Hereditary Metabolic Diseases Research Articles

Mucopolysaccharidoses from the perspective of patients and family members

The aim of this study was to understand the impacts of mucopolysaccharidoses (MPS), a group of hereditary metabolic diseases with a chronic and progressive course, on children diagnosed with this condition and their family members. It is a qualitative research conducted with six children and five accompanying family members who attend the Reference Center for Inborn Errors of Metabolism (CETREIM). Data collection occurred through sociodemographic questionnaires and semi-structured individual interviews, recorded in audio and subsequently submitted to Content Analysis technique. The results indicate the presence of three main thematic axes: 1) Discovery and understanding of the diagnosis; 2) Repercussions and consequences of illness; 3) Coping strategies. The results highlight the ways in which children and family members define, interpret, and take positions regarding this diagnosis, indicating reverberations in the social and psychological spheres of different orders in these two groups, emphasizing that the rupture with normality permeates the condition of subject and identity, being marked by the repercussions of the disease and diagnosis.

Clinical Course of Methylmalonic Aciduria in Siblings: Two Clinical Cases

Background. Methylmalonic aciduria (MMA) is a rare disease from the group of hereditary metabolic diseases. The MMA clinical picture is polymorphic and meanwhile similar to other metabolic disorders. Determination of specific metabolites in biological fluids and molecular genetic testing are crucial to diagnose this disease. Timely diagnosis mainly determines the treatment efficacy and, therefore, the prognosis of MMA development. Clinical case description. Two siblings with MMA caused by methylmalonyl-CoA mutase deficiency (OMIM #251000) have shown duplication chr6-49459106-T-TA: NM_000255.4c.360dupT (p.Lys121fs) in homozygous state in exon 2 of the MMUT gene. The disease was diagnosed in the first child with underlying metabolic crisis that finally led to irreversible changes in organs and systems and lethal outcome. The diagnosis in the second child was established antenatally, thus, therapy was initiated from the first day of life. Favorable clinical course of the disease was observed during 5 months of follow-up. Conclusion. Timely MMA diagnosis (antenatal or during neonatal screening) is crucial for effective management and relatively favorable life prognosis for infants.

Pediatrics 2 experience, Neuropediatrics and neurometabolic diseases unit on phenylcetonuria: About 36 patients

Phenylketonuria (PKU) is a hereditary metabolic disease of phenylalanine metabolism, linked to a deficiency of phenylalanine hydroxylase or its cofactor, an enzyme allowing the transformation of phenylalanine into tyrosine, resulting in an increase in blood and brain concentration. of PHA, comprising an intellectual disability with cognitive and behavioral disorders if it is not treated. We report 36 cases of phenylketonuria followed in the pediatric department 2, born to consanguineous parents in 58.4% of cases and non-consanguineous in 41.6%, the male sex represents the majority with 22 cases and female with 14 cases, The age of diagnosis minimum 3 days of life and maximum 16 years and the current age of patients minimum 4 years and maximum 37 years with comorbidities like epilepsy, motor disorders, behavioral disorders, Autism Spectrum Disorder and mental retardation and about 70% have a regular monitoring. Through this series we will support the epidemiological, clinical, paraclinical and therapeutic particularities of patients with phenylketonuria. Early diagnosis of the disease makes it possible to initiate treatment early, which is mainly based on a diet low in phenylalanine for life in order to improve the progressive prognosis and avoid irreversible after-effects.

CRIM-negative infantile Pompe disease, long-term observation of the effect of enzyme replacement therapy: a clinical case

Background. Infantile-onset form of Pompe disease (IOPD) comprises a progressive and fatal disease in the absence of pathogenetic treatment. Enzyme replacement therapy using biologically active recombinant human alglucosidase alfa is considered as a treatment option to increase the life expectancy of patients with early diagnosis and timely initiation of therapy.Case description. A child aged 5 months was delivered to the Cardiology Department of Children’s Republican Clinical Hospital (Tatarstan, Russia) for examination and clarification of the diagnosis. The patient’s parents complained of his shortness of breath, unproductive cough, cyanosis of the nasolabial triangle when restless, weakness, lethargy during breastfeeding session, as well as decreased appetite up to refusal to eat, constantly enlarged tongue. The examination revealed macroglossia and hypersalivation, pseudohypertrophy of calf muscles, dyspnea involving the accessory muscles, hepatomegaly, diffuse muscular hypotonia. Laboratory tests revealed an increase in alanine aminotransferase level greater than four times the normal values, aspartate aminotransferase level — more than nine times, a significant rise of creatine phosphokinase and lactate dehydrogenase, as well as natriuretic peptide. Echocardiography revealed significant myocardial hypertrophy of both the left and right ventricles. Complaints, medical history, clinical examination, and all of the above changes in laboratory and instrumental examinations suggested a group of hereditary metabolic diseases (Pompe disease), confirmed by a pronounced decrease in the activity of the alpha-glucosidase enzyme to 0.12 μmol/l/h in dry blood spots with subsequent molecular genetic study and detection of compound-heterozygous mutations in the GAA gene. It was decided to initiate specific enzyme replacement therapy by intravenous administration of a recombinant form of human acidic alpha-glucosidase (alglucosidase alfa) at a dose of 20 mg/kg/injection in a frequency of once every 2 weeks. In addition, CRIM (cross-reactive immunological material)-negative status determined immune tolerance therapy, including the most studied combination of three drugs: rituximab, methotrexate, and intravenous immunoglobulin, as a response to enzyme replacement therapy. Long-term observation of the effect of enzyme replacement therapy brought positive results in the form of new motor skills, decreased content of intracellular enzymes and natriuretic peptide, reduction of myocardial hypertrophy of the left and right ventricles. In the future, the child needs lifelong treatment.Conclusion. Awareness of physicians about Pompe disease will prevent the growth in diagnostic errors and neglected cases. In case of early confirmation, the effectiveness of currently available ERT increases: the possibility to stop the disease progression, to reverse its individual clinical manifestations, and to improve the patient’s quality of life.

Effect of Protection Polymer Coatings on the Performance of an Amperometric Galactose Biosensor in Human Plasma.

Galactose monitoring in individuals allows the prevention of harsh health conditions related to hereditary metabolic diseases like galactosemia. Current methods of galactose detection need development to obtain cheaper, more reliable, and more specific sensors. Enzyme-containing amperometric sensors based on galactose oxidase activity are a promising approach, which can be enhanced by means of their inclusion in a redox polymer coating. This strategy simultaneously allows the immobilization of the biocatalyst to the electroactive surface and hosts the electron shuttling units. An additional deposition of capping polymers prevents external interferences like ascorbic or uric acid as well as biofouling when measuring in physiological fuels. This work studies the protection effect of poly(2-methacryloyloxyethyl phosphorylcholine-co-glycidyl methacrylate (MPC) and polyvinylimidazole-polysulfostyrene (P(VI-SS)) when incorporated in the biosensor design for the detection of galactose in human plasma.

SEPSIS-LIKE СИНДРОМ У НОВОРОЖДЕННОГО РЕБЕНКА ПРИ НАРУШЕНИИ ЦИКЛА ОБРАЗОВАНИЯ МОЧЕВИНЫ

Sepsis-like syndrome is a septic–like syndrome. The pathogenesis of Sepsis-like syndrome is based on the hyperproduction of proinflammatory cytokines. Hereditary metabolic disorders, including in violation of the urea formation cycle, can occur with the clinic of Sepsis-like syndrome. Ammonium easily penetrates the blood-brain barrier, causes neurotoxic effects, damages glial cells, increases osmolarity, which leads to cerebral edema. The symptoms are similar to hypoxic-ischemic lesions of the central nervous system, meningoencephalitis, intrauterine infections, which leads to a differential diagnostic search for causes and the need to exclude an infectious disease. The article presents a clinical case of a newborn with a Sepsis-like syndrome clinic. The girl was born from 2 births naturally at the age of 38 weeks. In the first day of life, there were signs of respiratory failure. She was on mixed feeding. From the 5th day of life, the deterioration of the condition caused by the syndrome of central nervous system depression, with an increase in depression of consciousness up to coma, the development of seizures. Differential diagnosis was performed with intrauterine infections, sepsis, as there was leukocytosis in the blood, increased ESR, ferritin, procalcitonin, and seeding from the cerebrospinal fluid of Micoplasma hominis. The presence of low urea content in the blood serum, up to its absence, made it possible to suspect hereditary metabolic diseases with a violation in the urea cycle. The conducted examinations revealed a total increase in the concentration of amino acids in the blood using the method of tandem mass spectrometry, metabolites in urine and hyperammonemia up to 354 mcg/dl. The newborn received antibacterial therapy, anticonvulsant therapy, sodium benzoate, and was transferred to a specialized therapeutic mixture "Nutrigen". Despite the therapy, neurological symptoms increased and the girl died at the age of 3 months. This clinical case showed the difficulties of differentiation. diagnosis of causes in the presence of Sepsis-like syndrome in newborn children.

Hyperargininemia: A Rare Diagnosis in Adulthood.

Hyperargininemia is a rare inherited metabolic disorder of the urea cycle with an autosomal recessive transmission. It occurs due to a deficiency of the enzyme arginase I and causes progressive neurological damage. Very few cases are diagnosed in adulthood, with the majority being diagnosed before the age of 4. Currently, this condition is diagnosed by a mass spectrometry technique in neonatal screening, which has been implemented in Portugal since 2007; births before that were not screened for this entity. We present a case of a 23-year-old woman referred to the internal medicine and neurology departments with a history of two hospital admissions for rhabdomyolysis at the age of 18, consanguineous parents, learning difficulties and multiple falls since the age of 8. In addition, the patient also had behavioural changes so she had psychological counselling at school, but lacked family support. Neurological examination showed mild proximal paraparesis, and spastic and paraparetic gait. The aetiological study revealed a pathological variant in homozygosity ARG1 and increased blood levels of arginine. Therefore, the diagnosis of hyperargininemia was confirmed. Compared to other urea cycle disorders, hyperargininemia is the rarest one. It is important to recognise the characteristic clinical features and diagnose it early because a favourable outcome can be achieved with appropriate treatment. This case shows a delayed diagnosis of hyperargininemia and highlights the importance of the internist's role in diagnosing rare diseases. Hyperargininemia is a rare hereditary metabolic disease of the urea cycle and the rarest of the disorders affecting this cycle.The diagnosis is almost always made within the first four years of life and very few are diagnosed in adulthood.Early diagnosis is essential to reduce the progression of neurological damage, through appropriate treatment.

An effective integrated program of neonatal screening - as a modern direction of diagnosis of hereditary metabolic diseases in children (literature review)

An effective integrated program of neonatal screening - as a modern direction of diagnosis of hereditary metabolic diseases in children (literature review)

Acute heart failure in a neonate

The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.

Preimplantation genetic testing for monogenic disorders (PGT-M) offers an alternative strategy to prevent children from being born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes: a retrospective study.

Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases. In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases. After PGT-M, unaffected (i.e., normal) embryos after genetic detection were transferred into the uterus of their corresponding mothers. A total of 43 carrier couples with the following hereditary neurological diseasesor metabolic diseases dominated by nervous system phenotypesunderwent PGT-M: Duchenne muscular dystrophy (13 families); methylmalonic acidemia (7 families); spinal muscular atrophy (5 families); infantile neuroaxonal dystrophyand intellectual developmental disorder(3 families each); Cockayne syndrome(2 families); Menkes disease, spinocerebellar ataxia, glycine encephalopathy with epilepsy,Charcot-Marie-Tooth disease, mucopolysaccharidosis, Aicardi-Goutieres syndrome, adrenoleukodystrophy, phenylketonuria, amyotrophic lateral sclerosis, and Dravet syndrome (1 family each). After 53 PGT-M cycles,the final transferable embryo rate was 12.45%, the clinical pregnancy rate was 74.19%, and the live birth rate was 89.47%;a total of 18 unaffected (i.e., healthy) children were born to these families. This study highlights the importance of PGT-M in preventing children born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes.

Phenylketonuria Incidence based on the Results of the Neonatal Screening Program and Evaluation of this Program-based Surveillance Data System in Sirjan City from 2012 to 2019

Background PKU is the most common hereditary metabolic disease. Considering the severe complications caused by the lack of timely diagnosis of this disease, it is important to carry out the newborn screening process properly. Aim This study aims to determine the incidence of phenylketonuria (PKU) based on the results of the neonatal screening program and evaluate the indicators of this program in Sirjan City from 2012 to 2019. Methods The present study was across-section descriptive, and all screening babies were examined from 2012 to 2019. Screening information was obtained from data recorded in the neonatal screening program and patient information from the national form of epidemiological investigation of genetic diseases in the Kerman Health Department. Excel software was used to draw charts. Descriptive statistics were used to describe the variables. Information was provided as a frequency table and chart. Results The overall screening coverage was 95.3%. Among this, 93.2% of infants were screened during the 3 to 5 days of life. The incidence of PKU was found to be 1.33 in 10,000 live births. Around 0.44% of the samples were inappropriate, and the percentage of inappropriate samples was from the beginning of the program and monitored across each year. On the first visit to the PKU treatment center, 50% of infants were below 2 weeks. About 100% of patients identified in screening were the first child in the family, and around 83.3% of parents were consanguineous. Conclusion The incidence of PKU in Sirjan is in line with the national average. Implementation of the screening program showed a significant impact on the timely diagnosis and the onset of patients. It is necessary to increase household awareness about the consequences of consanguineous marriages, especially in areas with a high prevalence of PKU.

Hereditary Amino Acid Metabolism Disorders and Urea Cycle Disorders: to Practicing Physician

Hereditary amino acid metabolism disorders (aminoacidopathies) are clinically and genetically heterogeneous group of hereditary metabolic diseases caused by enzymes deficiency involved in amino acid metabolism, that finally leads to progressive damage of central nervous system, liver, kidneys, and other organs and systems. Hereditary urea cycle disorders occur because of enzyme deficiency leading to impaired urea synthesis and hyperammoniemia in patients. The age of disease onset and clinical manifestations severity range from milder, intermittent forms to severe, manifesting in the first hours of life. Expanded neonatal screening (implemented in Russian Federation at 01.01.2023) allows to diagnose diseases from these groups in the first days of life, to prescribe timely pathogenetic therapy. Altogether it helps to prevent the development of disease severe complications. Raising awareness about hereditary aminoacidopathies and urea cycle disorders among pediatricians, neonatologists, neurologists, gastroenterologists, ophthalmologists is a topical issue of modern pediatrics.

Selective screening for inborn errors of metabolism using tandem mass spectrometry in West Kazakhstan children: study protocol.

To set the reference values of 51 metabolites in the child population, 750 healthy children will be included. The selective screening will be performed among 1,500 patients aged 1day to 18years with suspected hereditary metabolic disorders. The results of selective screening will be interpreted by comparison with the reference values established. Diagnosis will be based on clinical signs, blood levels of amino acids, acylcarnitines, succinylacetone, and urine levels of organic acids and tests for gene mutations. An assessment of 37 inborn errors of metabolism frequencies in high-risk children will be performed. The research will further develop the national as selective as expanded newborn screening programs. The study was registered in clinicaltrials. gov (https://www. gov/study/NCT05910151) on 16 June 2023.

Research progress on hereditary endocrine and metabolic diseases associated with sensorineural hearing loss

Hereditary endocrine and metabolic diseases , caused by genetic factors, exhibit complex and diverse symptoms, including the possibility of concurrent sensorineural deafness. Currently, there is a limited clinical understanding of hereditary endocrine and metabolic diseases that manifest with deafness, the pathogenesis remains unclear,and there is a lack of effective diagnostic and treatment methods. This article summarizes the research progress of hereditary endocrine and metabolic diseases complicated with deafness from the pathogenesis, clinical phenotype, diagnosis and treatment. Understanding the current research progress and integrating genetic analysis into clinical practice are crucial for accurate diagnosis and treatment, evaluating clinical efficacy, and providing effective genetic counseling for these diseases.

GM1 and GM2-Gangliosidosis: Clinical Features, Neuroimaging Findings and Electroencephalography.

Gangliosidosis is one of the hereditary metabolic diseases caused by the accumulation of Gangliosid in the central nervous system, leading to severe and progressive neurological deficits. Regarding phenotype, GM1 and GM2-Gangliosidosis are divided into Infantile, Juvenile, and Adult. In this study, thirty-seven patients with GM1 and GM2-Gangliosidosis were referred to the neurology department of Mofid Children's Hospital in Tehran, Iran, whose disease was confirmed from September 2019 to December 2021. This study assessed age, sex, and developmental status before the onset of the disease, clinical manifestations, brain imaging, and electroencephalography. 97.20% of patients were the result of family marriage. Approximately 80% of juvenile patients were developmentally normal before the onset of the disease. Developmental delay was more common among infantile GM1-Gangliosidosis than infantile GM2-Gangliosidosis, but in total, more than 50% of GM1&GM2-Gangliosidosis patients had reached their developmental milestone before the onset of the disease. With the onset of disease symptoms, 100% of patients regressed in terms of movement, 97.20% of them mentally, and 75% of them had seizures during the disease. The most common clinical findings were cherry-red spot, Mongolian spot, macrocephaly, organomegaly, hyperacusis, and scoliosis. The most common brain imaging findings included bilateral thalamus involvement, brain atrophy, PVL, and delayed myelination. The most common finding in electroencephalography was background low voltage with abnormal sharp waves. This study concluded that most of the patients are the result of family marriage, and most of the juvenile patients are developmentally normal before the onset of the disease. In addition, more than 50% of infantile patients reach their developmental milestones before the onset of the disease. The most common clinical findings of these patients are seizures, cherry-red spot, macrocephaly, hyperacusis, Mongolian spot, and bilateral involvement of the thalamus.

Selective Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry in Newborns of the West Kazakhstan: Pilot Study

Tandem mass spectrometry can detect and quantify many metabolites in a single blood spot to diagnose amino acid disorders, organic acids, fatty acid oxidation, and urea cycle disorders. The use of tandem mass spectrometry (MS/MS) is expanding for the implementation of newborn screening programs for inborn errors of metabolism and for selective screening of children of different ages. In Kazakhstan, the use of MS/MS in metabolic screening programs is not yet developed due to the high cost of equipment and consumables and the lack of special screening centers and specialists. Data on the prevalence of most inborn errors of metabolism in Kazakhstan are not presented in the literature. Aim: to perform selective screening for hereditary metabolic diseases among newborns in western Kazakhstan using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Methods: Selective screening was performed among 250 newborns with suspected hereditary metabolic disorders using tandem mass spectrometry. Results: The results of selective newborn screening were interpreted by comparison with reference values established for this group. Diagnosis was based on clinical signs, blood levels of amino acids, acylcarnitines, succinylacetone, urine organic acids, and gene mutation tests. An assessment of 37 inborn errors of metabolism frequencies in high-risk newborns was performed. Conclusion: The research will further develop the national as selective as expanded newborn screening programs.

Follow-up of Patients with Hereditary Metabolic Diseases during the 3 Years of the Pandemic in the Reference Center for Hereditary Metabolism Diseases of the Centro Hospitalar Universitário Lisboa Norte

Introduction:: The adult unit of the Reference Center for Hereditary Metabolism Diseases of the Centro Hospitalar Universitário Lisboa Norte was created in 2002. The team that supports this unit is made up of several specialists, including 2 Internal Medicine Doctors and 2 Nutritionists. The unit carries out its activity mainly in an outpatient clinic on Fridays. Between March 2020 and December 2022, the team adapted the support given to this unit, transforming some external appointments into non-face-to-face appointments in order to maintain contact with patients and reduce the deslocation to the CHULN. Methods:: The analysis reported below reflects the activity in face-to-face and non-face-to-face appointment of the medical team and nutrition team in the critical period. Results/Case Report:: A total of 220 patients were evaluated, 56.4% female and 43.6% male. Regarding the evaluated pathologies, these were divided into 3 groups: aminoacidopathies – 40%, organic aciduria – 6.5% and other metabolic diseases – 53.5%. During these three years a total of 580 nutrition appointments were scheduled, 457 face-to-face and 123 non-face-to-face. 32% of patients scheduled did not attend the appointments or it was not possible to make telephone contact. This percentage is divided into 90% face-to-face appointments and 10% nonface- to-face appointments. Regarding medical appointments, the total was 797, 667 of which were face-to-face and 130 non-face-to-face. 16.8% of absences were registered in face-to-face and non-face-to-face appointments. 98.5% of absences concern non-face-to-face appointments. Conclusion:: Despite the troubled period worldwide, support for these patients was always ensured, both by the Medical team and the Nutrition team. Despite the solutions found to keep patients safe, in this specific period, the % of absences from the outpatient clinic is quite high, and one of the main justifications presented by the patients is related to the fact that they are afraid to go to the hospital. With regard to absences recorded in non-face-to-face appointments, there were several situations in which patients reported not being able to answer the phone during their working hours.

Glycogen storage disease type Ib: modern understanding of the pathogenesis of neutropenia and prospects for its treatment with empagliflozin

Glycogen storage disease type Ib (GSD Ib) — is a disease from the group of hereditary metabolic diseases caused by insufficiency of the glucose-6-phosphate transporter (G6PT, SLC37A4), which leads to a violation of both glycogenolysis and gluconeogenesis and, as a consequence, to excessive accumulation of glycogen and fat in the liver, kidneys and intestinal mucosa. The main clinical manifestations and laboratory data include growth retardation, hepatomegaly, hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia. Complications of this disease are hepatocellular adenoma with a possible risk of malignancy, nephropathy and osteoporosis. A specific sign of GSD Ib is neutropenia with impaired neutrophil function, which creates prerequisites for recurrent infections and the development of inflammatory bowel disease. Until the present, enzyme replacement therapy of GSD Ib has not been developed, therefore, the main methods of treatment are a specialized diet with the addition of raw corn starch (for relief of hypoglycemia) and the use of granulocyte colony stimulating factor (for relief of neutropenia). However, the recent establishment of the role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction in GSD Ib has led to a reprofiling of indications for the use of empagliflozin, a type 2 renal sodium—glucose cotransporter inhibitor (SGLT2). In the modern literature, it is reported about a minor, but very successful experience of its use in patients with GSD Ib (outside the framework of official indications for use) and a beneficial effect on neutrophil dysfunction and its clinical consequences. Oddly enough, this hypoglycemic drug improved not only metabolic, but also glycemic control in patients with GSD Ib, despite the fact that the pathology is based on chronic hypoglycemia. More and more evidence points to the role of empagliflozin in the regulation of cellular homeostasis (for example, fatty acid metabolism, glucose, cholesterol, apoptosis and cell proliferation, in particular in the liver) by influencing the activity of sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK) and signal molecules such as -serine/threonine protein kinase (Akt) and a mechanical target of rapamycin (mTOR), which leads to an improvement in the structure and function of mitochondria, stimulation of autophagy, reducing oxidative stress and suppressing inflammation. Modulation of these pathways shifts oxidative metabolism from carbohydrates to lipids and leads to a key decrease in insulin levels, resistance to it, glucose and lipotoxicity. This review presents current data on the pathogenesis of neutropenia and the possibility of using empagliflozin for its relief in patients with GSD Ib.

Association of genes in hereditary metabolic diseases with diagnosis, prognosis, and treatment outcomes in gastric cancer.

Aberrant metabolism is a major hallmark of cancers and hereditary diseases. Genes associated with inborn metabolic errors may also play roles in cancer development. This study evaluated the overall impact of these genes on gastric cancer (GC). In total, 162 genes involved in 203 hereditary metabolic diseases were identified in the Human Phenotype Ontology database. Clinical and multi-omic data were acquired from the GC cohort of the Affiliated Hospital of Jiangsu University and other published cohorts. A 4-gene and 32-gene signature was established for diagnosis and prognosis or therapeutic prediction, respectively, and corresponding abnormal metabolism scores (AMscores) were calculated. The diagnostic AMscore showed high sensitivity (0.88-1.00) and specificity (0.89-1.00) to distinguish between GC and paired normal tissues, with area under the receiver operating characteristic curve (AUC) ranging from 0.911 to 1.000 in four GC cohorts. The prognostic or predictive AMscore was an independent predictor of overall survival (OS) in five GC cohorts and a predictor of the OS and disease-free survival benefit of postoperative chemotherapy or chemoradiotherapy in one GC cohort with such data. The AMscore adversely impacts immune biomarkers, including tumor mutation burden, tumor neoantigen burden, microsatellite instability, programmed death-ligand 1 protein expression, tumor microenvironment score, T cell receptor clonality, and immune cell infiltration detected by multiplex immunofluorescence staining. The AUC of the AMscore for predicting immunotherapy response ranging from 0.780 to 0.964 in four cohorts involving GC, urothelial cancer, melanoma, and lung cancer. The objective response rates in the low and high AMscore subgroups were 78.6% and 3.2%, 40.4% and 7%, 52.6% and 0%, and 72.7% and 0%, respectively (all p<0.001). In cohorts with survival data, a high AMscore was hazardous for OS or progression-free survival, with hazard ratios ranged from 5.79 to 108.59 (all p<0.001). Importantly, the AMscore significantly improved the prediction of current immune biomarkers for both response and survival, thus redefining the advantaged and disadvantaged immunotherapy populations. Signatures based on genes associated with hereditary metabolic diseases and their corresponding scores could be used to guide the diagnosis and treatment of GC. Therefore, further validation is required.

An oxygen-insensitive amperometric galactose biosensor based on galactose oxidase co-immobilized with an Os-complex modified redox polymer

Monitoring galactose levels in dairy products can help to prevent severe complications with a hereditary metabolic disease such as galactosemia, a life-threatening disease. The current state of the art requires the development of less expensive, more reliable and specific methods to determine galactose levels in food in a practical way. We report the development and optimization of an amperometric biosensor for determination of galactose in dairy products based on galactose oxidase (GaOx) co-immobilized with an osmium-complex modified redox polymer on glassy carbon electrodes. To attain the maximum catalytic currents based on mediated electron transfer, two Os-complex based polymers with different redox potentials and different enzyme:redox polymer ratios were studied. The optimized GaOx-modified electrode gave a maximum electrocatalytic response of galactose oxidation that was not affected by the presence of O2, indicating fast wiring of the enzyme by the Os-complex modified redox polymer. The biosensor that gave the best analytical parameters for galactose detection was further tested for measuring galactose concentration in lactose-containing and lactose-free milk and yogurt samples under aerobic conditions. The results obtained with the amperometric biosensor were validated by high-performance anion-exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD).