INTRODUCTION: Increased urinary tetraglucoside (Glc4) excretions are associated with abnormal glycogen metabolism. While Glc4 is an established biomarker for glycogen storage disease (GSD) type II, a traditional muscle G...INTRODUCTION: Increased urinary tetraglucoside (Glc4) excretions are associated with abnormal glycogen metabolism. While Glc4 is an established biomarker for glycogen storage disease (GSD) type II, a traditional muscle GSD, little data is available on excretions in liver GSD. METHODS: A single-center retrospective analysis was conducted on urinary Glc4 samples obtained during routine clinical care of 99 individuals with liver GSD, including 9 patients with Glc4 samples taken as part of the diagnostic work-up (i.e., before treatment) and 5 patients with Glc4 samples after liver transplantation. RESULTS: Glc4 excretions were increased at time of diagnosis in 1/1 GSD IIIa, 3/3 GSD IXa, 1/2 GSD IXa female carrier, 0/1 GSD IXb and 2/2 Fanconi-Bickel syndrome patients. In 8/9 of these patients with samples in the diagnostic work-up, subsequent follow-up samples were available, displaying that Glc4 excretions decreased after initiation of GSD management in 8/8 patients, and in 6/8 patients Glc4 excretions were within the reference range on last follow-up. Analysis of Glc4 samples in the monitoring phase revealed that, despite management, Glc4 excretions were elevated in the majority of GSD Ia (17/27) and Ib (6/10), and all GSD IIIa (19/19), GSD IIIb (4/4), and IXc (1/1) patients. In contrast, increased Glc4 excretions were less frequently observed in GSD IV (1/6), GSD VI (1/2), IXa (4/19), IXa female carrier (0/1), IXb (0/2), and Fanconi-Bickel syndrome (2/4) patients during clinical follow-up. After liver transplantation in a GSD Ia and a GSD Ib patient, Glc4 excretions normalized. CONCLUSION: Urinary Glc4 may be a useful additional biomarker in liver GSD patients, both in the diagnostic work-up and in the monitoring phase. Future studies could additionally assess the role of Glc4 as response biomarker in drug development. TAKE-HOME MESSAGE: Urinary Glc4 may be a useful additional biomarker in liver GSD patients, both in the diagnostic work-up and in the monitoring phase.
Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single...Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging. To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions. These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.
INTRODUCTION: All people with the rare, inherited, lysosomal disease mucopolysaccharidosis type II (MPS II) experience somatic manifestations, and approximately two-thirds develop neurological and cognitive impairment. T...INTRODUCTION: All people with the rare, inherited, lysosomal disease mucopolysaccharidosis type II (MPS II) experience somatic manifestations, and approximately two-thirds develop neurological and cognitive impairment. There is a well-documented need for novel therapies that target the central nervous system, but it is also clear that, despite enzyme replacement therapy having been available since 2006, somatic manifestations continue to have a substantial impact on quality of life, morbidity, and life expectancy. We conducted a targeted literature review to characterize the unmet needs related to the diagnosis, treatment, and monitoring of the somatic aspects of MPS II. METHODS: This review was conducted between July and September 2024. Peer-reviewed publications, abstracts, reports, and posters published between 2006 and 2024 were included. Records were identified from Embase, MEDLINE, and expert sources. Abstracts were screened, and full-text review, citation cross-check, and data extraction were performed. RESULTS: Of 1293 records identified, 365 were included for data extraction. The analysis identified four major unmet needs: (1) a lack of guidelines and recommendations to help enable early diagnosis and treatment initiation, and to advise on monitoring of disease progression and treatment effectiveness; (2) limitations in the ability of current treatments to address somatic manifestations that can lead to premature death, significant morbidity, and impaired quality of life; (3) a lack of strategies and guidelines for the transition from pediatric care to adult care; and (4) significant treatment- and disease-associated burden that affects people with MPS II and their caregivers. CONCLUSIONS: Significant unmet needs persist in the management of somatic manifestations of MPS II, despite the availability of approved therapies and irrespective of cognitive status. Consideration of these needs should help guide the development of novel disease management strategies, ultimately improving care for people with MPS II.
Pathogenic variants TOP3A gene have been recently described to cause a multisystem disorder associated with mitochondrial dysfunction in adults (Nicholls et al., 2018 [1]) and with a Bloom syndrome-like disorder in child...Pathogenic variants TOP3A gene have been recently described to cause a multisystem disorder associated with mitochondrial dysfunction in adults (Nicholls et al., 2018 [1]) and with a Bloom syndrome-like disorder in children (Martin et al., 2018 [2]). We present the case of an 11-year-old male with homozygosity for a novel variant in TOP3A with myopathy, ataxia, and atrioventricular conduction defect similar to the adult cases described in the literature. He developed dilated cardiomyopathy and presented in acute decompensated heart failure requiring left ventricular assist device support as a bridge to heart transplantation. Clinical and laboratory features showed mitochondrial dysfunction confirming pathogenicity of the TOP3A variants. However, unlike the other pediatric cases of TOP3A related disease reported so far, the features of Bloom syndrome were not evident in this patient.
BACKGROUND: Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis. AARS2 and DARS2 biallelic mut...BACKGROUND: Mitochondrial aminoacyl tRNA synthetase (mt-ARS) related disorders represent a widely heterogeneous group of diseases affecting the efficiency of mitochondrial protein synthesis. AARS2 and DARS2 biallelic mutations are associated with clinical syndromes prominently characterized by diffuse leukoencephalopathy with a highly variable age of onset, ranging from early infancy to adulthood. Preliminary in vitro results on patients' fibroblasts and some anecdotal reports on patients affected by mt-ARS related disease have suggested a possible benefit of supplementation with the specific substrate amino acid of the defective mt-ARS. METHODS: We recruited 6 adult patients affected by AARS2 (n = 2) and DARS2 (n = 4) related leukoencephalopathies and started an oral supplementation with alanine and aspartate, respectively, for a total duration of 2 years. Therapeutic efficacy and safety were assessed through clinical examinations, standardized scales, functional tests, quality of life (QoL) scores, brain MRI, and laboratory analyses. RESULTS: Overall, the treatment was safe and well tolerated by all patients, but efficacy endpoints were not met as no significant improvements were observed in global, cognitive, or motor scores.; nonetheless, all patients but one remained clinically stable. CONCLUSIONS: Despite inherent limitations of this pivotal trial, our findings suggest that specific amino acid supplementation is a safe intervention but do not yield a clear symptomatic benefit; nevertheless, we cannot exclude a potential role in stabilizing the clinical condition in adult patients with DARS2-related disorders.
Rossignol F, Pan KS, Perry MB
… +9 more, Bryant JC, O'Brien KJ, Castillo IJ, Spears KR, Ferreira CR, Murphey MD, Minn MJ, Gahl WA, Introne WJ
Mol Genet Metab
· 2025 Nov · PMID 41072243
·
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Alkaptonuria is associated with progressive spine disease beginning in young adulthood. Characteristic radiographic changes in the intervertebral discs are often the earliest detectable skeletal manifestations. We develo...Alkaptonuria is associated with progressive spine disease beginning in young adulthood. Characteristic radiographic changes in the intervertebral discs are often the earliest detectable skeletal manifestations. We developed a radiographic severity score measuring spine disease at 13 levels (C2-C7, T10-S1) based upon three parameters: 1) narrowing; 2) calcification; 3) vacuum disc phenomenon. 409 sets of radiographs from 136 participants were scored and divided into: 1) a cross-sectional cohort, with the most recent visit of each individual; 2) a longitudinal cohort, for participants with multiple visits. Correlations with age, sex, clinical measurements and patient-reported outcomes were performed. Both cohorts showed correlation of spinal disease score with age. Correlations were found with pain (SF-36, Pain Disability Index) and physical function (Schober's test, SF-36, Human Activity Profile). Intra- and inter-rater reliability were high for the total score (ICC > 0.95, p < 0.001), with a minimal detectable change of 2.6 points out of a total possible score of 78. This radiographic severity score is highly reliable, correlates with age, sex, and several clinical measures of physical function and pain, and allows for the detection of clinically meaningful changes. It can also be used as an outcome measure to monitor disease progression and response to therapy.
Mucopolysaccharidosis VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder (LSD) caused by pathogenic mutations in the ARSB gene, resulting in arylsulfatase (ARSB) deficiency and the lysosomal accum...Mucopolysaccharidosis VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder (LSD) caused by pathogenic mutations in the ARSB gene, resulting in arylsulfatase (ARSB) deficiency and the lysosomal accumulation of dermatan sulfate (DS) and chondroitin 4-sulfate (C4S). DS and C4S accumulation leads to multisystemic symptoms in MPS VI patients in cartilage, bone, heart valves, cornea, liver, and respiratory tract. Currently, enzyme replacement therapy (ERT) is the only approved treatment for patients with MPS VI, providing clinical benefits that include increased survival and improved quality of life. However, ERT has a limited impact on bone manifestations. Significant advances have been made in gene therapy (GT) using classical adeno-associated virus and the CRISPR/Cas9 system, providing promising alternatives in MPS VI. Importantly, hematopoietic stem cell transplantation (HSCT) in combination with GT may also offer a novel alternative. Additionally, substrate reduction therapy with odiparcil, immunomodulation, and stop codon read-through therapies have been explored in MPS VI. Future directions in MPS VI should include targeting cellular alterations, such as mitochondrial dysfunction, exploring cartilage-targeting alternatives, and implementing pharmacological chaperones. This manuscript highlights recent progress and emerging strategies for treating MPS VI.
CCDC115-CDG is a recently described combined N- and O-linked congenital disorder of glycosylation affecting Golgi apparatus homeostasis. To date, only thirteen patients have been reported with this condition. The clinica...CCDC115-CDG is a recently described combined N- and O-linked congenital disorder of glycosylation affecting Golgi apparatus homeostasis. To date, only thirteen patients have been reported with this condition. The clinical presentation is characterized by hepatosplenomegaly, elevated serum aminotransferases and alkaline phosphatase, often accompanied by psychomotor delay and hypotonia, hypercholesterolemia and copper metabolism anomalies, features that can mimic Wilson disease. Serum transferrin capillary electrophoresis shows a pattern compatible with abnormal Golgi N-glycosylation. We gathered phenotype descriptions and molecular data from all reported patients to better characterize this condition and explore potential genotype-phenotype correlation. Notably, we observed that homozygosity for the p.Leu31Ser variant is associated with higher serum transaminase levels. We also report the natural history of a patient, as clinical narratives are lacking in the literature for this condition. In summary, our report provides new insights into the natural history and genotype-phenotype correlation of CCDC115-CDG, key elements to focus on in ultra-rare conditions.
BACKGROUND: Infantile-onset Pompe disease (IOPD) is caused by a deficiency of the enzyme acid alfa glucosidase, resulting in glycogen accumulation in muscles and other tissues. Without treatment, affected infants typical...BACKGROUND: Infantile-onset Pompe disease (IOPD) is caused by a deficiency of the enzyme acid alfa glucosidase, resulting in glycogen accumulation in muscles and other tissues. Without treatment, affected infants typically die within two years. Enzyme replacement therapy (ERT) has significantly improved survival and functional outcomes, especially with early initiation, higher dosing, immune modulation, and newer therapeutic options. However, effective noninvasive tools to monitor disease progression and treatment response are still needed. Quantitative muscle ultrasound (QMUS) may serve as a useful alternative. OBJECTIVE: To evaluate the effectiveness and feasibility of QMUS for monitoring muscle involvement in IOPD. METHODS: This study assessed echo intensity (EI) measurements from QMUS in eight patients with IOPD receiving long-term ERT. EI was recorded annually in seven muscle groups. EI >50 units was considered abnormal, and a composite EI Sum Score was calculated. These values were compared with Gross Motor Function Measure (GMFM) scores using univariable regression. RESULTS: Patients began ERT at a median age of 7 weeks. QMUS assessments were performed, with ages ranging from 7 months to 21 years (median age of 9.5 years) at first evaluation. All patients had at least one muscle group with abnormal EI. Upper extremity EI was significantly lower (mean 47.3) than lower extremity muscle groups (mean 64.1, p = 0.002). Higher EI scores correlated with more severe myopathy and wheelchair use, while lower scores reflected better motor outcomes. CONCLUSIONS: QMUS is a promising noninvasive tool for monitoring muscle health in patients with IOPD receiving ERT. It may aid in assessing disease progression and treatment efficacy.
PURPOSE: This study was designed to more accurately estimate the prevalence of severe, infantile onset, rapidly progressive lysosomal acid lipase deficiency (LALD), an autosomal recessive disorder caused by the homoallel...PURPOSE: This study was designed to more accurately estimate the prevalence of severe, infantile onset, rapidly progressive lysosomal acid lipase deficiency (LALD), an autosomal recessive disorder caused by the homoallelic LIPA gene variant, c.260G>T; p.G87V in patients of Mizrahi Jewish ancestry. The previous estimates of LALD prevalence in Middle Eastern and Mizrahi Jewish populations, ranging from 1 in 12,100 to 1 in 4200, were based on historic, observational case reports and a population genetic screening of 165 Middle Eastern individuals and 162 Mizrahi Jews living in Southern California. METHODS: Carrier screening of 549 Mizrahi Jewish individuals for the c.260G>T; p.G87V LIPA variant and the common, c.894G>A; p.E8SJMLIPA variant, was carried out to determine their allele frequencies and expected prevalence of LALD in a larger Mizrahi population. RESULTS: This larger population screening study revealed a LIPA p.G87V Mizrahi founder variant allele frequency of 1 in 52.2, conferring a carrier frequency of 1 in 26.1. Therefore, the occurrence of infantile LALD was estimated to be one in 2724.8 Mizrahi Jewish conceptions in Southern California. CONCLUSION: The present, larger study found the prevalence of rapidly progressive, infantile LALD disease was ∼35 % greater than the previous prevalence estimate in the major U.S. Mizrahi Jewish population.
PURPOSE: This study explores the psychosocial impact of a positive newborn screen (NBS) result for four lysosomal storage disorders (LSDs) (Fabry disease, Krabbe disease, Mucopolysaccharidosis Type I, Pompe disease) acro...PURPOSE: This study explores the psychosocial impact of a positive newborn screen (NBS) result for four lysosomal storage disorders (LSDs) (Fabry disease, Krabbe disease, Mucopolysaccharidosis Type I, Pompe disease) across confirmatory results. METHODS: Parents whose child who had a positive NBS for one of the included LSDs were recruited for a retrospective cohort (n = 80) or prospective, longitudinal cohorts (n = 50). Surveys assessed uncertainty, anxiety, intrusive or avoidant thoughts, and perceived vulnerability of their child's health. In-depth interviews explored the NBS experience and psychosocial response. RESULTS: Participants experienced uncertainty and anxiety during confirmatory testing that improved as parents received more information. Retrospective cohort surveys showed ongoing levels of anxiety and perceived vulnerability in parents of children with carrier or pseudodeficiency results closer to those with true positive or inconclusive results than to false positives of undetermined cause. Interviews indicated some parents across cohorts and confirmatory results held uncertainty about their child's health, frequent thoughts about NBS, and vulnerable views of their child. CONCLUSION: This mixed-methods study provides evidence that NBS for LSDs may be associated with extended psychosocial impacts for some families, even if their child does not have an LSD. Lower false positive rates and additional counseling may limit the burden.
OBJECTIVE: Citrin deficiency (CD), caused by biallelic pathogenic variants in SLC25A13, remains underdiagnosed due to allelic heterogeneity, variants of uncertain significance (VUS), and technical limitations. This study...OBJECTIVE: Citrin deficiency (CD), caused by biallelic pathogenic variants in SLC25A13, remains underdiagnosed due to allelic heterogeneity, variants of uncertain significance (VUS), and technical limitations. This study aimed to improve the diagnosis of CD by identifying novel pathogenic SLC25A13 variants and characterizing the variant spectrum and geographic distribution in a large Chinese pediatric cohort. METHODS: Polymerase chain reaction (PCR)-based methods and Sanger sequencing were performed to identify pathogenic SLC25A13 variants in 220 pediatric patients with clinically suspected CD and their parents from 2016 to 2024. We functionally validated novel missense and splice-site variants using agc1-knockout yeast modeling and minigene assays, respectively. Data from these 191 newly diagnosed CD patients (2016-2024) were combined with data from 274 previously reported CD cases (2005-2016) and from 186 additional CD patients diagnosed via next-generation sequencing since 2016. The SLC25A13 variant spectrum and geographic distribution were then analyzed in this combined cohort. Statistical analyses were performed using Chi-square/Fisher's exact tests and one-way analysis of variance, as appropriate. RESULTS: A large cohort of 651 CD patients was assembled, and 13 novel pathogenic SLC25A13 variants were identified, including c.177_189del, c.188del, c.212 + 3 A > G, c.889G > T, c.1193 T > A, c.1210G > T, c.1352 T > A, c.1620del, c.1722del, c.1799_1800insAAA, c.1853_1855dup, c.1603_1609dup, and c.819-16 T > A. The most frequent variants were c.852_855del (57.56 %), c.1751-5_1751-4ins(2684) (10.06 %), c.1638_1660dup (8.42 %), and c.615 + 5G > A (7.93 %). The variant c.329-3_329-2ins(6072) ranked fifth at 2.13 %. In the Chinese mainland, the variant c.852_855del was most prevalent in southern and southwestern provinces, c.1638_1660dup was enriched in eastern coastal regions, and c.1751-5_1751-4ins(2684) reached its highest frequency in Sichuan Province (29.7 %). CONCLUSIONS: The study established the largest CD cohort to date, expanded the SLC25A13 variant spectrum, and delineated the distinct geographic distribution of these variants. These findings refined diagnostic protocols and emphasized the necessity for population-tailored genetic screening to optimize early diagnosis of CD.
Ngai YT, Young C, Parkinson-Lawrence EJ
… +8 more, Wimmer-Kleikamp S, Mittal P, Beard H, Briggs MT, Klingler-Hoffmann M, Brooks DA, Orgeig S, Hoffmann P
Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder resulting from a deficiency in the lysosomal enzyme alpha-L-iduronidase, which degrades heparan sulfate and dermatan sulfate glycosaminoglycans (G...Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder resulting from a deficiency in the lysosomal enzyme alpha-L-iduronidase, which degrades heparan sulfate and dermatan sulfate glycosaminoglycans (GAG) within endosome-lysosome compartments. MPS I patients demonstrate respiratory dysfunction with varying symptoms and severity during disease progression, which has been associated primarily with upper airway involvement and the thoracic cavity. However, the involvement of respiratory complications in patient morbidity and mortality suggests that we know relatively little about the pathogenic process in the lung. Using a proteomics approach, we analyzed lung tissues from a murine model of MPS I to identify proteins and molecular pathways contributing to respiratory pathology. A total of 7604 proteins were identified, of which 144 were significantly upregulated, 93 downregulated, and three proteins (GPNMB, SLC39A1, ABCC10) were uniquely detected in MPS I lung tissue compared to control lung tissue. Gene ontology analysis confirmed significant disruptions to lysosomal biogenesis, GAG degradation pathways, and extracellular matrix remodelling. Immunohistochemistry showed elevated LAMP I expression, which was consistent with the proteomic results and endosome-lysosome dysfunction being a key driver of disease pathogenesis in the MPS I lung. Our findings reveal novel proteomic alterations underlying distal lung pathology in MPS I and identify potential biomarkers that may have clinical utility for monitoring disease progression.
Mol Genet Metab
· 2025 · PMID 40939526
·
Full text
Glycogen storage diseases (GSDs) are rare, typically inherited, disorders caused by various defects in glycogen metabolism enzymes, generally resulting in the accumulation of glycogen in several tissues. Recently, two yo...Glycogen storage diseases (GSDs) are rare, typically inherited, disorders caused by various defects in glycogen metabolism enzymes, generally resulting in the accumulation of glycogen in several tissues. Recently, two young adult Basset Hound (BH) littermates were diagnosed with GSD via postmortem histopathology, with excess glycogen manifesting in both cardiac and smooth muscle. Using whole genome sequencing, a homozygous splice site donor variant was identified in exon 8 of RBCK1, a gene which encodes an E3 ubiquitin ligase, in both littermates, suggesting an autosomal recessive mode of inheritance. The presumptive loss of the splice site donor is predicted to result in premature termination in the mid-domain of the protein. Screening for the variant in related (n = 21) and unrelated (n = 124) BHs identified one additional affected littermate and nine familial heterozygous carriers. No variant alleles were present in the unrelated BH population, establishing the novelty of the identified mutation. RBCK1 variants have previously been associated with polyglucosan body myopathy type 1 (PGBM1), a type of GSD characterized by skeletal muscle myopathy, cardiomyopathy, and polyglucosan accumulation in humans. To date, no reported variants in RBCK1 have been identified in dogs or other large animals associated with GSD, making this the first naturally occurring large animal model of PGBM1 due to an RBCK1 defect.
Numerous genetic conditions are represented within the biochemical pathway for de novo cholesterol biosynthesis. Among the emerging disease-gene associations is CYP51A1, encoding a lanosterol demethylase enzyme. Bialleli...Numerous genetic conditions are represented within the biochemical pathway for de novo cholesterol biosynthesis. Among the emerging disease-gene associations is CYP51A1, encoding a lanosterol demethylase enzyme. Biallelic variants in CYP51A1 have been associated with congenital cataracts and variable liver disease but an appreciation of genotype/phenotype correlation is lacking due to the limited number of patients described. Here we report a 21 month-old female with congenital cataracts harboring compound heterozygous variants of uncertain significance in CYP51A1. Functional studies were performed to resolve the impact of these variants, demonstrating effects at the both the transcript and protein level, and clear evidence of pathogenicity. Molecular analysis of primary lymphoblastoid cells from the proband revealed defects in transcript expression, reduced protein abundance, and a loss of enzymatic function resulting in lanosterol accumulation and increased sensitivity to ferroptosis. These data provide supporting evidence of the association between CYP51A1 defects and congenital cataract that will aid in further establishing a genotype/phenotype correlation.
Newborn screening is one of the most successful public health programs that has improved outcomes for children with conditions that can cause long-term disability or even death if not treated quickly. With the introducti...Newborn screening is one of the most successful public health programs that has improved outcomes for children with conditions that can cause long-term disability or even death if not treated quickly. With the introduction of expanded newborn screening (NBS) and the use of tandem mass spectrometry, the number of core and secondary conditions recommended on the United States national NBS guideline called the Recommended Uniform Screening Panel (RUSP), rapidly grew to help screen for inborn errors of metabolism (IEM) [1]. A few years after this initiation and as more newborns were screened, there were several case reports of mothers who were diagnosed with an IEM condition or vitamin deficiency that was causing their child's abnormal newborn screening results. We conducted a PubMed literature search and identified reports of 14 maternal conditions identified via NBS and provide a comprehensive review of their findings. We define a maternal condition as biochemical or genetic findings that confirm the mother has the condition and the child is unaffected or an obligate carrier. This review could be useful for countries that plan to initiate expanded newborn screening in the future as well as for metabolic providers, who are involved in the confirmatory testing process for newborn screening referrals.
The polyisoprenoid lipid dolichol is critical for eukaryotic glycosylation. It is used as the membrane anchor for mono- or oligosaccharides transferred during N-glycosylation, O/C-mannosylation and glycosylphosphatidylin...The polyisoprenoid lipid dolichol is critical for eukaryotic glycosylation. It is used as the membrane anchor for mono- or oligosaccharides transferred during N-glycosylation, O/C-mannosylation and glycosylphosphatidylinositol anchor biosynthesis. Disorders affecting the synthesis or utilization of dolichol cause defective glycosylation and are therefore classified as Congenital Disorders of Glycosylation (CDG). CDG are a group of approximately 200 mostly autosomal recessive inherited metabolic disorders characterized by defective glycosylation of proteins and lipids. Through recently identified defects, we have gained new insights into dolichol synthesis, important to understand the pathological mechanisms in affected patients. This review provides an overview of dolichol synthesis and utilization and an update on CDG caused by disruption of these processes. Finally, we discuss the existing biomarkers for diagnosis of these disorders and the potential for effective therapies.
Triosephosphate isomerase (TPI) is a ubiquitously expressed enzyme encoded by the TPI1 gene. It catalyzes the interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in...Triosephosphate isomerase (TPI) is a ubiquitously expressed enzyme encoded by the TPI1 gene. It catalyzes the interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in the fifth step of glycolysis. TPI deficiency (TPI Df; MIM# 615512) is an autosomal recessive disorder due to biallelic pathogenic variants in TPI1. In keeping with other glycolytic enzymopathies, severe hemolytic anemia is a common finding. Additionally, many individuals with TPI Df develop neuromuscular symptoms, which is unusual for a glycolytic enzymopathy. There appears to be a genotype-phenotype correlation between a TPI1 p.Glu105Asp/null genotype and a severe life-limiting neuromuscular phenotype. Tpi1-deficient mice with a p.Glu105Asp/null genotype recapitulate the life-limiting neuromuscular phenotype seen in humans, but the exact pathomechanism remains unclear. Here we describe a 2-month-old male proband who presented with failure to thrive, respiratory failure, seizures, and severe hemolytic anemia, who passed away at 3 months of age. Trio whole genome sequencing showed compound heterozygous variants with the common p.Glu105Asp variant in trans to a newly described likely pathogenic splice site c.324 + 1G > C variant, predicted to cause nonsense mediated decay. Here we review our case as well as the literature to hypothesize a mechanism by which TPI Df due to a p.Glu105Asp/null genotype causes severe disease. Given the overall fatal nature of this condition, novel therapeutic approaches are urgently needed. Currently, treatments are experimental. Ketogenic diet and triheptanoin were effective in treating seizures in a TPI mutant Drosophila, known as TPI, although clinical data in humans is lacking. Additionally, bone marrow transplant has been shown to improve the hematologic phenotype in mice and has been done in an isolated number of patients. While there are no proven therapies available at this time, we hope this review will lead the discussion to consider future therapeutic options.