Hereditary spastic paraplegia (HSP) genes are emerging as new causes of neurodevelopmental disorders (NDDs). While the association of intellectual disability and autism spectrum disorder (ASD) with many complex forms of HSP is well established, little is known about a possible association with childhood-onset SPG7. To add new data on the phenotypic spectrum and associated NDDs in childhood-onset HSP. We report three patients with biallelic variants in SPG7. Consistent with previous reports, childhood-onset SPG7 manifests as a complex HSP phenotype, with clinical features that largely overlap those of the corresponding adult-onset form. In total, 57 patients with childhood-onset SPG7 have been reported in the literature to date, of whom 17% showed NDDs: intellectual disability and psychomotor delay were the most prevalent, whereas ASD and attention deficit-hyperactivity disorder were uncommon. Bi-allelic variants in SPG7 are a possible cause of neurodevelopmental disorders, therefore genetic testing in children should also consider genes typically linked to adult-onset motor disorders. The possible role of SPG7 in neural development calls for studies in in vivo models of brain development, to open the way for early diagnosis and intervention.

Sporadic late-onset cerebellar ataxia (SLOCA) is a syndrome defined by subacute or chronic and progressive ataxia occurring after the age of 40 years in individuals without a family history of ataxia. The 2022 publication of revised consensus diagnostic criteria for multiple system atrophy and the emergence of promising biomarkers provides a thorough diagnostic framework that now enables the diagnosis of numerous acquired causes of SLOCA, including autoimmune disorders and neurodegenerative diseases. The ongoing development and increased availability of DNA sequencing technology have uncovered several molecular causes of SLOCA besides spastic paraplegia type 7 and very late-onset Friedreich ataxia. These additional causes include sporadic genetic disorders, such as spinocerebellar atrophy type 27B, caused by GAA expansion in the FGF14 gene, and cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), caused by biallelic expansions in the RFC1 gene. This Review presents an updated clinical approach to the diagnosis and management of SLOCA that focuses on the most important developments in this field. Future challenges are also discussed, including the identification of additional missing genetic causes of SLOCA, especially via the use of long-read genome sequencing, improvements in SLOCA prognostication and the implementation of clinical trials of neuroprotective interventions.

Spastic ataxic syndrome is a combination of cerebellar ataxia with spasticity and other pyramidal features. Common causes of spastic ataxic syndrome include spinocerebellar ataxia (SCA) 1, SCA2, autosomal recessive ataxia of Charlevoix-Saguenay, Friedreich ataxia, and hereditary spastic paraplegia type-7. We report a 32-year-old female who presented with unsteadiness of gait, incoordination, and tremulousness of both hands for 10 years with microphthalmia, microdontia, dental caries, and syndactyly. Magnetic resonance imaging of the brain showed T2 fluid-attenuated inversion recovery hyper intensities in periventricular and lobar white matter and internal capsule. Thus, we report a genetically confirmed oculodentodigital dysplasia (ODDD), an autosomal dominant disorder, in an Indian patient who presented with spastic ataxic syndrome, a rarity that has not been reported so far.

Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous neurodegenerative disorder, primarily defined by progressive lower-limb spasticity and weakness. Among the numerous genes implicated, pathogenic variants in the spastic paraplegia 7 (SPG7) gene represent one of the most common causes of HSP, whereas mutations in SCN4A, a skeletal muscle ion channel gene, are typically associated with a diverse spectrum of phenotypes, including hyperkalemic and hypokalemic periodic paralysis, potassium-aggravated myotonia, and congenital paramyotonia. To date, however, the coexistence of pathogenic variants in SPG7 and SCN4A within the same pedigree, and their potential pathogenic interplay, has not been documented. In this study, we performed comprehensive genetic profiling, including whole-exome sequencing, mitochondrial genome analysis, dynamic mutation screening, copy number variation assessment, and Sanger sequencing. We identified a novel heterozygous SPG7 variant (c.578A>G; p.E193G) alongside a known pathogenic SCN4A missense mutation (c.2111C>T; p.T704M). Remarkably, individuals harboring both variants presented with highly complex phenotypes that combined classical HSP manifestations with ion channel dysfunctions, such as congenital paramyotonia and hypokalemic periodic paralysis. These findings provide the first evidence of a possible genetic interaction between SPG7 and SCN4A, expanding the recognized clinical and molecular spectrum of HSP. Our results underscore the diagnostic value of multi-gene testing in patients with atypical or overlapping neuromuscular symptoms and highlight the importance of considering potential polygenic contributions when interpreting the clinical heterogeneity of HSP.