Molecular Genetics and Metabolism Reports最新文献

{"title":"Integrating enzyme assay and molecular genetic testing for early diagnosis of infantile-onset Pompe disease: A case report","authors":"Anuradha Sharma,&nbsp;Minakshi Vashist,&nbsp;Rohit Kaushik,&nbsp;Gulshan Rohilla,&nbsp;Sonia Narwal","doi":"10.1016/j.ymgmr.2025.101283","DOIUrl":"10.1016/j.ymgmr.2025.101283","url":null,"abstract":"<div><h3>Background</h3><div>Infantile-onset Pompe disease is a severe lysosomal storage disorder caused by biallelic pathogenic variants in <strong><em>GAA</em></strong>, leading to deficient acid α-glucosidase activity.</div></div><div><h3>Case</h3><div>We report a 6-month-old South Indian male with recurrent respiratory infections, feeding difficulty, generalized hypotonia, and delayed motor milestones. <strong>Dried blood spot</strong>(DBS) enzyme assay demonstrated markedly reduced acid α-glucosidase activity, and molecular testing identified a homozygous pathogenic variant in <strong><em>GAA</em></strong> (c.2560C &gt; T; p.Arg854*). Parental segregation testing confirmed both parents as heterozygous carriers. Serum creatine phosphokinase was 853 U/L. A cardiac evaluation was recommended but not completed at the time of initial assessment.</div></div><div><h3>Conclusion</h3><div>This case underscores the diagnostic value of integrating enzyme and molecular testing when infantile-onset Pompe disease is suspected. While newborn screening for Pompe disease exists in some regions, it is not universally implemented, contributing to delays in diagnosis. Early identification allows appropriate counseling and consideration of available management pathways.</div></div><div><h3>Key clinical message</h3><div>Infantile-onset Pompe disease should be considered in infants presenting with hypotonia, recurrent respiratory infections, feeding difficulties, and delayed motor milestones. Combining dried blood spot enzyme assay with confirmatory molecular testing of the <strong><em>GAA</em></strong> gene enables timely diagnosis, informs counseling, and guides management even in settings where access to enzyme replacement therapy is limited.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101283"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucopolysaccharidoses: A biochemical study under limited resources","authors":"Fadoua Bouzid ,&nbsp;Houda El Fissi ,&nbsp;Khadija Karim ,&nbsp;Mohamed Said Sebbar ,&nbsp;Bouchaib Jabir ,&nbsp;Nouzha Chuis ,&nbsp;Fouad Msanda ,&nbsp;Najat Alif","doi":"10.1016/j.ymgmr.2025.101280","DOIUrl":"10.1016/j.ymgmr.2025.101280","url":null,"abstract":"<div><div>The mucopolysaccharidoses are a heterogeneous group of lysosomal storage disorders caused by deficiencies of enzymes involved in degradation of glycosaminoglycans. This study aimed to share our experience with biochemical investigations of these disorders under resource-limited conditions. Harmine extract was obtained from <em>Peganum harmala</em> seeds, and chromatography plates were homemade. Biochemical analysis involved urinary tests, including the Berry Spot test, the quantification of the glycosaminoglycans, as well as their characterization, and the analysis of deficient enzymes. The reference range values of glycosaminoglycans and activities of seven lysosomal enzymes, six of which are associated with these disorders were initially determined in samples of healthy subjects. The assay for β-galactosidase was described. These biochemical markers were then, evaluated in 29 patients, including 23 who were suspected of having different types of mucopolysaccharidoses and six who were diagnosed with the type I and undergoing enzymotherapy. The reference values of glycosaminoglycans and enzymes activities align with those reported in the literature. The reference value of β-galactosidase ranges from 83 to 311 nmol/17 h/mg. All the studied patients have shown the same positive pattern of Berry Spot Test in contrast of the healthy subjects. The level of GAGs was elevated by 1.1 to more than six fold but is decreased by more than six fold in patients with mucopolysaccharidosis type 1 undergoing enzymotherapy. The patients were categorized as follows: Hurler syndrome 34 %, Hunter syndrome 7 %, Sanfilippo syndrome 17 %, and Morquio syndrome 41 %. In patients for whom molecular defects were characterized, the mutations were correlated with the biochemical markers.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101280"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction in methylmalonic acidemia: A pilot study using Seahorse technology in peripheral blood","authors":"Sinziana Stanescu ,&nbsp;Olatz Villate ,&nbsp;Fernando Andrade ,&nbsp;Domingo Gonzalez-Lamuño ,&nbsp;Amaya Bélanger-Quintana ,&nbsp;Francisco Arrieta ,&nbsp;Maria-Luz Couce ,&nbsp;Alfonso Muriel ,&nbsp;Luis Aldamiz-Echevarria","doi":"10.1016/j.ymgmr.2025.101251","DOIUrl":"10.1016/j.ymgmr.2025.101251","url":null,"abstract":"<div><h3>Introduction</h3><div>Isolated methylmalonic acidemia (MMA) is an inborn error of metabolism due to the deficiency of the methylmalonic mutase enzyme. Many patients develop chronic complications such as basal ganglia lesions or kidney impairment. A growing body of evidence supports secondary mitochondrial dysfunction as the main cause for the development of these long-term complications, even in patients with good metabolic control. Currently, available methods to study mitochondrial function are often invasive, such as muscular or skin biopsy.</div></div><div><h3>Objectives</h3><div>This pilot study is aimed to develop a safe, non-invasive method to assess mitochondrial and glycolytic function in isolated MMA patients using lymphocytes.</div></div><div><h3>Materials and methods</h3><div>Mitochondrial bioenergetics and glycolysis were evaluated in lymphocytes from two <em>mut</em>^<em>0</em> MMA patients and two age- and sex-matched controls using Seahorse technology. <em>In vitro</em> treatments with triheptanoin, citrate, and resveratrol were performed.</div></div><div><h3>Results</h3><div>MMA lymphocytes showed significant impairment in mitochondrial respiration and glycolysis compared to healthy controls. Triheptanoin exposure improved ATP production and glycolytic flux (ECAR), but no significant changes were observed in oxygen consumption (OCR). Citrate and resveratrol had no measurable impact on bioenergetic parameters.</div></div><div><h3>Conclusions</h3><div>This exploratory study suggests that Seahorse technology can detect mitochondrial dysfunction in MMA lymphocytes. Further studies in larger cohorts are required to validate these findings and explore their clinical relevance.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101251"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis","authors":"Rebeka Kodríková ,&nbsp;Zuzana Pakanová ,&nbsp;Maroš Krchňák ,&nbsp;Veronika Krajčovičová ,&nbsp;Anna Šalingová ,&nbsp;Katarína Skalická ,&nbsp;Miriam Kolníková ,&nbsp;Peter Baráth ,&nbsp;Marek Nemčovič","doi":"10.1016/j.ymgmr.2025.101263","DOIUrl":"10.1016/j.ymgmr.2025.101263","url":null,"abstract":"<div><div>Congenital disorders of glycosylation (CDG) are a group of rare metabolic disorders caused by the defects in the glycosylation pathways of biomacromolecules leading to altered glycoprofiles in affected individuals. In this case study, we present a 3-year-old Slovak male patient with developmental delay, hearing impairment, epilepsy, microcephaly, facial dysmorphism, corpus callosum dysgenesis, and cardiac abnormalities. To elucidate the underlying cause, we performed LC-ESI-MS analysis of RapiFluor-labelled <em>N-</em>glycans released from blood serum glycoproteins. The results revealed an abnormal <em>N</em>-glycan profile, characterized by an increased relative abundance of truncated mannosylated structures (Hex3HexNAc2 and Hex4HexNAc2) and a decreased presence of higher-order mannose structures (Hex6-8HexNAc2). A molecular analysis was also conducted. Whole exome sequencing confirmed a diagnosis of ALG3-CDG with compound heterozygous variants: c.165C &gt; T (p.Gly55=) and c.1060C &gt; T (p.Arg354Cys) in the <em>ALG3</em> gene, encoding alpha-1,3-mannosyltransferase in the endoplasmic reticulum. This presented case highlights the importance of glycan profiling and genetic analysis in diagnosing congenital disorders of glycosylation, facilitating early intervention and management.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101263"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145219999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural history, clinical symptoms, and cognitive development of Japanese patients with mucopolysaccharidosis III","authors":"Joo-Hyun Seo ,&nbsp;Wakana Sou ,&nbsp;Yasutsugu Chinen ,&nbsp;Torayuki Okuyama","doi":"10.1016/j.ymgmr.2025.101267","DOIUrl":"10.1016/j.ymgmr.2025.101267","url":null,"abstract":"<div><h3>Abstract</h3><div>Mucopolysaccharidosis type III (MPS III) is an autosomal recessive lysosomal storage disorder characterized by severe progressive neurocognitive deterioration. Currently, no definitive treatment for MPS III is available, although novel therapies are being developed. This retrospective study characterized the natural history, clinical symptoms, treatment strategies, and cognitive development of MPS III in Japan, which will provide the basis for evaluating the efficacy of new therapies. Twelve patients (three with MPS IIIA, nine with MPS IIIB) registered in the Japan Registration System for Metabolic &amp; Inherited Diseases or their parents completed survey questions on patient background, diagnostic information, treatment history, and developmental age (DA). Mean age at diagnosis was 4 years and 7 months (standard deviation: 1 year and 6 months), with no notable difference between MPS IIIA and IIIB. All 12 patients had substantial developmental delay and progressive decline, as demonstrated by plotting DA against chronological age, as well as bone deformity, dysmorphic facial features (hirsutism), impaired motor and language development (language delay, hyperactivity, gait disorder), and sleep disturbance. Developmental delay had begun by approximately 3 years old when DA was usually first assessed, with regression occurring thereafter; regression was more gradual in MPS IIIB than in MPS IIIA. Most patients received daily care (e.g., tubal feeding) and medications to control symptoms (e.g., anticonvulsants). This was the first study to evaluate changes in DA, clinical symptoms, and treatment of patients with MPS III in Japan. These results can be used as natural history data in the future evaluation of new treatments.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101267"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renoprotective effects of SGLT2 inhibitors in patients with Fabry disease","authors":"Hayaki Okamoto,&nbsp;Shunsuke Goto,&nbsp;Mika Fujita,&nbsp;Hideki Fujii","doi":"10.1016/j.ymgmr.2025.101271","DOIUrl":"10.1016/j.ymgmr.2025.101271","url":null,"abstract":"<div><h3>Background</h3><div>Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterized by globotriaosylceramide (Gb3) accumulation, resulting in kidney and cardiac dysfunction. Although enzyme replacement therapy (ERT) and chaperone therapy are the standard therapies, progression of renal decline persists. Sodium–glucose co-transporter 2 (SGLT2) inhibitors exert renoprotective effects in chronic kidney disease (CKD), but their efficacy in FD remains unknown.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed data of 10 patients with FD treated with SGLT2 inhibitors and compared their renal outcomes to 18 patients with CKD without FD. The estimated glomerular filtration rate (eGFR) slope, urinary albumin-to-creatinine ratio (UACR), and plasma brain natriuretic peptide (BNP) levels were assessed 1 year before and after initiating SGLT2 inhibitor therapy. Linear mixed-effects models were employed for statistical analysis.</div></div><div><h3>Results</h3><div>In patients with FD, the annual eGFR decline significantly improved from −4.38 mL/min/1.73 m²/year (IQR: −10.57 to 0.59) before treatment to 1.25 (IQR: −4.16 to 9.74) after treatment (<em>p</em> &lt; 0.05). This improvement remained significant after adjusting for confounding factors. In contrast, the annual eGFR decline in patients with CKD without FD also tended to improve, albeit without significance. Notably, the initial eGFR decline usually seen with SGLT2 inhibitors in CKD was not observed in the FD cohort. UACR and plasma BNP levels remained unchanged after SGLT2 inhibitor therapy.</div></div><div><h3>Conclusions</h3><div>SGLT2 inhibitors substantially attenuated the decline in eGFR in patients with FD. These findings support their potential as a renoprotective adjunct in the management of FD.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101271"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and molecular spectrum of mucopolysaccharidosis IVA in Iraqi children: Allele-specific genotype–phenotype trends and novel GALNS variants","authors":"Saja Baheer Abdul Wahhab ,&nbsp;Rabab Farhan Thejeal","doi":"10.1016/j.ymgmr.2025.101281","DOIUrl":"10.1016/j.ymgmr.2025.101281","url":null,"abstract":"<div><h3>Background</h3><div>Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare lysosomal storage disorder that causes early-onset skeletal dysplasia and progressive multisystem involvement. Although international cohorts have been described, population-specific data from the Middle East remain limited.</div></div><div><h3>Objective</h3><div>This study aimed to characterize the clinical spectrum, functional status, and <em>GALNS</em> variant profile in Iraqi children with MPS IVA, and to assess diagnostic timing in comparison with international experience.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 33 children from 26 unrelated families with confirmed MPS IVA, recruited at the Children's Welfare Teaching Hospital in Baghdad between 2016 and 2022. Enzyme activity was measured on dried blood spots by LC-MS/MS, and <em>GALNS</em> variants were identified using next-generation sequencing with Sanger confirmation. Clinical evaluation included anthropometry, echocardiography, ophthalmologic and audiologic assessments, skeletal surveys, and functional endurance testing (6-min walk test and 3-min stair-climb).</div></div><div><h3>Results</h3><div>Fifteen distinct <em>GALNS</em> variants were identified, including five novel variants (three missense, two frameshift). The most common allele was c.949G &gt; A (p.Gly317Arg), consistently associated with severe phenotypes and absent enzyme activity. Universal skeletal dysplasia was observed, with frequent corneal clouding, cardiac valve disease, and reduced functional endurance. Symptoms typically appeared in early childhood, but definitive diagnosis was often delayed until later childhood or adolescence. Allele-specific genotype–phenotype trends were observed, though no statistically significant correlations could be established due to limited cohort size.</div></div><div><h3>Conclusion</h3><div>This first Iraqi cohort expands the <em>GALNS</em> variant spectrum and highlights persistent diagnostic delays despite early clinical manifestations. Early molecular confirmation, establishment of national registries, and multidisciplinary surveillance are essential to reduce long-term morbidity.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101281"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving sapropterin administration efficacy in PKU: Clinical practice case studies","authors":"Martina Tosi ,&nbsp;Anne Daly ,&nbsp;Catherine Ashmore ,&nbsp;Alex Pinto ,&nbsp;Suresh Vijay ,&nbsp;Elvira Verduci ,&nbsp;Sharon Evans ,&nbsp;Anita MacDonald","doi":"10.1016/j.ymgmr.2025.101252","DOIUrl":"10.1016/j.ymgmr.2025.101252","url":null,"abstract":"<div><div>In patients with phenylketonuria (PKU), sapropterin dihydrochloride (sapropterin) lowers blood phenylalanine (Phe) and may enhance Phe tolerance in sapropterin responsive patients. Attention to its administration, particularly the timing, and giving it with food with appropriate macronutrient composition, is important. We describe two boys with PKU who improved their Phe tolerance and metabolic control when they adjusted their method of sapropterin administration. Case 1: aged 7.2<del>5</del> years with mild PKU experienced a 40 % reduction in blood Phe after a 30-day sapropterin trial (20 mg/kg). Initially, he took sapropterin once daily dissolved in water. This increased his protein tolerance from 26 g to 50 g/day and reduced his protein equivalent from protein substitute to 20 g/day. His blood Phe was a median of 230 μmol/L (range: 130–300). After six months, twice-daily dosing further improved his protein tolerance to 60 g/day, with a lower median blood Phe (130 μmol/L, range: 80–220). By age 8 years, he swallowed tablets intact with meals, ate an unrestricted protein intake (∼80 g/day), stopped protein substitute, maintained excellent metabolic control with perceived cognitive improvement. Case 2: a boy who aged 4.9<del>92</del> years with mild PKU had a 33 % reduction in blood Phe after a 30-day sapropterin (20 mg/kg) trial. Initially, he took sapropterin once daily dissolved in water, increasing his protein tolerance from 14 g to 55 g/day, and reducing protein equivalent from protein substitute to 20 g/day. Median blood Phe was 240 μmol/L (range: 120–320). At age 6.9<del>2</del> years, twice-daily dosing and swallowing intact tablets further lowered his blood Phe, to a mean of 130 μmol/L (range: 100–130). He stopped dietary protein restriction and protein substitute intake. These case studies showed clinical and dietary benefits with adjustment of sapropterin administration. It was unclear if the improvements observed were associated with twice daily sapropterin administration, attention to taking it with fat containing meals, swallowing the tablets intact, or a combination of these. Further research to monitor the efficacy and safety of administration change is necessary.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101252"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute profound lactic alkalosis associated with NDUFV1 compound heterozygosity in a previously healthy 6-year-old female","authors":"Stephen G. Kaler ,&nbsp;William Fyke ,&nbsp;Angela Lignelli-Dipple ,&nbsp;Valentina Emmanuele ,&nbsp;Eun Bi Lee ,&nbsp;Hyein Kathy Lee ,&nbsp;Adiel Munk ,&nbsp;Jose Andres Morales Corado ,&nbsp;Alejandro Iglesias ,&nbsp;Priyanka Mehrotra","doi":"10.1016/j.ymgmr.2025.101249","DOIUrl":"10.1016/j.ymgmr.2025.101249","url":null,"abstract":"<div><div><em>NDUFV1</em> encodes NADH: ubiquinone oxidoreductase core subunit V1, a key component of mitochondrial Complex 1. Biallelic pathogenic variants in this gene produce a broad and variable phenotypic spectrum in affected individuals, including ophthalmoplegia, developmental delays, brain imaging abnormalities, and recurrent episodes of emesis and lactic acidemia. We report female siblings compound heterozygous for two missense variants (Arg40Gln, Val245Met) in <em>NDUFV1</em> with unusual presentations of this condition. The 6-year-old proband showed normal growth and neurodevelopment until recently when weight loss and recurrent vomiting were noticed and brain imaging abnormalities consistent with Complex 1 deficiency were documented. She developed lactic acidemia without a clear precipitating factor and that, incongruously, was associated with profound alkalosis with blood pH as high as 7.83. We describe management of her acute illness during a hospital admission with aggressive sodium bicarbonate and sodium acetate replacement, and eventual recognition that anxiety-related hyperventilation contributed substantially to her transient profound alkalosis. We review the complex interplay of lactic acidemia due to mitochondrial Complex 1 deficiency, metabolic acidosis from acute loss of bicarbonate, respiratory alkalosis from hyperventilation and hypocapnia, and other concomitant medical issues, as well as her distinctive neuroradiological findings. Her 14-year-old sister was diagnosed retrospectively despite an earlier initial presentation, and manifests greater neurocognitive effects, similar neuroradiological signs, but no history of acute metabolic decompensation. These cases expand the phenotypic spectrum of this rare inherited illness, provide new information about its presentation and intrafamilial variability, and offer insight relevant to management of life-threatening metabolic crises associated with this disorder.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101249"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timely intervention in HMG-CoA Lyase deficiency: The role of newborn screening, metabolic management, and genomic sequencing","authors":"Iskren Menkovic ,&nbsp;Neelam Makhijani ,&nbsp;Ludmila Francescatto ,&nbsp;Surekha Pendyal ,&nbsp;Christine Stanley ,&nbsp;Sarah P. Young ,&nbsp;Dwight D. Koeberl ,&nbsp;Dmitriy Niyazov ,&nbsp;Ashlee R. Stiles","doi":"10.1016/j.ymgmr.2025.101278","DOIUrl":"10.1016/j.ymgmr.2025.101278","url":null,"abstract":"<div><div>3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is a rare autosomal recessive metabolic disease caused by variants in the HMGCL gene leading to an impairment in leucine catabolism and ketone synthesis. In the United States, HMG-CoA lyase deficiency is listed on the recommended uniform screening panel as a core condition for newborn screening. A positive newborn screen will typically show an elevation of C5-hydroxylated species on the acylcarnitine profile using a dried-blood spot collected between 24 and 48 h of life. Initial follow-up testing generally includes a plasma acylcarnitine profile and a urine organic acid profile. Clinically, this metabolic alteration can lead to severe metabolic decompensation, presenting as hypoketotic hypoglycemia and, when left untreated, potential long-term neurological impairments. This report highlights the case of a 38-day-old male with an initial abnormal newborn screen. Follow-up testing showed moderate elevations of C5-hydroxylated and C6-dicarboxylated species on the plasma acylcarnitine profile and marked elevations of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric and 3-hydroxyisovaleric acid detected by urine organic acid analysis. These findings were consistent with a biochemical diagnosis of HMG-CoA lyase deficiency. Confirmatory molecular testing included targeted <em>HMGCL</em> sequencing including deletion/duplication analysis; the results of which were negative. Genome sequencing was then requested which identified a deep intronic complex variant of unknown significance within intron 1 of <em>HGMCL</em>. RNA sequencing studies were sent as follow-up which revealed that the level of expression of the HMGCL gene was negligible in comparison with tissue-matched controls, thus confirming the biochemical diagnosis of HMG-CoA lyase deficiency.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101278"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}