Molecular Genetics and Metabolism Reports最新文献

{"title":"Genetic variations in the IDUA gene in Tunisian MPS I families: Identification of a novel microdeletion disrupting substrate binding and structural insights","authors":"Mariem Rebai ,&nbsp;Yessine Amri ,&nbsp;Chaima Sahli ,&nbsp;Hajer Foddha ,&nbsp;Taieb Messaoud ,&nbsp;Hela Boudabous ,&nbsp;Hassen Ben Abdennebi ,&nbsp;Salima Ferchichi ,&nbsp;Latifa Chkioua","doi":"10.1016/j.ymgmr.2025.101222","DOIUrl":"10.1016/j.ymgmr.2025.101222","url":null,"abstract":"<div><h3>Background</h3><div>Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency in alpha-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans. MPS I presents with a broad spectrum of clinical phenotypes, ranging from severe to mild. This study aimed to identify genetic mutations in the IDUA gene among Tunisian families and assess their structural and functional implications.</div></div><div><h3>Patients and methods</h3><div>Genomic DNA was extracted from blood samples of four patients including two siblings from three Tunisian families. Polymerase chain reaction (PCR) followed by Sanger sequencing was performed to identify mutations in the IDUA gene. Bioinformatics tools, including the SWISS-MODEL server and DynaMut, were used for structural modeling and to predict the impact of the mutations on protein stability and flexibility.</div></div><div><h3>Results</h3><div>Two mutations in the IDUA gene were identified. A novel deletion mutation p.His356_Gln362del was discovered in two patients with severe MPS I phenotypes, while a previously reported missense mutation p.Pro533Arg was found in two patients with intermediate and mild phenotypes. Structural analysis revealed that the novel deletion disrupts the protein's substrate-binding site. This deletion causes structural deformation and leads to the elimination of the substrate binding site, resulting in a complete loss of enzymatic activity.</div><div>The missense mutation p.Pro533Arg affects the stability and flexibility of the protein, likely reducing substrate affinity. This substitution results in the introduction of a bulkier amino acid, requiring more space in the contact region between the β-sheet structure and the substrate-bound helix.</div></div><div><h3>Conclusion</h3><div>This study reports a novel deletion mutation in the IDUA gene in Tunisian MPS I patients, alongside a previously described mutation. The findings enhance understanding of the molecular basis of MPS I and provide insights into the structural effects of these mutations, which could aid in future diagnosis and therapeutic strategies. Future studies should explore the prevalence of the reported mutations in larger cohorts and investigate targeted therapies, such as pharmacological chaperones, to rescue enzymatic activity in patients carrying such mutations.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101222"},"PeriodicalIF":1.8,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850644","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":"Expert review in diagnostic, therapeutic and follow-up of Fabry disease in Latin America based on patient care standards","authors":"Roberto Giugliani ,&nbsp;Juan Politei ,&nbsp;Ana Martins ,&nbsp;Nelson Murillo ,&nbsp;Paula Rozenfeld ,&nbsp;Mauricio Lopera ,&nbsp;Sergio Salgado ,&nbsp;Gustavo Quirós ,&nbsp;Charles Marques ,&nbsp;Osvaldo Vieira ,&nbsp;Hernán Amartino ,&nbsp;Fernando Perretta ,&nbsp;Sandra Marques e Silva ,&nbsp;Joseph Brooks ,&nbsp;Laura Titievsky ,&nbsp;Jacobo Villalobos ,&nbsp;Cassiano Braga ,&nbsp;Harris A. Peñaranda","doi":"10.1016/j.ymgmr.2025.101218","DOIUrl":"10.1016/j.ymgmr.2025.101218","url":null,"abstract":"<div><h3>Background</h3><div>Fabry disease (FD) is an X-linked lysosomal sphingolipidosis. It is caused by pathogenic variants in the GLA gene with a consequent deficiency of the enzyme α-galactosidase A, resulting in the pathological accumulation of glycolipids - mainly globotriosyl ceramide (GL-3, GB3) and its deacylated product, globotriaosylsphingosine (Lyso-Gb-3) - in plasma and in a wide variety of cell types throughout the human body; it is characterized as a chronic, multisystemic disease with progressive evolution, which causes deterioration of the patient's quality of life and decreases survival and life expectancy.</div><div>In Latin America there are different limitations to the management of patients with Fabry disease, in most countries, access to diagnostic tools and treatment on time is complex and can sometimes suffer delays in its implementation. This situation is due to the high costs to health systems of follow-up and pharmacological therapy for Fabry patients, creating barriers to timely access.</div></div><div><h3>Conclusions</h3><div>Although medical criteria are fundamental in the choice of pharmacological therapy, the final decision should also rely on the patient's choice according to their expectations and the adherence and compliance with the treatment that they are willing to follow. As it has been described, there are currently three therapeutic options, for which the appropriate profile must be defined to achieve the best clinical outcomes, considering that it is a permanent treatment; experts consider that Fabry patients need comprehensive and interdisciplinary management to stop the progression and functional deterioration of the affected organs by its multiple systemic manifestations. In Latin-American countries, it is difficult to guarantee this comprehensive and coordinated management, due to limited public policies related to orphan diseases diagnosis, treatment and follow up.</div><div>It is considered crucial to structure support networks specialized in Fabry disease and generate partnerships with health institutions and other health system stakeholders, that would articulate and coordinate patients and relatives counseling and management, establish the specific pharmacological treatment to reduce the progression of the disease and the systemic involvement, deciding between the administration of enzyme replacement therapy or the most recent option of oral management with pharmacological chaperone both with proven effectiveness. This will be the decision of the attending physician, who will propose and advise the therapeutic choice that best suits the patient's needs.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101218"},"PeriodicalIF":1.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833426","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":"Five years of newborn screening for Pompe, Mucopolysaccharidosis type I, Gaucher, and Fabry diseases in Oregon","authors":"Sarah Viall ,&nbsp;Patrice Held","doi":"10.1016/j.ymgmr.2025.101221","DOIUrl":"10.1016/j.ymgmr.2025.101221","url":null,"abstract":"<div><div>In October 2018, the Oregon newborn screening program began screening for four lysosomal storage disorders (LSDs) Pompe, Mucopolysaccharidosis Type I (MPSI), Gaucher, and Fabry. The laboratory used two different methodologies, digital microfluidics and tandem mass spectrometry, to measure the four LSD enzyme activities. Accuracy and precision were improved and lower false positive rates were observed with use of the Revvity NeoLSD assay on the mass spectrometry platform, as compared to the Baebies digital microfluidics method. All newborn specimens with screen positive results were reflexed to a second-tier molecular assay to identify variants in the target gene. Over the first five years of screening, 139 cases were referred for confirmatory testing and clinical evaluation due to presence of pathogenic/likely pathogenic variant(<em>s</em>)or variant(s) of unknown significance. These identified newborns were evaluated at the Oregon Health &amp; Science University (OHSU) metabolic clinic in Portland, Oregon. However, due to the COVID-19 pandemic, clinicians had to pivot from in-person to virtual visits and triage on acuity, which impacted the time to diagnosis. Of referred babies, 3 are currently receiving treatment for their detected LSD. Over 50 babies have an inconclusive or possible late onset diagnosis with uncertain timeline for development of symptoms.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101221"},"PeriodicalIF":1.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833427","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":"Bilateral avascular necrosis: A rare complication of Fabry disease","authors":"Candela Romano ,&nbsp;Joel Wells ,&nbsp;Nicholas Stanzione ,&nbsp;Virginia Kimonis","doi":"10.1016/j.ymgmr.2025.101219","DOIUrl":"10.1016/j.ymgmr.2025.101219","url":null,"abstract":"<div><div>Fabry disease is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the <em>GLA</em> gene, which encodes for the α–galactosidase A enzyme responsible for degrading globotriaosylceramide. Its deficiency leads to the accumulation of GL3 in lysosomes, resulting in progressive multi-organ involvement, with predilection for the heart and kidneys.</div><div>Clinical features associated with Fabry disease include acroparesthesia, angiokeratomas, hypohidrosis, corneal whorls, chronic kidney disease, cardiomyopathy, and strokes. Osteopenia and osteoporosis are less known complications, with rare reported cases of avascular necrosis of the hips.</div><div>We report bilateral avascular necrosis in a 40-year-old-man diagnosed with Fabry at the age of 25 years. He carriers the familiar p.G328V <em>GLA</em> pathogenic variant. His Fabry features includes acroparesthesia, angiokeratomas, hypohidrosis, temperature and exercise intolerance, pain crises, abdominal pain and diarrhea, tinnitus, hearing loss, hypertrophic cardiomyopathy, palpitations, and chest pain. Family history reveals Fabry disease affecting multiple maternal relatives. The patient was recently diagnosed with avascular necrosis of the right hip requiring total arthroplasty due to failure of conservative treatment. Nine months later, he developed left hip pain attributed to avascular necrosis, also treated with total arthroplasty.</div><div>This case highlights a rare skeletal complication of Fabry disease, underscoring the need for early diagnosis, optimizing treatment of Fabry disease, managing atypical comorbidities, and vigilant monitoring of bone health.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101219"},"PeriodicalIF":1.8,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821376","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":"A study of Iraqi patients with homocysteine remethylation disorders in a tertiary pediatric centre","authors":"Mays R. Al-Tai ,&nbsp;Adel A. Kareem ,&nbsp;Nebal W. Saadi ,&nbsp;Tawfig Ben Omran ,&nbsp;Ban A. Abdul Majeed ,&nbsp;Ibrahim F. Ibrahim ,&nbsp;Lamia A. Alattar","doi":"10.1016/j.ymgmr.2025.101217","DOIUrl":"10.1016/j.ymgmr.2025.101217","url":null,"abstract":"<div><h3>Background</h3><div>Hyperhomocysteinemia is a group of inherited homocysteine metabolism disorders characterised by elevated blood homocysteine levels (total homocysteine &gt;15 μM). Homocystinuria is classified into two main homocysteine metabolism disorders. Classical Homocystinuria is caused by a deficiency of the pyridoxine-dependent enzyme cystathionine beta-synthase in the trans‑sulfuration pathway. Non-classical Homocystinuria is a group of disorders affecting the interconversion of methionine to homocysteine through the re-methylation pathway.</div></div><div><h3>Aim</h3><div>This study aims to describe the clinical, biochemical, and genetic profiles of patients with re-methylation disorders.</div></div><div><h3>Patients and methods</h3><div>A cohort study was conducted at the metabolic clinic of Children Welfare Teaching Hospital in Baghdad from the 1st of December 2021 to the 1st of December 2022. The study included fifteen patients who met the following criteria: (1) elevated serum homocysteine levels (&gt;15 μmol/L); (2) low or normal blood methionine levels (12–40 μmol/L). <strong>Results:</strong> fourteen MTHFR patients underwent statistical analysis, and one CblC patient was assessed separately. MTHFR patients comprised nine females and five males. The mean age at presentation was 7.1 years ±4.5, ranging from 1 to 16 years. Consanguineous marriages were reported in 13 patients. A family history of a similar disorder was documented in 73 % of cases. Among the families, four had two affected siblings. The two main reported clinical manifestations were gait disturbance (10/14, 71.4 %) and cognitive impairment/intellectual disability (6/14, 42.8 %). Brain MRI was conducted for all studied patients, with leukodystrophy being the most common finding (8/14, 57.1 %). Molecular testing revealed variants in <em>MTHFR</em> in 14 patients, and <em>MMACHC</em> in one patient.</div></div><div><h3>Conclusion</h3><div>According to this study, individuals with homocysteine re-methylation disorders can manifest symptomatology such as neuroregression, psychomotor delay, and whiter matter changes earlier than anticipated. And these disorders are amenable to treatment. Genetic testing is crucial in identifying the specific mutation type and guiding definitive treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101217"},"PeriodicalIF":1.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817547","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":"Cardiac manifestations in adult patients with inherited metabolic disease: A single-center experience","authors":"Flutura Sadiku ,&nbsp;Tobias Rutz ,&nbsp;Andrea Superti-Furga ,&nbsp;Pierre Monney ,&nbsp;Christel Tran","doi":"10.1016/j.ymgmr.2025.101216","DOIUrl":"10.1016/j.ymgmr.2025.101216","url":null,"abstract":"<div><h3>Background</h3><div>Inherited metabolic diseases (IMDs) can affect the heart, but data on cardiac manifestations in adults are scarce. This study examines the clinical and radiological features of cardiac complications in adults with IMDs.</div></div><div><h3>Methods</h3><div>This retrospective study included adult patients at our metabolic clinic with a biochemical and/or genetic diagnosis of IMD who underwent cardiac investigations. Records were reviewed for clinical features, echocardiograms, electrocardiograms, and treatment. Patients were categorized into three IMD subgroups: disorders of small molecules, complex molecules, and energy production.</div></div><div><h3>Results</h3><div>Of the 115 adult patients with IMD, 48 underwent cardiac testing (mean age 39.1 ± 14.8 years). Abnormal cardiac findings were reported in 23 of these patients (47.9 %, 14 men). Five (21.7 %) were symptomatic with dyspnea, peripheral edema, or chest pain. Fourteen patients (60.9 %) had heart muscle disease, 6 (26.1 %) had valvular involvement, and 5 (21.7 %) had arrhythmia. Valvular and heart muscle disease predominated in complex and small molecule disorders (3/4 and 7/9 respectively). Energy production disorders showed mixed involvement: heart muscle disease (5/10) and arrhythmia (5/10). Twelve of the 23 patients with abnormal findings (52.2 %) received specific cardiac therapy. All but one patient remained stable under treatment.</div></div><div><h3>Discussion</h3><div>In this cohort, cardiac disease was diagnosed in 23 of 115 adults with IMD (20 %), including structural heart defects and arrhythmia. The pattern and severity of cardiac involvement varied between disorders, with arrhythmia mainly associated with energy production disorders. Outcomes were favorable in most cases, likely due to collaboration between metabolic physicians and cardiologists and timely follow-up and treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101216"},"PeriodicalIF":1.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817549","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":"Disease profile in a cohort of Brazilian patients diagnosed with alpha-mannosidosis","authors":"Fabiano de Oliveira Poswar ,&nbsp;Tamires Silva Alves ,&nbsp;Daniel Rocha de Carvalho ,&nbsp;Hélio van der Linden Jr ,&nbsp;Charles Marques Lourenço ,&nbsp;Dafne Dain Gandelman Horovitz ,&nbsp;Anneliese Barth ,&nbsp;Carmen Silvia Curiati Mendes ,&nbsp;Ana Maria Martins ,&nbsp;Roberto Giugliani","doi":"10.1016/j.ymgmr.2025.101220","DOIUrl":"10.1016/j.ymgmr.2025.101220","url":null,"abstract":"<div><div>Alpha-mannosidosis (AM) is an ultrarare multisystemic disorder caused by alpha-mannosidase deficiency. This is the first comprehensive report on AM in Brazil, analyzing clinical and laboratory data from 14 patients diagnosed between 2001 and 2021. We summarize the patient diagnostic journey in the country, including the most common presenting symptoms, the time from disease onset to diagnosis and discuss other disease manifestations. Our findings may improve the disease awareness and understanding in the country.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101220"},"PeriodicalIF":1.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817550","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":"Two decades of experience of the Fabry Outcome Survey provides further confirmation of the long-term effectiveness of agalsidase alfa enzyme replacement therapy","authors":"Uma Ramaswami ,&nbsp;Guillem Pintos-Morell ,&nbsp;Christoph Kampmann ,&nbsp;Kathleen Nicholls ,&nbsp;Dau-Ming Niu ,&nbsp;Ricardo Reisin ,&nbsp;Michael L. West ,&nbsp;Christina Anagnostopoulou ,&nbsp;Jaco Botha ,&nbsp;Dalia Jazukeviciene ,&nbsp;Jörn Schenk ,&nbsp;Derralynn A. Hughes ,&nbsp;Roberto Giugliani","doi":"10.1016/j.ymgmr.2025.101215","DOIUrl":"10.1016/j.ymgmr.2025.101215","url":null,"abstract":"<div><h3>Background</h3><div>Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy.</div></div><div><h3>Methods</h3><div>The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts.</div></div><div><h3>Results</h3><div>A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0–20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2–87.6] vs 50.3 [34.5–70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years).</div></div><div><h3>Conclusions</h3><div>Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101215"},"PeriodicalIF":1.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817548","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":"Branched-chain amino acid transferase type 2 (BCAT2) deficiency: Report of an eighth case and literature review","authors":"Etienne Mondésert ,&nbsp;Juliette Bouchereau ,&nbsp;Manuel Schiff ,&nbsp;Jean-François Benoist ,&nbsp;Guilia Barcia ,&nbsp;Boris Keren ,&nbsp;Inès Mannes ,&nbsp;Clément Pontoizeau ,&nbsp;Charlotte Mansat ,&nbsp;Apolline Imbard","doi":"10.1016/j.ymgmr.2025.101213","DOIUrl":"10.1016/j.ymgmr.2025.101213","url":null,"abstract":"<div><div>Branched-chain amino acid transferase type 2 (BCAT2) deficiency is a rare autosomal recessive genetic condition, with only seven cases described to date. It results in an elevation of branched-chain amino acid (BCAA) plasma concentrations, predominantly on valine, with normal concentration of plasma allo-isoleucine and urine branched-chain α-keto acids (BCKA). Despite this constant biochemical feature, clinical consequences remain unclear with heterogeneous and far less severe than maple syrup urine disease (MSUD) reported phenotypes, one individual being even asymptomatic.</div><div>We report herein the eighth case of genetically confirmed BCAT2 deficiency, accompanied by a literature review and a discussion about the potential pathogenicity of this condition.</div><div>An 11-year-old boy presented with a rapidly reversible initial acute neurological episode suggesting an epileptic seizure. Abnormalities on cerebral magnetic resonance imaging and suspicion of cognitive impairment led to further metabolic investigations. BCAT2 deficiency has been mentioned in front of increased BCAAs (valine = 1667 μmol/L, leucine = 701 μmol/L, isoleucine = 561 μmol/L). A homozygous novel nonsense variant on <em>BCAT2</em> (c.34C &gt; T, p.Arg12*) was found on whole exome sequencing. After oral pyridoxine supplementation (200 mg/day), a decrease in BCAA concentrations was observed (valine = 984 μmol/L, leucine = 462 μmol/L, isoleucine = 302 μmol/L).</div><div>Laboratory and imaging findings were consistent with previously reported cases. However, clinical presentation of this case was atypical and could be related with epilepsy, although no other variant on epilepsy genes have been found. The relation between BCAT2 deficiency and these clinical findings is at this stage debated with regard to phenotypic variability. Further case-studies are needed to expand the knowledge about this condition.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101213"},"PeriodicalIF":1.8,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The recurrent p.Glu3Lys variant in EHHADH is responsible for Fanconi syndrome with early liver dysfunction and mitochondrial abnormalities","authors":"P. Rollier ,&nbsp;A. Cospain ,&nbsp;M. Barth ,&nbsp;V. Milon ,&nbsp;N. Gueguen ,&nbsp;C. Homedan ,&nbsp;V. Desquiret ,&nbsp;C. Bris ,&nbsp;E. Colin ,&nbsp;L. Damaj ,&nbsp;A. Ryckewaert ,&nbsp;P. Reynier ,&nbsp;S. Odent ,&nbsp;P. Amati-Bonneau ,&nbsp;V. Procaccio ,&nbsp;D. Bonneau ,&nbsp;A. Ziegler","doi":"10.1016/j.ymgmr.2025.101214","DOIUrl":"10.1016/j.ymgmr.2025.101214","url":null,"abstract":"<div><h3>Background</h3><div>The recurrent pathogenic variant c.7G&gt;A p.Glu3Lys in the <em>EHHADH</em> gene is responsible for an autosomal dominant form of Fanconi renotubular syndrome. This variant leads to mislocalization of peroxisomal EHHADH protein to the mitochondria, thereby impairing mitochondrial function. To date, this variant has been reported in only two unrelated families, with affected individuals presenting with isolated renotubular Fanconi syndrome. No other pathogenic variant has been documented in this gene.</div></div><div><h3>Methods</h3><div>A boy followed from four months-old to twelve years-old underwent clinical evaluation, mitochondrial analyses and exome sequencing.</div></div><div><h3>Results</h3><div>The four-month-old infant boy presented with hypoglycemia, ketonuria, lactic acidosis and hepatic cytolysis. Three months later, a Fanconi tubulopathy with nephrocalcinosis appeared. Mitochondrial respiratory chain analyses performed on hepatocytes showed a decreased activity of complex I and IV of the mitochondrial respiratory chain and a quantitative decrease of these complexes. Exome sequencing revealed the missense variant c.7G&gt;A p.Glu3Lys, inherited from his father who was asymptomatic at 54 years old. A diet supplemented in medium-chain fatty acids was experimented.</div></div><div><h3>Conclusion</h3><div>This case widens the phenotypic spectrum of the recurrent p.Glu3Lys variant in <em>EHHADH</em>, which may be responsible for Fanconi syndrome and early onset hepatic dysfunction with cytolysis and hypoglycemia. Medium-chain fatty acids supplemented diet did not improve the disease.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101214"},"PeriodicalIF":1.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}