Journal of Inherited Metabolic Disease最新文献

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

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

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

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

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

{"title":"Citrin deficiency—The East-side story","authors":"Johannes Häberle","doi":"10.1002/jimd.12772","DOIUrl":"10.1002/jimd.12772","url":null,"abstract":"<p>Citrin deficiency (CD) is a complex metabolic condition due to defects in <i>SLC25A13</i> encoding citrin, an aspartate/glutamate carrier located in the mitochondrial inner membrane. The condition was first described in Japan and other East Asian countries in patients who were thought to suffer from classical citrullinemia type 1, and was therefore classified as a urea cycle disorder. With an improved understanding of its molecular basis, it became apparent that a defect of citrin is primarily affecting the malate–aspartate shuttle with however multiple secondary effects on many central metabolic pathways including glycolysis, gluconeogenesis, de novo lipogenesis and ureagenesis. In the meantime, it became also clear that CD must be considered as a global disease with patients identified in many parts of the world and affected by <i>SLC25A13</i> genotypes different from those known in East Asian populations. The present short review summarizes the (hi)story of this complex metabolic condition and tries to explain the relevance of including CD as a differential diagnosis in neonates and infants with cholestasis and in (not only adult) patients with hyperammonemia of unknown origin with subsequent impact on the emergency management.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1129-1133"},"PeriodicalIF":4.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12772","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Newborn screening for acid sphingomyelinase deficiency in Illinois: A single center's experience","authors":"Rachel E. Hickey,&nbsp;Joshua Baker","doi":"10.1002/jimd.12780","DOIUrl":"10.1002/jimd.12780","url":null,"abstract":"<p>Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder (LSD) caused by reduced activity of the acid sphingomyelinase (ASM) enzyme, which leads to progressive storage of sphingomyelin and related lipids in the body. ASMD is caused by biallelic variants in the <i>SMPD1</i> gene, which encodes for the ASM enzyme. Current estimates of disease incidence range from 0.4 to 0.6 in 100 000 livebirths, although this is likely an underestimation of the true frequency of the disorder. While there is no cure for ASMD, comprehensive care guidelines and enzyme replacement therapy are available, making an early diagnosis crucial. Newborn screening (NBS) for ASMD is possible through measurement of ASM activity in dried blood spots and offers the opportunity for early diagnosis. In 2015, Illinois (IL) became the first to initiate statewide implementation of NBS for ASMD. This study describes the outcomes of screen-positive patients referred to Ann &amp; Robert H. Lurie Children's Hospital (Lurie). Ten infants were referred for diagnostic evaluation at Lurie, and all 10 infants were classified as confirmed ASMD or at risk for ASMD through a combination of molecular and biochemical testing. Disease incidence was calculated using data from this statewide implementation program and was ~0.79 in 100 000 livebirths. This study demonstrates successful implementation of NBS for ASMD in IL, with high screen specificity and a notable absence of false positive screens.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1363-1370"},"PeriodicalIF":4.2,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12780","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PompeQoL questionnaire: Development and validation of a new measure for children and adolescents with Pompe disease","authors":"Moritz Ilan Truninger,&nbsp;Helene Werner,&nbsp;Markus Andreas Landolt,&nbsp;Andreas Hahn,&nbsp;Julia B. Hennermann,&nbsp;Florian B. Lagler,&nbsp;Dorothea Möslinger,&nbsp;Charlotte Pfrimmer,&nbsp;Marianne Rohrbach,&nbsp;Martina Huemer","doi":"10.1002/jimd.12777","DOIUrl":"10.1002/jimd.12777","url":null,"abstract":"<p>Genetic disorders pose great challenges for affected individuals and their families, as they must cope with the irreversible nature of the disease and a life-long dependence on medical assistance and treatment. Children and adolescents dealing with Pompe disease (PD) often struggle to keep up with their peers in physical activities. To gain valuable insights into their subjective experiences and better understand their perception and coping related to daily challenges linked to their condition and treatment, the use of standardized questionnaires is crucial. This study introduces the novel PompeQoL 1.0 questionnaire for children and adolescents with PD, designed for comprehensive assessment of both disease-specific FDH and HRQoL through self- and proxy reports. Content validity was ensured through patients' and parents' involvement at the initial stages of development and in subsequent cognitive debriefing process. Participants found the questionnaire easy to understand, answerable, relevant, and comprehensive. Adjustments based on feedback from patients and their parents improved its utility as a patient- and observer-reported outcome measure. After careful item examination, 52 items were selected, demonstrating moderate to excellent test–retest reliability for most scales and initial evidence for satisfactory construct validity. The PompeQoL questionnaire stands as a valuable screening instrument for both clinical and research purposes. Future research should prioritize additional revisions and larger validation studies, focusing on testing the questionnaire in clinical practice and trials. Nevertheless, the PompeQoL 1.0 stands out as the first standardized measure providing insights into disease-specific FDH and HRQoL among children and adolescents with various forms of PD.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1348-1362"},"PeriodicalIF":4.2,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12777","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Isolated remethylation disorders: Do our treatments benefit patients?”","authors":"","doi":"10.1002/jimd.12770","DOIUrl":"10.1002/jimd.12770","url":null,"abstract":"<p>\u0000 <span>Schiff, M</span>, <span>Benoist, J-F</span>, <span>Tilea, B</span>, <span>Royer, N</span>, <span>Giraudier, S</span>, <span>Ogier de Baulny, H</span>. <span>Isolated remethylation disorders: do our treatments benefit patients?</span> <i>J Inherit Metab Dis</i>. <span>2011</span>; <span>34</span>: <span>137</span>-<span>145</span>. doi:10.1007/s10545-010-9120-8\u0000 </p><p>In the original published article, heading “Outcome of early-treated neonatal remethylation disorders”, subheading “Patient 6”, page 142, there is a mistake in the sentence “Molecular investigation revealed mutations in the MTR gene (cblG defect) (Table 1)”. It should read:</p><p>“Molecular investigation revealed mutations in the MTRR gene (cblE defect) (Table 1).”</p><p>And in Table 1: The last line in the second column “MTR (cblG) c.1348T&gt;G/c.1349C&gt;A (p.Ser450Ala/p.Ser450Tyr)” should be replaced by:</p><p>“MTRR (cblE) c.1285 C&gt;T/c.1910C&gt;T (p.Gln429X/ p.Ser637Leu)”</p><p>We apologize for this error.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 5","pages":"1112"},"PeriodicalIF":4.2,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12770","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New variants expand the neurological phenotype of COQ7 deficiency","authors":"María Alcázar Fabra,&nbsp;Abraham J. Paredes-Fuentes,&nbsp;Manuel Torralba Carnerero,&nbsp;Daniel J. Moreno Férnandez de Ayala,&nbsp;Antonio Arroyo Luque,&nbsp;Ana Sánchez Cuesta,&nbsp;Carmine Staiano,&nbsp;Paula Sanchez-Pintos,&nbsp;María Luz Couce,&nbsp;Miguel Tomás,&nbsp;Ana Victoria Marco-Hernández,&nbsp;Carmen Orellana,&nbsp;Francisco Martínez,&nbsp;Mónica Roselló,&nbsp;Alfonso Caro,&nbsp;Juan Silvestre Oltra Soler,&nbsp;Sandra Monfort,&nbsp;Alejandro Sánchez,&nbsp;Dolores Rausell,&nbsp;Isidro Vitoria,&nbsp;Mireia del Toro,&nbsp;Angels Garcia-Cazorla,&nbsp;Natalia A. Julia-Palacios,&nbsp;Cristina Jou,&nbsp;Delia Yubero,&nbsp;Luis Carlos López,&nbsp;Juan Diego Hernández Camacho,&nbsp;Guillermo López Lluch,&nbsp;Manuel Ballesteros Simarro,&nbsp;Juan Carlos Rodríguez Aguilera,&nbsp;Gloria Brea Calvo,&nbsp;María Victoria Cascajo Almenara,&nbsp;Rafael Artuch,&nbsp;Carlos Santos-Ocaña","doi":"10.1002/jimd.12776","DOIUrl":"10.1002/jimd.12776","url":null,"abstract":"<p>The protein encoded by <i>COQ7</i> is required for CoQ₁₀ synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ₁₀) in the second to last steps of the pathway. <i>COQ7</i> mutations lead to a primary CoQ₁₀ deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ₁₀ primary deficiency caused by five mutations in <i>COQ7</i>, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ₁₀ presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ₁₀ deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 5","pages":"1047-1068"},"PeriodicalIF":4.2,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12776","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}