Patients diagnosed with rare diseases and their and families search desperately to organize drug discovery campaigns. Alternative models that differ from default paradigms offer real opportunities. There are, however, no clear guidelines for the development of such models, which reduces success rates and raises costs. We address the main challenges in making the discovery of new preclinical treatments more accessible, using rare hereditary paraplegia as a paradigmatic case. First, we discuss the necessary expertise, and the patients\' clinical and genetic data. Then, we revisit gene therapy, de novo drug development, and drug repurposing, discussing their applicability. Moreover, we explore a pool of recommended in silico tools for pathogenic variant and protein structure prediction, virtual screening, and experimental validation methods, discussing their strengths and weaknesses. Finally, we focus on successful case applications.

Spastic paraplegia type 4 (SPG4), the predominant form of Autosomal Dominant Hereditary spastic paraplegia (AD-HSP), is characterized by variants in the SPAST gene. This study reports a unique case of a late-onset SPG4 in a Han Chinese male, manifesting primarily as gait disturbances from lower extremity spasticity. Uncovered through whole-genome sequencing, a previously undocumented frameshift variant, c.1545dupA in exon 14 of the SPAST gene, was identified. Notably, this variant was absent in asymptomatic parents with confirmed paternity and maternity status, suggesting a de novo variant occurrence. This discovery emphasizes the potential of de novo variants to exhibit a late-onset pure pattern, extending the SPG4 variant spectrum, and consideration of such variants should be given in HSP patients with a negative family history.

Biallelic variants of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene have been linked to neurodegenerative disorders ranging from severe neonatal encephalopathy to early-onset spastic paraplegia. We identified a novel homozygous variant, c.340G > T (p.Gly114Cys), in the HPDL gene in two siblings with autosomal recessive hereditary spastic paraplegia (HSP). Despite sharing the same likely pathogenic variant, the older sister had pure HSP, whereas her brother had severe and complicated HSP, accompanied by early-onset mental retardation and abnormalities in magnetic resonance imaging. Given the clinical heterogeneity and potential for treatable conditions in HPDL-related diseases, we emphasize the importance of genetic testing for the HPDL gene.

Selective dorsal rhizotomy (SDR) has been used to treat children with spastic cerebral palsy (CP), and its beneficial effect on quality of life and ambulation has been confirmed in long-term follow-up studies. However, the role of SDR in the treatment of spasticity in patients with hereditary spastic paraplegia (HSP) and related disorders is not well-established. Here, we report the first patient with the ZC4H2 variant who underwent SDR to treat spastic paraplegia. Abnormal gait was discovered during a regular checkup at the age of 3 years and 9 months, and she was diagnosed with spastic paraplegia. She was heterozygous for the ZC4H2 variant and underwent SDR at the age of 5 years and 11 months, which alleviated the spasticity. The patient underwent inpatient postoperative rehabilitation for 4 months and continued outpatient physiotherapy after discharge. The Gross Motor Function Measure-88 score and maximum walking speed decreased transiently 1 month postoperatively, but gradually recovered, and continuously improved 6 months postoperatively. SDR and postoperative intensive rehabilitation were effective in improving motor and walking functions up to 6 months after surgery, although long-term follow-up is needed to draw conclusions.

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Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with genetic and clinical heterogeneity characterized by spasticity and weakness of the lower limbs. It includes four genetic inheritance forms: autosomal dominant inheritance (AD), autosomal recessive inheritance (AR), X-linked inheritance, and mitochondrial inheritance. To date, more than 82 gene loci have been found to cause HSP, and SPG15 (ZFYVE26) is one of the most common autosomal recessive hereditary spastic paraplegias (ARHSPs) with a thin corpus callosum (TCC), presents with early cognitive impairment and slowly progressive leg weakness. Here, we reported a homozygous pathogenic variant in ZFYVE26. A 19-year-old Chinese girl was admitted to our hospital presenting with a 2-year progressive bilateral leg spasticity and weakness; early cognitive impairment; corpus callosum dysplasia; chronic neurogenic injury of the medulla oblongata supplied muscles; and bilateral upper and lower limbs on electromyogram (EMG). Based on these clinical and electrophysiological features, HSP was suspected. Exome sequencing of the family was performed by high-throughput sequencing, and an analysis of the patient showed a ZFYVE26 NM_015346: c.7111dupA p.(M2371Nfs*51) homozygous mutation. This case reported a new ZFYVE26 pathogenic variant, which was different from the SPG15 gene mutation reported earlier.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of neurogenetic diseases of the corticospinal tract, accompanied by distinct spasticity and weakness of the lower extremities. Mutations in the spastic paraplegia type 4 (SPG4) gene, encoding the spastin protein, are the major cause of the disease. This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.
METHODS: A 44-year-old male was admitted to our hospital for long-term right lower limb weakness, leg stiffness, and unstable walking. His symptoms gradually worsened, while no obvious muscle atrophy in the lower limbs was found. Neurological examinations revealed that the muscle strength of the lower limbs was normal, and knee reflex hyperreflexia and bilateral positive Babinski signs were detected. Members of his family also had the same symptoms. Using mutation analysis, a novel heterozygous duplication mutation, c.1053dupA, p. (Gln352Thrfs*15), was identified in the SPG4 gene in this family.
CONCLUSIONS: A Chinese family with HSP had a novel mutation of the SPG4 gene, which is autosomal dominant and inherited as pure HSP. The age of onset, sex distribution, and clinical manifestations of all existing living patients in this family were analyzed. The findings may extend the current knowledge on the existing mutations in the SPG4 gene.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders that currently have no cure. HSP type 11 (SPG11-HSP) is a complex form carrying mutations in the SPG11 gene. Neuropathological studies demonstrate that motor deficits in these patients are mainly attributed to axonal degeneration of the corticospinal tract (CST). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that can induce central nervous system plasticity and promote neurological recovery by modulating the excitability of cortical neuronal cells. Although rTMS is expected to be a therapeutic tool for neurodegenerative diseases, no previous studies have applied rTMS to treat motor symptoms in SPG11-HSP. Here, we report a case of SPG11-HSP with lower extremity spasticity and gait instability, which were improved by applying high-frequency rTMS (HF-rTMS) at the primary motor cortex (M1). Clinical and physiological features were measured throughout the treatment, including the Modified Ashworth Scale (MAS), Berg Balance Scale (BBS), the timed up and go (TUG) test and the 10-meter walk test time (10 MWT). The structure and excitability of the CST were assessed by diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS), respectively. After treatment, the patient gained 17 points of BBS, along with a gradual decrease in MAS scores of the bilateral lower extremity. In addition, the TUG test and 10 MWT improved to varying degrees. TMS assessment showed increased motor evoked potential (MEP) amplitude, decreased resting motor threshold (RMT), decreased central motor conduction time (CMCT), and decreased difference in the cortical silent period (CSP) between bilateral hemispheres. Using the DTI technique, we observed increased fractional anisotropy (FA) values and decreased mean diffusivity (MD) and radial diffusivity (RD) values in the CST. It suggests that applying HF-rTMS over the bilateral leg area of M1 (M1-LEG) is beneficial for SPG11-HSP. In this study, we demonstrate the potential of rTMS to promote neurological recovery from both functional and structural perspectives. It may provide a clinical rationale for using rTMS in the rehabilitation of HSP patients.

BACKGROUND: and Purpose: Hereditary spastic paraplegias (HSP) are a group of clinically diverse genetic disorders that share the neurologic symptom of difficulty in walking due to progressive serious muscle weakness and spasticity in the legs. This study describes a physiotherapy program for improving the functional ability of a child diagnosed with complicated HSP and reports the treatment results.
METHODS: A 10-year-old boy with complicated HSP received a physiotherapy intervention that included strengthening of the leg muscles and treadmill training for 1 h per session, three to four times a week for 6 weeks. Outcome measures included sit-to-stand, 10-m walk, 1-min walk tests, and gross motor function measures (dimensions D and E).
RESULTS: After the intervention, the sit-to-stand, 1-min walk, and 10-m walk test scores improved by 6.75 times, 2.57 m, and 0.05 m/s, respectively. Furthermore, the gross motor function measure dimensions D and E scores improved by 8% (46%-54%) and 5% (22%-27%), respectively. The gains in each parameter were maintained at the 3- and 6-month and 1-year follow-ups.
CONCLUSIONS: These results suggest that structured physiotherapy programs can benefit the functional rehabilitation of children with complicated HSP.

A 24-year-old man presented with insidious onset progressive gait disturbance and was finally diagnosed with autosomal recessive hereditary spastic paraplegia. Two novel mutations, including a frameshift mutation (c.5687_5691del) and a non-sense mutation (c.751C>T), were identified in the SPG11 gene of the patient through whole genome sequencing. The frameshift mutation of c.5687_5691del leads to a change in amino acid synthesis beginning with amino acid No. 1896 arginine and terminating at the 8th amino acid after the change (p. Arg1896MetfsTer8). The non-sense mutation (c.751C>T) causes the conversion of codon 251st encoding the amino acid Gln into a stop codon (p. Gln251Ter), resulting in premature termination of peptide synthesis. Although confirmation of compound-heterozygosity could not be performed, our findings enriched the phenotypic spectrum of SPG11 mutations related to hereditary spastic paraplegia.