JIMD reports最新文献

{"title":"Benefits of Integrated Social Care in the Management of Patients With Inborn Errors of Metabolism","authors":"A. Selvanathan,&nbsp;S. Nazir,&nbsp;K. van Wyk,&nbsp;E. Simpson,&nbsp;V. Holmes,&nbsp;R. Hutton,&nbsp;F. White,&nbsp;B. C. Schwahn","doi":"10.1002/jmd2.70023","DOIUrl":"https://doi.org/10.1002/jmd2.70023","url":null,"abstract":"<p>The current cornerstone of the management of many small-molecule inborn errors of metabolism (IEMs) is a combination of dietary therapy and medication, with evidence for improved clinical outcomes. However, the burden imposed on patients and families is substantial. Many families also have to manage this burden in conjunction with other medical, psychosocial, and financial stressors. Adherence to the recommended treatment can therefore be extremely challenging, sometimes leading to sustained derangement of biochemical parameters and/or clinical deterioration. The treating team needs to work with the family to determine an individualized optimal management strategy, with targets that can be pragmatically achieved. This paper focusses on the role of social care in assisting patients with a range of different small-molecule IEMs, as well as their families and the medical team. We provide six case vignettes that illustrate how social care involvement, in addition to enhanced psychosocial support from the clinical team, resulted in improved outcomes. This included assisting with adjustment to a new diagnosis, exploring and addressing barriers to treatment adherence, and provision of ‘early help’ community supports. In some instances where this was not sufficient and risk of harm to the child was considered significant, social care involvement facilitated graded escalation from a “child in need” approach to formal child protection measures. We identified challenges in engaging social workers external to the metabolic team. This included a need for greater education about the medical condition and the risks associated with undertreatment, lack of protected time for metabolic case management, and a lack of preventative involvement of social workers during the initial hospitalization (impacting on patient rapport). We advocate for the integration of social care within the metabolic team as part of a more holistic model of care.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atypical Presentation of IARS1-Related Disorder: Expanding the Phenotype and Genotype","authors":"Parith Wongkittichote,&nbsp;Kira E. Jonatzke,&nbsp;Benjamin T. Hyde,&nbsp;Lance W. Peterson,&nbsp;Mai He,&nbsp;Robert C. McKinstry,&nbsp;Anthony Antonellis,&nbsp;Marwan Shinawi","doi":"10.1002/jmd2.70020","DOIUrl":"https://doi.org/10.1002/jmd2.70020","url":null,"abstract":"<p>Aminoacyl-tRNA synthetases (ARSs) catalyze the formation of aminoacyl-tRNA, which is required for protein translation. A growing number of cases are associated with ARS deficiencies. Pathogenic variants in <i>IARS1</i> (MIM# 600709), encoding cytoplasmic isoleucyl-tRNA synthetase, have been associated with autosomal recessive growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH, OMIM# 617093). To date, 11 GRIDHH patients have been described. We identified a patient who presented with recurrent episodes of liver failure in the setting of preceding infection and neurocognitive delay, and who recently presented with a clinical picture consistent with chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis. Exome sequencing revealed that this patient is compound heterozygous for two <i>IARS1</i> variants: c.1193dupC;p.(Cys400LeufsTer32) and c.746A&gt;G;p.(Asp249Gly). The frameshift variant is predicted to cause a loss of function, and functional analysis of the p.Asp249Gly variant was performed using baker's yeast. Wild-type human <i>IARS1</i> has been shown to support robust yeast growth in the absence of the yeast ortholog, <i>ILS</i>, while human <i>IARS1</i> harboring p.Asp249Gly could not, indicating a loss-of-function effect. The proband was treated with isoleucine supplementation with subjective clinical improvement. Overall, we expand the molecular and clinical spectra of the <i>IARS1</i>-related disorder, highlight immune dysregulation as a possible novel manifestation of this disorder, and emphasize the utility of a yeast model system for functional studies. A larger cohort of patients is required to validate these observations and evaluate the efficacy of isoleucine supplementation for patients with GRIDHH.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atypical MEGDHEL Syndrome: A Milder Phenotype With Hepatic Presentation and Failure to Thrive Associated With a Homozygous Nonsense Variant of SERAC1","authors":"Rita Marchante Pita,&nbsp;Raquel Amaral,&nbsp;Laura Vilarinho,&nbsp;Luísa Diogo,&nbsp;Isabel Gonçalves,&nbsp;Susana Nobre","doi":"10.1002/jmd2.70017","DOIUrl":"https://doi.org/10.1002/jmd2.70017","url":null,"abstract":"<p>MEGDHEL syndrome, caused by a <i>SERAC1</i> gene defect, is clinically defined as the association of 3-MGA-uria (MEG), deafness (D), hepatopathy (H), encephalopathy (E), and Leigh-like features (L). Clinical presentation typically begins in the neonatal period, with neurological symptoms becoming more evident by 2 years of age. Severe liver involvement has also been reported. We report the case of a 3-year-old boy with increased transaminases and failure to thrive of unknown cause. He was born prematurely at 35 weeks and needed neonatal intensive care support for 24 h due to transient tachypnea. At 18 months, laboratory investigations for failure to thrive revealed elevated transaminases without cholestasis, which persisted on subsequent evaluations. Abdominal wall collateral veins were found during physical examination, and the liver ultrasound revealed steatosis, prompting the decision to proceed with a liver biopsy. Common causes of chronic liver disease were ruled out. Following liver biopsy, performed under general anesthesia, he had an episode of unexplained decompensation (metabolic acidosis, hyperlactatemia, and 3-methylglutaconic aciduria). The aciduria persisted upon subsequent evaluation. Liver histology showed macro/microvesicular steatosis (25%), portal tract inflammation, and mild fibrosis. Cardiac evaluation, along with brain magnetic resonance imaging and spectroscopy, was normal. Further investigations revealed decreased hepatic activity of respiratory mitochondrial chain complexes and marginal mtDNA depletion (28.1%). Analysis of the <i>SERAC1</i> gene showed homozygosity for p.Y259* (c.777T&gt;G, exon 9). This case report raises awareness for an atypical presentation of MEGDHEL syndrome associated with a homozygous nonsense variant of SERAC1 clinically characterized by mild hypertransaminasemia, failure to thrive, no neurological involvement, and starting in early childhood rather than infancy.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successful Pregnancy Management of a Woman With Severe Methylmalonic Acidemia","authors":"M. Woidy,&nbsp;K. Tsiakas,&nbsp;M. Mahmud,&nbsp;G. Eich,&nbsp;S. Loos,&nbsp;J. Lisfeld,&nbsp;S. Schultz,&nbsp;A. C. Tallarek,&nbsp;K. Hecher,&nbsp;T. B. Huber,&nbsp;A. C. Muntau,&nbsp;G. Gramer","doi":"10.1002/jmd2.70009","DOIUrl":"https://doi.org/10.1002/jmd2.70009","url":null,"abstract":"<p>Isolated methylmalonic acidemia (MMA) is a rare, genetically heterogeneous group of metabolic disorders resulting from a deficiency of the enzyme methylmalonyl-CoA mutase (MMUT), defects in the metabolism of its cofactor, adenosylcobalamin, or deficiency of the enzyme methylmalonyl-CoA epimerase. With improved awareness, earlier diagnosis, and advances in care, women with MMA are increasingly reaching childbearing age, and successful pregnancies have been documented in patients with milder forms of the disease. This report details, for the first time, the management and outcomes of pregnancy in a woman with severe mut⁰ deficiency and concomitant advanced chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD) requiring initiation of hemodialysis at 21 weeks' gestation. At 20 weeks, fetal ultrasound revealed fetal growth restriction (FGR), necessitating close monitoring and dietary adjustments to meet the patient's increased nutritional needs. Despite these challenges, she remained metabolically stable until delivery. At 35 weeks, she delivered a 1.64 kg male SGA newborn via cesarean section. The newborn presented with mild retrognathia, a soft palate cleft, mild hypospadias, mild ventriculomegaly, and hypoplasia of the corpus callosum and cerebellum without the need for immediate intervention. The mother experienced a mild metabolic decompensation on the fifth postpartum day, which was promptly managed by additional renal replacement therapy. At 3 months postpartum, both mother and child were doing well, with no further metabolic complications observed. This case report demonstrates that pregnancy in patients with severe mut⁰ deficiency is challenging and requires a close interdisciplinary management but can be carried out with a favorable outcome.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orthotopic Liver Transplantation in a Patient With GALT p.Ser135Leu/Null","authors":"Kara Simpson,&nbsp;Erin L. MacLeod,&nbsp;Julia Clayton,&nbsp;Nada A. Yazigi,&nbsp;M. Estela Rubio-Gozalbo,&nbsp;Judith L. Fridovich-Keil,&nbsp;Gerard T. Berry,&nbsp;Nicholas Ah Mew","doi":"10.1002/jmd2.70016","DOIUrl":"https://doi.org/10.1002/jmd2.70016","url":null,"abstract":"<p>We report the case of a now 12-year-old male compound heterozygous for a novel <i>GALT</i> null variant and the p.Ser135Leu variant, associated with clinical variant galactosemia. This patient presented with fulminant liver failure at age 2 months requiring liver transplant. Despite initial detection by newborn screening, a misinterpretation of results led to delayed diagnosis and treatment. While the p.Ser135Leu <i>GALT</i> variant is often associated with a milder long-term phenotype, this case highlights that newborns compound heterozygous for p.Ser135Leu and a null variant are at risk of end-stage liver disease if not immediately switched to a low-galactose diet. Surprisingly, despite the transplant with an ostensibly normal liver and continued dietary galactose restriction, this patient continues to show mildly elevated RBC Gal-1-P and urine galactitol.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutrition With Skimmed Breast Milk in an Infant With Long Chain 3-Hydroxyacyl-coA Dehydrogenase Deficiency","authors":"Clara Alonso-Diaz,&nbsp;Diana Escuder-Vieco,&nbsp;Pilar Quijada-Fraile,&nbsp;Delia Barrio-Carreras,&nbsp;Patricia Pérez-Mohand,&nbsp;Elena Martín-Hernández,&nbsp;Carmen Rosa Pallas-Alonso,&nbsp;Nadia Raquel García-Lara","doi":"10.1002/jmd2.70018","DOIUrl":"https://doi.org/10.1002/jmd2.70018","url":null,"abstract":"<p>The current standard diet for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the first months of life includes a special formula low in long-chain triglycerides (LCT) and enriched in medium-chain triglycerides (MCT). It involves the interruption of breastfeeding, withholding its nutritional and nonnutritional benefits. We describe the clinical case of a late preterm with 36 weeks gestational age diagnosed with LCHADD through newborn screening (NBS) who developed necrotizing enterocolitis (NEC) and sepsis due to <i>Escherichia coli</i> (<i>E. coli</i>) at 7 days of life. During hospital admission, the patient was fed skimmed breast milk supplemented with MCT oil and a low-fat MCT-enriched formula. Because the family wished to continue pumping milk after discharge, they were trained to defat milk using a non-refrigerated benchtop centrifuge. At home, a similar feeding regime was followed for 4 months. Hospital and home-produced skimmed breast milk met the dietary treatment requirement of &lt; 1.0 g/dL of fat content. Growth and development during the first 5 months of life were normal, with an improved serum acylcarnitine profile and no decompensation. In this report, we demonstrated that breast milk defatting is a safe and feasible option for patients with LCHADD during hospital admission and at home, providing the benefits of human milk in these patients. This approach could influence dietary management guidelines for metabolic disorders or expand breast milk feeding options for medically complex infants.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mental and Physical Health in Wilson Disease Patients With SARS-CoV-2 Infection and Relevance of Long-COVID","authors":"Isabelle Mohr,&nbsp;Maximilian Brand,&nbsp;Christophe Weber,&nbsp;Andrea Langel,&nbsp;Jessica Langel,&nbsp;Patrick Michl,&nbsp;Viola Yuriko Leidner,&nbsp;Alexander Olkus,&nbsp;Sebastian Köhrer,&nbsp;Uta Merle","doi":"10.1002/jmd2.70021","DOIUrl":"https://doi.org/10.1002/jmd2.70021","url":null,"abstract":"<p>SARS-CoV-2 infection and Long COVID (LC) might lead to a significant deterioration of physical and mental health. Wilson disease (WD) patients have a chronic liver and/or neuropsychiatric disease, making it particularly interesting to investigate LC in WD. 51 WD patients were retrospectively examined, evaluating physical and mental health by a survey and neuropsychological tests (SF-12, PSQI, ISI, Epworth, Chalder-fatigue scale, PHQ-9, GAD-7, PSS, FLei) before and ~11 months after SARS-CoV-2 infection. LC was defined as the development of new, at least moderately severe symptoms (shortness of breath, chest pain, fatigue, brain fog, exercise capacity, concentration disturbances) and/or worsening of pre-existing symptoms. 70.6% had predominant hepatic and 29.4% had neuropsychiatric symptoms at WD diagnosis. Median age was 39 years; 56.1% were female. Patients were in stable maintenance phase with a median treatment duration of 23 years. When compared to before COVID-19, WD patients had significantly worse physical life quality, sleeping quality, and fatigue. After COVID-19, a high percentage of WD patients reported concentration disorders (60%), fatigue (55%), reduced exercise capacity (50%), shortness of breath (40%), chest pain (20%) and feeling of brain fog (15%). 39.2% (<i>n</i> = 20) of the WD patients were classified as LC. This LC-WD subgroup showed significantly impaired quality of life, a high stress level, and sleeping disturbances, fatigue, depression, anxiety, and cognitive impairment. A large proportion of WD patients experience LC symptoms, reduced life quality, and sleeping disorders after SARS-CoV-2 infection. WD patients post-infection should be well monitored and supported if they develop persisting symptoms or neuro-psychological problems.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment and Improved Outcomes of Three Adult Patients With Guanidinoacetate Methyltransferase (GAMT) Deficiency","authors":"Angela Lee,&nbsp;Judith Weisenberg,&nbsp;Elizabeth Toolan,&nbsp;Marwan Shinawi","doi":"10.1002/jmd2.70019","DOIUrl":"https://doi.org/10.1002/jmd2.70019","url":null,"abstract":"<p>Guanidinoacetate methyltransferase (GAMT) deficiency is a creatine synthesis disorder caused by biallelic pathogenic variants in <i>GAMT</i>. Early diagnosis and treatment can lead to normal neurocognitive outcomes, which has prompted its recent addition to the Recommended Uniform Screening Panel. Treatment typically includes creatine and ornithine supplementation, with or without arginine restriction or sodium benzoate. Here, we present the clinical outcomes of 3 adult patients with GAMT deficiency who began creatine and ornithine supplementation at varying ages. One patient started on treatment at 14 months of age and has had near-normal neurocognitive outcomes, highlighting the positive clinical impact of early treatment. Our findings also emphasize the need to continue treatment throughout adulthood, but further research is required to understand the natural history and determine the optimal treatment of GAMT deficiency in adults.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-Reported Liver Disease and the Burden of Erythropoietic Protoporphyria","authors":"Hetanshi Naik,&nbsp;Kristen Wheeden,&nbsp;Hilary H. Colwell,&nbsp;Susan D. Mathias,&nbsp;Chelsea Norregaard,&nbsp;Melanie Chin,&nbsp;William Savage,&nbsp;Manisha Balwani","doi":"10.1002/jmd2.70015","DOIUrl":"https://doi.org/10.1002/jmd2.70015","url":null,"abstract":"<p>Erythropoietic protoporphyria (EPP) and X-linked protoporphyria are metabolic disorders that cause skin phototoxicity and potential liver damage. We compared symptoms and impacts of phototoxic reactions, health-related quality of life, and healthcare utilization (HCU) between individuals with and without self-reported liver disease (elevated liver enzymes or liver fibrosis) using an online questionnaire containing validated patient-reported outcome measures and original items. Among 164 participants, 15.2% self-reported liver disease. Sixty-four percent of those with liver disease rated their general health “much worse” than those without EPP, versus 35% of those without liver disease. Those with liver disease had a higher frequency of prodromal symptoms and more frequently reported that their most recent phototoxic reaction impacted their ability to perform daily activities (76% versus 55% for those without liver disease) and resulted in difficulty in doing chores (88% versus 60%) or going for a walk, run, or bike ride (84% versus 60%). A higher percentage of those with liver disease reported feeling anxious (92% versus 78%), isolated (100% versus 80%), and lonely (96% versus 72%) than those without liver disease. The mean number of hours missed from work and school in the past month was higher for those with liver disease (work: 10.9 h; school: 7.7 h) than those without liver disease (3.6 h for both). EPP-related HCU in the previous 12 months was higher for those with liver disease than those without liver disease, including more physician visits (mean of 16.5 versus 6.0) and emergency room visits (mean of 9.0 versus 1.9).</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neonatal Cholestasis Progressing to a Multisystem Syndrome With Liver Cirrhosis in Two Siblings With FARSA Deficiency: An Evolving Hepatological Phenotype","authors":"Y. Aelvoet,&nbsp;P. Verloo,&nbsp;A. Vanlander,&nbsp;S. Vande Velde,&nbsp;S. Van Biervliet,&nbsp;P. De Bruyne,&nbsp;L. Hoste,&nbsp;A. Dheedene,&nbsp;L. Pottie,&nbsp;A. Hoorens,&nbsp;M. Mendes,&nbsp;R. De Bruyne","doi":"10.1002/jmd2.70013","DOIUrl":"https://doi.org/10.1002/jmd2.70013","url":null,"abstract":"<p>Biallelic variants in <i>FARSA</i> or <i>FARSB</i> are associated with reduced cytoplasmic phenylalanyl-tRNA synthetase (FARS1) activity and underlie a multisystem syndrome characterized by growth limitation, developmental delay, brain calcifications, interstitial lung disease (ILD), and liver involvement. ILD is an early characteristic feature marked by bilateral ground-glass opacification, subpleural cysts, and cholesterol pneumonitis and seems to be the leading cause of disease burden and death. A 7-year-old Iraqi girl was referred with idiopathic liver disease. Her previous medical history revealed neonatal jaundice, failure to thrive (FTT), mild motor development delay, and variceal bleeding at the age of 6 years in Iraq. She was diagnosed with liver cirrhosis, severe splenomegaly, profound thrombocytopenia, and hypoalbuminemia. Her younger brother presented to our hospital at the age of 2 months with neonatal cholestasis progressing to hepatic failure with impaired synthetic function. He suffered from coagulopathy, intractable hypoalbuminemia, FTT with axial hypotonia, multiple infectious episodes, and a prothrombotic state. Whole exome sequencing revealed compound heterozygous missense variants p.(Pro226Leu) and p.(Arg475Trp) in <i>FARSA</i> (OMIM: 602918) in both siblings. Even in the absence of overt clinical symptoms, chest computer tomography following diagnosis showed ILD in both siblings. Decreased FARS1 activity was measured in fibroblasts of both patients. We are the first to report on two siblings with neonatal jaundice evolving to severe liver disease as a cardinal symptom of cytosolic FARS deficiency. We emphasize the importance of performing a pulmonary workup in the diagnostic process of liver failure of unknown origin for detection of ILD as a clue to diagnosis.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}