A case of inherited glycosylphosphatidylinositol deficiency caused by PGAP3 variant with uniparental isodisomy on chromosome 17.

BACKGROUND: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17. METHOD: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. RESULTS: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency. CONCLUSION: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia.

Closing the gap: An urgent need for newborn screening of organic acid disorders in developing countries.

Organic acid disorders are rare inherited metabolic disorders of key metabolic pathways. For the identification of specific organic acids, investigation of urinary metabolites and genetic testing are required through newborn screening programmes. Delayed diagnosis leads to complications, such as cardiac attacks, respiratory problems, neuro-developmental disorders, intellectual disability, and even premature death. The burden of such inherited disorders is quite high in developing countries of South Asia due to high rate of consanguinity in the region. Unfortunately, such disorders are left untreated due to the lack of screening facilities in such countries. The current narrative review was planned to highlight the urgent need for closing this gap and implementing effective newborn screening programmes for organic acid disorders in developing countries. The implementation of effective programmes is crucial for reducing morbidity and mortality, and for improving the quality of life for the affected children and of their families, thus promoting global health equity.

Suspected Pseudocholinesterase Deficiency During Left Thyroid Lobectomy and Isthmusectomy: A Case Report.

BACKGROUND: Pseudocholinesterase (butyrylcholinesterase) deficiency is an acquired or inherited condition in which decreased plasma levels of the pseudocholinesterase enzyme lead to an inability to metabolize the neuromuscular blocking agents succinylcholine and mivacurium, prolonging their paralytic effects. This often results in delayed extubation and additional intensive care requirements in the postoperative period. CASE DESCRIPTION: We describe a case of suspected pseudocholinesterase deficiency in a previously healthy 59-year-old female who underwent a left thyroid lobectomy and isthmusectomy. The patient received 120 mg of succinylcholine chloride before intubation. The patient did not meet extubation criteria following the completion of the procedure approximately two hours after receiving succinylcholine chloride. The patient was transferred to the ICU for respiratory support and for the medication to clear from the patient's system. The patient regained muscle control approximately four hours after receiving succinylcholine chloride and was extubated without complication. The patient shared post-extubation that she had a blood relative with the diagnosis of pseudocholinesterase deficiency. CONCLUSION: Pseudocholinesterase deficiency is rare but can result in potentially serious complications following the administration of succinylcholine chloride, mivacurium, or ester local anesthetics due to reduced metabolism and subsequently increased pharmacodynamic effects. Given the widespread use of succinylcholine chloride as a neuromuscular blocking agent, such as in this case, providers must be aware of the presentation, pathophysiology, diagnosis, and management. Additionally, this case demonstrates the importance of thoroughly inquiring about any personal or family history of anesthetic complications during a preoperative assessment.

Diagnóstico prenatal de clorhidrorrea congénita: reporte de caso / Prenatal diagnosis of congenital chloride diarrhea: A case report

La clorhidrorrea congénita es un trastorno genético infrecuente pero importante caracterizado por una alteración grave del balance hidroelectrolítico como resultado de un defecto en la absorción intestinal de cloruros. Los niños afectados presentan diarrea persistente, deshidratación y malnutrición; el control médico y del desarrollo son complejos. Mejorar la detección prenatal es esencial para facilitar la atención del paciente, las intervenciones tempranas y el asesoramiento genético informado. Sin embargo, a pesar de los avances de la medicina, la naturaleza compleja y la escasa frecuencia de esta entidad, constituyen un desafío para la detección prenatal. En este estudio, se reporta el caso de una embarazada donde los estudios por imágenes de resonancia magnética fetales identificaron en forma efectiva las características típicas de la clorhidrorrea congénita. Se proveen conocimientos sobre las complejidades del diagnóstico y se sugieren caminos para las estrategias de detección temprana de esta enfermedad.

Congenital chloride diarrhea (CCD) is a rare but significant genetic disorder characterized by severe electrolyte imbalances resulting from impaired intestinal chloride absorption. Affected children experience persistent diarrhea, dehydration, and malnutrition, complicating medical and developmental care. The enhancement of prenatal detection is crucial for improved patient management, early interventions, and informed genetic counseling. However, despite advancements in medicine, the complex nature and rarity of CCD make prenatal detection challenging. In this study, we report a fetal case where prenatal magnetic resonance imaging (MRI) effectively identified the distinctive characteristics of CCD, providing insights into the complexities of diagnosis and suggesting avenues for enhanced early detection strategies.

Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction.

Introduction: Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids. Methods: In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots. Results: Mice lacking GR in BMAds (BMAd-Nr3c1 -/-) and control mice (BMAd-Nr3c1 +/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and µCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1 -/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle. Discussion: In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.

[Uric Acid Metabolism, Uric Acid Transporters and Dysuricemia].

Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.

Computer-assisted patient identification tool in inborn errors of metabolism - potential for rare disease patient registry and big data analysis.

BACKGROUND: Patient registries are crucial for rare disease management. However, manual registry construction is labor-intensive and often not user-friendly. Our goal is to establish Hong Kong's first computer-assisted patient identification tool for rare diseases, starting with inborn errors of metabolism (IEM). METHODS: Patient data from 2010 to 2019 was retrieved from electronic databases. Through big data analytics, patient data were filtered based on specific IEM-related biochemical and genetic tests. Clinical notes were analyzed using a rule-based natural language processing technique called regular expression. The algorithm classified each extracted paragraph as "IEM-related" or "not IEM-related." Pathologists reviewed the paragraphs for curation, and the algorithm's performance was evaluated. RESULTS: Out of 46,419 patients with IEM-related tests, the algorithm identified 100 as "IEM-related." After pathologists' validation, 96 cases were confirmed as true IEM, with 1 uncertain case and 3 false positives. A secondary ascertainment yielded a sensitivity of 92.3% compared to our previously published IEM cohort. CONCLUSIONS: Our artificial intelligence approach provides a novel method to identify IEM patients, facilitating the creation of a centralized, computer-assisted rare disease patient registry at the local and national levels. This data can potentially be accessed by multiple stakeholders for collaborative research and to enhance healthcare management for rare diseases.

The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.

Enteric duplication cysts in paediatric population along with literature review / Quistes de duplicación entérica en población pediátrica y revisión de la literatura

The clinical presentation of enteric duplication cysts is dependent on the location of the cyst with symptoms varying from nausea and vomiting to abdominal distension, pain and perforation. Four patients were identified who were diagnosed with enteric duplication cysts within the period from 2019 to 2023. Three of the patients presented with signs of intestinal obstruction-abdominal distension and pain, while one had an antenatally detected abdominal mass. There were three boys and one girl with ages ranging from 4 months to 14 years. Three cases of ileal and one case of caecal duplication cyst were reported. Most of the cases showed ileal/caecal mucosa while one case demonstrated ectopic gastric mucosa. The treatment of these cysts includes surgical excision. Although radiological investigations help in arriving at a provisional diagnosis, the final diagnosis can be confirmed only after histopathological examination. Early treatment prevents complications and results in a good prognosis for the patient. (AU)

La presentación clínica de los quistes de duplicación entérica depende de la ubicación del quiste, y los síntomas varían desde náuseas y vómitos hasta distensión abdominal, dolor y perforación. Se identificaron cuatro pacientes que fueron diagnosticados con quistes de duplicación entérica en el período de 2019 a 2023. Tres de los pacientes presentaron signos de obstrucción intestinal (distensión abdominal y dolor), mientras que uno tenía una masa abdominal detectada prenatalmente. Eran tres niños y una niña con edades comprendidas entre 4 meses y 14 años. Se notificaron tres casos de quiste de duplicación ileal y un caso de quiste de duplicación cecal. La mayoría de los casos mostraron mucosa ileal/cecal, mientras que un caso mostró mucosa gástrica ectópica. El tratamiento de estos quistes incluye la escisión quirúrgica. Aunque las investigaciones radiológicas ayudan a llegar a un diagnóstico provisional, el diagnóstico final solo puede confirmarse después del examen histopatológico. El tratamiento precoz previene complicaciones y redunda en un buen pronóstico para el paciente. (AU)

Identifying Metabolic Diseases That Precipitate Neonatal Seizures.

Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly controlled neonatal epilepsy. Diagnosing neonatal-onset metabolic conditions proves a difficult task for clinicians; however, routine state newborn screening panels now include many IEMs. Three in particular-pyridoxine-dependent epilepsy, maple syrup urine disease, and Zellweger spectrum disorders-are highly associated with neonatal epilepsy and neurocognitive injury yet are often misdiagnosed. As research surrounding biomarkers for these conditions is emerging and gene sequencing technologies are advancing, clinicians are beginning to better establish early identification strategies for these diseases. In this literature review, the authors aim to present clinicians with an innovative clinical guide highlighting IEMs associated with neonatal-onset seizures, with the goal of promoting quality care and safety.

Congenital chloride diarrhoea in a Chinese infant with a compound heterozygous SLC26A3 mutation.

INTRODUCTION: Congenital chloride diarrhoea (CCD) is an autosomal recessive condition that causes secretory diarrhoea and potentially deadly electrolyte imbalances in infants because of solute carrier family 26 member 3 (SLC26A3) gene mutations. CASE PRESENTATION: A 7-month-old Chinese infant with a history of maternal polyhydramnios presented with frequent watery diarrhoea, severe dehydration, hypokalaemia, hyponatraemia, failure to thrive, metabolic alkalosis, hyperreninaemia, and hyperaldosteronaemia. Genetic testing revealed a compound heterozygous SLC26A3 gene mutation in this patient (c.269_270dup and c.2006 C > A). Therapy was administered in the form of oral sodium and potassium chloride supplements, which decreased stool frequency. CONCLUSIONS: CCD should be considered when an infant presents with prolonged diarrhoea during infancy, particularly in the context of maternal polyhydramnios and dilated foetal bowel loops.

A newborn Screening Programme for Inborn errors of metabolism in Galicia: 22 years of evaluation and follow-up.

BACKGROUND: There is a notable lack of harmonisation in newborn screening (NBS) programmes worldwide. The Galician programme for early detection of inborn errors of metabolism (IEM) was one of the first NBS programmes in Europe to incorporate mass spectrometry (July 2000). This programme currently screens for 26 IEMs in dried blood and urine samples collected 24-72 h after birth. RESULTS: In its 22-year history, this programme has analysed samples from 440,723 neonates and identified 326 cases of IEM with a prevalence of 1:1351. The most prevalent IEMs were hyperphenylalaninaemia (n = 118), followed by medium chain acyl-CoA dehydrogenase deficiency (MCADD, n = 26), galactosaemia (n = 20), and cystinurias (n = 43). Sixty-one false positives and 18 conditions related to maternal pathologies were detected. Urine samples have been identified as a useful secondary sample to reduce the rate of false positives and identify new defects. There were 5 false negatives. The overall positive value was 84.23%. The fatality rate over a median of 12.1 years of follow-up was 2.76%. The intelligence quotient of patients was normal in 95.7% of cases, and school performance was largely optimal, with pedagogic special needs assistance required in < 10% of cases. Clinical onset of disease preceded diagnosis in 4% of cases. The age at which first NBS report is performed was reduced by 4 days since 2021. CONCLUSIONS: This study highlights the benefits of collecting urine samples, reduce NBS reporting time and expanding the number of IEMs included in NBS programmes.

Tracing the lipidome in inborn errors of metabolism.

Inborn errors of metabolism (IEM) represent a heterogeneous group of more than 1800 rare disorders, many of which are causing significant childhood morbidity and mortality. More than 100 IEM are linked to dyslipidaemia, but yet our knowledge in connecting genetic information with lipidomic data is limited. Stable isotope tracing studies of the lipid metabolism (STL) provide insights on the dynamic of cellular lipid processes and could thereby facilitate the delineation of underlying metabolic (patho)mechanisms. This mini-review focuses on principles as well as technical limitations of STL and describes potential clinical applications by discussing recently published STL focusing on IEM.

Exploration of clinical and ethical issues in an expanded newborn metabolic screening programme: a qualitative interview study of healthcare professionals in Hong Kong.

INTRODUCTION: The Newborn Screening Programme for Inborn Errors of Metabolism (NBSIEM) enables early intervention and prevents premature mortality. Residual dried bloodspots (rDBS) from the heel prick test are a valuable resource for research. However, there is minimal data regarding how stakeholders in Hong Kong view the retention and secondary use of rDBS. This study aimed to explore views of the NBSIEM and the factors associated with retention and secondary use of rDBS among healthcare professionals in Hong Kong. METHODS: Between August 2021 and January 2022, semi-structured interviews were conducted with 30 healthcare professionals in obstetrics, paediatrics, and chemical pathology. Key themes were identified through thematic analysis, including views towards the current NBSIEM and the retention and secondary use of rDBS. RESULTS: After implementation of the NBSIEM, participants observed fewer patients with acute decompensation due to undiagnosed inborn errors of metabolism. The most frequently cited clinical utilities were early detection and improved health outcomes. Barriers to rDBS storage and its secondary use included uncertain value and benefits, trust concerns, and consent issues. CONCLUSION: This study highlighted healthcare professionals' concerns about the NBSIEM and uncertainties regarding the handling or utilisation of rDBS. Policymakers should consider these concerns when establishing new guidelines.