Spastic paraplegia type 4 (SPG4; also known as SPAST-HSP), the most prevalent variant among pure Hereditary Spastic Paraplegias (HSPs), is clinically characterized by progressive spasticity and weakness in the lower limbs. The present neuroimaging study specifically investigated possible changes in the corticospinal (CST) and thalamo-cortical tracts (TCT) structural integrity and broader cortical, subcortical and spinal pathways, topographically related to upper and lower limbs in SPG4. Forty patients with SPG4 and 40 age- and sex-matched healthy controls underwent 3 T MRI scanning. MRI analyses included: (1) global and primary motor areas cortical thickness; (2) cortical, basal ganglia, thalamic and cerebellar volumetry; (3) diffusion-based probabilistic tractography of CST and TCT serving the arms and legs; and (4) spinal cord area. SPG4 patients showed significant reductions in thalamic volumes as well as spinal cord area when compared with controls. The volume reduction in thalamic regions correlated with disease severity and spasticity-related impairments. Structural changes in CST and TCT tracts in SPG4 patients were prominent in bundles topographically related to the lower limbs compared with the upper limbs. Our findings point to significant thalamic atrophy as well as white matter tract degeneration topographically related to the lower limbs in SPG4 patients. The findings overall suggest new potential markers for disease progression and functional decline in SPG4 patients.

Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Hereditary spastic paraplegia (HSP) describes a group of rare genetic neurological diseases characterized by a common clinical presentation made of progressive motor weakness and spasticity of the lower limbs. The global prevalence is estimated at 3.6 individuals per 100,000 inhabitants. The age of onset of first symptoms, the severity and the rate of progression are highly variable between different HSP subtypes, ranging from juvenile forms that present in the first years of life, to the later-onset forms, sometimes presenting after the age of 60. The medical history most often reveals an insidious onset of gait disturbances due to lower limb stiffness. The clinical examination reveals the key symptoms of HSP: pyramidal signs of the lower limbs with motor weakness predominantly involving the proximal muscles. As the condition progresses, moderate upper limb involvement as well as bladder and sphincter disorders may be present. When associated with other neurological or extra-neurological signs such as cerebellar ataxia, optic neuropathy, cardiomyopathy, or intellectual disability, HSP is referred to as "complex". This is in contrast to the pure forms of HSP, where the pyramidal syndrome of the lower limbs occurs in isolation, which will be treated here. HSPs are a genetically heterogeneous group of disorders involving numerous distinct molecular pathways. However, regardless of the initial mechanism, they share a common pathophysiology characterized by primary first motor-neuron involvement. Lesions tend to predominate in the spinal cord, following a phenomenon of retrograde degeneration ("dying-back") of the corticospinal tract. The diagnostic approach will first aim to eliminate all non-genetic acquired forms of spastic paraplegia as well as other various differential diagnoses. More than 100 genes and disorders are grouped under the term HSP, with age of onset, disease progression and clinical presentation being highly variable. Pure forms of HSP are primarily inherited in an autosomal dominant or recessive manner. Genetic counseling for the patient and their family is ideally provided by a clinical geneticist once the precise molecular diagnosis has been obtained. The management of pure HSP is multidisciplinary. Its goal is to prevent complications and to propose symptomatic treatment at all stages of the disease. It is primarily based on motor rehabilitation through physiotherapy and physical activity. Psychological support should be offered from the moment the diagnosis is announced and throughout the follow-up. Multidisciplinary follow-up is coordinated by the primary care physician, in consultation with the expert pediatric neurologist/neurologist or neurogeneticist, and equally involves a physical medicine and rehabilitation physician and paramedical professionals (such as physiotherapists, social workers, occupational therapists, and psychologists).

TFG mutations have previously been implicated in autosomal recessive hereditary spastic paraplegia (HSP), also known as SPG57. This study aimed to investigate the clinical and molecular features of TFG mutations in a Taiwanese HSP cohort. Genetic analysis of TFG was conducted in 242 unrelated Taiwanese HSP patients using a targeted resequencing panel covering the entire coding regions of TFG. Functional assays were performed using an in vitro cell model to assess the impact of TFG variants on protein function. Additionally, other representative TFG mutant proteins were examined to understand the broader implications of TFG mutations in HSP. The study identified a novel homozygous TFG c.177A>C (p.(Lys59Asn)) variant in a family with adolescent-onset, pure form HSP. Functional analysis revealed that the Lys59Asn TFG variant, similar to other HSP-associated TFG mutants, exhibited a low affinity between TFG monomers and abnormal assembly of TFG homo-oligomers. These structural alterations led to aberrant intracellular distribution, compromising TFG's protein secretion function and resulting in decreased cellular viability. These findings confirm that the homozygous TFG c.177A>C (p.(Lys59Asn)) variant is a novel cause of SPG57. The study expands our understanding of the clinical and mutational spectrum of TFG-associated diseases, highlighting the functional defects associated with this specific TFG variant. Overall, this research contributes to the broader comprehension of the genetic and molecular mechanisms underlying HSP.

Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. HSPD1 encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in HSPD1 have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous HSPD1 variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for HSPD1 variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val). Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis. Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly. We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.