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Saini AG, Gunasekaran PK, Chaudhary I, Bhatia V. Severe Microcephaly and Metabolic Epilepsy due to Asparagine Synthetase Deficiency. Ann Indian Acad Neurol 2023; 26:570-572. [PMID: 37970270 PMCID: PMC10645261 DOI: 10.4103/aian.aian_414_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 05/30/2023] [Accepted: 06/24/2023] [Indexed: 11/17/2023] Open
Affiliation(s)
- Arushi G. Saini
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pradeep K. Gunasekaran
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Inzamam Chaudhary
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vikas Bhatia
- Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Camici M, Garcia-Gil M, Allegrini S, Pesi R, Bernardini G, Micheli V, Tozzi MG. Inborn Errors of Purine Salvage and Catabolism. Metabolites 2023; 13:787. [PMID: 37512494 PMCID: PMC10383617 DOI: 10.3390/metabo13070787] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
Cellular purine nucleotides derive mainly from de novo synthesis or nucleic acid turnover and, only marginally, from dietary intake. They are subjected to catabolism, eventually forming uric acid in humans, while bases and nucleosides may be converted back to nucleotides through the salvage pathways. Inborn errors of the purine salvage pathway and catabolism have been described by several researchers and are usually referred to as rare diseases. Since purine compounds play a fundamental role, it is not surprising that their dysmetabolism is accompanied by devastating symptoms. Nevertheless, some of these manifestations are unexpected and, so far, have no explanation or therapy. Herein, we describe several known inborn errors of purine metabolism, highlighting their unexplained pathological aspects. Our intent is to offer new points of view on this topic and suggest diagnostic tools that may possibly indicate to clinicians that the inborn errors of purine metabolism may not be very rare diseases after all.
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Affiliation(s)
- Marcella Camici
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
| | - Mercedes Garcia-Gil
- Unità di Fisiologia Generale, Dipartimento di Biologia, Università di Pisa, Via San Zeno 31, 56127 Pisa, Italy
- CISUP, Centro per l'Integrazione Della Strumentazione Dell'Università di Pisa, 56127 Pisa, Italy
- Centro di Ricerca Interdipartimentale Nutrafood "Nutraceuticals and Food for Health", Università di Pisa, 56126 Pisa, Italy
| | - Simone Allegrini
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
- CISUP, Centro per l'Integrazione Della Strumentazione Dell'Università di Pisa, 56127 Pisa, Italy
- Centro di Ricerca Interdipartimentale Nutrafood "Nutraceuticals and Food for Health", Università di Pisa, 56126 Pisa, Italy
| | - Rossana Pesi
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
| | - Giulia Bernardini
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Vanna Micheli
- Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro 2, 53100 Siena, Italy
- LND Famiglie Italiane ODV-Via Giovanetti 15-20, 16149 Genova, Italy
| | - Maria Grazia Tozzi
- Unità di Biochimica, Dipartimento di Biologia, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy
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Wang XC, Wang T, Liu RH, Jiang Y, Chen DD, Wang XY, Kong QX. Child with adenylosuccinate lyase deficiency caused by a novel complex heterozygous mutation in the ADSL gene: A case report. World J Clin Cases 2022; 10:11082-11089. [PMID: 36338215 PMCID: PMC9631162 DOI: 10.12998/wjcc.v10.i30.11082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/08/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene. It can cause severe neurological impairment and diverse clinical manifestations, including epilepsy.
CASE SUMMARY Here, we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy. Magnetic resonance imaging showed myelin hypoplasia. Electroencephalography findings supported a diagnosis of epilepsy. Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene: The splicing mutation c.154-3C>G and the missense mutation c.71C>T (p. Pro24Leu). Considering the patient’s clinical presentation and genetic test results, the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL, which may have led to ADSL deficiency. Finally, the child was diagnosed with ADSL deficiency.
CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency, thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency. Additionally, we describe epilepsy that occurs in patients with ADSL deficiency.
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Affiliation(s)
- Xing-Chen Wang
- Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Ting Wang
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining 272000, Shandong Province, China
| | - Rui-Han Liu
- Department of Pediatrics, Affiliated Hospital of Jining Medical University, Jining 272000, China
- College of TCM, Shandong University of Traditional Chinese Medicine, Jinan 250012, Shandong Province, China
| | - Yan Jiang
- Clinical Medical College, Jining Medical University, Jining 272000, Shandong Province, China
| | - Dan-Dan Chen
- Clinical Medical College, Jining Medical University, Jining 272000, Shandong Province, China
| | - Xin-Yu Wang
- Clinical Medical College, Jining Medical University, Jining 272000, Shandong Province, China
| | - Qing-Xia Kong
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining 272000, Shandong Province, China
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Sharma Y, Saini AG, Kaur R, Bhatia V, Didwal G, Kumar P, Uppala R. Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants: A Case Series and Review of Literature. Neuropediatrics 2022; 53:167-175. [PMID: 35098521 DOI: 10.1055/s-0042-1742322] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency associated with mutations in the ITPA gene is a recently characterized purine pathway defect that presents with early infantile epileptic encephalopathy and lethal course. This disorder is rare, and only 12 cases are reported worldwide. METHODS We report two additional cases of ITPA-associated neurodegeneration and two pathogenic compound heterozygous variants. We also reviewed the previously published cases of ITPA-associated encephalopathy. RESULTS Both cases presented with progressive infantile-onset encephalopathy, severe developmental delay, microcephaly, facial dysmorphism, and epilepsy. Together with the presented two cases, 14 cases were available for analysis. The mean age of presentation was 16.7 ± 12.4 months (range 3-48 m). The most common clinical features at presentation were developmental delay, seizures, microcephaly, and hypotonia, seen in all 14 (100%) patients. The mean age of seizure onset was 4.75 months (range 2-14 m). Cardiomyopathy was noted in 42% of patients where it was explicitly evaluated (n = 5/12). Consanguinity was reported in 77% of the cases. The cardinal neuroradiological features are T2-signal abnormalities and diffusion restriction in the long tracts, especially the posterior limb of the internal capsule and the optic radiation. The majority of the patients died before 4 years of age (85.7%). CONCLUSION ITPA-related encephalopathy presents with infantile-onset neurodegeneration, progressive microcephaly, and epilepsy. Progressive brain atrophy and diffusion restriction in the white matter tracts are important radiological clues.
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Affiliation(s)
- Yashu Sharma
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arushi Gahlot Saini
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Rajdeep Kaur
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Vikas Bhatia
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Gunjan Didwal
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pawan Kumar
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Revathi Uppala
- Genetics Division, Sandor Specialty Diagnostic Pvt Ltd, Hyderabad, Telangana, India
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Chi JT, Lin PH, Tolstikov V, Oyekunle T, Alvarado GCG, Ramirez-Torres A, Chen EY, Bussberg V, Chi B, Greenwood B, Sarangarajan R, Narain NR, Kiebish MA, Freedland SJ. The influence of low-carbohydrate diets on the metabolic response to androgen-deprivation therapy in prostate cancer. Prostate 2021; 81:618-628. [PMID: 33949711 PMCID: PMC8167376 DOI: 10.1002/pros.24136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/21/2021] [Accepted: 04/12/2021] [Indexed: 01/17/2023]
Abstract
BACKGROUND Prostate cancer (PC) is the second most lethal cancer for men. For metastatic PC, standard first-line treatment is androgen deprivation therapy (ADT). While effective, ADT has many metabolic side effects. Previously, we found in serum metabolome analysis that ADT reduced androsterone sulfate, 3-hydroxybutyric acid, acyl-carnitines but increased serum glucose. Since ADT reduced ketogenesis, we speculate that low-carbohydrate diets (LCD) may reverse many ADT-induced metabolic abnormalities in animals and humans. METHODS In a multicenter trial of patients with PC initiating ADT randomized to no diet change (control) or LCD, we previously showed that LCD intervention led to significant weight loss, reduced fat mass, improved insulin resistance, and lipid profiles. To determine whether and how LCD affects ADT-induced metabolic changes, we analyzed serum metabolites after 3-, and 6-months of ADT on LCD versus control. RESULTS We found androsterone sulfate was most consistently reduced by ADT and was slightly further reduced in the LCD arm. Contrastingly, LCD intervention increased 3-hydroxybutyric acid and various acyl-carnitines, counteracting their reduction during ADT. LCD also reversed the ADT-reduced lactic acid, alanine, and S-adenosyl methionine (SAM), elevating glycolysis metabolites and alanine. While the degree of androsterone reduction by ADT was strongly correlated with glucose and indole-3-carboxaldehyde, LCD disrupted such correlations. CONCLUSIONS Together, LCD intervention significantly reversed many ADT-induced metabolic changes while slightly enhancing androgen reduction. Future research is needed to confirm these findings and determine whether LCD can mitigate ADT-linked comorbidities and possibly delaying disease progression by further lowering androgens.
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Affiliation(s)
- Jen-Tsan Chi
- Department of Molecular Genetics and Microbiology, Center for Genomics and Computational Biology
- Corresponding Authors: Jen-Tsan Chi: , 1-919-6684759, 101 Science Drive, DUMC 3382, CIEMAS 2177A, Durham, NC 27708, Stephen J. Freedland: , 1-310-423-3497, 8635, W. Third St., Suite 1070W, Los Angeles, CA 90048
| | - Pao-Hwa Lin
- Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina USA
| | | | - Taofik Oyekunle
- Duke Cancer Institute, Duke University Medical Center, Durham, NC USA
| | | | - Adela Ramirez-Torres
- Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, CA
| | | | | | - Bo Chi
- Department of Molecular Genetics and Microbiology, Center for Genomics and Computational Biology
| | | | | | | | | | - Stephen J. Freedland
- Center for Integrated Research in Cancer and Lifestyle, Cedars-Sinai, Los Angeles, CA
- Durham VA Medical Center, Durham, NC, USA
- Corresponding Authors: Jen-Tsan Chi: , 1-919-6684759, 101 Science Drive, DUMC 3382, CIEMAS 2177A, Durham, NC 27708, Stephen J. Freedland: , 1-310-423-3497, 8635, W. Third St., Suite 1070W, Los Angeles, CA 90048
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