JIMD reports最新文献

{"title":"Screening and surveillance of hepatocellular carcinoma by serum des-gamma-carboxy prothrombin in patients with glycogen storage disease type Ia","authors":"A. B. Schreuder,&nbsp;R. J. Overduin,&nbsp;N. C. Peltenburg,&nbsp;L. de Boer,&nbsp;F. A. J. A. Bodewes,&nbsp;T. G. J. Derks","doi":"10.1002/jmd2.12414","DOIUrl":"https://doi.org/10.1002/jmd2.12414","url":null,"abstract":"<p>No sensitive tumor marker for hepatocellular carcinoma (HCC) is available for patients with glycogen storage disease type Ia (GSDIa), in whom alpha-fetoprotein and carcino-embryonic antigen levels often remain normal. We describe increased levels of the HCC tumor marker des-gamma-carboxy prothrombin (DCP) in GSDIa patients with HCC. In one case DCP levels normalized after liver transplantation. We recommend including DCP as a screening HCC tumor marker in the surveillance of patients with GSDIa.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 4","pages":"207-211"},"PeriodicalIF":0.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12414","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536970","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":"The phenotypic spectrum of PTCD3 deficiency","authors":"Baiba Lace,&nbsp;Eissa Faqeih,&nbsp;Namik Kaya,&nbsp;Zita Krumina,&nbsp;Johannes A. Mayr,&nbsp;Ieva Micule,&nbsp;Nathan Thompson Wright,&nbsp;Melanie T. Achleitner,&nbsp;Hanan AlQudairy,&nbsp;Sander Pajusalu,&nbsp;Janis Stavusis,&nbsp;Pawel Zayakin,&nbsp;Inna Inashkina","doi":"10.1002/jmd2.12424","DOIUrl":"https://doi.org/10.1002/jmd2.12424","url":null,"abstract":"<p>The <i>PTCD3</i> gene product (protein PTCD3 or MRPS39) forms the entry channel of the mitochondrial small ribosomal subunit and binds to single-stranded mRNA. Here, we expand on the clinical manifestations of <i>PTCD3</i> pathogenic variants by describing an early-onset patient with Leigh-like syndrome and two patients with milder form of disease, with combined oxidative phosphorylation deficiency. A 34-year-old male and his 33-year-old sister both have horizontal nystagmus, pronounced rough tremor, truncal ataxia, dysmetria, spasticity and hyperreflexia. The basal respiration rate decreased significantly for the male patient and his mother (<i>p</i> &lt; 0.0001) compared to the controls. The whole genome sequencing analysis revealed two heterozygous variants in the <i>PTCD3</i>: c.1182T&gt;A, p.(Tyr394Ter) and c.805C&gt;T, p.(His269Tyr). Tyr394Ter variant ablates the C-terminal half of the protein, including a significant portion of the central fold. In silico modelling for the variant His269Tyr shows that the inclusion of the slightly larger tyrosine sidechain is well tolerated, with no significant change in either the position or the movement of the surrounding area. The third case is a 9-year-old boy, who has a global developmental delay, central hypotonia, hyperreflexia and abnormal MRI. <i>PTCD3</i> pathogenic variant c.538+4A&gt;G was identified by whole exome sequencing. To test the variant's effect on splicing, an RT-PCR experiment was performed, which revealed skipping of an out-of-frame exon 7.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 5","pages":"297-304"},"PeriodicalIF":0.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12424","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165785","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":"The neuronal ceroid lipofuscinosis type 2 – associated variants: An analysis of alterations in the TPP1 gene and genotype–phenotype correlation in Ukraine","authors":"Nataliia Olkhovych,&nbsp;Nataliia Pichkur,&nbsp;Nataliia Mytsyk,&nbsp;Rodolfo Tonin,&nbsp;Svitlana Kormoz,&nbsp;Iryna Hregul,&nbsp;Nataliia Samonenko,&nbsp;Tetiana Shklyarskaya,&nbsp;Volodymyr Olkhovych,&nbsp;Olexandr Buryak,&nbsp;Amelia Morrone,&nbsp;Nataliia Gorovenko","doi":"10.1002/jmd2.12423","DOIUrl":"10.1002/jmd2.12423","url":null,"abstract":"<p>The neuronal ceroid lipofuscinosis type 2 (CLN2) is a heterogeneous group of neurodegenerative lysosomal storage disorders caused by autosomal recessive inheritance of two pathogenic variants in trans in the <i>TPP1</i> gene. Classical late-infantile CLN2 disease has a very well-defined natural history. However, a small number of patients with TPP1 enzyme deficiency present a later onset or protracted disease course within this group there are phenotypic variants. Our work aimed to identify pathological variants in the <i>TPP1</i> gene that conditioned the development of CLN2 disease in Ukrainian patients, to compare these variants with those found in patients from other European and non-European regions, and to make genotype–phenotype associations for this disease. The phenotypes and genotypes of the 48 CLN2-affected individuals belonging to 43 families were profiled through clinical data collection, enzyme analysis, and genotyping. In most patients, genotype and phenotype correlation are in keeping with the data of previous studies. The clinical signs of the disease in patients with new, previously undescribed variants, allowed us to augment existing data about genotype–phenotype correlations for CLN2 disease. The combination of genotype and clinical form of the disease demonstrated that predicting the type and clinical course of the disease based on genotype is very complicated. The data we obtained supplements existing information on genotype–phenotypic correlations in this rare disease, which, in turn, lays the foundation for a personalized approach to the management of this disease.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 4","pages":"272-279"},"PeriodicalIF":0.0,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12423","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140981000","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":"Transient response to high-dose niacin therapy in a patient with NAXE deficiency","authors":"Fatema Al-Amrani,&nbsp;Khalid Al-Thihli,&nbsp;Eiman Al-Ajmi,&nbsp;Amna Al-Futaisi,&nbsp;Fathiya Al-Murshedi","doi":"10.1002/jmd2.12425","DOIUrl":"10.1002/jmd2.12425","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>NAXE-encephalopathy or early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL-1) and NAXD-encephalopathy (PEBEL-2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood. Anecdotal reports suggest that niacin, through its role in nicotinamide adenine dinucleotinde (NAD) de novo synthesis, corrects biochemical derangement, and slows down disease progression. Reports so far have supported this observation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We describe a patient with a confirmed PEBEL-1 diagnosis and report his clinical response to niacin therapy. Moreover, we systematically searched the literature for PEBEL-1 and PEBEL-2 patients treated with niacin and details about response to treatment and clinical data were reviewed. Furthermore, we are describing off-label use of a COX2 inhibitor to treat niacin-related urticaria in NAXE-encephalopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>So far, seven patients with PEBEL-1 and PEBEL-2 treated with niacin were reported, and all patients showed a good response for therapy or stabilization of symptoms. We report a patient exhibiting PEBEL-1 with an unfavorable outcome despite showing initial stabilization and receiving the highest dose of niacin reported to date. Niacin therapy failed to halt disease progression or attain stabilization of the disease in this patient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Despite previous positive results for niacin supplementation in patients with PEBEL-1 and PEBEL-2, this is the first report of a patient with PEBEL-1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 4","pages":"212-225"},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12425","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140995868","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":"A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency","authors":"Khalid Al-Thihli,&nbsp;Nadia Al Hashmi,&nbsp;Aaisha Al Balushi,&nbsp;Asila Al-Habsi,&nbsp;Eiman Al-Ajmi,&nbsp;Fatma Al-Jasmi,&nbsp;Fathiya Al-Murshedi","doi":"10.1002/jmd2.12426","DOIUrl":"10.1002/jmd2.12426","url":null,"abstract":"<p>Carbonic anhydrase VA (CA-VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in <i>CA5A.</i> Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA-VA deficiency caused by homozygosity for a founder mutation, c.59G&gt;A p.(Trp20*) in <i>CA5A</i>. The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features. Two adult patients were asymptomatic, 7/18 patients had recurrent hyperammonemia, 7/18 patients developed variable degree of developmental delay, 9/11 patients had hyperCKemia, and 7/18 patients had failure to thrive. Microcephaly was seen in three patients and one patient developed a metabolic stroke. The same variant had been reported already in a single South Asian patient presenting with neonatal hyperammonemic encephalopathy and subsequent development of seizures and developmental delay. This report highlights the limitations of current understanding of the pathomechanisms involved in this disorder, and calls for further evaluation of the possible role of genetic modifiers in this condition.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 4","pages":"226-232"},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12426","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140998044","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":"Elevated homocysteine is negatively correlated with plasma cystathionine β-synthase activity in givosiran-treated patients","authors":"Mark A. Keibler,&nbsp;Gautham V. Sridharan,&nbsp;Marianne T. Sweetser,&nbsp;Simina Ticau","doi":"10.1002/jmd2.12416","DOIUrl":"https://doi.org/10.1002/jmd2.12416","url":null,"abstract":"<p>Givosiran is a subcutaneously administered, liver-targeted RNA interference (RNAi) therapeutic that has been approved for treating acute hepatic porphyria (AHP). Elevation in plasma homocysteine (hyperhomocysteinemia) has been reported in AHP patients, and treatment with givosiran has been reported to further increase homocysteine levels in some patients. The mechanism of homocysteine elevation during givosiran treatment is unknown, but has been hypothesized to be mediated by a reduction in activity of cystathionine β-synthase (CBS), which uses homocysteine as a substrate. A liquid chromatography-tandem mass spectrometry-based assay was adapted to measure circulating CBS activity. Using plasma collected from the Phase III ENVISION study, CBS activity was measured to directly evaluate whether it is associated with elevated homocysteine levels in givosiran-treated patients. CBS activity was reduced following givosiran treatment and both homocysteine and methionine levels were inversely correlated with CBS activity. Following administration of a supplement containing vitamin B₆, a cofactor for CBS, in four patients during the trial, plasma CBS activity was found to increase, mirroring a corresponding decrease in homocysteine levels. These results support the hypothesis that elevated homocysteine levels following givosiran treatment result from a reduction of CBS activity and that vitamin B₆ supplementation lowers homocysteine levels by increasing CBS activity.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 4","pages":"262-271"},"PeriodicalIF":0.0,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12416","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536871","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":"Enasidenib-induced hepatitis in an individual with Type II D2-hydroxyglutaric aciduria","authors":"Jessica I. Gold,&nbsp;Arianna K. Stefanatos,&nbsp;Jamie L. Fraser,&nbsp;Adeline Vanderver,&nbsp;Sanmati Cuddapah","doi":"10.1002/jmd2.12421","DOIUrl":"10.1002/jmd2.12421","url":null,"abstract":"<p>Type II D-2-Hydroxyglutaric aciduria (T2D2HGA) is caused by a gain-of-function pathogenic variant in Isocitrate Dehydrogenase 2 (IDH2). Patients with T2D2HGA commonly present with developmental delay, seizures, cardiomyopathy, and arrhythmias. The recently approved IDH2-inhibitor Enasidenib targets the p.Arg140Gln pathogenic <i>IDH2</i> variant and decreases production of D2HGA. We present a 7-year-old female with T2D2HGA due to the p.Arg140Gln variant. She was diagnosed at 3-years-old after presenting with global developmental delay, leukoencephalopathy, communicating hydrocephalus, seizures, and dilated cardiomyopathy. At age 3 years 11 months, 50 mg Enasidenib daily was initiated. Primary outcomes included seizure frequency, hospital admissions, development, and cardiac structure. Laboratories were monitored biweekly for common Enasidenib side effects. Our patient tolerated Enasidenib well. Urine 2-HGA decreased significantly from 244 mg/g creatinine to undetectable within 2 weeks of treatment. Inpatient admissions decreased from 8 during the 2 years preceding treatment to 1 during treatment. She has been seizure-free since Enasidenib initiation. Echocardiography showed improvement in dilated cardiomyopathy with normal left ventricular systolic function. Developmental assessment demonstrated improvements in gross motor, fine motor, language, and socialization domains. Treatment was complicated by mild elevations in alanine transaminase (118 IU/L, range 0–28) and creatine kinase (334 U/L, range 45–198) that resolved by decreasing Enasidenib dosing frequency to three times weekly. Enasidenib is a viable treatment for Type II D2HGA with benefits including developmental gains, fewer acute medical interventions, and cardiomyopathy improvement. While drug-induced hepatitis is a novel adverse effect of Enasidenib, it can be ameliorated by decreasing dose frequency.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 3","pages":"156-162"},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140695457","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":"Normal transferrin glycosylation does not rule out severe ALG1 deficiency","authors":"Inez Bosnyak,&nbsp;Mustafa Sadek,&nbsp;Wasantha Ranatunga,&nbsp;Tamas Kozicz,&nbsp;Eva Morava","doi":"10.1002/jmd2.12415","DOIUrl":"10.1002/jmd2.12415","url":null,"abstract":"<p>ALG1-CDG is a rare, clinically variable metabolic disease, caused by the defect of adding the first mannose (Man) to N-acetylglucosamine (GlcNAc₂)-pyrophosphate (PP)-dolichol to the growing oligosaccharide chain, resulting in impaired N-glycosylation of proteins. N-glycosylation has a key role in functionality, stability, and half-life of most proteins. Therefore, congenital defects of glycosylation typically are multisystem disorders. Here we report a 3-year-old patient with severe neurological, cardiovascular, respiratory, musculoskeletal and gastrointestinal symptoms. ALG1-CDG was suggested based on exome sequencing and Western blot analysis. Despite her severe clinical manifestations and genetic diagnosis, serum transferrin glycoform analysis was normal. Western blot analysis of highly glycosylated proteins in fibroblasts revealed decreased intercellular adhesion molecule 1 (ICAM1), but normal lysosomal associated membrane protein 1 and 2 (LAMP1 and LAMP2) expression levels. Glycoproteomics in fibroblasts showed the presence of the abnormal tetrasacharide. Reviewing the literature, we found 86 reported ALG1-CDG patients, but only one with normal transferrin analysis. Based on our results we would like to highlight the importance of multiple approaches in diagnosing ALG1-CDG, as normal serum transferrin glycosylation or other biomarkers with normal expression levels can occur.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 3","pages":"135-143"},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12415","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140698118","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":"Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?","authors":"Alexandre Nguyen,&nbsp;Samuel Deshayes,&nbsp;Marie Nowoczyn,&nbsp;Apolline Imbard,&nbsp;Lamisse Mansour-Hendili,&nbsp;Alexandre Cesbron,&nbsp;Jean François Benoist,&nbsp;Manuel Schiff","doi":"10.1002/jmd2.12422","DOIUrl":"10.1002/jmd2.12422","url":null,"abstract":"<p>Methionine synthase reductase deficiency (cblE) is a rare autosomal recessive inborn error of cobalamin metabolism caused by pathogenic variants in the methionine synthase reductase gene (<i>MTRR</i>). Patients usually exhibit early-onset bone marrow failure with pancytopenia including megaloblastic anemia. The latter can remain isolated or patients may present developmental delay and rarely macular dysfunction. Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation. We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH &gt;11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by hydroxocobalamin dose escalation. There was no obvious trigger apart from a parvovirus B19 infection in one of the patients. This is the first report of such complications in adulthood. The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage. Bone marrow infection with parvovirus B19 can complicate this genetic disease with erythroblastopenia even in the absence of an immunocompromised status, as in other congenital hemolytic anemias. The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 3","pages":"163-170"},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12422","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140701259","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":"Computational structural genomics and clinical evidence suggest BCKDK gain-of-function may cause a potentially asymptomatic maple syrup urine disease phenotype","authors":"Emily Singh,&nbsp;Young-In Chi,&nbsp;Jessica Kopesky,&nbsp;Michael Zimmerman,&nbsp;Raul Urrutia,&nbsp;Donald Basel,&nbsp;Jessica Scott Schwoerer","doi":"10.1002/jmd2.12419","DOIUrl":"10.1002/jmd2.12419","url":null,"abstract":"<p>Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acid metabolism caused by a defect in the branched-chain α-ketoacid dehydrogenase (BCKD) complex (OMIM #248600). The hallmark presentation is encephalopathic crisis in neonates, but can also present with metabolic decompensation, developmental delays, and feeding difficulties. Biochemical evidence for MSUD includes elevated branched-chain amino acids (BCAA) and the pathognomonic presence of alloisoleucine. The BCKD complex contains several subunits associated with autosomal recessive MSUD, while its regulatory proteins have less well-defined disease associations. We report on two families with the same <i>BCKDK</i> variant (c.1115C&gt;G (p.Thr372Arg)). Probands were detected on newborn screening and demonstrated biochemical evidence of MSUD. The variant was identified in reportedly asymptomatic parents and additional family members who had elevated BCAA and alloisoleucine, following an autosomal dominant pattern of inheritance. To better define the functional effect of the variant on the kinase, we completed molecular modeling using sequence-based (2D), structural-based (3D), and dynamic-based (4D) analyses. The <i>BCKDK</i> variant modeling indicated a gain-of-function which leads to impaired BCAA catabolism consistent with the biochemical evidence in this cohort. Combining the evidence gained from molecular modeling with the absence of metabolic decompensation in our patients and several adult family members, despite encountering stressors typically problematic in classic MSUD, we suggest that heterozygous gain-of-function variants in <i>BCKDK</i> may represent a novel biochemical phenotype of MSUD with a benign clinical course.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"65 3","pages":"144-155"},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.12419","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140731819","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}