Feasibility of newborn screening for pyridoxine-dependent epilepsy.

Background: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy historically characterized by seizures that are resistant to antiseizure medications. Treatment with pyridoxine and lysine reduction therapies are associated with seizure control and improved developmental outcomes. In rare circumstances, patients have died prior to diagnosis and treatment with pyridoxine, and many patients are diagnosed after six months of age when lysine reduction therapies have limited efficacy.

Hypoxia-mediated rescue of retinal ganglion cells deficient in mitochondrial complex I is independent of the hypoxia-inducible factor pathway.

Continuous exposure to environmental hypoxia (11% O) has been shown to markedly slow the progressive degeneration of retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy with RGC-specific deletion of the key mitochondrial complex I accessory subunit ndufs4. As a first step toward identifying the therapeutic mechanism of hypoxia in this model, we conducted a series of experiments to investigate the role of the hypoxia-inducible factor (HIF) regulatory pathway in RGC neuroprotection. Vglut2-Cre; ndufs4 mice were crossed with strains bearing floxed alleles of the negative HIF regulatory vhl or of the two major HIF α-subunit isoforms, Hif1α and Hif2α.

Generation of an Armcx1 Conditional Knockout Mouse.

Armadillo repeat-containing X-linked protein-1 (Armcx1) is a poorly characterized transmembrane protein that regulates mitochondrial transport in neurons. Its overexpression has been shown to induce neurite outgrowth in embryonic neurons and to promote retinal ganglion cell (RGC) survival and axonal regrowth in a mouse optic nerve crush model. In order to evaluate the functions of endogenous Armcx1 in vivo, we have created a conditional Armcx1 knockout mouse line in which the entire coding region of the Armcx1 gene is flanked by loxP sites.

A multi-centre case series of patients with coexistent intracranial hypertension and malignant arterial hypertension.

Objective: To describe the clinical characteristics, outcomes, and management of a large cohort of patients with concomitant malignant arterial hypertension and intracranial hypertension.

Methods: Design: Retrospective case series.

Subjects: Patients aged ≥ 18 years with bilateral optic disc oedema (ODE), malignant arterial hypertension and intracranial hypertension at five academic institutions.

Continuous Hypoxia Reduces Retinal Ganglion Cell Degeneration in a Mouse Model of Mitochondrial Optic Neuropathy.

Purpose: To test whether continuous hypoxia is neuroprotective to retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy.

Methods: RGC degeneration was assessed in genetically modified mice in which the floxed gene for the complex I subunit NDUFS4 is deleted from RGCs using Vlgut2-driven Cre recombinase. Beginning at postnatal day 25 (P25), Vglut2-Cre;ndufs4loxP/loxP mice and control littermates were housed under hypoxia (11% oxygen) or kept under normoxia (21% oxygen).

Ophthalmic manifestations of MEPAN syndrome.

Background: Mitochondrial enoyl CoA reductase protein-associated neurodegeneration (MEPAN) syndrome is an ultra-rare autosomal recessive disorder caused by loss-of-function mutations in the MECR gene. The syndrome is characterized by dystonia in early childhood, basal ganglia signal abnormalities on MRI, and subsequent optic atrophy, with relative sparing of cognition. We characterize the ophthalmic manifestations observed in a patient with MEPAN syndrome, as a detailed account of ocular findings has not been published to date.

Association Between Lysine Reduction Therapies and Cognitive Outcomes in Patients With Pyridoxine-Dependent Epilepsy.

Background And Objectives: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies (LRTs) reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to examine the association between treatment with LRTs and cognitive outcomes.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) in adulthood: A Dutch pilot study exploring clinical and patient-reported outcomes.

Background: Little is known about pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) in adulthood, as the genetic basis of the disorder has only been elucidated 15 years ago. This creates a knowledge gap for physicians, pediatric patients and their parents, which was aimed to address in this study using clinical data as well as patient-reported outcome measures (PROMs) for the patient's perspective.

Methods: Dutch, genetically confirmed PDE-ALDH7A1 patients ≥18 years were eligible for inclusion.

Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy.

Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function.

At this junction….

An 81-year-old woman developed painful vision loss to hand motions in the right eye over a several-day period. Dilated fundus examination revealed no acute pathology, but automated perimetry showed a superotemporal visual field defect in the asymptomatic left eye, suggestive of a junctional defect. Magnetic resonance imaging demonstrated enhancement of the right optic nerve extending to its junction with the optic chiasm.

Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy.

BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop.

Traumatic chiasmopathy following mild trauma in a patient with thyroid orbitopathy.

Purpose: Traumatic injury to the optic chiasm is rare and most frequently caused by high-velocity head trauma. It classically results in bitemporal hemianopsia and often presents in conjunction with multiple other traumatic injuries, such as skull fractures and cerebrospinal fluid leaks. We present the case of a 40-year-old woman with pre-existing thyroid orbitopathy who struck her forehead after a fall from standing height.

Neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein associated disorder-optic neuritis: a comprehensive review of diagnosis and treatment.

Optic neuritis (ON) is the most common cause of acute optic neuropathy in patients younger than 50 years of age and is most frequently idiopathic or associated with multiple sclerosis. However, the discovery of aquaporin-4 immunoglobulin G (IgG) and myelin oligodendrocyte glycoprotein (MOG)-IgG as biomarkers for two separate central nervous system inflammatory demyelinating diseases has revealed that neuromyelitis optica spectrum disorder (NMSOD) and MOG-IgG-associated disease (MOGAD) are responsible for clinically distinct subsets of ON. NMOSD-ON and MOGAD-ON both demonstrate tendencies for bilateral optic nerve involvement and often exhibit a relapsing course with the potential for devastating long-term visual outcomes.

Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability.