Sarafoglou K, Lam C, Edmondson AC
… +14 more, Miller A, Starosta RT, Zeighami A, Horikoshi S, Vreugdenhil H, Scaglia F, Kozicz T, Tan QKG, Miller BS, Martínez-Duncker I, Berry GT, McWilliams P, Morava E, Addo Y
Mol Genet Metab
· 2026 Jun · PMID 42030611
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BACKGROUND: Growth faltering is prevalent in 96% of children with Phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG). Published long-term growth data is extremely limited. Growth and weight patterns of...BACKGROUND: Growth faltering is prevalent in 96% of children with Phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG). Published long-term growth data is extremely limited. Growth and weight patterns of PMM2-CDG children differ from the general population limiting the utility of existing normative growth charts to track development trajectory in comparison to peers with PMM2-CDG. OBJECTIVE: Create PMM2-CDG disease-specific height-, weight-, and BMI-for-age reference growth charts (0-20 years). METHODS: De-identified growth data was provided by Frontiers in Congenital Disorders of Glycosylation Consortium, CDG Care, Minnesota Partnership for Biotechnology and Medical Genomics, and Glycomine, Inc. Semi-parametric modeling techniques were used to develop PMM2-CDG-specific charts along with nodal-point analyses for quantifying and examining PMM2-CDG growth differences relative to Centers for Disease Control (CDC) reference using one-sided quantile tests. RESULTS: Data of 156 children (females n = 75) with PMM2-CDG from 1614 visits were used to create height-, weight- and BMI-for-age growth curves. Median follow-up was 8.5 years (SD 4.5) for females and 6.8 years (SD 4.4) for males. CDG females were 13 cm shorter than their CDC reference peers at 20 years (150 vs 163 cm), and males were 16 cm shorter (160 vs 176 cm). All weight and height nodal points were significantly different (p < 0.05) at each age (4, 8, 12, 16, 20 years). CONCLUSION: PMM2-CDG specific reference charts can help enable the detection of deviations from peer growth patterns, aid in early detection of coexisting endocrinopathies, help guide treatment decisions and evaluate the effectiveness of new disease-modifying treatments in clinical trials.
Mol Genet Metab
· 2026 Jun · PMID 42025243
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The Urea cycle disorders (UCDs) represent a group of rare inborn errors of metabolism that have impaired nitrogen handling from the breakdown of protein, with ensuing acute episodic or chronic hyperammonemia and neurotox...The Urea cycle disorders (UCDs) represent a group of rare inborn errors of metabolism that have impaired nitrogen handling from the breakdown of protein, with ensuing acute episodic or chronic hyperammonemia and neurotoxicity. Although advances in newborn screening, molecular diagnosis, and therapeutic interventions have improved survival, neurocognitive, behavioral, and psychiatric sequelae remain prevalent in those with both neonatal onset as well as later onset partial deficiencies. The mechanisms of brain injury in UCDs are complex and multifactorial, and in some cases are not fully known. Common themes include astrocytic dysfunction, altered neurotransmitter cycling, oxidative stress, and energy failure. Neuromonitoring including EEG and Neuroimaging has become a cornerstone in elucidating these mechanisms in UCD patients, offering objective biomarkers to detect subclinical injury, guide management, and evaluate treatment efficacy. This review synthesizes current neuroimaging therapies used in routine clinical practice (structural MRI, Diffusion imaging), as well as research focused and emerging imaging modalities including magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), functional MRI (fMRI), and functional near-infrared spectroscopy (fNIRS) and discusses their translational potential beyond diagnostic entities as prognostic and therapeutic biomarkers in UCDs. Novel approaches such as glutamine chemical exchange saturation transfer (GlnCEST) imaging and multimodal integration with omics data may offer a framework for predictive modeling and precision-guided care. The validation of imaging biomarkers across multicenter studies and across field strengths represents a critical next step in the evolution of neuroimaging from descriptive to quantitative, prognostic, and regulatory endpoints in metabolic disorders. Important issues in multicenter harmonization will be addressed but not discussed in detail.
The glycoproteinoses represent a mechanistically related group of ultra-rare lysosomal disorders characterized by progressive neurodegeneration, multisystem involvement, and a profound lack of disease-modifying therapies...The glycoproteinoses represent a mechanistically related group of ultra-rare lysosomal disorders characterized by progressive neurodegeneration, multisystem involvement, and a profound lack of disease-modifying therapies. These nine distinct disorders, α-mannosidosis, β-mannosidosis, aspartylglucosaminuria, fucosidosis, galactosialidosis, mucolipidosis II, mucolipidosis III, sialidosis, and Schindler disease, share a convergent clinical burden of progressive neurodegeneration, skeletal dysplasia, sensorineural hearing loss, ataxia, recurrent infections, and premature mortality. Despite advances in molecular diagnosis and growing interest in gene- and enzyme-based therapeutics, clinical development across this disease class has stalled. The principal barrier is not biological feasibility, but the absence of regulatory-ready clinical outcome assessments and biomarkers capable of capturing meaningful disease progression and treatment response, particularly within the central nervous system. This review examines the shared translational challenges that currently limit therapeutic advancement in glycoproteinoses, with emphasis on outcome measurement, biomarker validation, and trial interpretability in ultra-rare populations. We highlight recurrent limitations of existing approaches, including reliance on non-validated functional measures, peripheral biomarkers with poor correlation to neurologic disease burden, and fragmented natural history datasets. Building on these insights, we propose a harmonized, cross-disease framework that integrates standardized functional assessments with disease-relevant biochemical profiling to support efficient natural history studies and enable regulatory-aligned clinical trials. Adoption of this unified strategy may accelerate therapeutic development across the glycoproteinoses and serve as a model for other ultra-rare lysosomal disorders.
INTRODUCTION: Children with leukodystrophy experience progressive physical and cognitive decline, which can lead to suffering. Palliative care consultation can help with multimodal symptom management, building trust with...INTRODUCTION: Children with leukodystrophy experience progressive physical and cognitive decline, which can lead to suffering. Palliative care consultation can help with multimodal symptom management, building trust with medical teams, and managing advanced care planning in children with severe neurological impairment. OBJECTIVES: To evaluate palliative care's role, timing, and impact on end-of-life for children with leukodystrophy. METHODS: Single-center retrospective chart review conducted on patients (0-18 years) with leukodystrophy at Children's Healthcare of Atlanta from 2016 to 2023. RESULTS: 206 patient charts were included. Of all patients with leukodystrophy, 26% (53/206) had a palliative care consultation. It took average interval of 2.4 years from date of diagnosis to palliative care consultation. The hospitalist team (38%) and ICU team (26%) placed most referrals. Of the cohort, 20% (41/206) of the patients had died, average age of death 5.2 years. Of deceased, 63% (27/41) had a palliative care consult. 54% (22/41) of the deceased were enrolled in hospice. 29% (11/41) of deceased had full code status, 42% (16/41) were DNR/DNI, and 29% (11/41) were exclusively DNR. Most patients with leukodystrophy who died did so in the hospital, 37% (n = 13) of whom died in the ICU and 17% (n = 6) on the acute care floors. More than a quarter of those that died, 40% (n = 14), died at home. In the deceased, those enrolled in hospice were more likely DNR/DNI and to die at home instead of the hospital (p = 0.019, p < 0.001). In the deceased, there was no statistical difference in number of days admitted nor in number of hospitalizations in the last year of life between those enrolled and not enrolled in hospice (p = 0.871, p = 0.077). CONCLUSION: Pediatric patients and caregivers can benefit from goals of care conversations and advanced care planning while navigating the neurodegenerative disease process. There are unique psychosocial and medical needs in leukodystrophy population, and many opportunities to improve neuro-palliative integration early in the disease course for children with leukodystrophy.
Sturm D, Hölscher C, Martínez IA
… +11 more, Harst A, Konstantinidi A, Alam S, Burock R, Vakhrushev SY, Hoffmann M, Ruppert T, Rapp E, Halim A, Thiel C, Strahl S
Protein O-mannosylation is initiated by the ER-resident enzymes POMT1 and POMT2, both of which carry multiple N-glycans essential for solubility and activity. Although congenital disorders of glycosylation type I (CDG-I)...Protein O-mannosylation is initiated by the ER-resident enzymes POMT1 and POMT2, both of which carry multiple N-glycans essential for solubility and activity. Although congenital disorders of glycosylation type I (CDG-I) disrupt the early N-glycosylation process, their impact on POMT biogenesis and O-mannosylation has remained unclear. Here, we show that ALG3-dependent elongation of the N-glycan precursor is required to maintain normal abundance of POMT1 and POMT2. In ALG3-deficient HEK293 cells, POMTs carry truncated Man-type N-glycans and their steady-state protein levels are reduced by more than half, despite unchanged transcript levels. In vitro, reduced POMT abundance resulted in a proportional decrease in mannosyltransferase activity. However, O-mannosylation in cells remained unaffected: α-dystroglycan displayed normal matriglycan extension and a highly O-mannosylated KIAA1549 reporter showed unaltered site occupancy and core structures. These data indicate that POMT activity operates with substantial catalytic reserve under basal conditions, sufficient to tolerate significant reduction in enzyme levels without impairing substrate modification. Our work identifies ALG3-mediated N-glycan maturation as a determinant of POMT stability, highlights buffering capacity that preserves substrate O-mannosylation despite reduced enzyme abundance, and provides a mechanistic framework for how N-glycosylation defects could modulate POMT-dependent glycosylation in disease.
Malvagia S, Daniotti M, Tonin R
… +18 more, Ferri L, Ombrone D, Forni G, Scolamiero E, Funghini S, Rinaldi M, Falliano S, Paoli A, Mura M, Raspini F, Poggiali S, Scaturro G, Sacchini M, Donati MA, Procopio E, Guerrini R, Morrone A, la Marca G
BACKGROUND: Lysosomal storage disorders (LSDs) comprise a heterogeneous group of inherited metabolic diseases that lead to severe, irreversible complications if diagnosis is delayed. Newborn screening (NBS) provides a cr...BACKGROUND: Lysosomal storage disorders (LSDs) comprise a heterogeneous group of inherited metabolic diseases that lead to severe, irreversible complications if diagnosis is delayed. Newborn screening (NBS) provides a crucial opportunity for early identification and timely initiation of disease-modifying interventions. METHODS: We analyzed 234,642 newborns screened over a 10-year period in Tuscany, Italy, for Fabry disease (FD), Pompe disease (PD), and mucopolysaccharidosis type I (MPS I), using evolving methodologies, including tandem mass spectrometry and digital microfluidics-based assays. We report the epidemiological data, molecular characterization, and the clinical impact of our screening program. Approximately 18% of screened newborns were of non-Italian origin, predominantly from Chinese, North African, and sub-Saharan African communities, providing unique insights into the genetic landscape of LSDs in a multiethnic population. RESULTS: We identified 422 initial positive screens (recall rate 0.18%), of which 170 were confirmed on second dried blood spot (DBS). Molecular analysis revealed 17 late-onset PD individuals (incidence 1:13,802), 24 FD individuals, including five classical and 19 late-onset phenotypes (incidence 1:9776 total, 1:46,928 classical). No MPS I cases were confirmed, despite 45 positive initial screens. Nineteen novel variants were detected across the three genes: 4 in GAA, 5 in GLA, and 10 in IDUA. Evidence of regional founder effects emerged for the GLA variants c.335G > A and c.640-823 T > C. CONCLUSIONS: Our 10-year experience demonstrates the effectiveness of NBS for LSDs while highlighting important challenges, particularly the high burden of pseudodeficiencies and variants of uncertain significance (VUS). In MPS I screening, the substantial prevalence of pseudodeficiency alleles underscores the need for robust second-tier testing strategies to improve positive predictive value, especially in ethnically diverse populations.
AIM: This study aimed to compare the clinical, biochemical, and nutritional outcomes of classical nonketotic hyperglycinemia (NKH) patients treated with a ketogenic diet (KD) versus a glycine-restricted diet (GRD). METHO...AIM: This study aimed to compare the clinical, biochemical, and nutritional outcomes of classical nonketotic hyperglycinemia (NKH) patients treated with a ketogenic diet (KD) versus a glycine-restricted diet (GRD). METHODS: This retrospective study included patients with classical nonketotic hyperglycinemia treated with either a KD (n = 8) or a GRD (n = 6). Seizure frequency, seizure scores, antiepileptic drug (AED) use, motor function (GMFCS-E&R), swallowing difficulties, plasma glycine levels, and nutritional parameters were evaluated before and after dietary treatment. RESULTS: Baseline characteristics did not differ significantly between groups. Post-treatment assessments showed no significant differences in GMFCS scores, swallowing function, or plasma glycine levels. However, KD resulted in significantly reduced seizure frequency and seizure scores, and decreased AED use compared with GRD. Within-group analysis showed significant seizure control in the KD group, whereas seizure frequency increased in the GRD group. An increase in LDL cholesterol was observed in KD group, as expected; other nutritional parameters remained stable. Mortality was similarly high in both groups. CONCLUSION: Neither diet altered biochemical parameters or motor outcomes. However, KD provided better seizure control compared to GRD, supporting its role as a useful adjunctive therapy in NKH.
van Kuilenburg ABP, Mandel H, Moady TA
… +21 more, Sloma R, Fedida A, Leen R, Jansen-Meijer J, Paperna T, Sheffer VF, Dobritzsch D, Hochwald O, van der Wel NN, Grootemaat AE, Chulsky S, Rootman MS, Eran A, Yousef MA, Dinwiddie A, Manor J, van Karnebeek CDM, Kalfon L, Hershkovitz T, Tal G, Falik Zaccai TC
INTRODUCTION: Niemann-Pick disease type C1 (NPC1, OMIM 257220) is a rare, progressive, and fatal autosomal recessive lysosomal storage disorder caused by pathogenic variants in the NPC1 gene. These variants disrupt intra...INTRODUCTION: Niemann-Pick disease type C1 (NPC1, OMIM 257220) is a rare, progressive, and fatal autosomal recessive lysosomal storage disorder caused by pathogenic variants in the NPC1 gene. These variants disrupt intracellular lipid trafficking, leading to the accumulation of cholesterol and glycosphingolipids and resulting in severe, multisystem dysfunction for which no cure currently exists. MATERIALS AND METHODS: To investigate the potential founder effect and shared ancestry of the p.Ala1035Val variant, we analyzed 30 genetically confirmed NPC1 cases, comprising 18 Brazilian (12 of whom were homozygous) and 12 Portuguese participants (3 of whom were homozygous), each carrying at least one p.Ala1035Val allele. Diagnosis was established by clinical evaluation, biochemical assays, and filipin staining, with molecular confirmation by NPC1 genotyping. RESULTS: All analyzed individuals exhibited a conserved haplotype across the SNVs in exons 6 (c.644 A > G, p.His215Arg), 12 (c.1926G > C, p.Ile642Met), 17 (c.2572 A > G, p.Ile858Val), and 18 (c.2793C > T, p.Asn931=), strongly supporting a shared founder effect consistent with an Iberian-associated ancestral background. Among Brazilian (n = 14), visceral involvement occurred in 10/14 (71.4%), predominantly hepatosplenomegaly (6/14, 42.9%), and developmental/cognitive alterations in 10/14 (71.4%), followed by ataxia or gait disturbance in 4/14 (28.6%). Among the Portuguese (n = 3), all presented with visceral involvement, characterized by hepatosplenomegaly (3/3, 100%); one had developmental delay (1/3, 33.3%), and none exhibited ataxia/gait disturbance. Despite the small sample size, clinical patterns appeared similar between the two groups, with differences likely reflecting sampling variability. DISCUSSION: These findings expand the known variant spectrum of NPC1 in Brazilian and Portuguese populations, supporting a possible founder effect resulting from Portuguese colonisation. They also highlight the clinical value of haplotype analysis as a tool for tracing disease origin and improving stratification in medical settings. Furthermore, they emphasise the importance of refining early diagnostic strategies to optimise patient management and improve outcomes in NPC, while highlighting the need for larger, multicenter studies to corroborate this hypothesis and refine its clinical and genetic implications.
INTRODUCTION AND OBJECTIVE: Mutations in the GBA1 gene, particularly the severe L444P variant, are among the strongest known genetic risk factors for Parkinson's disease (PD). Prior meta-analyses published before 2018 in...INTRODUCTION AND OBJECTIVE: Mutations in the GBA1 gene, particularly the severe L444P variant, are among the strongest known genetic risk factors for Parkinson's disease (PD). Prior meta-analyses published before 2018 included fewer studies and often pooled multiple mutations, prompting this updated, mutation-specific systematic review and meta-analysis. METHODS: Standard systematic review and meta-analytic methods were used, including predefined eligibility criteria, literature search, and pooled analysis of odds ratios (ORs) for PD in GBA1 L444P carriers versus non-carriers. RESULTS: We included 51 studies comprising 33,752 PD patients and 34,101 controls across multiple continents. In random-effects meta-analysis, heterozygous GBA1 L444P carriers had markedly higher odds of PD than non-carriers (pooled OR 9.19, 95% CI 6.94-12.16), with similar estimates across sensitivity and leave-one-out analyses. Cumulative meta-analysis showed early variability but stable pooled ORs around 7-9 from 2008 to 2010 onward. Ancestry-specific pooled ORs were consistently elevated across populations, with overlapping confidence intervals and no significant subgroup differences. Funnel and Galbraith plots and Egger's test showed no evidence of substantial small-study effects or publication bias. CONCLUSIONS: This updated synthesis demonstrates that heterozygous GBA1 L444P carriage confers a consistently large increase in PD risk across populations, with robust pooled estimates across multiple sensitivity analyses. Although overall statistical heterogeneity was negligible, wide confidence intervals in several ancestry subgroups highlight imprecision due to sparse data and internal heterogeneity, underscoring the need for broader and more equitable genetic testing, improved risk estimation in underrepresented populations, and targeted research on severe GBA1 variants to inform genetic counseling and PD risk discussions. REGISTRATION: PROSPERO Registration Number: CRD420251182022. Registration details available at the PROSPERO database.
Muenzer J, Dant M, Dickson PI
… +15 more, Ellinwood NM, Fuller M, Giugliani R, Hemsley K, Jones S, Klein T, Lampe C, Mitchell J, Muschol N, O'Neill C, Okuyama T, Scarpa M, Stewart F, Stevens B, Stephens K
Mucopolysaccharidoses (MPS) are a group of rare genetic disorders in which a deficiency of specific lysosomal enzymes results in abnormal glycosaminoglycans (GAG) catabolism. The biochemistry of MPS is well understood, a...Mucopolysaccharidoses (MPS) are a group of rare genetic disorders in which a deficiency of specific lysosomal enzymes results in abnormal glycosaminoglycans (GAG) catabolism. The biochemistry of MPS is well understood, and the primary event is a defect in GAG metabolism, leading to intralysosomal substrate accumulation and secondary lysosomal dysfunction. The MPS are heterogeneous disorders with physical and/or neurologic involvement with unmet medical needs. The severe or neuronopathic forms of MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS VII (Sly syndrome), and all classical forms of MPS III (Sanfilippo syndrome A-D) will develop cognitive impairment. Individuals with MPS I, MPS II, and MPS VII have elevated dermatan sulfate (DS) and heparan sulfate (HS) in their urine, while individuals with MPS III only have elevated HS. The predominant GAG observed in cerebrospinal fluid (CSF) in all individuals with neuronopathic MPS (nMPS) is HS. CSF HS correlates with brain tissue HS in MPS animal models. Therefore, the reduction of CSF HS reflects a decrease in brain tissue HS. CSF HS disaccharides can be reliably measured using mass spectrometry. However, regulatory challenges persist in accepting HS as a biomarker. Traditional trial designs with randomization are not feasible given the heterogeneity of nMPS and are unethical in a progressive neurodegenerative disease. Many countries have approval pathways using biomarkers, but they are underutilized. In summary, this review provides evidence supporting the use of CSF HS as a biomarker of treatment efficacy for the brain disease in individuals with nMPS.
OBJECTIVE: Newborn screening (NBS) now allows for early detection and clinical monitoring in infants and children with late-onset Pompe disease (LOPD), potentially identifying those needing early enzyme replacement thera...OBJECTIVE: Newborn screening (NBS) now allows for early detection and clinical monitoring in infants and children with late-onset Pompe disease (LOPD), potentially identifying those needing early enzyme replacement therapy (ERT). Early symptom onset has been reported in LOPD, but with a paucity of information on when to initiate ERT and on outcomes with early treatment. We report our experience at Duke University Medical Center with seven symptomatic children diagnosed with LOPD by NBS, compound heterozygous for the common IVS1 variant c.-32-13 T > G and a second pathogenic or likely pathogenic variant, started early on ERT. METHODS: All participants underwent periodic multidisciplinary evaluations including kinematic analysis of posture/movement; standardized assessments of gross motor, speech-language, and feeding/swallowing; serum and urine biomarker analysis; and quantitative muscle ultrasound. RESULTS: Prior to initiation of ERT, all participants showed kinematic deficits and persistently elevated serum creatine kinase (CK). Median age at ERT initiation was 8.2 months (range: 2-20 months) with 6/7 showing standardized motor scores ≤10th percentile +/or declining. All started on alglucosidase alfa, later transitioning to avalglucosidase alfa without complications. At latest evaluation, all demonstrated motor improvement and normalization of CK. CONCLUSION: Data presented here supports existing evidence that infants and children with LOPD can present with early symptom onset and may benefit from early ERT. While further study is needed, we showcase the early features of LOPD, benefits from early ERT, and the importance of comprehensive multidisciplinary evaluation of LOPD diagnosed via NBS, allowing timely intervention for those that may benefit from early ERT.
BACKGROUND: Citrin deficiency is an autosomal recessive metabolic disorder caused by pathogenic variants in SLC25A13, which manifests as an age-dependent spectrum ranging from neonatal intrahepatic cholestasis (NICCD) to...BACKGROUND: Citrin deficiency is an autosomal recessive metabolic disorder caused by pathogenic variants in SLC25A13, which manifests as an age-dependent spectrum ranging from neonatal intrahepatic cholestasis (NICCD) to adolescent and adult citrin deficiency (AACD, formerly CTLN2). Early detection through newborn screening (NBS) would be a prerequisite for early treatment, but conventional NBS based on citrulline and other metabolite levels has only limited sensitivity. This study aimed to develop a simple and accurate quantitative real-time PCR (qPCR)-based newborn screening (NBS) method using dried blood spots (DBSs) as a first-tier screening test to detect the six most common SLC25A13 variants in Japan. METHODS: DBS samples from 1055 healthy newborns and 19 patients with confirmed variants were analyzed. Four variants (c.674C > A, c.852_855delTATG, c.1177 + 1G > A, and c.1311 + 1G > A) were screened using the TaqMan™ SNP genotyping system, and two large insertion/deletion variants (c.1638_1660dup and c.1750_1751[insNM_138459.3:2672_24;1750 + 72_1751-4dup]) were screened using a SYBR™ Green-based qPCR system with variant-specific primers. Results of qPCR were confirmed by Sanger sequencing. RESULTS: In all 19 known patients with citrin deficiency, the assay correctly identified the pathogenic alleles. Among 1055 newborns, heterozygous variants were detected in 19 cases (five c.852_855delTATG, thirteen c.1177 + 1G > A, and one c.1311 + 1G > A). The overall allele frequency (0.0090) was consistent with that reported in the Japanese genome database (jMorp, 0.0102), corresponding to an estimated carrier frequency of approximately 1 in 56 individuals. The assay reliably distinguished wild-type, heterozygous, and homozygous genotypes using a single DBS punch. CONCLUSION: We established a cost-effective, rapid, and reliable qPCR-based NBS system that detects the six most prevalent SLC25A13 variants using DBSs. This method is compatible with current NBS workflows and could improve early detection and intervention for citrin deficiency in Japan and, with adaptation of the target variants, in any other (not only) East Asian population.
Congenital disorders of glycosylation (CDG) are a large, rapidly expanding group of inherited disorders with variable phenotypes. More than 200 CDGs have been reported, many in only a small number of patients. Untargeted...Congenital disorders of glycosylation (CDG) are a large, rapidly expanding group of inherited disorders with variable phenotypes. More than 200 CDGs have been reported, many in only a small number of patients. Untargeted next-generation sequencing methods have led to the discovery of most CDGs, shortening the time to diagnosis in many cases. However, novel missense variants are frequently identified, and genotypes involving variants of uncertain significance often require additional testing. Our laboratory has received an increased number of referrals for CDG biochemical genetic testing, particularly for transferrin and apolipoprotein CIII isoform profiles, after variants in genes associated with the glycosylation pathway have initially been identified by molecular genetic testing. In this study, we quantified this practice and its outcomes by conducting a retrospective review of cases submitted to our laboratory for biochemical genetic testing from January 2022 through March 2025. Equivocal or uncertain molecular genetic testing results for a gene associated with a CDG were submitted for 89 patients from 87 families at the time that biochemical genetic testing was ordered. Molecular findings were reported for 52 different genes, of which PMM2 (n = 13), MAN1B1 (n = 6), and ALG13 (n = 6) were the most frequent. Two patients were excluded from further analysis due to the presence of variants in multiple genes associated with CDGs. For 23 of the 87 patients (26.4%), the CDG suspected on the basis of genotype could be supported or confirmed by biochemical genetic testing. For another 36 patients (41.4%), the suspected CDG could be excluded due to normal results, and for 16 patients (18.4%), a definitive diagnosis could not be established because the available biochemical genetic tests were not expected to be informative. In 11 cases (12.6%), the outcome was uncertain. In conclusion, health care professionals should be judicious when seeking biochemical genetic confirmation of genotypes suggestive of a CDG. Although molecular findings of uncertain significance require confirmation, not all CDGs can be identified with currently available biochemical genetic testing.
Tay-Sachs disease (TSD) is a lysosomal storage disorder caused by pathogenic variants in the HEXA gene, resulting in deficient activity of β-hexosaminidase A (Hex-A). Loss of Hex-A function leads to the intralysosomal ac...Tay-Sachs disease (TSD) is a lysosomal storage disorder caused by pathogenic variants in the HEXA gene, resulting in deficient activity of β-hexosaminidase A (Hex-A). Loss of Hex-A function leads to the intralysosomal accumulation of GM2 ganglioside, disrupting lysosomal homeostasis and triggering neurodegenerative processes, including neuronal death, demyelination, neuroinflammation, gliosis, and microglial activation. Current understanding of TSD pathophysiology, as well as the development and preclinical evaluation of therapeutic strategies, has relied heavily on a wide range of cellular and animal models. This review summarizes and critically discusses the main experimental models of TSD and their applications. Cellular models include patient-derived skin fibroblasts and induced pluripotent stem cells (iPSCs), which have been instrumental for mechanistic studies and therapeutic screening; however, their limited capacity to recapitulate tissue-level complexity highlights the need for advanced systems such as organoids and three-dimensional tissues. Animal models encompass naturally occurring TSD in species such as dogs, sheep, and deer, as well as genetically engineered mouse models, including single- and double-knockout strains. Given that mice partially bypass the Hex-A deficiency through neuraminidase-mediated GM2 degradation, double-knockout models have been crucial for dissecting the role of neuraminidases in disease modulation. Although no model fully reproduces the human disease phenotype, these systems have provided a robust foundation for pre-clinical testing and the translation of experimental therapies into clinical trials. Continued refinement and integration of these models will be essential for advancing effective treatments for Tay-Sachs disease.
Berry GT, Vos EN, Demirbas D
… +16 more, Brucker W, Gilmartin A, Lehtinen MK, Yang E, Prabhu SP, Chen J, Huang X, Qi W, Bennett MJ, Haynes RL, Rodan L, Poduri A, Pearl PL, Rotenberg A, He M, Rubio-Gozalbo ME