Autosomal Dominant Spastic Paraplegia Research Articles

Reticulon 2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to scarcity of supporting evidence. In our study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite Reticulon-2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with Reticulon-2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN, and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Novel TFG mutation causes autosomal-dominant spastic paraplegia and defects in autophagy

BackgroundMutations in the tropomyosin receptor kinase fused (TFG) gene are associated with various neurological disorders, including autosomal recessive hereditary spastic paraplegia (HSP), autosomal dominant hereditary motor and sensory neuropathy with...

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

KIF1A (kinesin family member 1A)-related disorders encompass a variety of diseases. KIF1A variants are responsible for autosomal recessive and dominant spastic paraplegia 30 (SPG, OMIM610357), autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSN2C, OMIM614213), and autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV syndrome), formerly named mental retardation type 9 (MRD9) (OMIM614255). KIF1A variants have also been occasionally linked with progressive encephalopathy with brain atrophy, progressive neurodegeneration, PEHO-like syndrome (progressive encephalopathy with edema, hypsarrhythmia, optic atrophy), and Rett-like syndrome. The first Polish patients with confirmed heterozygous pathogenic and potentially pathogenic KIF1A variants were analyzed. All the patients were of Caucasian origin. Five patients were females, and four were males (female-to-male ratio = 1.25). The age of onset of the disease ranged from 6 weeks to 2 years. Exome sequencing identified three novel variants. Variant c.442G>A was described in the ClinVar database as likely pathogenic. The other two novel variants, c.609G>C; p.(Arg203Ser) and c.218T>G, p.(Val73Gly), were not recorded in ClinVar. The authors underlined the difficulties in classifying particular syndromes due to non-specific and overlapping signs and symptoms, sometimes observed only temporarily.

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.

In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

A Japanese hereditary spastic paraplegia family with a rare nonsynonymous variant in the SPAST gene

Spastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4:c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a “likely pathogenic” variant.5 Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

[Autosomal dominant spastic paraplegias].

To estimate the proportion and spectrum of infrequent autosomal dominant spastic paraplegias in a group of families with DNA-confirmed diagnosis and to investigate their molecular and clinical characteristics. Ten families with 6 AD-SPG: SPG6 (n=1), SPG8 (n=2), SPG9A (n=1), SPG12 (n=1), SPG17 (n=3), SPG31 (n=2) were studied using clinical, genealogical, molecular-genetic (massive parallel sequencing, spastic paraplegia panel, whole-exome sequencing, multiplex ligation-dependent amplification, Sanger sequencing) and bioinformatic methods. Nine heterozygous mutations were detected in 6 genes, including the common de novo mutation p.Gly106Arg in NIPA1 (SPG6), the earlier reported mutation p.Val626Phe in WASHC5 (SPG8) in isolated case and the novel p.Val695Ala in WASHC5 (SPG8) in a family with 4 patients, the novel mutation p.Thr301Arg in RTN2 (SPG12) in a family with 2 patients, the novel mutation c.105+4A>G in REEP1 (SPG31) in a family with 4 patients and the reported earlier p.Lys101Lys in REEP1 (SPG31) in a family with 3 patients, the known de novo mutation p.Arg252Gln in ALDH18A1 (SPG9A) in two monozygous twins; the common mutation p.Ser90Leu in BSCL2 (SPG17) in a family with 3 patients and in isolated case, reported mutation p.Leu363Pro in a family with 2 patients. SPG6, SPG8, SPG12 and SPG31 presented 'pure' phenotypes, SPG31 had most benign course. Age of onset varied in SPG31 family and was atypically early in SPG6 case. Patients with SPG9A and SPG17 had 'complicated' paraplegias; amyotrophy of hands typical for SPG17 was absent in a child and in an adolescent from 2 families, but may develop later.

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

BackgroundSpastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population.MethodsClinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel ‘spastic paraplegias’ with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole -exome sequencing.ResultsAD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others.ConclusionAD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.

Autosomal dominant spastic paraplegia in four generations of Yakut family linked to dynamin 2 mutation

Autosomal dominant spastic paraplegia in four generations of Yakut family linked to dynamin 2 mutation

Determinants of age at onset in a Portuguese cohort of autosomal dominant spastic paraplegia

BackgroundHereditary spastic paraplegias present a high variability of age at onset, ranging from childhood to older age. Our objective was to identify the determinants of age at onset in autosomal dominant HSP (AD-HSP) in a large cohort of patients and families. MethodsWe included 239 patients from 89 families identified in the Portuguese multisource population-based survey of hereditary ataxias and spastic paraplegias. Patients were systematically examined by a team of neurologists, admitted for complete clinical workup and tested for SPG3, SPG4 and SPG31. ResultsAverage age at onset was 38.2 years in the first generation, 32.3 years in the second and 17.5 years in the third, with a significant decrease of average age at onset between generations (p < .001). A decrease in the average age at onset was seen in all genotypes (SPG4: p < .001; SPG3: p = .15; SPG31: p < .001). In families with more than one generation (n = 38), this decrease was observed in 78.9%. In multivariate linear regression model, the independent effect of generation in anticipation of age at onset was confirmed (p < .001), adjusting for family, genotype and mutation. We also observed a significant lower age at onset in patients with missense versus truncating mutations (p = .015) in patients with SPG4. ConclusionThese results confirm the impact of missense mutations in an earlier age at onset in SPG4 patients. Even though the age at onset could be affected by subjectivity, our results are consistent with the presence of an anticipation phenomenon in AD-HSP.

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.

KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly ‘pure’ spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0–57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6–7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia.

Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes. The exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes. The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of Ubap1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures. Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic Ubap1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of Ubap1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.

Major Mutation in the SPAST Gene in Patients with Autosomal Dominant Spastic Paraplegia from the Republic of Bashkortostan

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders with a predominant lesion of the pyramidal tract. To date, mutations responsible for the disease have been identified in more than 70 genetic loci. The main causes of HSP development are mutations in the SPAST gene, but major mutations are rare for this disease. Study of HSP patients from 63 unrelated families from the Bashkortostan Republic (BR) identified the c.283delG (p.Ala95Profs*66) mutation in the SPAST gene in families of Tatar ethnicity with a high frequency. In the general cohort of unrelated patients from the Bashkortostan Republic, its frequency was 19%, and in the cohort of Tatar patients, it was 44%. HSP was found to be inherited in an autosomal dominant manner in all families with this mutation. The clinical symptoms of the disease in most of these families corresponded to the uncomplicated phenotype, typical of the SPG4 form of HSP.

Clinico-Investigative Profile of Hereditary Spastic Paraplegia in Children.

Introduction:Hereditary spastic paraplegia (HSP) is a group of neurogenetic disorders seen mainly in adults. With the advancement in genetics, more than 78 types of HSP have been identified, with increasing identification of HSP in children. However, there is scant literature on this from India.Materials and Methods:Retrospective chart review of patients with HSP diagnosed in the last 6 years was done. The data were extracted and analyzed.Results:A total of 11 patients had a diagnosis of HSP (genetically confirmed), with mean age of presentation at 21.7 months. The main symptom at the time of presentation was delayed walking and/or abnormal gait in the form of tip-toeing and scissoring of limbs. The mean delay in diagnosis was 5.2 years after initial presentation. MRI of the presented children showed mainly thinning of corpus callosum and white-matter changes. All of them had gradual worsening spasticity, despite physiotherapy and drugs. Except one, all children had recessive form of spastic paraplegia. Child with autosomal dominant spastic paraplegia had heterozygous mutation in SPAST gene, which is known to present in the first 2 years of life.Conclusions:HSP is probably not uncommon. Recessive form of HSP is more frequently seen in children. Because of lack of awareness, there is delay in reaching the final diagnosis.

Kinesins in neurological inherited diseases: a novel motor-domain mutation in KIF5A gene in a patient from Southern Italy affected by hereditary spastic paraplegia.

Kinesins are a family of proteins for anterograde transport of the molecules from the neuronal cell body and their impairment has been widely associated with neurodegeneration of the motor neurons. KIF5A gene causes autosomal dominant spastic paraplegia 10, a neurological disorder characterized by spasticity and weakness of the lower limbs (SPG10). We carried out a screening of KIF5A gene in 50 subjects affected by HSP negative to diagnostic test for SPG4, ATL1 and REEP1. We identified a novel variation p.Ile255Met in a 58-year-old man who developed progressive gait disturbance due to spastic paraparesis complicated by axonal neuropathy.

A novel KIF5A gene variant causes spastic paraplegia and cerebellar ataxia.

Mutations in the kinesin family member 5A (KIF5A) gene are mainly associated with autosomal dominant spastic paraplegia 10 (SPG10). The additional complicated symptoms of SPG10 commonly include a wide spectrum. However, cerebellar ataxia is only noticed in a very few patients. Herein, we described a large autosomal dominant family, in which the affected individuals presented with progressive spastic paraparesis and marked cerebellar ataxia. Exome sequencing revealed that a novel variant in the KIF5A gene might be responsible for the phenotype. The obvious cerebellar ataxia indicated that the KIF5A gene should be included in the expanding gene list for spasticity‐ataxia spectrum.

De novo REEP2 missense mutation in pure hereditary spastic paraplegia.

Alterations in proteins that regulate endoplasmic reticulum morphology are common causes of hereditary spastic paraplegia (SPG1‐78, plus others). Mutations in the REEP1 gene that encodes an endoplasmic reticulum‐shaping protein are well‐known causes of SPG31, a common autosomal dominant spastic paraplegia. A closely‐related gene, REEP2, is mutated in SPG72, with both autosomal and recessive inheritances. Here, we report a patient with a pure hereditary spastic paraplegia due to a de novo missense mutation (c.119T > G, p.Met40Arg) in REEP2 at a highly‐conserved residue very close to another known pathogenic missense change. This represents only the second autosomal dominant SPG72 missense mutation reported.

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

BackgroundThe hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.MethodsWe performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.ResultsMost HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.ConclusionsOur findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.

Two novel mutations in gene SPG4 in patients with autosomal dominant spastic paraplegia

Hereditary spastik paraplegias (HSP) are a group of neurodegenerative disorders with primary lesion of the pyramidal tract. The most frequent autosomal dominant form of the disease in Europeans is HSP associated with mutations in the spastin gene (SPG4). Analysis of the gene SPG4 was carried out in 52 unrelated families with HSP from Bashkortostan by SSCP and following sequencing. Previously undescribed frameshift mutations c.322del29 (p.Val108SerfsX18) and c.885del10 (p.Thr295ThrfsX16) were detected in two unrelated families. Clinical studies have shown that, in both families, the disease corresponds to an uncomplicated form of hereditary spastic paraplegia, a main feature of which is the lower spastic paraparesis without any other symptoms.

SCA1 patients may present as hereditary spastic paraplegia and must be included in spastic-ataxias group.

The combination of cerebellar ataxia and spasticity is common. However, autosomal dominant genetic diseases presenting with spastic-ataxia are a smaller group. Pyramidal signs have been frequently observed in several SCA subtypes, particularly in spinocerebellar ataxia type 1. We prospectively evaluated the pyramidal signs and spasticity in SCA1 patients, and correlated the data with genetic and clinical features. In this study, we observed that spasticity may be an early and presenting feature of SCA1, since 3 patients had pyramidal signs and spasticity as the first neurological sign. SCA1 patients with spasticity were significantly younger. SCA1 may rarely present with pure spastic paraplegia, resembling hereditary spastic paraplegia, before the appearance of cerebellar signs. This observation may confuse the neurologist when a genetic testing is requested for an autosomal dominant spastic paraplegia, directing research to hereditary spastic paraplegia group.