We report the case of a 27-year-old man with a history of speech delay and chronic, progressive movement disorder. He first developed gait difficulty at the age of 12. Given clinical signs of bradykinesia and resting tremor, he received a clinical diagnosis of childhood-onset parkinsonism. Treatment with oral levodopa initially improved symptoms, but after 2 years, he developed motor fluctuations and dyskinesias. Additional signs of spasticity and brain MRI showing a thin corpus callosum prompted genetic testing that identified a heterozygous pathogenic variant in the PRKN gene. However, he exhibited a progressive loss of response to chronic dopaminergic therapy, first with oral and later with continuous levodopa-carbidopa intestinal gel infusion, with disease progression over 7 years. This progression led to further genetic testing and the diagnosis of hereditary spastic paraplegia type 15 (SPG 15). Advancing motor symptoms prompted deep brain stimulation and botulinum toxin injections, although these had limited benefit. This case highlights the challenges of diagnosing and managing juvenile-onset parkinsonism and the value of comprehensive genetic analysis in evaluating genotypic-phenotypic correlations. Hereditary spastic paraplegias (HSPs) are a rare group of neurodegenerative disorders with diverse clinical and genetic features. They can be inherited in autosomal dominant, recessive, X-linked, or mitochondrial patterns. The SPG15 subtype (or HSP-ZFYVE26), caused by pathogenic variants in the ZFYVE26 gene, is a common form of autosomal recessive HSP. Presenting symptoms vary but commonly include cognitive impairment with a history of speech delay or learning disability and balance impairment or clumsiness from spasticity of the lower limbs.

BACKGROUND The most frequently mutated gene in hereditary spastic paraplegia (HSP) is SPAST. Only symptomatic treatment is available for this disease. Fampridine has been successfully used to treat gait disturbances in some patients with HSP. A positive effect of fampridine has not been previously reported in HSP4 caused by the c.683-2A>C variant in the SPAST gene. CASE REPORT We report the case of a 63-year-old woman with hypogeusia and hyposmia for several years, pollakiuria, gait disturbances, reduced walking speed, occasional dysphagia, constipation and delayed defecation, occasional memory problems, right-sided hearing loss, and exercise-induced myalgia and muscle cramps. Genetic testing revealed the c.683-2A>C variant in SPAST. Her 69-year-old sister also had pollakiuria since her youth, and since the age of 50 had frequent stumbling, unsteadiness, spasticity, and positional vertigo. At age 62, our patient began taking fampridine (4-aminopyridine) and has since experienced significant relief. Fampridine led to an improvement in spasticity, gait disorders, and walking speed, as documented by the 6-meter walk test, spastic paraplegia rating scale, and multidimensional self-esteem scale. CONCLUSIONS This case shows that HSP4 can progress slowly over a period of 7 years and can present with typical phenotypic characteristics of the disease as it progresses. The rate of progression can vary among affected family members, and people with HSP4 can still work even in old age and do not necessarily need antispastic drugs. This case also provides preliminary evidence that fampridine may be a viable symptomatic treatment option for patients with HSP4, including those with the mutation c.683-2A>C. It justifies further prospective, controlled studies in a larger SPAST-HSP population.

Hereditary spastic paraplegia (HSP) refers to a group of genetic neurodegenerative diseases marked by gradually worsening spasticity and hyperreflexia in the lower extremities. This study aimed to describe the clinical and genetic characteristics of Korean patients with spastic paraplegia. We retrospectively reviewed medical records of 69 patients with spastic paraplegia from 54 unrelated families between 2002 and 2024. Genetic, clinical, electrophysiological, and radiological features were comprehensively analyzed. Causative genes were identified in 34 (63%) of 54 unrelated families; SPAST, detected in 26 families, was the most prevalent. Seven novel pathogenic variants were identified. Clinically, the median age of symptom onset was 25 years [14.0-37.0]. Out of 69 patients with spastic paraplegia, 51 (74%) presented with the pure form of spastic paraplegia, which included all patients with SPG4. Spastic gait was a universal feature in all patients. Urinary dysfunction was present in 42 (61%) patients. Additional neurologic manifestations included peripheral neuropathy 9 (13%), cognitive impairment 5 (7%), upper limb weakness 4 (6%), dysarthria 4 (6%), dysphagia 3 (4%), ataxia 3 (4%), and scoliosis 1 (3%). Brain MRI findings demonstrated a thin corpus callosum in two patients with SPG11; all patients with SPG4 had normal findings. Spine MRI revealed spinal cord atrophy in 16 (27%) patients, including 6 (21%) patients with SPG4. The study comprehensively reviewed genetic and clinical spectra of spastic paraplegia in Korean patients, emphasizing the predominance of SPAST as the causative gene and underscoring the genetic and phenotypic heterogeneity of spastic paraplegia.

Neurodegenerative upper motor neuron (UMN) syndromes ranging from primary lateral sclerosis (PLS) to pure and complicated types of hereditary spastic paraplegia (HSP) remain challenging to differentiate clinically, especially in the early stages of disease. As they share the hallmark of spastic paraparesis, easily accessible biomarkers are warranted to facilitate an early diagnosis. We examined serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) as diagnostic biomarkers to differentiate PLS from HSP, represented by two paradigmatic subtypes: SPG4, the most common type of pure HSP, and adrenomyeloneuropathy (AMN), a common complicated form of HSP. In addition to sNfL and sGFAP raw levels, we used age-adjusted z-scores to account for age-related biomarker level increases. In our cohort of 18 PLS patients, 18 AMN patients, 25 SPG4 patients and 60 controls, sNfL z-scores were higher in PLS than in SPG4 (p < 0.001), AMN (p = 0.03), and controls (p < 0.001). Furthermore, sNfL z-scores allowed distinguishing PLS from SPG4 (AUC 0.82, 95% CI 0.67-0.98) and-slightly less accurate-from AMN (AUC 0.77, 95% CI 0.60-0.95). sGFAP z-scores did not differ significantly between groups. Our study suggests that serum NfL, but not GFAP, is a potential diagnostic biomarker in degenerative UMN diseases and may help to differentiate PLS from pure and complicated forms of HSP. Our results indicate that axonal degeneration-the source of NfL release-is predominant over astrocytic pathology-the source of GFAP release-in PLS, AMN, and SPG4.

Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessive neurological disorder caused by mutations in the CYP7B1 gene, which encodes cholesterol 7α-hydroxylase, an essential enzyme in cholesterol metabolism. These mutations lead to elevated levels of 25- and 27-hydroxycholesterol, oxysterols known to be neurotoxic and blood-brain-barrier permeable. Their accumulation contributes significantly to SPG5 pathogenesis, resulting in spastic gait disturbance and severely impaired quality of life. Using a Cyp7b1-/- mouse model that mirrors the metabolic phenotype of SPG5, we developed a gene therapy approach to correct oxysterol imbalance. We designed an AAV8-TTR-hCYP7B1 vector to deliver the CYP7B1 gene specifically to the liver. Following intravenous administration, oxysterol levels in blood and liver were rapidly normalized, even at low doses (1E10), with no observed toxicity at the highest tested dose (1E11). Despite these promising peripheral results, oxysterol levels in the brain, particularly 27-hydroxycholesterol, remained only partially corrected six weeks post-treatment. Our findings suggest that while liver-targeted gene therapy is effective at restoring peripheral cholesterol metabolism, a successful therapeutic strategy for SPG5 must also address central nervous system involvement. We conclude that successful treatment of SPG5 would require a novel gene therapeutic approach that also targets the CNS.