Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy syndrome (PMSE/STRADA-related disease) is a rare neurodevelopmental disorder characterized by megalencephaly, early-onset drug-resistant epilepsy, neurocognitive impairment, and high early mortality, often due to status epilepticus. PMSE is caused by a multiexon deletion in the STRADA/LYK5 gene, encoding STRADA protein, which regulates the mechanistic target of rapamycin (mTOR) pathway. GABAergic inhibitory interneurons (INs) critically modulate excitatory:inhibitory balance in cortical networks, and IN deficits contribute to epileptogenesis in several epileptic encephalopathies. However, no studies to date have investigated INs in PMSE. We demonstrate that Strada/STRADA loss causes a reduction of multiple IN subtypes in the cerebral cortex and a corresponding increase in the striatum, representative of the remnant ganglionic eminence progenitor origin, in both Strada-/- mice and in a case of human PMSE brain tissue, suggestive of an IN migration defect. RNA sequencing comparing wildtype control to Strada-/- mouse cortex and striatum corroborates these findings, revealing increased IN-related gene expression (e.g., Dlx2) in the striatum. mTOR-associated genes (Lamp5, Cryab) are differentially expressed in the developing cortex, and cytoskeletal-associated genes (e.g., Tppp3, Kank4, Map1a) are differentially expressed in the developing cortex and mature striatum of Strada-/- mice. Functional validation confirms enlarged INs in Strada/STRADA-deficient brain, associated with mTOR hyperactivation. Together, these results suggest that STRADA/Strada loss may contribute to failed IN migration, the first such report in a developmental mTORassociated megalencephaly syndrome, highlighting INs as a therapeutic target for seizure prevention in PMSE.

The endoplasmic reticulum (ER) serves as a key hub for protein homeostasis, maintaining a strict quality-control system that ensures only properly folded proteins reach their destinations, while misfolded proteins are degraded via ER-associated degradation (ERAD) or selective ER-phagy. JKAMP, which encodes an ER-resident transmembrane protein involved in ERAD, has not previously been associated with human disease. Here, we report bi-allelic loss-of-function variants in JKAMP in 14 affected individuals from 10 unrelated families presenting with a neurodevelopmental syndrome characterized by intellectual disability, developmental delay, seizures, hypotonia, microcephaly, and dysmorphic features. An in vivo zebrafish model lacking jkamp recapitulated key aspects of the human disorder, including developmental abnormalities and impaired myelin production, further corroborating its pathogenic role. Mechanistic studies identified GPR37, a brain-enriched orphan G protein-coupled receptor (GPCR) and known JKAMP interactor, as a critical downstream effector. GPR37 plays essential roles in dopaminergic signaling, inflammatory pain regulation, neuroprotection, and myelination. Loss of JKAMP resulted in defective folding and degradation of GPR37, leading to its accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. These findings establish JKAMP as a previously unrecognized contributor to human neurodevelopment and uncover a pathogenic mechanism linking ER protein quality control to GPCR regulation and neurological disease.

Surplus calories are used to prevent protein catabolism in patients with maple syrup urine disease (MSUD) but can also lead to obesity and its related complications. At present, there are no evidence-based guidelines to inform weight loss strategies for patients with inborn errors of metabolism. Obese MSUD patients often resist weight loss due to the fear of metabolic decompensation, and their dietary options are limited by dependence on medical foods with fixed nutritional composition. We examined the anthropometric and biochemical effects of metformin in nine adults with severe (classic) MSUD who were instructed to reduce their calorie intake from medical food by 10%. Eight participants (67% female) completed the 52-week study; one withdrew following elective liver transplantation. Baseline median age, body mass index (BMI), and glycosylated hemoglobin (HgbA1C) were 33.8 years (IQR 25.3–41.6), 38.3 kg/m² (IQR 31.6–42.2), and 5.3% (IQR 5.0–5.6), respectively. We titrated the daily metformin dose to a median of 2000 mg (IQR 1000–2000) by week 25, at which time seven (88%) participants successfully reduced total calories from medical food by 10%. Metformin was generally well tolerated. Diarrhea was the most common treatment-related complication, affecting 56% of participants, and limited dose escalation in two (22%) of them. No participant achieved the primary outcome of a > 10% BMI change. However, metformin therapy allowed for modest and significant reductions in weight (−2.8%, p = 0.023), BMI (−2.8 kg/m2, p = 0.016), and calories from medical food without altering plasma leucine concentrations or the proportion of dietary protein from intact sources. Serum triglycerides, high-density lipoprotein, and HgbA1C did not change over the study period. Based on these clinical observations, we conclude that classic MSUD patients can safely use metformin to aid weight loss without triggering metabolic instability, and may therefore tolerate more aggressive weight loss strategies.

Sorbitol dehydrogenase (SORD) deficiency, due to biallelic loss-of-function variants in the SORD gene, is a recently recognized cause of autosomal recessive hereditary neuropathy. Specific diagnosis is difficult on clinical grounds alone, and molecular genetic testing of SORD is complicated by the presence of a pseudogene. Biochemical testing of serum sorbitol is suggested as a potential biomarker. We report a novel urine biochemical profile of elevated excretion of sorbitol and a second polyol, xylitol, to aid in the identification of individuals with SORD-related neuropathy.

Congenital pancreatic lipase deficiency (CPLD, OMIM #614338) is a rare exocrine pancreatic disorder presenting in late infancy with steatorrhea, fat-soluble vitamin deficiency, and low pancreatic lipase activity. Variants of the pancreatic triglyceride lipase (PNLIP) gene have been linked to CPLD. Six children from four Amish families exhibited CPLD symptoms and two had decreased fecal elastase levels when tested. A novel homozygous PNLIP variant, c.869G>A (p.S290N), was identified in these children. This study aimed to characterize the PNLIP variant to understand its mechanism underlying CPLD. The variant impact was first evaluated using computational modeling. Functional analyses included activity assays, cellular PNLIP partition assessments, and endoplasmic reticulum (ER) stress evaluation in transfected cells. Computational modeling showed that p.Ser290 is highly conserved across species and the variant causes steric hindrance resulting in protein misfolding. Functional assays revealed that the PNLIP variant had a complete loss of activity compared to the wild type (WT), with defects in catalytic function and secretion. Immunoblotting showed reduced PNLIP variant in the medium and increased accumulation in the detergent-insoluble fraction consistent with protein misfolding. Variant-expressing cells had elevated levels of BiP, an ER stress marker, and increased Xbp1 mRNA splicing, suggesting an elevated ER stress and unfolded protein response (UPR). In conclusion, the PNLIP p.S290N variant causes CPLD through a loss-of-function mechanism, characterized by loss of enzymatic activity and defective secretion due to protein misfolding. Further studies are needed to determine whether the misfolding variant protein induces proteotoxicity, potentially increasing the risk of pancreatic injury including chronic pancreatitis.