患儿，男，7岁8月龄，因“步态异常4年余”就诊，患儿1岁前运动发育同正常同龄儿，1岁2月龄会独站，1岁6月龄独走，走路不稳，容易摔倒。3岁起逐渐出现双下肢运动功能倒退，走路踮脚，摇摆步态，呈缓慢加重。体格检查示双下肢肌力4级，肌张力增高，伴共济失调体征，深腱反射减弱，锥体束征阳性。头颅磁共振成像显示双侧侧脑室后角旁及双侧内囊后肢T2加权像及液体衰减反转恢复序列高信号。肌电图示下运动单位病变。基因检测示ENTPD1基因纯合变异c.523G>C。患儿确诊常染色体隐性遗传性痉挛性截瘫64型。.

Hereditary spastic paraplegia (HSP) represents a genetically heterogeneous group of neurodegenerative disorders characterized by progressive axonal degeneration of corticospinal upper motor neurons, leading to lower limb-predominant spasticity and weakness. To date, 83 HSP subtypes have been reported, exhibiting either pure or complicated phenotypes. Among these, spastic paraplegia type 64 (SPG64) is an ultra-rare form of complicated HSP caused by biallelic variants in ENTPD1, which encodes an ectonucleotidase involved in purine metabolism. In this study, we report a proband presenting with neurodevelopmental regression, dysmorphic features and sensorimotor polyneuropathy, followed comprehensively for 6 years. Genetic analysis identified a novel homozygous NM_001776:c.1174C>T;p.Gln392Ter variant in ENTPD1. A literature review reveals that 39 individuals with SPG64 have been reported, with clinical manifestations including cognitive decline (38/39), speech abnormalities (30/39) and brain malformations (16/31). However, aspects of the full phenotypic spectrum remain to be fully characterized. Notably, this case represents the first documented patient with long-term follow-up, providing valuable clinical insights into disease progression over time. Neuroimaging in the proband demonstrated the involvement of the posterior limb of the internal capsule and the 'ear of the lynx' sign, which was not previously reported in SPG64. Furthermore, the presence of sensorimotor polyneuropathy supports that neuropathy may be a previously unappreciated component of SPG64. Our findings highlight the importance of deep phenotyping and long-term follow-up in fully understanding the nature of this unique HSP subtype.

Spastin is a microtubule-severing AAA+ ATPase that is highly expressed in neuronal cells and plays a crucial role in axonal growth, branching, and regeneration. This machine oligomerizes into hexamers in the presence of ATP and microtubule carboxy-terminal tails (CTTs). Conformational changes in spastin hexamers, powered by ATP hydrolysis, apply forces to the microtubule, ultimately leading to the severing of the filament. Mutations disrupt the normal function of spastin, impairing its ability to sever microtubules effectively and leading to abnormal microtubule dynamics in neurons characteristic of the set of neurodegenerative disorders called hereditary spastic paraplegias (HSP). Experimental studies have identified the HSP-related R591S (Drosophila melanogaster numbering) mutation as playing a crucial role in spastin. Given its significant role in HSP, we employed a combination of molecular dynamics simulations with machine learning and graph network-based approaches to identify and quantify the perturbations caused by the R591S HSP mutation on spastin's dynamics and allostery with functional implications. We found that the functional hexamer, upon HSP-related mutation, loses the ability to execute the primary motion associated with the severing action. The study of allosteric changes upon the mutation showed that the regions that are most perturbed are those involved in the formation of the interprotomer contacts. The mutation induces rigidity in the allosteric networks of the motor, making it more likely to experience loss of function as applied perturbations would not be easily dissipated by passing through a variety of alternative paths as in the wild-type (WT) spastin.

Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.

Hereditary spastic paraplegias (HSP) are a group of inherited, neurodegenerative disorders characterized by progressive gait impairment, lower extremity spasticity and increased patellar reflexes. More than 80 types of HSP have been defined to date. In complicated forms, lower limb spasticity and gait impairment is accompanied by an additional neurological finding. Autosomal recessive (AR) HSPs are usually identified in complicated forms and occur more frequently in countries where consanguineous marriage is more widespread. Next generation sequencing techniques, developed in the last decade, have led to the identification of many new types of HSP and reduced the "diagnostic odyssey." Whole exome sequencing (WES) can diagnose up to 75% of undiagnosed HSP patients. Targeted genetic analysis with good clinical phenotyping gives the best diagnostic yields for rare diseases. Clinical heterogeneity is prominent in AR complicated HSP. However, some clinical features complicating the disease or magnetic resonance imaging findings, including thin corpus callosum or white matter abnormalities, can help to distinguish some types. AR spastic paraplegia type 64 (SPG64) is a very rare HSP, caused by a mutation in the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) gene, first described in 2014. To date only nine patients from five families have been reported. We present two siblings with a novel pathogenic variant in ENTPD1, diagnosed by WES, as the sixth published family. We propose that early onset in childhood, cognitive impairment, dysarthria/anarthria, dystonia and areflexia may be the distinctive features of SPG64 and more clinical evidence from families with pathogenic ENTPD1 variants is warranted.