Methylene tetrahydrofolate reductase (MTHFR) deficiency is a rare inherited metabolic disorder that impairs myelination and brain development, leading to primary clinical manifestations, particularly neurological deficits. The aim of this study was to comprehensively describe the clinical presentation, biochemical profile, and molecular spectrum of patients with MTHFR deficiency. This multicenter, retrospective, descriptive study evaluated the medical records of 19 patients diagnosed with MTHFR deficiency at ten metabolic disease centers. A total of 13 patients had early-onset disease. In the early-onset group, all patients had varying degrees of neurodevelopmental delay. The median diagnostic delay from the first symptom to diagnosis was 3 months in early-onset cases and 118 months in late-onset cases. MTHFR deficiency exhibits a broad clinical spectrum, with acute deterioration possible even in chronically affected patients. MTHFR deficiency should be considered among treatable neurometabolic disorders in patients with otherwise unexplained neurodevelopmental or neuropsychiatric manifestations, particularly when accompanied by additional neurological findings.

Pathogenic variants in ATP1A3 are classically associated with alternating hemiplegia of childhood, CAPOS syndrome, and rapid-onset dystonia-parkinsonism. However, the phenotypic spectrum of ATP1A3-related disease has expanded considerably in recent years, including atypical presentations with spasticity and hereditary spastic paraplegia-like phenotypes. We describe a 43-year-old woman who developed a progressive upper motor neuron syndrome characterized by spastic paraparesis, generalized hyperreflexia, bilateral Babinski signs, inexhaustible ankle clonus, spastic dysarthria, dysphagia, and mild cerebellar involvement. Extensive metabolic, autoimmune, infectious, neurophysiological, neuroimaging, and genetic investigations failed to identify an alternative diagnosis. Targeted next-generation sequencing identified a heterozygous ATP1A3 NM_152296.4:c.2984G>A, p.(Arg995His). Familial segregation analysis demonstrated a confirmed de novo occurrence with biological parentage verification. The variant affects a highly conserved residue within the transmembrane M8 domain, is absent from population databases, and is predicted to be deleterious by multiple in silico tools. According to ACMG/AMP criteria, the variant fulfilled PM2 and PP3 and is currently classified as a variant of uncertain significance (VUS). This case suggests a possible expansion of the phenotypic spectrum of ATP1A3-related disease and represents, to our knowledge, the first reported adult-onset primary lateral sclerosis-like phenotype associated with an ATP1A3 variant. These findings suggest that ATP1A3 should be considered in the genetic evaluation of unexplained adult-onset upper motor neuron syndromes.

Hereditary spastic paraplegia (HSP) comprises a clinically and genetically diverse group of inherited neurodegenerative disorders unified by slowly progressive, usually symmetrical lower-limb spasticity secondary to corticospinal tract degeneration. For practising neurologists, the first step is recognising when a presentation is consistent with HSP and when it is not, and then carefully excluding treatable causes. We outline a pragmatic approach to assessing HSP, highlighting the broad clinical spectrum, 'red flags' that should trigger re-evaluation and the common acquired and genetic mimics. We summarise the relevant clinical and supportive investigations that can narrow the differential diagnosis. We also discuss the strengths and limitations of contemporary genetic testing. Finally, we focus on practical management: multidisciplinary care, spasticity treatments, and proactive recognition and management of additional symptoms outside of spasticity.

Ischemic gastritis (IG) and ischemic duodenitis (ID) are rare due to the extensive anastomotic vascular supply arising from the celiac trunk. Profound splanchnic hypoperfusion is required to induce a clinically significant ischemic insult. Etiologies typically include systemic hypotension, vasculitis, or thromboembolism. Patients with IG/ID often face high morbidity and mortality given the severity of ischemia required to induce extensive mucosal damage, leaving clinicians to balance prolonged bowel rest and early enteral feeding. We present the case of an 18-year-old man with spastic quadriplegic cerebral palsy and developmental delay who developed severe IG/ID in the setting of severe hemorrhagic shock. He presented to our institution with hemodynamic instability, profound anemia, and signs of upper gastrointestinal bleeding. Endoscopic evaluation found the patient to have severe IG/ID necessitating prolonged bowel rest and total parenteral nutrition (TPN). After evidence of mucosal recovery on surveillance endoscopy, he was gradually transitioned from TPN to enteral nutrition and successfully discharged to a long-term care facility. This report describes the successful reintroduction of enteral feeding in a patient with severe IG/ID after prolonged bowel rest. The use of surveillance endoscopy to guide the gradual reintroduction of enteral feeding, alongside careful TPN weaning, allowed for the successful discharge of a patient with IG/ID, a condition associated with poor outcomes.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is an ultra-rare neurological disorder caused by a mutation in the FA2H gene. Defective production of this gene leads to abnormal myelin formation, which subsequently causes neurodegeneration and brain iron accumulation. This case report presents the case of a 7-year-old boy from Pakistan who was born to consanguineous parents. The initial symptom presented at two and a half years of age with seizures. His clinical course progressively worsened, manifesting as gait disturbances, dystonia, and regression of milestones. By the age of 7, he was unable to walk without support. On examination, the patient had a spastic diplegic gait with plantarflexion contracture in both lower limbs. Brain Magnetic Resonance Imaging (MRI) findings reported abnormal T2-weighted hyperintensities, predominantly involving the parietal white matter, which is suggestive of FAHN. Finally, the diagnosis was confirmed by genetic analysis with the identification of a strong homozygous c.704G>A (p.Arg235 His) missense mutation in the FA2H gene.