搜索结果：Journal of inherited metabolic disease

Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients, and "not effective" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.

Adult Refsum disease (ARD; OMIM 266510) is a degenerative autosomal recessive condition typically diagnosed in adulthood. It affects visual, auditory and nervous system function. It is characterised by plasma, neuro-ophthalmological and adipose tissue accumulation of the dietary-derived phytanic acid (PA). This guidance reviews the clinical aspects of ARD and discusses interventions to address various co-morbidities of the disease. This GRADE-aligned guidance is based on a review of the literature and a consensus statement reflecting the conclusions of professionals with experience in the diagnosis and management of ARD. This statement reviews clinical aspects of ARD and discusses current and potential interventions to address various symptoms of the disease. It provides an overview of the clinical phenotype, reviews the clinical, biochemical, and genetic findings in ARD, and the neurological and ophthalmological investigations needed at diagnosis and during follow-up. It highlights the importance of dietary management and its role in situations such as acute hospital admissions for inter-current illness. Furthermore, it provides guidance on the acute management of decompensation in ARD and outlines when therapeutic plasma exchange/lipoprotein plasmapheresis should be considered. Greater clinician and patient awareness will lead to early diagnosis and improved outcomes. Implementation of a low PA diet before further end organ involvement offers the best prognosis. Life-long dietary therapy, along with therapeutic plasma exchange/lipoprotein apheresis during acute decompensations, remains the mainstay of management. Patients should have access to a multidisciplinary team to ensure specialist dietary input and supportive management of comorbidities.

Glucokinase and ATP-sensitive potassium (KATP) channels in pancreatic β-cells control insulin secretion in response to glucose stimulation to maintain glucose homeostasis. It is well established that loss-of-function (LOF) variants in GCK, which encodes glucokinase, are diabetogenic, whereas LOF variants in KATP channel genes lead to congenital hyperinsulinism (HI) and hypoglycemia. However, how the co-occurrence of GCK and KATP channel variants manifests in glycemic phenotypes is unknown. This study presents a multiplex pedigree with a heterozygous GCK deletion along with a heterozygous ABCC8 variant that results in the E1209K missense variant in the regulatory subunit of the KATP channel sulfonylurea receptor 1 (SUR1). The three-generation pedigree exhibits a complex spectrum of dysglycemia depending on genotype and age at referral. Individuals harboring the heterozygous GCK deletion alone present with maturity-onset diabetes; those harboring the heterozygous ABCC8 E1209K variant alone exhibit HI resulting from the LOF of KATP channels, with some developing diabetes later in life; and those harboring both GCK and ABCC8 variants escape HI but not diabetes. This unique pedigree offers insights into the complex interplay between LOF genetic variants of glucokinase and KATP channels in age-dependent dysglycemia. Genetic variants causing loss of function (LOF) of glucokinase or ATP-sensitive potassium (KATP) channels underlie diabetes or congenital hyperinsulinism, respectively, but how the co-occurrence of such variants affects glucose control is unknown. This study presents genotypes and clinical phenotypes in a pedigree with LOF variants in both GCK and the pancreatic KATP channel. Heterozygous glucokinase deletion masked infantile hyperinsulinemia and hypoglycemia caused by a heterozygous LOF KATP channel variant. Carriers of the LOF KATP variant exhibited a shift from hypoglycemia to diabetes, as has been reported previously in some carriers of KATP LOF variants.

Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disorder caused by deficient activity of lysosomal alpha-galactosidase A (AGAL, E.C. 3.2.1.22) due to pathogenic variants in the GLA gene (HGNC:4296, Xq22.1). Plasmatic deacylated globotriaosylceramide (lysoGb3) is elevated in FD patients as a reflection of lysosomal accumulation of Gb3. Specific (AGALopathic) GLA variants have been recently shown to accumulate within the secretory pathway and trigger endoplasmic reticulum stress and unfolded protein response rather than result in profound enzymatic deficiency. In part due to lack of integrative measures of clinical severity and biochemical/molecular parameters, specific impacts and consequences of X-chromosomal inactivation (XCI) on clinical manifestation in FD female heterozygotes still remain to be fully understood. Our study aimed at evaluation of XCI (% of inactive wt GLA allele) in untreated female FD heterozygotes with classic FD (n = 17), late-onset FD (n = 19) and individuals carrying GLA variants (p.(L394P) (n = 7), p.(A143T) (n = 4), and p.(D313Y) (n = 4)) with predominant AGALopathic effects. XCI was correlated with age of the patients, clinical phenotype, (residual) AGAL activity, and lysoGb3. AGAL activity corresponded to XCI independently of the type of the GLA mutation. The best separation of the clinical phenotypes (classic FD, late-onset FD and AGALopathy) was achieved by correlating XCI to the ratio of AGAL activity to lysoGb3. This three parametric calculated marker was then confronted with the Mainz Severity Score Index (MSSI) to generate an Integrative Clinical-Laboratory quotient (ICLq). ICLq discriminated the three female patient groups and demonstrated group-dependent differences in its average age-related increase.

Inherited metabolic diseases (IMDs) are a diverse group of rare genetic disorders that disrupt metabolic pathways, leading to severe clinical manifestations. Disease models ranging from complex animal models to simple in vitro systems have provided insights into IMDs, but each has limitations. Organoids, three-dimensional in vitro models, bridge this gap by replicating key metabolic functions that are absent in most simple 2D cell models. While organoids do not fully mimic organ complexity, they effectively model disease-specific metabolic defects, as seen in methylmalonic acidemia, Wilson's disease, and cystic fibrosis. Recognizing that function is more critical than organ resemblance, we propose focusing on the specific function of interest rather than selecting a model solely based on its derivation from the most affected organ. Focusing on specific biological processes enables precise, disease-relevant studies that drive novel therapeutic strategies and personalized medicine.

Metabolic testing of cerebrospinal fluid (CSF) is essential for early diagnosis of neurometabolic disorders. However, the large number of differential diagnoses, the phenotypic variance within a clinical picture, and the disease rarity complicate targeted metabolic diagnostics. To improve diagnosis the aim is to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) based CSF panel (NeuroMetabolom) which enables a quick, reliable, extensive and cheap method requiring small amounts of analysis material replacing classical single platform analyses. The novel LC-MS/MS NeuroMetabolom method enables measuring all known standard metabolites in CSF, including purines/pyrimidines, sepiapterin, γ-Aminobutyric acid (GABA), and vitamin B6 metabolites, with significantly reduced sample volume and measurement time. Due to their different biochemical interactions several runs with different sample preparation, running time and columns are necessary within the LC-MS/MS. Age-dependent reference values have been established. Positive controls with consistently detectable metabolite patterns were used to assess analytical reliability. The method has been implemented into routine diagnostics practice. The LC-MS/MS panel enables a simple, comprehensive, and rapid diagnostic approach, reducing time to diagnosis and facilitating early initiation of treatment. Instead of 650 μL, only 250 μL CSF is now required and the analysis time for all metabolites is reduced from 280 to 65.3 min excluding preparation and setup time. Furthermore, the panel is adaptable and can be regularly expanded to include additional clinically relevant metabolites. The novel LC-MS/MS panel, together with a neurometabolomic approach, offers a promising avenue to timely clinical diagnosis. Trial Registration: German Clinical Trials Register: DRKS00007878.

Caregiver-reported outcome measures (CROMs) complement clinical assessments of neurodevelopmental functions (NDF) in pediatric rare disease trials. This scoping review summarizes use of CROMs of NDF across bodily function, activity, and participation domains of the International Classification of Functioning, Disability, and Health (ICF) model in pediatric lysosomal storage disorders (LSDs), characterizes assessed neurodevelopmental domains, and outlines considerations for CROM selection within a comprehensive functional assessment strategy. We applied JBI methodology and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Primary articles reporting CROM of NDF use in children with LSDs ≤ 12 years old were identified. Study characteristics, design, and CROMs utilized were extracted. CROMs were classified as condition-general or disease-specific. CROM content was mapped to neurodevelopmental domains (activities of daily living [ADL], cognition, communication, physical, social-emotional function). Ninety-eight articles published in the last 10 years reported on 38 distinct CROMs of NDF across > 20 LSDs. Nearly all studies (93%) used ≥ 1 condition-general CROM of NDF, most commonly the Vineland Adaptive Behavioral Scales or the Pediatric Quality of Life Inventory. Eleven disease-specific CROMs were reported, typically alongside condition-general measures. Physical, ADL, and social-emotional domains were indexed most consistently. CROMs were endpoints in 32 LSD clinical trials. Findings illustrate the variety and common trends of CROMs of NDF used in pediatric LSD studies. This review informs selection of complementary caregiver-reported endpoints in LSD trials based on a well-defined, clinically meaningful construct; alignment with other endpoints and expert consensus; and operational practicality.

Polyprenal reductase is an enzyme encoded by the SRD5A3 gene, which is involved in the synthesis of dolichol from polyprenol. Dolichol serves as a carrier for glycan precursors or monosaccharides in N-linked glycosylation. Pathogenic variants in SRD5A3 can result in a congenital disorder of glycosylation (CDG), SRD5A3-CDG, which is inherited in an autosomal recessive manner. Most plasma proteins are glycosylated and changes in the glycosylation of several glycoproteins are associated with pathological consequences. Despite the critical role of SRD5A3 in glycosylation, the impact of its deficiency on the glycosylation of serum proteins remains largely unexplored. In this study, we used tandem mass tag-based multiplexed quantitative approach to analyze serum N-glycoproteomics and proteomics in SRD5A3-CDG patients and controls. We quantified 2200 serum N-glycopeptides from 359 N-glycosites from 204 serum proteins. Extensive hypoglycosylation of serum proteins was observed in patients, with 245 of 291 altered glycopeptides decreased in SRD5A3-CDG. Altered glycopeptides included those derived from haptoglobin, plasma serine protease inhibitor, alpha-1-B glycoprotein, alpha-2-macroglobulin, and ceruloplasmin. Some of these proteins have previously been reported to be associated with liver dysfunction, anemia, and coagulopathy, which could underlie similar clinical features observed in SRD5A3-CDG patients. Overall, our study provides novel insights into alterations in the glycosylation status of specific serum proteins in SRD5A3-CDG. Some of these alterations could be further pursued to develop glycopeptide-based biomarkers as the current diagnosis of SRD5A3-CDG by screening assays remains challenging. In addition, knowledge of altered glycoproteins could enhance our understanding of the disease spectrum and potentially unveil additional therapeutic avenues.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, which encodes for Alpha Galactosidase-A (α-Gal A). α-Gal A deficiency leads to glycosphingolipid accumulation, like globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), resulting in systemic symptoms and reduced lifespan. Current treatments such as enzyme replacement therapy (ERT) and chaperone therapy are noncurative and have limitations. Gene therapy is an interesting alternative approach that may overcome most of these limitations, and different approaches are currently being tested. Here, we developed a gene therapy approach using rAAV2/8 vectors, delivered intravenously, that target the liver to produce and secrete functional α-Gal A into circulation. This enzyme is then captured by organs expressing mannose-6-phosphate receptors, reducing glycosphingolipid accumulation in affected tissues. We generated a codon-optimized GLA cDNA with enhanced translatability that was expressed under a strong liver-specific promoter. In a dose escalation study in juvenile Gla knock-out (ko) mice, the lowest dose (3.0E11vg/kg) resulted in 85%-95% clearance of lyso-Gb3 in plasma and tissues, while doses of 3.0E12 vg/kg and higher showed 98%-100% clearance of the glycosphingolipid. All AAV doses were more effective than systemic α-Gal A administration (ERT). Long-term treatment showed normal levels of lyso-Gb3 in plasma and tissues, and corrected neuropathic involvement, as shown in the hot plate test. This study provides a proof-of-concept showing that the tested liver-specific gene therapy vector is capable of preventing disease progression in juvenile Fabry mice at relatively low doses and shows potential in treating both early- and late-onset FD in patients.

Despite the implementation of newborn screening (NBS), developmental outcomes in individuals with Cobalamin C (CblC) deficiency remain variable, and ocular manifestations are common. Therapy with hydroxocobalamin (OH-Cbl) is recommended by clinical guidelines, and increasing the dosage may improve outcomes. In this study, we evaluated the developmental and ocular outcomes of individuals with CblC deficiency identified through NBS. We conducted a retrospective analysis of 21 patients with CblC deficiency who were referred after abnormal NBS results and were followed at our center for a median of 9.0 years (0.9-16.1 years). Treatment was initiated at a median age of 9 days (range 4-18 days). All patients received OH-Cbl at a median dosage of 0.16 mg/kg/d (range 0.03-0.36 mg/kg/d) over the follow-up period and followed a regular diet. Thirteen patients presented with neonatal symptoms, but at the last follow-up, 52% of individuals had disease-related symptoms, including seizures in one patient and developmental impairment in 10 cases. Neuropsychological testing was performed in 15 patients and showed cognitive impairment in more than half of them. Ten individuals had ocular manifestations with a median age of onset of 17.5 months (range 3-50 months); of these, nine patients had developmental impairment. 48% of patients were asymptomatic at the last follow-up. Despite early intervention, a substantial proportion of individuals exhibited developmental impairments or ocular manifestations, and neonatal onset appears to be associated with disease severity. Early treatment seems to prevent epilepsy. The potential role of genotype-phenotype correlations, particularly in relation to dosage response, warrants further investigation.

Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up-regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down-regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short-term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4-week study in pre-symptomatic MPS IIIA mice (3- or 6-mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer-term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.

As a group, patients with classic galactosemia (CG) demonstrate a high prevalence of long-term complications despite early detection and life-long dietary restriction of galactose, which is the current standard of care. Individual outcomes, however, vary widely. For decades, research teams have sought to identify potential environmental, metabolic, and/or galactose-1-phosphate uridylyltransferase (GALT) allelic differences that might explain this variability-with limited success. Among large cohorts, only severe brain-related disease in infancy has been associated with increased prevalence of complications, and only the presence of predicted or detected residual GALT activity has been associated with decreased prevalence. While significant, these factors fail to account for the majority of long-term outcome variability in CG. Here, we tested whether genetic factors, both inside and outside the GALT locus, might contribute to variability in speech/voice/language, cognitive, and/or motor outcomes among patients. Specifically, we compared outcomes among 66 sets of affected siblings who share both GALT genotype and genetic background, 54 unrelated CG patients who share GALT genotype (p.Gln188Arg/p.Gln188Arg) but not genetic background, and 52 unrelated CG patients who share neither GALT genotype nor genetic background. Heritability estimates for all three complications demonstrate substantial genetic contributions, with point estimates of 100% heritability for all three. Less than 8% of this heritability appears due to residual GALT activity from hypomorphic GALT alleles. Combined with prior data demonstrating clustering of all three outcomes, these results offer compelling evidence for the existence of genetic modifiers of developmental outcomes in CG beyond the GALT locus.

Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5&#x2009;years. Mean time on olipudase alfa was 4.2&#x2009;&#xb1;&#x2009;1.0&#x2009;years; mean compliance was 90%&#x2009;&#xb1;&#x2009;13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1%&#x2009;&#xb1;&#x2009;10.8% at baseline vs. 66.5%&#x2009;&#xb1;&#x2009;13.3% at final assessment; mean change from baseline of 35.9%&#x2009;&#xb1;&#x2009;27.5% (p&#x2009;<&#x2009;0.0001). Mean baseline spleen volume of 11.5&#x2009;&#xb1;&#x2009;4.6 multiples of normal (MN) decreased to 4.8&#x2009;&#xb1;&#x2009;2.1 MN at final assessment, mean change from baseline -57.5%&#x2009;&#xb1;&#x2009;10.1% (p&#x2009;<&#x2009;0.0001) and mean baseline liver volume (1.5&#x2009;&#xb1;&#x2009;0.4&#x2009;MN) decreased to 0.95&#x2009;&#xb1;&#x2009;0.23&#x2009;MN at final assessment, (mean change from baseline -36.8%&#x2009;&#xb1;&#x2009;11.5%, p&#x2009;<&#x2009;0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by intracellular retention of mutant Z (Pi*Z) alpha-1 antitrypsin (AAT) within hepatocytes, resulting in progressive liver disease. Currently, no approved pharmacological therapies exist for AATD-associated hepatic injury. Emerging preclinical evidence indicates that inhibition of mammalian target of rapamycin (mTOR) ameliorates liver pathology in AATD; however, the status of mTOR activity and its regulatory mechanisms under Pi*Z AAT-induced cellular stress remains incompletely understood. In this study, we investigated alterations in mTOR signaling and its upstream regulatory pathways using a gene-edited human hepatocyte model harboring the Pi*Z mutation (Huh7.5Z cells) and a Pi*Z AAT transgenic mouse model. Attenuation of mTORC1 activity was observed in both cellular and murine Pi*Z models. In vitro analyses demonstrated activation of AMP-activated protein kinase (AMPK&#x3b1;), a key inhibitory regulator of mTORC1, accompanied by paradoxical activation of Akt and the unfolded protein response (UPR) branch ATF6&#x3b1;. Pharmacological inhibition of mTOR significantly reduced intracellular Pi*Z AAT accumulation, alleviated ER stress, and suppressed apoptotic signaling through enhancement of autophagy. These findings reveal that hepatocytes adapt to Pi*Z AAT-induced stress through coordinated regulation of mTOR by AMPK, Akt, and ATF6&#x3b1; pathways. This study provides mechanistic insight into metabolic and stress-response signaling in AATD and identifies mTOR modulation as a promising therapeutic strategy for AATD-associated liver disease.

Free sialic acid storage disorder (FSASD) is a lysosomal storage disorder that results from biallelic pathogenic variants in the SLC17A5 gene. This gene codes for sialin, a 12-transmembrane domain protein that exports the charged sugar N-acetylneuraminic acid (Neu5Ac; sialic acid) out of the lysosome. Dysfunctional sialin causes accumulation of free sialic acid within lysosomes and a range of clinical manifestations, such as intellectual disability, facial dysmorphisms, and increased urinary excretion of free sialic acid. These findings, along with characteristic brain abnormalities on MRI, make the diagnosis of FSASD. Despite recognition of the clinical and imaging phenotype, the natural history of FSASD has not been extensively elucidated. Therefore, we prospectively characterized the clinical, molecular, laboratory, and imaging findings of eight children with FSASD in order to pursue biomarker discovery with collaborators in a consortium of FSASD investigators. Our cohort displayed a high prevalence of ophthalmologic and auditory abnormalities, including myopia, exotropia, and abnormal ABR. Prominent features include impaired CNS myelination, a very thin corpus callosum, documentation of varying levels of intellectual disability, elevated urine, plasma, and CSF free sialic acid levels, and essentially normal endocrine, hematologic, and immunologic parameters. The consistent finding of delayed but progressive myelination suggests that quantitative assessment of myelination by MRI and 1H MRS should be added to the list of potential clinical outcome measures for future clinical trials.

Gaucher disease is a rare, autosomal recessive disease, with decreased activity of lysosomal glucocerebrosidase (GCase) due to changes in the GBA1 gene. There is no cure for Gaucher disease, and standard treatment involves the use of enzyme replacement therapy or substrate reduction therapy. We describe the first case of Gaucher disease that was treated with an autologous transplant of lentivirus-transduced CD34+ cells. Enzyme therapy was stopped 4&#x2009;weeks prior to Day 0 of transplant. At 5&#x2009;years of follow-up, dried blood spot GCase enzyme levels have remained in the normal range; there has been a consistent and sustained reduction of lyso-GB1 and liver volume, and hematological indices such as leukocyte count, hemoglobin, and platelet count have remained in the normal range despite no additional therapy for the Gaucher disease. This case shows a sustained response to a single dose of lentiviral gene therapy for Gaucher disease.

Among primates the human brain is the largest in size, exhibiting a higher neuronal density and connectivity. The prolonged expansion and subsequent connectome reorganization of the human brain have been suggested to promote higher cognitive and behavioral abilities. The notable variations in cognitive functions between human and nonhuman primates do not exclusively reside in neuronal abundance and connectivity but are also linked to a higher complexity in glial cells' morphology and functions at earlier time points, during embryonic brain development. Here we discuss two features of the human brain and their reciprocal connection. One feature is the high metabolic need of the developing and adult human brain. The other is its prolonged maturation, also known as neoteny. Even though the human brain occupies only a small percentage of the body mass, it is the highest consumer of glucose and oxygen. Among all brain cells, neurons have a great energy demand. Comparative studies suggest that increased glucose consumption and energy metabolism are positively correlated with higher cognitive abilities in humans. In line with the essential role of metabolism as a regulator of brain functions, recent breakthrough works have uncovered the correlation between metabolism and the timing of brain and neuron maturation during evolution. In this review, we specifically focus on the role of time in the evolution of the human brain and its synapses, focusing on the involvement of tissue, cellular, and subcellular metabolism.

Glycogen storage disease type Ia (GSD Ia) is a rare autosomal recessive inherited disorder of carbohydrate metabolism, caused by a deficiency in glucose 6-phosphatase-&#x3b1; (G6PC1). Patients primarily suffer from failure to thrive, hepatomegaly, and severe fasting intolerance, biochemically characterized by hypoketotic, hypoglycemia, and hyperlipidemia. Because of clinical and biochemical heterogeneity, identifying biomarkers is imperative for prognosis and monitoring. An untargeted proteomics workflow was employed for identifying protein changes in liver and plasma from hepatocyte-specific G6pc knockout mice under fed and fasted conditions. This links the effect of hepatic G6Pase/G6pc deficiency to circulating protein biomarkers and allows assessment of the relationship with different clinical circumstances and long-term complications. In the liver, the main differences between hepatic GSD Ia mice versus controls were observed in proteins related to carbohydrate and lipid metabolism, proteasome, ribosome, NAD+ metabolism, and mitochondria. In GSD Ia mouse plasma, proteins were mainly down-regulated in the complement and coagulation cascades. Effects in hepatic GSD Ia mice were in general more pronounced under fasting conditions. Several potential biomarkers that showed significant alterations in both liver and plasma were identified. These include proteins involved in carbohydrate and lipid metabolism (e.g., UGP2, ALDOB, and FASN), complement and coagulation cascades (SERPINA1E, C8b, and MBL2), 20S proteasome subunits (PSMA4, PSMA7, and PSMB5), and the electron transport chain (SDHA). Their consistent changes observed in both the liver and circulation indicate their potential as circulating biomarkers reflecting liver condition. Together with their reported associations with liver diseases, we hypothesize that they could monitor hepatic complications.

Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, life-limiting genetic disorder characterized by cardiomyopathy, skeletal muscle myopathy, neutropenia, gastrointestinal issues, and fatigue. Formal analyses of survival and clinical progression remain limited. Barth Syndrome Foundation has maintained an intake database (n&#x2009;=&#x2009;502), representing >&#x2009;80% of the known global population, as well as a patient-inputted registry for a subset of individuals (n&#x2009;=&#x2009;162) with up to 11&#x2009;years of longitudinal outcome data. We estimate the survival curve, identify factors associated with mortality, characterize clinical manifestations over time, and evaluate causes of death. Death disproportionately affected young children, with a 59% transplant-free survival rate for those age <&#x2009;5. The risk of death plateaued between ages 5-25 before rising again. Heart transplantation (HR&#x2009;=&#x2009;0.316, 95% CI: 0.162-0.619, p&#x2009;<&#x2009;0.001) and living in a developed country (HR&#x2009;=&#x2009;0.109, 95% CI: 0.018-0.659, p&#x2009;<&#x2009;0.05) were associated with reduced risk of death. Clinical manifestations increased with age, with musculoskeletal/fatigue (66%) being most frequent. Top causes of death were cardiac-related complications, with cardiomyopathy/heart failure (51.3%), mostly in young children <&#x2009;5, and arrhythmia/cardiac arrest (15%). This is the most comprehensive longitudinal assessment of BTHS survival, mortality risk, and clinical manifestation progression. Early childhood is a period of high mortality risk, driven in large part by heart failure. Although risk of death and hospitalizations plateaued between ages 5-25, the clinical burden of BTHS increases throughout the lifespan. Our results may guide clinical care, identify time windows for optimal intervention, and help clinicians better recognize BTHS clinical features.