Subtype Of Hereditary Spastic Paraplegia Research Articles

Clinical and genetic characteristics in a Chinese cohort of complex spastic paraplegia type 4.

Spastic paraplegia type 4 (SPG4), caused by SPAST mutations, is the most predominant subtype of hereditary spastic paraplegia. Most documented SPG4 patients present as pure form, with the complex form rarely reported. We described the clinical and genetic features of 20 patients with complex phenotypes of SPG4 and further explored the genotype-phenotype correlations. We collected detailed clinical data of all SPG4 patients and assessed their phenotypes. SPAST gene mutations were identified by Multiplex ligation-dependent probe amplification in combination with whole exome sequencing. We further performed statistical analysis in genotype and phenotype among patients with various manifestations and different variants. Out of 90 SPG4 patients, 20 patients (male:female = 16:4) with additional neurologic deficits, namely complex form, were included in our study. The bimodal distribution of age of onset at 0-10 and 21-40 years old is concluded. On cranial MRI, obvious white matter lesions can be observed in five patients. We identified 9 novel and 8 reported SPAST mutations, of which 11 mutations were located in AAA (ATPase associated with various cellular activities) domain. The AAA cassette of spastin is the hottest mutated region among complex SPG4.All patients with cognitive impairment (CI) are males (n = 9/9). Additionally, 80% patients with ataxia are due to frameshift mutations (n = 4/5). Overall, our study summarized and analyzed the genetic and phenotypic characteristics of complex SPG4, making up over 1/5 of in-house SPG4 cohort, among which CI and ataxia are the most common features. Further studies are expected to explore the underlying mechanisms.

DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins.

Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. One subtype of HSP, known as SPG54, is caused by biallelic mutations in the DDHD2 gene. The primary pathological feature observed in patients with SPG54 is the massive accumulation of lipid droplets (LDs) in the brain. However, the precise mechanisms and roles of DDHD2 in regulating lipid homeostasis are not yet fully understood. Through Affinity Purification-Mass Spectroscopy (AP-MS) analysis, we identify that DDHD2 interacts with multiple members of the ATG8 family proteins (LC3, GABARAPs), which play crucial roles in lipophagy. Mutational analysis reveals the presence of two authentic LIR motifs in DDHD2 protein that are essential for its binding to LC3/GABARAPs. We show that DDHD2 deficiency leads to LD accumulation, while enhanced DDHD2 expression reduces LD formation. The LC3/GABARAP-binding capacity of DDHD2 and the canonical autophagy pathwayboth contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a small molecule that tethers LC3 to LDs to enhance their autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide valuable insights into the regulatory roles of DDHD2 in LD catabolism and offer a potential therapeutic approach for treating SPG54 patients.

The role of the PLA2G6 gene in neurodegenerative diseases.

PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features. Usually, it encompasses three autosomal recessive diseases, including infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (NBIA) 2A, atypical neuronal dystrophy with childhood-onset or NBIA2B, and adult-onset dystonia-parkinsonism form named PARK14, and possibly a certain subtype of hereditary spastic paraplegia. PLAN is caused by variants in the phospholipase A2 group VI gene (PLA2G6), which encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation. In this review, we discuss PLA2G6 gene structure and protein, functional findings, genetic deficiency models, various PLAN disease phenotypes, and study strategies in the future. Our primary aim is to provide an overview of genotype-phenotype correlations of PLAN subtypes and speculate on the role of PLA2G6 in potential mechanisms underlying these conditions.

Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients.

New cellular imaging-based method to distinguish the SPG4 subtype of hereditary spastic paraplegia.

Microtubule defects are a common feature in several neurodegenerative disorders, including hereditary spastic paraplegia. The most frequent form of hereditary spastic paraplegia is caused by mutations in the SPG4/SPAST gene, encoding the microtubule severing enzyme spastin. To date, there is no effective therapy available but spastin-enhancing therapeutic approaches are emerging; thus prognostic and predictive biomarkers are urgently required. An automated, simple, fast and non-invasive cell imaging-based method was developed to quantify microtubule cytoskeleton organization changes in lymphoblastoid cells and peripheral blood mononuclear cells. It was observed that lymphoblastoid cells and peripheral blood mononuclear cells from individuals affected by SPG4-hereditary spastic paraplegia show a polarized microtubule cytoskeleton organization. In a pilot study on freshly isolated peripheral blood mononuclear cells, our method discriminates SPG4-hereditary spastic paraplegia from healthy donors and other hereditary spastic paraplegia subtypes. In addition, it is shown that our method can detect the effects of spastin protein level changes. These findings open the possibility of a rapid, non-invasive, inexpensive test useful to recognize SPG4-hereditary spastic paraplegia subtype and evaluate the effects of spastin-enhancing drug in non-neuronal cells.

Copy number variations in SPAST and ATL1 are rare among Brazilians.

Copy number variations (CNV) may represent a significant proportion of SPG4 and SPG3A diagnosis, the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP). We aimed to assess the frequency of CNVs in SPAST and ATL1 and to update the molecular epidemiology of HSP families in southern Brazil. A cohort study that included 95 Brazilian index cases with clinical suspicion of HSP was conducted between April 2011 and September 2022. Multiplex Ligation Dependent Probe Amplification (MLPA) was performed in 41 cases without defined diagnosis by different massive parallel sequencing techniques (MPS). Diagnosis was obtained in 57/95 (60%) index cases, 15/57 (26.3%) being SPG4. Most frequent autosomal recessive HSP subtypes were SPG7 followed by SPG11, SPG76 and cerebrotendinous xanthomatosis. No CNVs in SPAST and ATL1 were found. Copy number variations are rare among SPG4 and SPG3A families in Brazil. Considering the possibility of CNVs detection by specific algorithms with MPS data, we consider that this is likely the most cost-effective approach to investigate CNVs in these genes in low-risk populations, with MLPA being reserved as an orthogonal confirmatory test.

Research on clinical and molecular genetics of hereditary spastic paraplegia 11 patients in China.

The hereditary spastic paraplegia (HSP) is a rare hereditary disease in nervous system due to the damage of corticospinal tract. HSP has various inheritance modes, including autosomal dominant inheritance, autosomal recessive inheritance, X-linked inheritance, and mitochondrial inheritance in some cases. At present, there are at least 80 subtypes of HSP. Hereditary spastic paraplegia type 11 (SPG11) is the most common subtype in autosomal recessive inheritance, and its pathogenic factor is KIAA1840 gene, which encodes spatacsin protein. A total of 52 SPG11 patients aged from 4-24 years old have been reported. Their initial symptoms were gait disturbance and/or mental retardation. As the disease develops, they may present with mental retardation, sphincter disturbance, decreased vision, ataxia, amyotrophy, pes arcuatus, ophthalmoplegia, peripheral neuropathy, and others. Except agenesis of the corpus callosum and periventricular white matter changes, patients might show cortical atrophy, ventricular dilation, and cerebellar atrophy, and so on. Chinese SPG11 patients manifested significant clinical and genetical heterogeneity and no obvious gender difference. Of them, 37 pathogenic mutations of KIAA1840 gene were detected, which all introduced truncated mutation of spatacsin protein. KIAA1840 gene frameshift mutation is the most common type of mutation.

A novel homozygous mutation in ERLIN1 gene causing spastic paraplegia 62 and literature review

Hereditary spastic paraplegia (HSP) is a group of genetic neurodegenerative disorders, which is characterized by the presence of progressive spasticity and weakness in bilateral lower limbs. Spastic paraplegia 62 (SPG62) caused by the endoplasmic reticulum lipid raft associated 1 (ERLIN1) gene mutation is a rare subtype of HSP. Herein, we report the case of the first Chinese SPG62 patient, explore the potential pathogenic mechanism and review ERLIN1-related HSP patients. A 23-year-old man had progressive difficulty in walking and gait abnormalities for more than 11 years. Physical examination showed slightly reduced muscle strength (5-/5) and elevated muscle tone in the lower limbs and hyperreflexia in four limbs. Genetic analysis identified a novel splicing site mutation in ERLIN1 gene (c.504+1G > A), which was predicted to disturb the normal splicing process of mRNA by bioinformatic tools. Minigene experiment further confirmed the mutation c.504+1G > A could cause erroneous deletion of Exon 7 in the mRNA, which may change the conserved prohibitin (PHB) domain of erlin-1 and affect the function of erlin1/2 complex. Thus, we identified a pathogenic mutation of ERLIN1 splicing site causing delayed-onset pure HSP. This study widened the genetic and phenotypic spectrum of SPG62.

New phenotype of RTN2-related spectrum: Complicated form of spastic paraplegia-12.

ObjectiveSpastic paraplegia‐12 (SPG12) is a subtype of hereditary spastic paraplegia caused by Reticulon‐2 (RTN2) mutations. We described the clinical and genetic features of three SPG12 patients, functionally explored the potential pathogenic mechanism of RTN2 mutations, and reviewed RTN2‐related cases worldwide.MethodsThe three patients were 31, 36, and 50 years old, respectively, with chronic progressive lower limb spasticity and walking difficulty. Physical examination showed elevated muscle tone, hyperreflexia and Babinski signs in the lower limbs. Patients 1 and 3 additionally had visual, urinary, and/or coordination dysfunctions. Patient 2 also had epileptic seizures. RTN2 mutations were identified by whole‐exome sequencing, followed by Sanger sequencing, segregation analysis, and phenotypic reevaluation. Functional examination of identified mutations was further explored.ResultsThree variants in RTN2 were identified in Patient 1 (c.103C>T, p.R35X), Patient 2 (c.230G>A, p.G77D), and Patient 3 (c.337C>A, p.P113T) with SPG, respectively. Western blotting revealed the p.R35X with smaller molecular weight than WT and other two missense mutants. Immunostaining showed the wild type colocalized with endoplasmic reticulum (ER) in vitro. p.R35X mutant diffusely distributes in the cytoplasm, losing colocalization with ER. p.G77D and p.P113T co‐localized with ER, which was abnormally aggregated in clumps.InterpretationIn this study, we identified three cases with complicated SPG12 due to three novel RTN2 mutations, respectively, presenting various phenotypes: classic SPG symptoms with (1) visual abnormalities and sphincter disturbances or (2) seizures. The phenotypic heterogeneity might arise from the abnormal subcellular localization of mutant Reticulon‐2 and improper ER morphogenesis, revealing the RTN2‐related spectrum is still expanding.

An integrated modelling methodology for estimating global incidence and prevalence of hereditary spastic paraplegia subtypes SPG4, SPG7, SPG11, and SPG15

BackgroundHereditary spastic paraplegias (HSPs) are progressively debilitating neurodegenerative disorders that follow heterogenous patterns of Mendelian inheritance. Available epidemiological evidence provides limited incidence and prevalence data, especially at the genetic subtype level, preventing a realistic estimation of the true social burden of the disease. The objectives of this study were to (1) review the literature on epidemiology of HSPs; and (2) develop an epidemiological model of the prevalence of HSP, focusing on four common HSP genetic subtypes at the country and region-level.MethodsA model was constructed estimating the incidence at birth, survival, and prevalence of four genetic subtypes of HSP based on the most appropriate published literature. The key model parameters were assessed by HSP clinical experts, who provided feedback on the validity of assumptions. A model was then finalized and validated through comparison of outputs against available evidence. The global, regional, and national prevalence and patient pool were calculated per geographic region and per genetic subtype.ResultsThe HSP global prevalence was estimated to be 3.6 per 100,000 for all HSP forms, whilst the estimated global prevalence per genetic subtype was 0.90 (SPG4), 0.22 (SPG7), 0.34 (SPG11), and 0.13 (SPG15), respectively. This equates to an estimated 3365 (SPG4) and 872 (SPG11) symptomatic patients, respectively, in the USA.ConclusionsThis is the first epidemiological model of HSP prevalence at the genetic subtype-level reported at multiple geographic levels. This study offers additional data to better capture the burden of illness due to mutations in common genes causing HSP, that can inform public health policy and healthcare service planning, especially in regions with higher estimated prevalence of HSP.

Tract-specific damage at spinal cord level in pure hereditary spastic paraplegia type 4: a diffusion tensor imaging study

SPG4 is a subtype of hereditary spastic paraplegia (HSP), an upper motor neuron disorder characterized by axonal degeneration of the corticospinal tracts and the fasciculus gracilis. The few neuroimaging studies that have focused on the spinal cord in HSP are based mainly on the analysis of structural characteristics. We assessed diffusion-related characteristics of the spinal cord using diffusion tensor imaging (DTI), as well as structural and shape-related properties in 12 SPG4 patients and 14 controls. We used linear mixed effects models up to T3 in order to analyze the global effects of 'group' and 'clinical data' on structural and diffusion data. For DTI, we carried out a region of interest (ROI) analysis in native space for the whole spinal cord, the anterior and lateral funiculi, and the dorsal columns. We also performed a voxelwise analysis of the spinal cord to study local diffusion-related changes. A reduced cross-sectional area was observed in the cervical region of SPG4 patients, with significant anteroposterior flattening. DTI analyses revealed significantly decreased fractional anisotropy (FA) and increased radial diffusivity at all the cervical and thoracic levels, particularly in the lateral funiculi and dorsal columns. The FA changes in SPG4 patients were significantly related to disease severity, measured as the Spastic Paraplegia Rating Scale score. Our results in SPG4 indicate tract-specific axonal damage at the level of the cervical and thoracic spinal cord. This finding is correlated with the degree of motor disability.

Anticipation Can Be More Common in Hereditary Spastic Paraplegia with SPAST Mutations Than It Appears.

Hereditary spastic paraplegia (HSP) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness. Different patterns of inheritance have been identified in HSP. Most autosomal-dominant HSPs (AD-HSPs) are associated with mutations of the SPAST gene (SPG4), leading to a pure form of HSP with variable age-at-onset (AAO). Anticipation, an earlier onset of disease, as well as aggravation of symptoms in successive generations, may be correlated to SPG4. Herein, we suggested that anticipation might be a relatively common finding in SPG4 families. Whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands. Data were analyzed, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis. Multiplex ligation-dependent probe amplification (MLPA) was done for seven probands. Clinical features of the probands were recorded, and the probable anticipation was checked in these families. Other previous reported SPG4 families were investigated to anticipation. Our findings showed that SPG4 was the common subtype of HSP; three families carried variants in the KIF5A, ATL1, and MFN2 genes, while five families harbored mutations in the SPAST gene. Clinical features of only SPG4 families indicated decreasing AAO in affected individuals of the successive generations, and this difference was significant (p-value <0.05). It seems SPAST will be the first candidate gene in families that manifests a pure form of AD-HSP and anticipation. Therefore, it may be a powerful situation of genotype-phenotype correlation. However, the underlying mechanism of anticipation in these families is not clear yet.

Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes.

Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes. We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates. We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n=84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum. Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum. Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease. © 2021 International Parkinson and Movement Disorder Society.

Expanding the Spectrum of AP5Z1‐Related Hereditary Spastic Paraplegia (HSP‐SPG48): A Multicenter Study on a Rare Disease

Expanding the Spectrum of <scp><i>AP5Z1‐</i></scp>Related Hereditary Spastic Paraplegia (<scp>HSP‐SPG48</scp>): A Multicenter Study on a Rare Disease

Spinal Cord Gray and White Matter Damage in Different Hereditary Spastic Paraplegia Subtypes.

Spinal cord damage is a hallmark of hereditary spastic paraplegias, but it is still not clear whether specific subtypes of the disease have distinctive patterns of spinal cord gray (GM) and white (WM) matter involvement. We compared cervical cross-sectional GM and WM areas in patients with distinct hereditary spastic paraplegia subtypes. We also assessed whether these metrics correlated with clinical parameters. We analyzed 37 patients (17 men; mean age, 47.3 [SD, 16.5] years) and 21 healthy controls (7 men; mean age, 42.3 [SD, 13.2] years). There were 7 patients with spastic paraplegia type 3A (SPG3A), 12 with SPG4, 10 with SPG7, and 8 with SPG11. Image acquisition was performed on a 3T MR imaging scanner, and T2*-weighted 2D images were assessed by the Spinal Cord Toolbox. Statistical analyses were performed in SPSS using nonparametric tests and false discovery rate-corrected P values < .05. The mean disease duration for the hereditary spastic paraplegia group was 22.4 [SD, 13.8] years and the mean Spastic Paraplegia Rating Scale score was 22.8 [SD, 11.0]. We failed to identify spinal cord atrophy in SPG3A and SPG7. In contrast, we found abnormalities in patients with SPG4 and SPG11. Both subtypes had spinal cord GM and WM atrophy. SPG4 showed a strong inverse correlation between GM area and disease duration (ρ = -0.903, P < .001). Cervical spinal cord atrophy is found in some but not all hereditary spastic paraplegia subtypes. Spinal cord damage in SPG4 and 11 involves both GM and WM.

Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey.

Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients. We studied 21 patients from 17 families. Six of them presented with recessive inheritance. All index patients were screened for ATL1 and SPAST gene mutations to determine the prevalence of the most frequent types of HSP in our cohort. Whole exome sequencing was performed for an AD-HSP family, in combination with homozygosity mapping for five selected AR-HSP families. Two novel causative variants were identified in PLP1 and SPG11 genes, respectively. Distribution of HSP mutations in our AD patients was found to be similar to European populations. Our genetic studies confirmed that clinical analysis can be misleading when defining HSP subtypes. Genetic testing is an important tool for diagnosis and genetic counselling. However, in the majority of AR HSP cases, a genetic diagnosis is not possible.

Mutation analysis of CAPN1 in Chinese populations with spastic paraplegia and related neurodegenerative diseases

BackgroundMutations in CAPN1 have recently been reported to cause the spastic paraplegia 76 (SPG76) subtype of hereditary spastic paraplegia (HSP). To investigate the role of CAPN1 in spastic paraplegia and other neurodegenerative diseases, including spinocerebellar ataxia (SCA), early-onset Parkinson's disease (EOPD), and amyotrophic lateral sclerosis (ALS) we conducted a mutation analysis of CAPN1 in a cohort of Chinese patients with SPG, SCA, EOPD, and ALS. MethodsVariants of CAPN1 were detected in the three cohorts by Sanger or whole-exome sequencing, and all exons and exon-intron boundaries of CAPN1 were analysed. ResultsA novel CAPN1 splicing variant (NM_001198868: c.338-1G > A) identified in a familial SPG/SCA showed a complex phenotype, including spastic paraplegia, ataxia, and extensor plantar response. This mutation was confirmed by Sanger sequencing and completely co-segregated with the phenotypes. Sequencing of the cDNA from the three affected patients detected a guanine deletion (c.340_340delG) that was predicted to result in an early stop codon after 61 amino acids (p. D114Tfs*62). No CAPN1 pathogenic mutation was found in the EOPD or ALS groups. ConclusionOur data reveal a novel CAPN1 mutation found in patients with SPG/SCA and emphasize the spastic and ataxic phenotypes of SPG76, but CAPN1 may not play a major role in EOPD and ALS.

A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration.

At the end of 19th century, Adolf von Strümpell and Sigmund Freud independently described the symptoms of a new pathology now known as hereditary spastic paraplegia (HSP). HSP is part of the group of genetic neurodegenerative diseases usually associated with slow progressive pyramidal syndrome, spasticity, weakness of the lower limbs, and distal-end degeneration of motor neuron long axons. Patients are typically characterized by gait symptoms (with or without other neurological disorders), which can appear both in young and adult ages depending on the different HSP forms. The disease prevalence is at 1.3-9.6 in 100 000 individuals in different areas of the world, making HSP part of the group of rare neurodegenerative diseases. Thus far, there are no specific clinical and paraclinical tests, and DNA analysis is still the only strategy to obtain a certain diagnosis. For these reasons, it is mandatory to extend the knowledge on genetic causes, pathology mechanism, and disease progression to give clinicians more tools to obtain early diagnosis, better therapeutic strategies, and examination tests. This review gives an overview of HSP pathologies and general insights to a specific HSP subtype called spastic paraplegia 31 (SPG31), which rises after mutation of REEP1 gene. In fact, recent findings discovered an interesting endoplasmic reticulum antistress function of REEP1 and a role of this protein in preventing τ accumulation in animal models. For this reason, this work tries to elucidate the main aspects of REEP1, which are described in the literature, to better understand its role in SPG31 HSP and other pathologies.

Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report

BackgroundPathogenic variants in KIF1A (kinesin family member 1A) gene have been associated with hereditary spastic paraplegia (HSP) type 30 (SPG30), encopassing autosomal dominant and recessive, pure and complicated forms.Case presentationWe report the long-term follow-up of a 19 years-old boy first evaluated at 18 months of age because of toe walking and unstable gait with frequent falls. He developed speech delay, mild intellectual disability, a slowly progressive pyramidal syndrome, microcephaly, bilateral optic subatrophy and a sensory axonal polyneuropathy. Brain MRI showed cerebellar atrophy, stable along serial evaluations (last performed at 18 years of age). Targeted NGS sequencing disclosed the de novo c.914C > T missense, likely pathogenic variant on KIF1A gene.ConclusionsWe report on a previously unpublished de novo heterozygous likely pathogenic KIF1A variant associated with slowly progressive complicated SPG30 and stable cerebellar atrophy on long-term follow-up, adding to current knowledge on this HSP subtype.

Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown. A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted. The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity. Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.