2026-07-06 | Homocystinuria presenting with cerebral venous thrombosis: a case report highlighting progressive thrombosis.
Homocystinuria is a hereditary metabolic disorder primarily caused by defects in enzymes involved in methionine metabolism, resulting in excessive accumulation of homocysteine and its metabolites in the blood and urine. Cerebral venous sinus thrombosis (CVST), premature atherosclerosis, and other thromboembolic events are among the most serious clinical manifestations of homocystinuria. We report a 13-year-old boy who initially presented with headache, followed by progressive disturbance of consciousness and status epilepticus. Cranial magnetic resonance imaging (MRI) revealed superior sagittal sinus thrombosis. He was transferred to a tertiary hospital, where he underwent emergency thrombus aspiration under digital subtraction angiography (DSA) guidance and received low-molecular-weight heparin (LMWH) anticoagulation. Although endovascular aspiration combined with LMWH controlled the seizures, his venous thrombosis continued to progress. He subsequently developed lower-extremity deep vein thrombosis, acute pulmonary embolism, and ventricular fibrillation. Clinical biochemical evaluation and genetic testing confirmed classic homocystinuria. Targeted therapy with warfarin, aspirin, vitamin B6, folic acid, and betaine resulted in a favorable prognosis. Early etiological screening, including genetic testing, should be prioritized in young patients with unexplained or recurrent thrombosis to optimize treatment and prognosis. Rational use of anticoagulants combined with targeted metabolic therapy (vitamin B6, folic acid, betaine) and antiplatelet therapy is critical for improving outcomes in such patients.
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2026-06-06 | Structural basis for a filamentous morpheein model of human cystathionine beta-synthase.
Human cystathionine beta-synthase (CBS) is a vital enzyme that regulates sulfur amino acid metabolism, hydrogen sulfide production, and cellular redox balance. Using a multidisciplinary approach, we demonstrate that CBS functions as a filamentous morpheein, with its stability, turnover, and activity governed by dynamic quaternary structural transitions. Three distinct filamentous assemblies were resolved by cryo-EM and are mediated by the oligomerization loop (residues 516-525): (i) ligand-free trans-dimers that form trans-basal filaments with basal stability and activity, (ii) adenosylornithine-bound cis-dimers that assemble into stabilized cis-basal filaments and (iii) S-adenosylmethionine-bound allo-dimers, which, together with cis-dimers, form highly stable, allo-activated stacked filaments. These reversible filamentous assemblies redefine CBS biology by integrating oligomerization and allosteric regulation within a morpheein framework. These findings provide a transformative perspective on CBS function and open avenues for pharmacological targeting of dysregulated CBS in various diseases including homocystinuria, cancer, and Down syndrome.
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2026-05-11 | Homocystinuria in a consanguineous indigenous family from rural Honduras: a ten-year follow up and literature review of familial cases.
Homocystinuria (HCU) is a rare autosomal recessive metabolic disorder, characterized by a mutation in the enzyme cystathionine beta-synthase and abnormally high levels of homocysteine in the blood. HCU that runs in a family is rare; prior to this report, there have been only 150 familial cases described in the literature. Here, we describe a familial cluster of HCU in four children in "Family V," a consanguineous indigenous family from rural Honduras with a 10-year clinical follow up. We describe the diagnosis, presentation and progression of three patients who were diagnosed in 2015; critical findings include substantial vision loss in Patients 1 and 2, and a significant decline in language ability in Patient 3. We also describe the presentation of Patient 4, a grandchild who we diagnosed with probable HCU based on symptoms very similar to his siblings and highly suspicious for HCU. Additionally, we completed a narrative review of previously published familial HCU cases, using PubMed and Google Scholar, to highlight common phenotypic trends in familial HCU patients. In the reported familial cases, 57% had CNS complications, 48% had ocular complications, and 30% had cardiovascular complications.
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2026-04-14 | Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice.
Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 1012 or 3 × 1013 vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy.
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2026-03-07 | Assessing the nutritional value and health risks of special low‑protein foods: narrative review.
Special low-protein foods (SLPFs) are essential for patients with disorders of inherited amino acid metabolism that require lifelong dietary protein restriction to prevent severe neurocognitive effects and even death. Conditions such as phenylketonuria (PKU), tyrosinemia (TYR), maple syrup urine disease (MSUD), homocystinuria (HCU), and urea cycle disorders (UCD) depend on these foods to support metabolic control and dietary adherence. SLPFs provide satiety, energy, and help prevent catabolism, but their nutritional composition poses challenges. Most SLPFs are formulated using isolated starches as the primary macronutrient base. Hydrocolloid fibers are commonly added to improve texture, consistency, shelf life, and water or gas retention. These ingredients form the backbone of SLPFs production and are consistently used across different regions worldwide, reflecting a standardized approach to their formulation. However, their potential adverse effects include suppression of gut microbiota, gut dysbiosis, increased inflammatory markers, overweight, and obesity, all of which raise cardio‑metabolic risks. Strengthening the nutritional quality of SLPFs through natural plant sources may help mitigate their potential adverse outcomes while ensuring patients’ dietary needs are met. Therefore, it is important to explore natural low‑protein alternatives that can both support sustainable food production and promote long‑term health benefits.
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