Journal of Inherited Metabolic Disease最新文献

{"title":"Health and well-being of maturing adults with classic galactosemia","authors":"Olivia S. Garrett,&nbsp;Jared J. Druss,&nbsp;E. Naomi Vos,&nbsp;Yu-Ting Debbie Fu,&nbsp;Stephanie Lucia,&nbsp;Patricia E. Greenstein,&nbsp;Anna Bauer,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Karolina M. Stepien,&nbsp;Cameron Arbuckle,&nbsp;Olga Grafakou,&nbsp;Uta Meyer,&nbsp;Nele Vanhoutvin,&nbsp;Adriana Pané,&nbsp;Annet M. Bosch,&nbsp;Estela Rubio-Gozalbo,&nbsp;Gerard T. Berry,&nbsp;Judith L. Fridovich-Keil","doi":"10.1002/jimd.12786","DOIUrl":"10.1002/jimd.12786","url":null,"abstract":"<p>Long-term outcomes in classic galactosemia (CG) have been studied previously, but all prior studies have relied on cohorts of patients that were small in number, or heavily skewed toward children and young adults, or both. Here, we extend what is known about the health and well-being of maturing adults with CG by analyzing the results of anonymous custom surveys completed by 92 affected individuals, ages 30–78, and 38 unaffected sibling controls, ages 30–79. The median age for patients was 38.5 years and for controls was 41 years. These study participants hailed from 12 different countries predominantly representing Europe and North America. Participants reported on their general life experiences and outcomes in seven different domains including: speech/voice/language, cognition, motor function, cataracts, bone health, psychosocial well-being, and gastrointestinal health. We also queried women about ovarian function. Our results indicated a prevalence of long-term complications across all outcome domains that aligned with levels previously reported in younger cohorts. Given the sample size and age range of participants in this study, these findings strongly suggest that the adverse developmental outcomes commonly linked to CG are not progressive with age for most patients. We also tested four candidate modifiers for possible association with each of the outcomes followed, including: days of neonatal milk exposure, rigor of dietary galactose restriction in early childhood, current age, and home continent. We observed no associations that reached even nominal significance, except for the following: cataracts with neonatal milk exposure (<i>p</i> = 2.347e−04), cataracts with age (<i>p</i> = 0.018), and bone health with home continent (<i>p</i> = 0.03).</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular mechanisms of acute rhabdomyolysis in inherited metabolic diseases","authors":"Hortense de Calbiac,&nbsp;Apolline Imbard,&nbsp;Pascale de Lonlay","doi":"10.1002/jimd.12781","DOIUrl":"10.1002/jimd.12781","url":null,"abstract":"<p>Acute rhabdomyolysis (RM) constitutes a life-threatening emergency resulting from the (acute) breakdown of skeletal myofibers, characterized by a plasma creatine kinase (CK) level exceeding 1000 IU/L in response to a precipitating factor. Genetic predisposition, particularly inherited metabolic diseases, often underlie RM, contributing to recurrent episodes. Both sporadic and congenital forms of RM share common triggers. Considering the skeletal muscle's urgent need to rapidly adjust to environmental cues, sustaining sufficient energy levels and functional autophagy and mitophagy processes are vital for its preservation and response to stressors. Crucially, the composition of membrane lipids, along with lipid and calcium transport, and the availability of adenosine triphosphate (ATP), influence membrane biophysical properties, membrane curvature in skeletal muscle, calcium channel signaling regulation, and determine the characteristics of autophagic organelles. Consequently, a genetic defect involving ATP depletion, aberrant calcium release, abnormal lipid metabolism and/or lipid or calcium transport, and/or impaired anterograde trafficking may disrupt autophagy resulting in RM. The complex composition of lipid membranes also alters Toll-like receptor signaling and viral replication. In response, infections, recognized triggers of RM, stimulate increased levels of inflammatory cytokines, affecting skeletal muscle integrity, energy metabolism, and cellular trafficking, while elevated temperatures can reduce the activity of thermolabile enzymes. Overall, several mechanisms can account for RMs and may be associated in the same disease-causing RM.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term neurodevelopmental outcomes following liver transplantation for metabolic disease-a single centre experience","authors":"Catherine Patterson,&nbsp;Anna Gold,&nbsp;Stephanie So,&nbsp;Leila Kahnami,&nbsp;Michaela Dworsky-Fried,&nbsp;Eva Mamak,&nbsp;Alaine Rogers,&nbsp;Andreas Schulze,&nbsp;Birgit Ertl-Wagner,&nbsp;Vicky Ng,&nbsp;Yaron Avitzur","doi":"10.1002/jimd.12785","DOIUrl":"10.1002/jimd.12785","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>This study describes the neurodevelopmental outcome of children with urea cycle disorders (UCD) and organic acidemias (OA) preliver transplant (LT), 1-year, and 3-years post-LT. We performed a retrospective chart review of children with OA or UCD transplanted between January 2014 and December 2021. Standardized motor and cognitive assessment scores were collected from children who had ≥1 motor/cognitive assessment at any timepoint. Pre-LT brain magnetic resonance imaging (MRI) was graded. Associations between demographic/medical variables and neurodevelopmental outcomes were explored. Twenty-six children (64% male) underwent LT at a median age of 1.4 (interquartile range 0.71, 3.84) years. Fifteen (58%) had a UCD diagnosis, 14 (54%) required dialysis for hyperammonemia, and 10 (42%) had seizures typically around diagnosis. The proportion of children with gross motor scores &gt;1 standard deviation (SD) below the mean increased across timepoints, and ≥50% demonstrated general intellect scores &gt;2 SD below the mean at each timepoint. The following significant associations were noted: UCD diagnoses with lower general intellect scores (<i>p</i> = 0.019); arginosuccinate lyase deficiency diagnosis with lower visual motor scores at 3-years post-LT (<i>p</i> = 0.035); a history of seizures pre-LT with lower general intellect (&gt;2SD below the mean) at 3-years post-LT (<i>p</i> = 0.020); dialysis pre-LT with lower motor scores (&gt;1 SD below the mean) at 1-year post-LT (<i>p</i> = 0.039); pre-emptive LT with higher general intellect scores at 3-years post-LT (<i>p</i> = 0.001). MRI gradings were not associated with developmental scores. In our single centre study, children with UCD or OA had a higher prevalence of developmental impairment post-LT compared to population norms. Earlier screening, pre-emptive transplant, and rehabilitation may optimize long-term outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodevelopmental profiles of 14 individuals with phosphomannomutase deficiency (PMM2-CDG)","authors":"Tara Weixel,&nbsp;Dee Adedipe,&nbsp;Glennis Muldoon,&nbsp;Christina Lam,&nbsp;Donna Krasnewich,&nbsp;Audrey Thurm,&nbsp;Lynne Wolfe","doi":"10.1002/jimd.12782","DOIUrl":"10.1002/jimd.12782","url":null,"abstract":"<p>PMM2-CDG (formerly CDG-1a), the most common type of congenital disorders of glycosylation, is inherited in an autosomal recessive pattern. PMM2-CDG frequently presents in infancy with multisystemic clinical involvement, and it has been diagnosed in over 1000 people worldwide. There have been few natural history studies reporting neurodevelopmental characterization of PMM2-CDG. Thus, a prospective study was conducted that included neurodevelopmental assessments as part of deep phenotyping. This study, Clinical and Basic Investigations into Known and Suspected Congenital Disorders of Glycosylation (NCT02089789), included 14 participants (8 males and 6 females ages 2–33 years) with a confirmed molecular diagnosis of PMM2-CDG. Clinical features of PMM2-CDG in this cohort were neurodevelopmental disorders, faltering growth, hypotonia, cerebellar atrophy, peripheral neuropathy, movement disorders, ophthalmological abnormalities, and auditory function differences. All PMM2-CDG participants met criteria for intellectual disability (or global developmental delay if younger than age 5). The majority never attained certain gross motor and language milestones. Only two participants were ambulatory, and almost all were considered minimally verbal. Overall, individuals with PMM2-CDG present with a complex neurodevelopmental profile characterized by intellectual disability and multisystemic presentations. This systematic quantification of the neurodevelopmental profile of PMM2-CDG expands our understanding of the range in impairments associated with PMM2-CDG and will help guide management strategies.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term cardiovascular outcomes and mortality with enzyme replacement therapy in patients with mucopolysaccharidosis type II","authors":"Ji Hee Kwak,&nbsp;Yong Jun Choi,&nbsp;Sinae Kim,&nbsp;Aram Yang","doi":"10.1002/jimd.12779","DOIUrl":"10.1002/jimd.12779","url":null,"abstract":"<p>Mucopolysaccharidosis type II (MPS II) is a rare multisystemic lysosomal disorder in which cardiac issues can lead to serious dysfunction and an increased risk of fatal cardiac failure. However, studies on major adverse cardiac event (MACE) outcomes in MPS II are lacking. This study evaluated the cardiovascular outcomes and impact of enzyme replacement therapy (ERT) in patients with MPS II in South Korea. In this national cohort study, utilizing data from the National Health Insurance Database, we evaluated 127 patients with MPS II over a 14-year period to investigate the effects of ERT on MACE and all-cause mortality. We tracked MACE incidence, defined by hospitalizations for cardiovascular events, from diagnosis and adjusted the hazard ratios for MACE using Cox modeling. Over an average follow-up period of 7.3 years, we identified 16 cases of MACE among patients (17.35 per 1000 person-years; 95% confidence interval, 10.74–26.83). Patients receiving ERT exhibited a significantly lower incidence of MACE than untreated patients, with cumulative incidences showing a marked difference of 8.3 years. Notably, initiating ERT at earlier stages post-diagnosis was associated with improved outcomes, underscoring the importance of timely treatment. The key risk factors for MACE included specific arrhythmias, a history of invasive procedures, and depression. Early ERT significantly reduced MACE risk and increased survival in patients with MPS II. This underscores the importance of prompt treatment initiation and comprehensive care to address key risk factors and advocates for an expanded therapeutic strategy to enhance MPS II outcomes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update","authors":"Kristýna Čunátová,&nbsp;Erika Fernández-Vizarra","doi":"10.1002/jimd.12751","DOIUrl":"10.1002/jimd.12751","url":null,"abstract":"<p>Mitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I–V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1278-1291"},"PeriodicalIF":4.2,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12751","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The natural history of dihydrolipoamide dehydrogenase deficiency in Israel","authors":"Ben Pode-Shakked,&nbsp;Yuval E. Landau,&nbsp;Nava Shaul Lotan,&nbsp;Joshua Manor,&nbsp;Nitsan Haham,&nbsp;Eyal Kristal,&nbsp;Eli Hershkovitz,&nbsp;Guy Hazan,&nbsp;Yarden Haham,&nbsp;Shlomo Almashanu,&nbsp;Yair Anikster,&nbsp;Orna Staretz-Chacham","doi":"10.1002/jimd.12778","DOIUrl":"10.1002/jimd.12778","url":null,"abstract":"<p>Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in <i>DLD</i> were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six <i>DLD</i> variants were noted, the most common of which was the c.685G&gt;T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A&gt;T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 5","pages":"895-902"},"PeriodicalIF":4.2,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12778","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of urinary 6-oxo-pipecolic acid as a biomarker for ALDH7A1 deficiency","authors":"Youssef Khalil,&nbsp;Emma Footitt,&nbsp;Reddy Vootukuri,&nbsp;Michael F. Wempe,&nbsp;Curtis R. Coughlin II,&nbsp;Spyros Batzios,&nbsp;Matthew P. Wilson,&nbsp;Viktor Kožich,&nbsp;Peter T. Clayton,&nbsp;Philippa B. Mills","doi":"10.1002/jimd.12783","DOIUrl":"10.1002/jimd.12783","url":null,"abstract":"<p>ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in <i>ALDH7A1,</i> a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ¹-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal and multisystem effectiveness of 3.9 years of migalastat in a global real-world cohort: Results from the followME Fabry Pathfinders registry","authors":"Derralynn A. Hughes,&nbsp;Gere Sunder-Plassmann,&nbsp;Ana Jovanovic,&nbsp;Eva Brand,&nbsp;Michael L. West,&nbsp;Daniel G. Bichet,&nbsp;Antonio Pisani,&nbsp;Albina Nowak,&nbsp;Roser Torra,&nbsp;Aneal Khan,&nbsp;Olga Azevedo,&nbsp;Anna Lehman,&nbsp;Aleš Linhart,&nbsp;Jasmine Rutecki,&nbsp;Joseph D. Giuliano,&nbsp;Eva Krusinska,&nbsp;Peter Nordbeck","doi":"10.1002/jimd.12771","DOIUrl":"10.1002/jimd.12771","url":null,"abstract":"<p>Fabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to <i>GLA</i> variants. The effects of migalastat were examined in a cohort of 125 Fabry patients with migalastat-amenable <i>GLA</i> variants in the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient-focused registry evaluating outcomes for current Fabry disease treatments. We report annualised estimated glomerular filtration rate (eGFR) and Fabry-associated clinical events (FACEs) in a cohort of patients who had received ≥3 years of migalastat treatment in a real-world setting. As of August 2022, 125 patients (60% male) had a mean migalastat exposure of 3.9 years. At enrolment, median age was 58 years (males, 57; females, 60) with a mean eGFR of 83.7 mL/min/1.73 m² (<i>n</i> = 122; males, 83.7; females, 83.8) and a median left ventricular mass index of 115.1 g/m² (<i>n</i> = 61; males, 131.2; females, 98.0). Mean (95% confidence interval) eGFR annualised rate of change in the overall cohort (<i>n</i> = 116) was −0.9 (−10.8, 9.9) mL/min/1.73 m²/year with a similar rate of change observed across patients with varying levels of kidney function at enrolment. Despite population age and baseline morbidity, 80% of patients did not experience a FACE during the mean 3.9 years of migalastat exposure. The incidence of renal, cardiac, and cerebrovascular events was 2.0, 83.2, and 4.1 events per 1000 patient-years, respectively. These data support a role of migalastat in preserving renal function and multisystem effectiveness during ≥3 years of migalastat treatment in this real-world Fabry population.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The therapeutic landscape of citrin deficiency","authors":"Toni Vuković,&nbsp;Li Eon Kuek,&nbsp;Barbara Yu,&nbsp;Georgios Makris,&nbsp;Johannes Häberle","doi":"10.1002/jimd.12768","DOIUrl":"10.1002/jimd.12768","url":null,"abstract":"<p>Citrin deficiency (CD) is a recessive, liver disease caused by sequence variants in the <i>SLC25A13</i> gene encoding a mitochondrial aspartate–glutamate transporter. CD manifests as different age-dependent phenotypes and affects crucial hepatic metabolic pathways including malate–aspartate-shuttle, glycolysis, gluconeogenesis, de novo lipogenesis and the tricarboxylic acid and urea cycles. Although the exact pathophysiology of CD remains unclear, impaired use of glucose and fatty acids as energy sources due to NADH shuttle defects and PPARα downregulation, respectively, indicates evident energy deficit in CD hepatocytes. The present review summarizes current trends on available and potential treatments for CD. Baseline recommendation for CD patients is dietary management, often already present as a self-selected food preference, that includes protein and fat-rich food, and avoidance of excess carbohydrates. At present, liver transplantation remains the sole curative option for severe CD cases. Our extensive literature review indicated medium-chain triglycerides (MCT) as the most widely used CD treatment in all age groups. MCT can effectively improve symptoms across disease phenotypes by rapidly supplying energy to the liver, restoring redox balance and inducing lipogenesis. In contrast, sodium pyruvate restored glycolysis and displayed initial preclinical promise, with however limited efficacy in adult CD patients. Ursodeoxycholic acid, nitrogen scavengers and <span>L</span>-arginine treatments effectively address specific pathophysiological aspects such as cholestasis and hyperammonemia and are commonly administered in combination with other drugs. Finally, future possibilities including restoring redox balance, amino acid supplementation, enhancing bioenergetics, improving ureagenesis and mRNA/DNA-based gene therapy are also discussed.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1157-1174"},"PeriodicalIF":4.2,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12768","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}