precursors, tissue that could be further studied in vivo following transplantation. mES cells possess a robust capacity for hematopoietic specification in vitro and further lend themselves to the study of specific genetic lesions in vivo. 7-9 Modest, short-term hematopoietic reconstitution of lethally irradiated murine hosts was first shown possible with mES cells differentiated in vitro for 4 days, 10 suggesting that true hematopoietic stem cells (HSCs) might be capable of being derived from ES cells. These studies were followed by focused attempts to augment the inherent hematopoietic capacity of mES cells. Early experiments made use of the BCR/ABL fusion gene to promote hematopoietic proliferation in mES cells, 11-13 although experimental animals succumbed to leukemia. Hypothesizing ...

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Megaloblastic Anæmia in the Lesch-Nyhan Syndrome

Cited by 45 publications

References 6 publications

A new point mutation in a hypoxanthine phosphoribosyltransferase-deficient patient

A new point mutation in a hypoxanthine phosphoribosyltransferase-deficient patient

Adenine and Folic Acid in the Lesch-Nyhan Syndrome

Scientific and clinical opportunities for modeling blood disorders with embryonic stem cells

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