Molecular Genetics And Metabolism[JOURNAL]
Sun
200 papers
"Nobody listened to us for years": Parents' experiences of provider communication in the diagnostic odyssey.
Nguyen MM, Mahfoozi S, Bonner D … +7 more , Martschenko DO, Giri A, Tang C, Undiagnosed Diseases Network, Bernstein JA, Wheeler MT, Halley MC
Mol Genet Metab · 2025 Dec · PMID 41232198 · Full text
BACKGROUND: Well-recognized challenges in rare disease diagnosis include limited awareness of rare diseases among healthcare providers and barriers to accessing genetic testing. Less well understood are the ways in which...
BACKGROUND: Well-recognized challenges in rare disease diagnosis include limited awareness of rare diseases among healthcare providers and barriers to accessing genetic testing. Less well understood are the ways in which communication between parents of undiagnosed children and providers may impact access to diagnosis, as well as quality of care broadly. We sought to characterize key dynamics of communication between parents of undiagnosed children and healthcare providers during the diagnostic odyssey. METHODS: Parents of undiagnosed children undergoing genomic sequencing were recruited from clinical and research settings and Facebook groups. Participants completed up to three sequential, in-depth interviews. Data were analyzed inductively to identify key themes. RESULTS: Parents (n = 36) identified three key dimensions of their experiences communicating with providers during the diagnostic odyssey, including examples of both effective and challenging communication related to: 1) providers' availability and responsiveness; 2) trust and validation of their concerns by providers; and 3) communication across multiple providers. Parents also described employing divergent strategies, such as increased persistence and advocacy, or minimized communication and resignation, in response to challenges. CONCLUSIONS: Our study identified ways in which parent-provider communication can facilitate or hinder access to diagnosis and care for children with undiagnosed diseases. However, communication challenges were not universal, suggesting opportunities for intervention. Additional research is needed to identify interventions to improve parent-provider interactions during the diagnostic odyssey and to systematically evaluate the impact on time to diagnosis, access to care and patient health outcomes.
Clinical characteristics and real-world outcomes in patients with mucopolysaccharidosis II over 18 years: final report of the Hunter Outcome Survey.
Muenzer J, Botha J, Amartino H … +12 more , Giugliani R, Harmatz P, Kampmann C, Link B, Lin SP, Molter D, Raiman J, Scarpa M, Tylki-Szymańska A, Jain S, Whiteman DAH, Burton BK
Mol Genet Metab · 2025 Dec · PMID 41232197 · Publisher ↗
BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare, progressive, X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase has been approved for the treatment of patients...
BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare, progressive, X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase has been approved for the treatment of patients with MPS II since 2005. The Hunter Outcome Survey (HOS; NCT03292887) was established as a condition of approval to monitor the long-term safety and effectiveness of idursulfase. Here, we report the final results from HOS. METHODS: HOS was a multicenter, long-term, observational registry that enrolled patients with a biochemically and/or genetically confirmed diagnosis of MPS II who were untreated or treated with idursulfase and/or bone marrow transplant. Patients were enrolled prospectively (alive at enrollment) and retrospectively (deceased at enrollment). For prospectively enrolled patients, it was requested that data from routine examinations were recorded after each follow-up visit and/or a minimum of every 6 months. The safety population (SP) included patients who received at least one dose of idursulfase and were alive at HOS entry. The treatment outcomes population (TOP) included patients who received at least one dose of idursulfase and were alive at HOS entry, excluding patients who received a bone marrow transplant, patients for whom an informed consent form could not be generated by the center, and patients with a missing date of birth. Safety and effectiveness endpoints were analyzed with descriptive statistics. RESULTS: In total, 1332 patients were enrolled in HOS. For patients in the SP (N = 1014), the median (10th percentile, 90th percentile) age at initiation of ERT with idursulfase was 5.7 (1.6, 18.1) years, ranging from 0.0 to 65.5 years. In the TOP (N = 989), a consistent and sustained decline in urinary glycosaminoglycan levels, trends of sustained improvements in walking capacity and left ventricular mass index, and reductions in liver and spleen size were observed. Treated patients also demonstrated a median increase in survival time of approximately 10 years and a 57.9 % lower risk of death compared with an unmatched cohort of untreated patients. In the SP, 691 patients (68.1 %) experienced at least one adverse event and 269 (26.5 %) experienced at least one infusion-related reaction (IRR); most were mild or moderate in severity. There was no relationship observed between anti-drug antibody status and IRR rates. CONCLUSION: Data from HOS, collected for over 18 years, represent the largest dataset of patients with MPS II to date. The effectiveness and safety profile of idursulfase support its use for the long-term treatment of patients with MPS II.
Propionic acidemia and methylmalonic aciduria: A portrait of the first 3 years-Admissions and complications.
Chapman KA, Ah Mew N, Mickle N … +2 more , Starin D, MacLeod E
Mol Genet Metab · 2025 Dec · PMID 41232196 · Publisher ↗
BACKGROUND: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are organic acidurias that can present with metabolic acidosis and hyperammonemia, often leading to frequent hospital admission. While recent studies h...
BACKGROUND: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are organic acidurias that can present with metabolic acidosis and hyperammonemia, often leading to frequent hospital admission. While recent studies have provided guidelines for management and diagnosis of these conditions, there is a lack of research detailing the frequency and reasons for hospital admission in the first three years of life. METHODS: As part of a quality improvement project, data were extracted from medical records of all patients with PA and MMA (born between 2000 and 2024) who were seen at Children's National Hospital (CNH) during their first three years of life, time of data pull, or up to point of liver transplant. We collected data on the number of individuals with PA or MMA in our patient population, the age at which they first presented, and the reason for their hospital admission. RESULTS: Our cohort included 11 individuals with MMA, all of whom had MMUT mutations, representing a total of 12 different variants. Additionally, 15 individuals with PA were reported. Of these, 2 individuals with PA did not undergo genetic testing, 5 had 7 separate variants in PCCA gene, and 8 had 10 different variants in PCCB gene. The mean number of hospitalizations for metabolic decompensation was 4.45 ± 6.6 for the MMA cohort and 8.7 ± 6.7 for the PA cohort, with no statistically significant difference between the groups. The MMA cohort experienced a total of 49 admissions, 16 (33 %) of which occurred in the first year of life. In the PA cohort, there were 130 total admissions, with 56 (43 %) occurring in the first year. The most frequent reason for admission in both groups was vomiting. DISCUSSION/CONCLUSIONS: Individuals with PA and MMA are frequently hospitalized (accounting for 5-6 % of their first three years of life) which likely impacts development and overall health. Data such as those presented in this study are crucial for improving our understanding of disease progression in these rare conditions. This information can help guide future research, support the development of the clinical guidelines, and provide healthcare providers with valuable insights to better educate families on risks and expectations. Using these data, we have altered our counseling at the time of diagnosis to better prepare families for their child's course.
MEHMO syndrome: Review and proposed classification as an eIF2-related neuroendocrinopathy.
Dang Do AN, Navid F, Young-Baird SK
Mol Genet Metab · 2025 Dec · PMID 41207135 · Full text
MEHMO syndrome (OMIM#300148) is a rare, X-linked, multisystemic condition that predominantly involves endocrinologic and neurologic dysfunctions. Initial naming of the syndrome emphasizes the presentation of Mental disab...
MEHMO syndrome (OMIM#300148) is a rare, X-linked, multisystemic condition that predominantly involves endocrinologic and neurologic dysfunctions. Initial naming of the syndrome emphasizes the presentation of Mental disability, Epileptic seizures, Hypogonadism/Hypogenitalism, Microcephaly, and Obesity. This review provides a synthesis of the genetics, genotypes, and phenotypes of publicly available information on EIF2S3 and MEHMO syndrome. Identification and confirmation of variants in the gene EIF2S3 as the genetic underpinning of the syndrome's pathophysiology and reports of additional cases suggest a consideration for a re-definition of the acronym and a re-classification of the condition along with others as eIF2-related neuroendocrinopathies. This would allow for more standardized and encompassing characterization of the group of eIF2-related disorders, that in turn would support and continue to spur further research progress in basic pathophysiology, disease diagnosis and monitoring, and biomarker and therapeutic discoveries.
Correlation of Plasma Lyso-GL1 Levels with Clinical Phenotype and Treatment Decisions in Patients with Gaucher Disease.
Cheung C, Fierro L, McDonough C … +7 more , Stauffer C, Kaplan R, Bier L, Yu C, Evard R, Ganesh J, Balwani M
Mol Genet Metab · 2025 Dec · PMID 41205343 · Publisher ↗
In Gaucher disease (GD), clinical management is complicated by heterogeneity and the lack of standardized guidelines for treatment initiation. As patients are being identified pre-symptomatically or as mildly affected th...
In Gaucher disease (GD), clinical management is complicated by heterogeneity and the lack of standardized guidelines for treatment initiation. As patients are being identified pre-symptomatically or as mildly affected through carrier and newborn screening programs, timing of treatment is an increasingly important issue. This study evaluated the utility of plasma lyso-GL1 as an objective biomarker to inform treatment decisions. Retrospective data were analyzed from 240 GD patients with lyso-GL1 levels measured primarily at a single laboratory between June 2018 and September 2023. The study population included both adult (n = 194, 80.8 %) and pediatric (n = 46, 19.2 %) patients predominantly diagnosed with type 1 GD (n = 234, 97.5 %) and self-identified as Jewish (82.1 %). Among 25 patients who initiated GD-specific treatment during the study period with available pre-treatment lyso-GL1 data, the median age at treatment initiation was 33 years. In this group, the median baseline lyso-GL1 was 91.6 ng/mL, which declined to 19.5 ng/mL following treatment with a median follow-up of 2.9 years. In contrast, untreated patients had a median baseline lyso-GL1 of 14.2 ng/mL, which increased to 17.0 ng/mL over a similar follow-up period. Logistic regression and receiver operating characteristic analysis identified a lyso-GL1 threshold of 78.9 ng/mL that effectively discriminated treatment status in GD1 patients, with an area under the curve of 0.865, sensitivity of 73 %, and specificity of 96 %. The predictive performance of this identified threshold was comparable to that reported in a previous study, underscoring the reproducibility and potential utility of lyso-GL1 as a reliable and objective biomarker to guide treatment initiation in Gaucher disease.
Mild pancreatic fibrosis with preserved exocrine function and increased visceral adipose tissue in m.3243A>G carriers: A magnetic resonance imaging study.
Nielsen SR, Gjela M, Stoico MP … +7 more , Drewes AM, Olesen SS, Højlund K, Pedersen IS, Brock C, Frøkjær JB, Frederiksen AL
Mol Genet Metab · 2025 Dec · PMID 41205342 · Publisher ↗
BACKGROUND: Carriers of the mitochondrial variant m.3243A>G have a high risk of diabetes mellitus and frequently report gastrointestinal symptoms, suggesting a dual endocrine and exocrine pancreas dysfunction. Whether ch...
BACKGROUND: Carriers of the mitochondrial variant m.3243A>G have a high risk of diabetes mellitus and frequently report gastrointestinal symptoms, suggesting a dual endocrine and exocrine pancreas dysfunction. Whether changes in pancreatic morphology, abdominal or ectopic fat distribution contribute to these conditions, remains unknown. METHODS: Twelve m.3243A>G carriers with diabetes, 11 carriers without diabetes, and 23 healthy controls underwent abdominal magnetic resonance imaging (MRI). T1 relaxation time and magnetic resonance elastography (MRE) stiffness estimated pancreatic fibrosis. Pancreas volume was assessed by MRI and combined with faecal elastase measurements to evaluate exocrine pancreatic function. The ectopic fat content of muscle and the pancreas was estimated using proton density fat fraction, alongside abdominal fat measurements of cross-sectional areas (CSA) of visceral and subcutaneous adipose tissue. The homeostasis model assessment 2 (HOMA2) was used to estimate insulin resistance (HOMA2-IR). RESULTS: Compared to healthy controls, carriers with diabetes had an increased median [IQR] T1 relaxation time (909 ms [868-1085] vs. 823 ms [785-852], p < 0.001) and MRE stiffness (1.32 kPa [1.24-1.43] vs. 1.23 kPa [1.12-1.28], p = 0.03). There was no difference in pancreas volume or evidence of exocrine pancreatic dysfunction evaluated by faecal elastase. Visceral adipose tissue CSA median [IQR] was increased in m.3243A>G carriers compared to controls (61.0 cm [26.4-100.9] vs. 27.9 cm [17.2-65.0], p = 0.03) and correlated positively with HOMA2-IR (r = 0.7, p < 0.001). CONCLUSION: Increased T1 relaxation time and MRE stiffness indicate mild pancreatic fibrosis in m.3243A>G carriers with diabetes, without further evidence of exocrine insufficiency. Visceral fat was increased in m.3243A>G carriers and associated with insulin resistance, implying metabolic dysregulation.
Identification of variants of the MTR gene in patients with the cblG inborn error of cobalamin metabolism diagnosed by somatic cell complementation analysis.
Watkins D, Zacharias C, Arbabian-Urquilla K … +6 more , Ragupathi K, Gilfix BM, Jimenez D, Anastasio N, Rivière JB, Rosenblatt DS
Mol Genet Metab · 2025 Dec · PMID 41202372 · Publisher ↗
PURPOSE: The cblG inborn error of vitamin B metabolism is associated with pathogenic variants in the MTR gene, which encodes methionine synthase. Approximately 50 patients with the disorder have been reported, and 54 pot...
PURPOSE: The cblG inborn error of vitamin B metabolism is associated with pathogenic variants in the MTR gene, which encodes methionine synthase. Approximately 50 patients with the disorder have been reported, and 54 potentially causal MTR variants published. METHODS: We performed next generation sequencing and copy number variant analysis of MTR on genomic DNA from 29 cblG patients, including 7 patients that had been previously sequenced with incomplete results. All patients had been diagnosed using somatic cell complementation analysis. RESULTS: We identified two potential causal variants in each of the patients analyzed, although parental phasing was not done. 39 different variants were identified, including 24 not previously described in the published literature. The most common identified causal variant was c.3518C > T, p.P1173L (8 alleles). The previously identified deep intronic variants c.340-166 A > T and c.609 + 1088G > A were also seen frequently (6 alleles each). Among the newly identified variants, the most common were c.2020C > T p.Arg674Cys (3 alleles) and c.1325C > A, p.Ala442Glu (2 alleles). CONCLUSION: Identification of pathogenic or likely pathogenic variants was enhanced by knowledge of complementation status which has become less frequent as somatic cell testing becomes less readily available.
Commentary on the article "Progressive activation of the astrocyte A1 phenotype underlies microglia-astroglia crosstalk and contributes to neuroinflammation in neuronopathic MPS".
Gao Y, Wang W, Leng J
Mol Genet Metab · 2025 Dec · PMID 41197177 · Publisher ↗
Abstract loading — click title to view on PubMed.
Barth syndrome: Natural history in infants and young children.
Vishwanath S, Brockmeyer A, Hornby B … +2 more , Thompson WR, Vernon HJ
Mol Genet Metab · 2025 Dec · PMID 41177130 · Publisher ↗
Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by pathogenic variants in TAFAZZIN. It is characterized by cardiomyopathy, neutropenia, growth delay, skeletal myopathy, and developmental concerns....
Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by pathogenic variants in TAFAZZIN. It is characterized by cardiomyopathy, neutropenia, growth delay, skeletal myopathy, and developmental concerns. Advances in genetic testing have enabled earlier diagnoses, creating opportunities to better define the natural history of disease in infancy and early childhood. We conducted a longitudinal, observational study of 21 male patients (ages 0-48 months) with genetically confirmed BTHS evaluated at the Barth Syndrome Interdisciplinary Clinic at Kennedy Krieger Institute. Data collected included perinatal history, growth, feeding, cardiac function, hematologic findings, gross motor development, quality of life, and pain assessment. Gross motor skills were assessed via milestone acquisition and the Peabody Developmental Motor Scales (PDMS-2/3). Quality of life was evaluated using the PedsQL™ parent-proxy questionnaire. The most common presenting features were cardiomyopathy (n = 10) and failure to thrive (n = 6), with an average age at diagnosis of 5.5 months, which was significantly earlier than historical cohorts. Eighteen patients developed cardiac dysfunction, 25 % required heart transplantation, and one death occurred due to cardiopulmonary arrest. Feeding difficulties were frequent, with 16 patients affected and 7 requiring gastrostomy tubes. Growth delay was common, though height/weight ratios were often preserved. Neutropenia was present in 19 patients, with variable severity and infection risk. Gross motor development was delayed, particularly for standing and walking, with progressive deficits on PDMS subtests. Quality of life scores indicated substantial impairment, especially in fatigue and general functioning domains. Pain was rarely reported. We conclude that infants and toddlers with BTHS present with significant cardiac, growth, and developmental abnormalities. Earlier diagnosis facilitated by genetic testing allows for earlier intervention and monitoring. These findings highlight the need for proactive cardiac surveillance, nutritional support, and early therapeutic interventions to optimize outcomes, and they provide critical endpoints for future clinical trials in this young age group.
Clinical utility of untargeted urine oligosaccharide screening.
Pino GB, Quade MA, Schultz MJ … +8 more , White AL, Peck DS, Studinski Jones AL, Gavrilov DK, Oglesbee D, Tortorelli S, Matern D, Hall PL
Mol Genet Metab · 2025 Dec · PMID 41175544 · Publisher ↗
High-resolution urine oligosaccharide screening with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been clinically available for 10 years and has been used to help diagno...
High-resolution urine oligosaccharide screening with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been clinically available for 10 years and has been used to help diagnose a wide spectrum of disorders. The untargeted nature of MALDI-TOF MS analysis gives it broad clinical utility. Here we report characteristic profiles for several disorders that had not previously been described using this method, including lysosomal disorders, congenital disorders of glycosylation, and glycogen storage disorders. In addition, we review the clinical performance of the assay in our laboratory and provide basic test performance information for each condition. A total of 4445 analyses performed with 4145 unique patient samples generated 139 confirmed and presumptive positive results and 16 false-positive results. The disorder with the highest rate of false positivity was Pompe disease, which has an oligosaccharide profile similar to that seen in formula-fed infants. The positive predictive value of urine oligosaccharide screening with MALDI-TOF MS was 89.7 % across all conditions. For 10 of the 16 conditions detected during the study period, no false-positive results occurred. No known false-negative results were reported for any of the targeted conditions. Urine oligosaccharide analysis with MALDI-TOF MS, which uses an accessible specimen type and offers quick turnaround time, is an effective initial screening method for patients with a clinical presentation suggestive of a lysosomal disorder.
Oral D-mannose therapy during pregnancy in a woman with MPI-CDG: A case report and management review.
Martzolff L, Raynor A, Lebredonchel E … +13 more , Marescaux S, Desprez D, Douillard C, Federici L, Alamome I, Trillot N, Alili JM, Harroche A, Borgel D, Wicker C, Terrade JE, Bruneel A, De Lonlay P
Mol Genet Metab · 2025 Dec · PMID 41172867 · Publisher ↗
Mannose 6-phosphate isomerase deficiency is a rare disorder of N-glycosylation leading to impaired coagulation, enteropathy, hypoglycemia and liver disease. D-mannose is the only available treatment. We report the case o...
Mannose 6-phosphate isomerase deficiency is a rare disorder of N-glycosylation leading to impaired coagulation, enteropathy, hypoglycemia and liver disease. D-mannose is the only available treatment. We report the case of a pregnant woman with MPI-CDG and the management of D-mannose therapy during pregnancy. D-mannose was discontinued at 6 weeks' gestation, due to the potential fetal toxicity observed particularly in animal models, but severe digestive symptoms and hypoglycemia relapsed. We decided to readminister D-mannose therapy at 10 weeks' gestation although data on teratogenecity in humans are lacking. Symptoms resolved rapidly when D-mannose was resumed. Monitoring of transferrin glycoforms profile and coagulation parameters allowed to gradually increase D-mannose dosage throughout pregnancy. The patient delivered at 38 weeks' gestation after an intrauterine growth retardation was noted. The infant was 2.390 kg at birth with a low Apgar score but rapidly recovered. Low dose D-mannose treatment administered from 10 weeks' gestation could be a safe option for women with MPI-CDG.
Nationwide Study of the Epidemiology and Clinical Features of X-Linked Adrenoleukodystrophy in Denmark.
Videbæk CS, Dunø M, Lindquist SG … +6 more , Larsen VA, Kjær MW, Melgaard L, Nielsen JE, Grønborg SW, Lund AM
Mol Genet Metab · 2025 Dec · PMID 41166774 · Publisher ↗
BACKGROUND AND OBJECTIVE: This nationwide, single-cohort study provides a comprehensive analysis of the epidemiology of X-linked adrenoleukodystrophy (ALD) in Denmark. We examined incidence, age at symptom onset, and sex...
BACKGROUND AND OBJECTIVE: This nationwide, single-cohort study provides a comprehensive analysis of the epidemiology of X-linked adrenoleukodystrophy (ALD) in Denmark. We examined incidence, age at symptom onset, and sex-stratified survival outcomes to explore differences in symptom development. Findings were compared with international cohorts to contextualize the Danish results. METHODS: We included all individuals with genetically confirmed ALD residing in Denmark, with no age restrictions. Patients were born between 1911 and 2020. Clinical data were retrospectively extracted from medical records. Where available, dried blood spots collected at birth and stored in the Danish National Biobank were analyzed using liquid chromatography-mass spectrometry to quantify C26:0-lysophosphatidylcholine (C26:0-LPC). Cumulative incidence functions were used to estimate the risk of developing specific ALD phenotypes over time. RESULTS: A total of 113 individuals (49 males, 64 females) met inclusion criteria. The point prevalence of ALD was 1.42 per 100,000, and the average birth incidence from 1932 to 2023 was 1.81 per 100,000 (males: 1.7; females: 1.9). Thirty-four distinct pathogenic ABCD1 variants were identified, with c.1679C > T, p.(Pro560Leu) being the most common (21 cases). By age 60, 76 % of males had developed adrenomyeloneuropathy (AMN), 44 % had developed cerebral ALD (cALD), and 44 % had adrenal insufficiency. Among females, 80 % had developed AMN by the same age. AMN was associated with the longest diagnostic delay, averaging 8 years in males and 9 years in females. DISCUSSION: This study offers a rare, nationwide view of ALD spanning over a century of births alongside measurement of C26:0-LPC in historical, neonatally collected dried blood spot cards from 14 individuals in this cohort. While the birth incidence aligns with some other natural history studies, it remains lower than in countries with universal newborn screening. The high frequency of AMN in both sexes highlights the need for greater clinical awareness. Notably, our findings confirm that the majority of women with ALD will develop neurological symptoms over time, challenging the long-standing perception of female carriers as largely asymptomatic. The relatively low detection of cALD and adrenal insufficiency in adults suggests possible underdiagnosis and calls for improved long-term follow-up, especially in adult neurology and endocrinology.
Accumulation of complex I assembly intermediates in a novel presentation of RTN4IP1-related disorder with developmental delay, ataxia and dyskinesia.
Thys L, Beysen D, Janssens K … +7 more , Jansen AC, Gueguen N, LeMao M, Fontaine F, Allouche S, Lenaers G, Meuwissen M
Mol Genet Metab · 2025 Nov · PMID 41161158 · Publisher ↗
BACKGROUND: Biallelic variants in RTN4IP1 (OPA10) are associated with a wide phenotypic spectrum including optic atrophy with or without ataxia, impaired intellectual development and seizures (OMIM 616732). Brain imaging...
BACKGROUND: Biallelic variants in RTN4IP1 (OPA10) are associated with a wide phenotypic spectrum including optic atrophy with or without ataxia, impaired intellectual development and seizures (OMIM 616732). Brain imaging ranges from normal to white matter changes and cerebral atrophy. Earlier literature has reported a combined complex I and IV deficiency in RTN4IP1 cases. RESULTS: We report on three siblings, compound heterozygous for novel RTN4IP1 variants who presented with a movement disorder with pronounced dyskinesia along with developmental delay, optic atrophy and ataxia. Furthermore, atypical brain MRI findings with symmetrical bilateral substantia nigra abnormalities were observed in two of them. Blue native polyacrylamide gel electrophoresis performed on fibroblasts of two patients revealed a defect in the complex I assembly process. CONCLUSION: Thus, we expand the clinical spectrum of RTN4IP1-associated disease with movement disorder, substantia nigra abnormalities and complex I assembly defects.
Should the "mitochondrial cocktail" be a default option? An opinion.
Stacpoole PW, Cederbaum SD
Mol Genet Metab · 2025 Dec · PMID 41161075 · Publisher ↗
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Letter to the editors: Supervised machine learning prediction of genotype-phenotype correlations in PMM2-CDG, in response to Pajusalu et al. [].
Boonnak J
Mol Genet Metab · 2025 Nov · PMID 41130016 · Publisher ↗
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Clinical utility of the ATP hydrolysis assay for the diagnosis of complex V deficiency in cultured skin fibroblasts.
Friederich MW, Van Hove JLK
Mol Genet Metab · 2025 Nov · PMID 41124875 · Full text
Complex V catalyzes the formation of ATP from ADP and P through the dissipation of the proton gradient generated during the process of oxidative phosphorylation. Most complex V genetic disorders are caused by missense mu...
Complex V catalyzes the formation of ATP from ADP and P through the dissipation of the proton gradient generated during the process of oxidative phosphorylation. Most complex V genetic disorders are caused by missense mutations in the mtDNA-encoded subunits, a (MT-ATP6) and A6L (MT-ATP8). Nuclear DNA-encoded gene mutations are increasingly recognized as causes of complex V defects and exhibited both autosomal recessive and autosomal dominant inheritance. Most identified variants are novel and confirmation by functional assays is important especially for variants demonstrating autosomal dominant inheritance. A kinetic spectrophotometric assay of the Complex V enzymatic hydrolysis activity has been reported. Here we report the clinical utility of this assay for the diagnosis of complex V deficiency after optimization and validation for the diagnosis of isolated complex V disorders due to both nuclear and mitochondrial DNA encoded variants and also for use in combined respiratory chain deficiencies. This assay was able to identify all nuclear DNA-encoded complex V deficiencies, whereas a decrease in complex V activity was observed in some patient cell lines with combined deficiencies. However, this assay only identified 50% of the mitochondrial DNA-encoded complex V deficiencies due to pathogenic variants in MT-ATP6/8. In conclusion, the enzymatic assay of complex V has best clinical utility for nuclear DNA-encoded complex V defects.
Adenylosuccinate synthetase deficiency and purine nucleotide cycle disruption impair neuromuscular function in Caenorhabditis elegans.
Patil RR, Franklin LP, Jin MD … +1 more , Hanna-Rose W
Mol Genet Metab · 2025 Nov · PMID 41101294 · Full text
The critical role of the purine nucleotide cycle (PNC) in human health is underscored by the fact that mutations in adenylosuccinate synthetase (ADSS) and adenylosuccinate lyase (ADSL), two of its three enzymes, are asso...
The critical role of the purine nucleotide cycle (PNC) in human health is underscored by the fact that mutations in adenylosuccinate synthetase (ADSS) and adenylosuccinate lyase (ADSL), two of its three enzymes, are associated with severe inborn errors of purine metabolism. We use Caenorhabditis elegans to investigate the biological roles of the PNC and to characterize developmental and behavioral functions of ADSS and ADSL. Here we report that adss-1, which encodes ADSS in C. elegans, is required for fertility and locomotion. adss-1 loss-of-function mutants also have small body size, and their development is severely delayed. These phenotypes are shared with adsl-1, which encodes ADSL, suggesting that an intact PNC is required for C. elegans development. Interestingly, adss-1 and adsl-1 each have unique phenotypes not shared with the other. adss-1-specific phenotypes include excessive excitatory (or decreased inhibitory) synaptic transmission at the neuromuscular junction and impaired mechanosensation, suggesting an important function in the nervous system. We have also established a powerful model for further investigation of how ADSS activity impacts mobility, providing insight into the poorly understood molecular mechanisms driving phenotypic outcomes in ADSS1 deficiency.
Effectiveness of newborn screening for X-linked disorders in females: A scoping review.
Geiger H, Furuta Y, Phillips JA … +1 more , Tinker RJ
Mol Genet Metab · 2025 Nov · PMID 41101293 · Publisher ↗
PURPOSE: Newborn screening (NBS) identifies thousands of infants annually with conditions amenable to early intervention. Although several X-linked (XL) conditions in NBS panels are viewed as primarily male disorders, em...
PURPOSE: Newborn screening (NBS) identifies thousands of infants annually with conditions amenable to early intervention. Although several X-linked (XL) conditions in NBS panels are viewed as primarily male disorders, emerging evidence shows females also present clinically. This scoping review evaluates NBS efficacy for detecting XL conditions in females. METHODS: Twelve XL genetic disorders were identified through cross-referencing the Recommended Uniform Screening Panel, American College of Medical Genetics ACT sheets, and available literature. A systematic search and scoping review identified studies reporting NBS outcomes. RESULTS: All twelve XL disorders reviewed affect females, often with milder phenotypes, likely due to X-inactivation. However, only 6/12 (50 %) of these conditions had relevant NBS data, and female cases were rare. Only 92/221 (42 %) of the studies included detected female cases. Skewed X-inactivation may modulate expression, leading to biomarker levels within reference ranges and reducing detection. CONCLUSIONS: Although XL conditions affect both sexes, current NBS protocols rarely detect females or don't report sex-specific data at all. This absence highlights broader gaps in how screening outcomes are reported. Addressing these limitations may require sex-specific biomarker thresholds, alternative biomarkers, or genetic testing. Such efforts are necessary to ensure that NBS programs equitably serve all affected newborns.
Novel murine model provides insights into early-onset of kidney disease in glycogen storage disease type Ib.
Pratap K, Lee C, Zhang L … +4 more , Chen HD, Arnaoutova I, Mansfield BC, Chou JY
Mol Genet Metab · 2025 Nov · PMID 41101292 · Full text
Glycogen storage disease type Ib (GSD-Ib), caused by a deficiency of the glucose-6-phosphate transporter (G6PT), is characterized by impaired glucose homeostasis and progressive renal dysfunction. Using G6pt-deficient (G...
Glycogen storage disease type Ib (GSD-Ib), caused by a deficiency of the glucose-6-phosphate transporter (G6PT), is characterized by impaired glucose homeostasis and progressive renal dysfunction. Using G6pt-deficient (G6pt-/-) mice, which closely recapitulate the pathophysiology of GSD-Ib, we previously demonstrated that GSD-Ib nephropathy is marked by disrupted renal homeostasis, acute kidney injury, and fibrosis. However, due to the severity of the metabolic defect, G6pt-/- mice typically fail to survive beyond three weeks of age, limiting the study of disease progression in adulthood. To overcome this limitation, we generated liver human G6PT-augmented, kidney G6PT-deficient (L-hG6PT/K) mice, which restore hepatic G6PT expression to support survival while maintaining G6PT deficiency in the kidney. We show that adult L-hG6PT/K mice develop renal abnormalities similar to those seen in 3-week-old global G6pt-/- mice. Importantly, unlike the younger cohort, 12-week-old L-hG6PT/K mice exhibit a progressive decline in renal function accompanied by marked fibrosis. These findings establish L-hG6PT/K mice as a robust and physiologically relevant model for investigating the mechanisms and progression of GSD-Ib nephropathy in mature animals.
Functional ability profiles in beta-propeller protein-associated neurodegeneration (BPAN).
Gavazzi F, Pierce SR, Smith V … +14 more , Yang E, Skorup J, Pucci K, Kotes E, Glanzman AM, Cusack SV, Levy T, Dubbs H, Wiener E, Woidill S, Vithayathil J, Jawad A, Thakur N, Adang LA
Mol Genet Metab · 2025 Nov · PMID 41101291 · Publisher ↗
BACKGROUND: Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare neurodevelopmental degenerative disorder caused by pathogenic variants in WDR45 leading to brain iron accumulation. Its rarity and complex...
BACKGROUND: Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare neurodevelopmental degenerative disorder caused by pathogenic variants in WDR45 leading to brain iron accumulation. Its rarity and complex clinical course make it difficult to select appropriate clinical outcome assessments (COAs). This study evaluates established COAs for feasibility and effectiveness in capturing BPAN's functional ability profiles exploring cognitive, motor, and behavioral features. METHODS: We performed an observational study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We administered the Gross Motor Function Measure-88 (GMFM-88), the Leiter International Performance Scale (Leiter-3), and the Vineland Adaptive Behavior Scale (VABS-3). A Rasch validated version of the GMFM-88, the GMFM-66, was derived from the GMFM-88 data. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Statistical analyses were performed to compare performance across cohorts and assess correlations, with significance defined as p < 0.05. RESULTS: Fifty-three individuals (43 females, 10 males) with molecularly confirmed BPAN participated. The VABS-3 (n = 53) showed a decline in adaptive skills over time, with significant differences between Communication and Socialization Domain performance (Kruskal-Wallis test with Dunn's correction p < 0.0001). GMFM-88 assessments (n = 32) showed a median performance of 33.4 %. Patient participation/behavior affected data completeness. The more limited GMFM-66 correlated better with the VABS-3 Gross Motor subdomain than the GMFM-88 (r = 0.94, r = 0.73, respectively). The Leiter-3 (n = 36) demonstrated significant non-verbal cognitive impairment, although there were behavioral challenges which impacted implementation. Longitudinal VABS-3 data revealed a median - 2.9 points/year decline in Adaptive Behavior Composite scores, reflecting progressive functional loss. DISCUSSION: This study highlights key considerations for selecting COAs in BPAN. The panel of COAs should accommodate the behavioral challenges associated with BPAN that can limit participant compliance with testing. The abbreviated GMFM-66 was a more reliable tool to capture motor skills. Similarly, behavioral difficulties impacted Leiter-3 performance, which demonstrated general impairment in non-verbal cognitive skills. The VABS-3 effectively tracked adaptive function decline, demonstrating feasibility for longitudinal monitoring. Future studies should expand cohort size, refine assessment strategies, and align measures with disease progression to optimize clinical trial readiness.
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