Autosomal recessive spastic paraplegia 35 (SPG35), also known as Fatty acid hydroxylase-associated neurodegeneration (FAHN), is a rare recessive neurodegenerative disorder with or without ataxia, dystonia, and other neurological findings. It is caused by genetic variants in FA2H, which encodes fatty acid 2-hydroxylase. To report the clinical, electrophysiological, radiological, and genetic profile of patients diagnosed with FAHN. We performed a retrospective chart review of genetically proven cases of FAHN from our database. We identified eight patients (6 females) with genetically proven FAHN. All patients presented with first-decade onset pyramidal syndrome with or without ataxia and with radiological findings of callosal atrophy, peri-ventricular white matter hyperintensity, and cerebellar atrophy. Iron accumulation was observed in four of them. Whole exome sequencing revealed seven unique variants including three missense variants (c.83G>C;p.Arg28Pro, c.130C>A;p.Pro44Thr, and c.703C>T;p.Arg235Cys), a stop-gain variant (c.379C>T;p.Arg127Ter), a frameshift deletion variant (c.536delT;p.Leu179Argfs*62), a in-frame deletion variant (c.200_202del;p.His67del) and a in-frame duplication variant (c.86_97dup;p.Arg29_Arg32dup). The variants p.Pro44Thr, p.Arg28Pro, p.Arg29_Arg32dup, and p.His67del are located in the iron-binding region, and the p.Arg235Cys in the hydroxylase domain. The other two variants, p.Arg127Ter and p.Leu179Argfs*62, predictively cause protein truncation, leading to loss of the transmembrane domain and the fatty acid hydroxylase domain, which in turn may result in disruption of fatty acid alpha-hydroxylase activity of FA2H. Our study identifies novel variants associated with FA2H in FAHN patients, highlighting their possible roles in iron binding and in the loss of the transmembrane and catalytic domains.

Fatty-acid-hydroxylase-associated neurodegeneration (FAHN) is a rare neurodegenerative disorder caused by loss-of-function mutations in the FA2H gene, leading to impaired enzymatic activity and resulting in myelin sheath instability, demyelination, and axonal degeneration. In this study, we established a human in vitro model using neurons and oligodendrocytes derived from induced pluripotent stem cells (hiPSCs) of a FAHN patient. This coculture system enabled the investigation of myelination processes and myelin integrity in a disease-relevant context. Analyses using immunofluorescence and Western blot revealed impaired expression and localisation of key myelin proteins in oligodendrocytes and cocultures. FA2H-deficient cells showed reduced myelination, shortened internodes, and disrupted formation of the nodes of Ranvier. Additionally, we identified autophagy defects-a hallmark of many neurodegenerative diseases-including reduced p62 expression, elevated LC3B levels, and impaired fusion of autophagosomes with lysosomes. This study presents a robust hiPSC-based model to study FAHN, offering new insights into the molecular pathology of the disease. Our findings suggest that FA2H mutations compromise both the structural integrity of myelin and the efficiency of the autophagic machinery, highlighting potential targets for future therapeutic interventions. The purpose of this overview is to: 1.. Briefly describe the clinical characteristics of neurodegeneration with brain iron accumulation (NBIA); 2.. Review the genetic causes of NBIA; 3.. Review the differential diagnosis of NBIA with a focus on genetic conditions; 4.. Provide an evaluation strategy to identify the genetic cause of NBIA in a proband (when possible); 5.. Review high-level management of NBIA; 6.. Inform genetic counseling of family members of an individual with NBIA.

Neurodegeneration with brain iron accumulation (NBIA) refers to a group of rare genetic disorders characterized by abnormal iron deposition in the basal ganglia and brainstem due to impaired iron homeostasis. Disease severity and manifestations vary according to the underlying genetic mutation and age of presentation; however, most subtypes share progressive neurological features such as dystonia, Parkinsonism, spasticity, cognitive decline, and intellectual disability. In this review, we first outline the physiological role of iron in the central nervous system, emphasizing its importance for neurotransmitter synthesis, myelination, and mitochondrial metabolism, and discuss how disruption of homeostatic mechanisms may lead to ferroptosis and neuronal injury. We then explore the role of neuroimaging in the diagnosis of NBIA, with a focus on MRI as the modality of choice. Finally, we provide an overview of the clinical and imaging features of the major NBIA subtypes, highlighting both shared characteristics and distinctive patterns. Covered NBIA include primary disorders of iron metabolism, such as neuroferritinopathy and aceruloplasminemia, and secondary disorders with disrupted iron regulation, including Pantothenate Kinase-Associated Neurodegeneration, Phospholipase A2 Group VI-Associated Neurodegeneration, Mitochondrial Membrane Protein-Associated Neurodegeneration, Beta-Propeller Protein-Associated Neurodegeneration, Fatty Acid Hydroxylase-Associated Neurodegeneration, Coenzyme A Synthetase Protein-Associated Neurodegeneration, Woodhouse-Sakati syndrome, and Kufor-Rakeb Disease. By integrating genetics, pathophysiology, and imaging, this review aims to improve recognition of NBIA and support comprehensive clinical management.

Fatty acid 2-hydroxylase (FA2H) is encoded by the FA2H gene, with mutations therein leading to the neurodegenerative condition, spastic paraplegia-35 (SPG35). We aim to elucidate the genetic underpinnings of a nonconsanguineous Chinese family diagnosed with SPG35 by examining the clinical manifestations, scrutinizing genetic variants, and establishing the role of FA2H mutation in lipid metabolism. Using next-generation sequencing analysis to identify the pathogenic gene in this pedigree and family cosegregation verification. The use of lipidomics of patient pedigree peripheral blood mononuclear cells further substantiated alterations in lipid metabolism attributable to the FA2H exon 1 deletion. The proband exhibited gait disturbance from age 5 years; he developed further clinical manifestations such as scissor gait and dystonia. His younger sister also presented with a spastic gait from the same age. We identified a homozygous deletion in the region of FA2H exon 1, spanning from chr16:74807867 to chr16: 74810391 in the patients. Lipidomic analysis revealed significant differences in 102 metabolites compared with healthy controls, with 62 metabolites increased and 40 metabolites decreased. We specifically zeroed in on 19 different sphingolipid metabolites, which comprised ceramides, ganglioside, etc., with only three of these sphingolipids previously reported. This is the first study of lipid metabolism in the blood of patients with SPG35. The results broaden our understanding of the SPG35 gene spectrum, offering insights for future molecular mechanism research and laying groundwork for determining metabolic markers.

Essential tremor (ET) is characterized by action tremor of the upper limbs, head tremor and voice tremor. Dystonic tremor (DT) is produced by muscle contractions in a body affected by dystonia. Deep brain stimulation (DBS) of ventral intermediate nucleus of the thalamus (VIM) is the most well-known advanced treatment for medication-refractory tremor. However, decline in efficacy overtime has led to explore other targets. This study aimed to measure the efficacy of bilateral dual targeting ViM/caudal Zona Incerta (cZI) stimulation on tremor control. A secondary aim was to evaluate if there was a difference in the efficacy between ET and DT. 36 patients were retrospectively recruited at the Walton NHS Foundation Trust, Liverpool, UK. Patients were assessed pre-operatively, and then at 1-year, 3-years, and 5-years post-operatively with the following scales: Fahn-Tolosa-Marin tremor rating (FTMTR) scale, EuroQol-5D, and Hospital Anxiety and Depression Scale. Bilateral ViM-cZI DBS significantly improved overall tremor score by 45.1% from baseline to 3-years post-operatively (p < 0.001). It continued to show improvement in overall FTMTR score by 30.7% at 5-years but this failed to meet significance. However, there was no significant improvement of mood or quality of life (QoL) scores. ET group on average showed a significant better clinical outcome compared to the DT group (p > 0.001). Our study found that bilateral ViM-cZI DBS treatment had a favourable effect on motor symptoms sustained over the 5-years in tremor patients, especially in ET group. There was limited effect on mood and QoL with similar trends in outcomes for both tremor types.