Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review

Abstract

Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation. While we reviewed the pertinent literature, we also report three new patients with SPG35, highlighting the possible absence of white matter lesions even after a long neuroimaging follow-up. Three-dimensional modeling of the mutated proteins was helpful to elucidate the role of the site of mutations and the correlation with the residual enzyme activity as determined in cultured skin fibroblasts.

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…Mutations affecting the cytochrome b5-like heme binding domain and the fatty acid hydroxylase domain result in a reduction of the enzyme’s activity, as well as the possible disruption of the interaction of these domains with iron-containing ligands [ 145 ]. The reduction of the enzymatic activity or its complete depletion, caused by the different mutations located throughout the protein, could explain the variability in the severity of the phenotypes.…”

Complex dystonias: an update on diagnosis and care

“…NBIAs are an expanding group of progressive diseases characterized by abnormal accumulation of iron in the brain, particularly the basal ganglia, caused by different mutations with different modes of inheritance (see Table 2; Akcakaya et al 2019;Mari et al 2018;Rattay et al 2019;Haack et al 2012;Marchi et al 2019) leading to neurodegeneration. Most patients present with movement disorders, particularly dystonia and parkinsonism.…”

Neurodegeneration with Brain Iron Accumulation Disorders: Valuable Models Aimed at Understanding the Pathogenesis of Iron Deposition

“…A recent in silico protein modelling report demonstrated that the FAHN causative missense mutations alter the heme-binding site or disrupt the hydroxylase domain impairing the enzyme catalytic activity. However, the mechanism by which reduced FA2H activity generates the iron deposition was not investigated [79].…”