Autosomal Recessive Hereditary Spastic Paraplegia Research Articles

Homozygosity mapping and next generation sequencing for the genetic diagnosis of hereditary ataxia and spastic paraplegia in consanguineous families

IntroductionGenetic inheritance plays key roles in patients with ataxia and/or spastic paraplegia in consanguineous families. This study aims to clarify the genetic spectrum of patients with autosomal recessive hereditary ataxia and spastic paraplegias (AR-HA/HSPs) in consanguineous families. MethodsA total of 36 AR-HA/HSPs consanguineous pedigrees from China were recruited into this study. Next generation sequencing (NGS), guided by homozygosity mapping (HM), was applied to identify the pathogenic variants in known genes or novel candidate genes. ResultsWe totally made molecular diagnosis in 47.2% (17/36) of AR-HA/HSPs families. Among them, 13 AR-HAs carried pathogenic variants in SETX (n = 4), SACS (n = 2), STUB1, HSD17B4, NEU1, ADCK3, TPP1, PLA2G6 and MTCL1, while four AR-HSPs carried pathogenic variants in SPG11, ZFYVE26, ATP13A2 and ABCD1. One homozygous nonsense mutation in MRPS27 was identified in an AR-HA family, which was potentially a novel candidate gene of AR-HA. ConclusionHM and NGS can serve as an efficient molecular diagnostic tool for AR-HA/HSPs in consanguineous families. Our findings provide a better understanding of genetic architecture of AR-HA/HSPs in consanguinity and broaden the clinical-genetic spectrum of the disease.

Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia.

ObjectiveTo establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC).MethodsPhysical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out.ResultsThe 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s–30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis.ConclusionsOur study further broadens the clinical spectrum associated with ATP13A2 mutations.

Case Series of Autosomal Recessive Hereditary Spastic Paraplegia in Adults

Case Series of Autosomal Recessive Hereditary Spastic Paraplegia in Adults

Clinical characteristics and variant analysis of five pedigrees with hereditary spastic paraplegia

To explore the clinical and genetic characteristics of five pedigrees affected with hereditary spastic paraplegia(HSP). Clinical data of the five pedigrees was collected, and high-throughput sequencing was carried out to detect potential variants. Sanger sequencing were used to verify the results. The probands of pedigree 1 and 2 were found to harbor heterozygous SPAST gene variants, namely c.1196C>T and c.1523T>A. The proband of pedigree 3 harbored compound heterozygous variants of FA2H gene (c.61G>C and c.688G>A). Proband from pedigree 4 harbored compound heterozygous variants of SPG11 gene (c.6812+4_6812+7delAGTA and c.915delT). The proband of pedigree 5 harbored compound heterozygous variants of SPG7 gene (c.1703_1704delAG and c.1937-1G>C). Based on the American College of Medical Genetics and Genomics(ACMG) guidelines, all variants were predicted to be likely pathogenic. Among these, SPAST gene c.1523T>A, FA2H gene c.61.G>C, SPG11 gene splicing region c.6812+4_6812+7delAGTA, c.915delT, SPG7 gene c.1703_1704delAG and splicing region c.1937-1G>C variants were unreported previously. The probands of pedigrees 1 and 2 were diagnosed with autosomal dominant hereditary spastic paraplegia type 4, for which pedigree 2 showed incompletely penetrance. Pedigrees 3, 4, and 5 were diagnosed with autosomal recessive hereditary spastic paraplegia type 35, 11 and 7, respectively. Above result provided a reference for clinical diagnosis and genetic counseling for the affected pedigrees.

Description of combined ARHSP/JALS phenotype in some patients with SPG11 mutations.

Background SPG11 mutations can cause autosomal recessive hereditary spastic paraplegia (ARHSP) and juvenile amyotrophic lateral sclerosis (JALS). Because these diseases share some clinical presentations and both can be caused by SPG11 mutations, it was considered that definitive diagnosis may not be straight forward.MethodsThe DNAs of referred ARHSP and JALS patients were exome sequenced. Clinical data of patients with SPG11 mutations were gathered by interviews and neurological examinations including electrodiagnosis (EDX) and magnetic resonance imaging (MRI).ResultsEight probands with SPG11 mutations were identified. Two mutations are novel. Among seven Iranian probands, six carried the p.Glu1026Argfs*4‐causing mutation. All eight patients had features known to be present in both ARHSP and JALS. Additionally and surprisingly, presence of both thin corpus callosum (TCC) on MRI and motor neuronopathy were also observed in seven patients. These presentations are, respectively, key suggestive features of ARHSP and JALS.ConclusionWe suggest that rather than ARHSP or JALS, combined ARHSP/JALS is the appropriate description of seven patients studied. Criteria for ARHSP, JALS, and combined ARHSP/JALS designations among patients with SPG11 mutations are suggested. The importance of performing both EDX and MRI is emphasized. Initial screening for p.Glu1026Argfs*4 may facilitate SPG11 screenings in Iranian patients.

Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of rare motor neuron disorders characterized by progressive weakness and spasticity of the lower limbs. HSP type 11 (SPG11-HSP) is linked to pathogenic variants in the SPG11 gene and it represents the most frequent form of complex autosomal recessive HSP. The majority of SPG11-HSP patients exhibit additional neurological symptoms such as cognitive decline, thin corpus callosum, and peripheral neuropathy. Yet, the mechanisms of SPG11-linked spectrum diseases are largely unknown. Recent findings indicate that spatacsin, the 280 kDa protein encoded by SPG11, may impact the autophagy-lysosomal machinery. In this update, we summarize the current knowledge of SPG11-HSP. In addition to clinical symptoms and differential diagnosis, our work aims to link the different clinical manifestations with the respective structural abnormalities and cellular in vitro phenotypes. Moreover, we describe the impact of localization and function of spatacsin in different neuronal systems. Ultimately, we propose a model in which spatacsin bridges between neurodevelopmental and neurodegenerative phenotypes of SPG11-linked disorders.

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.

An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18)

Hereditary spastic paraplegia (HSP) is a heterogeneous inherited disorder that manifests with lower extremity weakness and spasticity. HSP can be inherited by autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have shown that, although rare, mutations in a single gene can lead to multiple patterns of inheritance of HSP. We enrolled the HSP family showing autosomal dominant inheritance and performed genetic study to find the cause of phenotype in this family. We recruited five members of a Korean family as study participants. Four of the five family members had pure HSP. Part of the family members underwent whole-exome sequencing (WES) to identify the causative mutation. As the result of WES and Sanger sequencing analysis, a novel missense mutation (c.452 C > T, p.Ala151Val) of ERLIN2 gene was identified as the cause of the autosomal dominant HSP in the family. Our study suggests that the ERLIN2 gene leads to both autosomal recessive and autosomal dominant patterns of inheritance in HSP. Moreover, autosomal dominant HSP caused by ERLIN2 appears to cause pure HSP in contrast to autosomal recessive ERLIN2 related complicated HSP (SPG18).

Rare novel CYP2U1 and ZFYVE26 variants identified in two Pakistani families with spastic paraplegia

BakgroundHereditary Spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of degenerative disorders characterized by progressive spasticity and weakness of the lower limbs. This study aimed to identify causative gene variants in two unrelated consanguineous Pakistani families presented with 2 different forms of HSP. MethodsWhole exome sequencing (WES) was performed in the two families and variants were validated by Sanger sequencing and segregation analysis. AnalysisIn family A, a homozygous pathogenic variant in ZFYVE26 was identified in one family. While in family B, a frameshift variant in CYP2U1 was identified in 4 affected individuals presented with clinical features of SPG56. Our study is the first report of ZFYVE26 mutations causing HSP in the Pakistani population and the second report of CYP2U1 in a Pakistani family. ConclusionsOur findings enhance the clinical and genetic variability associated with two rare autosomal recessive HSP genes, highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool.

Chinese families with autosomal recessive hereditary spastic paraplegia caused by mutations in SPG11

BackgroundSpastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population.MethodsTargeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing.ResultsA total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations. Six mutations were novel; 2 were classified as pathogenic, 1 were considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration.ConclusionsThe results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.

Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.

Case report: SPG11 hereditary spastic paraplegia with no thinning in the corpus callosum

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSPTCC) is a type of complicated hereditary spastic paraparesis, which caused by SPG11 mutations. SPG11 ARHSPTCC is characterized by the thin corpus callosum, progressive spastic paraparesis, and cognitive decline. In addition to other neurological symptoms such as seizures, cerebellar ataxia, speech and swallowing problems, extrapyramidal signs and skeletal deformities may also occur. The neuroradiological findings typically include thinning of the anterior corpus callosum (TCC), periventricular white matter changes and cortical atrophy. We herein report two Saudi Arabian siblings with genetically confirmed SPG11 ARHSP with no thinning in the corpus callosum. The brothers, aged 20 and 34 years, presented with a typical presentation of SPG11 ARHSP; including bilateral progressive lower limbs weakness, spasticity, and unsteadiness. Brain MRI of the younger sibling showed mild periventricular deep white matter T2 hyperintensity changes, mainly at the parietooccipital lobe. And diffuse cortical gray and white matter atrophic changes. While the older sibling had a normal brain MRI. Autosomal recessive hereditary spastic paraparesis with SPG 11 mutations may rarely have absence of corpus collosal involvement. This may perhaps be due to the timing of the MRI or other genetic features. Longitudinal MRI studies are required to determine if the collosal involvement develops later in the disease course.

SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia.

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10-15). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

BackgroundAlthough many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.MethodsIn this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants.ResultsWe identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in SPG11, two (p.T55 M, p.S308 T) in AP5Z1, one (p.S242 N) in ALDH18A1, one (p.D597fs) in GBA2, and one (p.Q486X) in ATP13A2 in 8 index patients and their family members. Mutations in ALDH18A1, AP5Z1, CAPN1 and ATP13A2 genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in ALDH18A1 decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in AP5Z1 induced lysosomal dysfunction.ConclusionOur results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

Molecular Genetic Diversity and DNA Diagnostics of Hereditary Spastic Paraplegia

Abstract—Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative disorders predominantly characterized by damage to the pyramidal tract. The major, single symptom of HSP is progressive weakness and spasticity of lower extremities, which ultimately leads to difficulties in walking. HSP has various types of inheritance and clinical characteristics. The development of molecular genetics and the emergence of high-throughput sequencing techniques, such as New Generation Sequencing (NGS) in particular, revealed a pronounced genetic heterogeneity of HSP. Currently, about 80 genetic loci for HSP are designated as spastic paraplegia genes (SPGs) (with numbering according to the mapping history), and the vast majority of causative genes within loci have been identified. The most frequent autosomal dominant forms of HSP are SPG4 and SPG3; SPG11, SPG15, SPG7 are common autosomal recessive HSPs. The mechanisms of HSP molecular pathogenesis are variable and encompassing defects of neuronal membrane transport and the disturbance of myelination processes, lipid metabolism, mitochondrial dysfunctions, etc. The differential diagnosis for HSPs is difficult due to the existence of many geno- and phenocopies within the other neuropathologies that can be partially distinguished by neuroimaging methods. The only method for the precise diagnostics of HSP and the number of genomic copies is DNA diagnostics—the search for mutations in individual genes and/or the analysis of many genes simultaneously by NGS methods (gene panel, whole-exome sequencing, and whole-genome sequencing). Such DNA diagnostics opens up the opportunity to perform prenatal or preimplantation analysis of the fetus for families carrying HSP mutations to predict the risk of HSP inheritance. Currently, HSP treatment is directed against individual symptoms (antispastic drugs, etc.), and the discovery of the pathogenic action of different genes requires the development of new therapeutic approaches.

CAPN1 mutations: Expanding the CAPN1-related phenotype: From hereditary spastic paraparesis to spastic ataxia

Aims and objectiveTo characterize the phenotype of CAPN1 (SPG76) mutations in patients diagnosed with hereditary spastic paraplegia (HSP). BackgroundThe CAPN1 gene, located on chromosome 11q13.1, is a protein-coding gene involved in neuronal plasticity, migration, microtubular regulation and cerebellar development. Several families with CAPN1 mutations have recently been reported to present with autosomal recessive (AR) HSP and/or ataxia. MethodPatients with HSP were identified through neurological and genetic clinics with detailed phenotyping. Whole exome sequencing revealed novel pathogenic CAPN1 mutations in four patients from 3 families. ResultsAffected families were of Turkish, Japanese, and Punjabi descent and all were consanguineous. Onset of spastic paraplegia in the four patients was between 20 and 37 years. Two also had mild ataxia. Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy). ConclusionsThe phenotype of AR CAPN1 mutations appears to be spastic paraplegia with or without ataxia; onset is most commonly in adulthood. Eye movement abnormalities, skeletal defects, peripheral neuropathy and amyotrophy can sometimes be seen. Occasionally, patients can present with ataxia, illustrating the genotypic and phenotypic overlap between HSP and spastic ataxia. With the advent of exome sequencing, mutations in more than one gene can be identified, which may contribute to the phenotypic variation, even within a family.

Autosomal recessive hereditary spastic paraplegia type SPG35 due to a novel variant in the FA2H gene in a Czech patient

Biallelic pathogenic variants in FA2H gene have been repeatedly described as a cause of hereditary spastic paraplegia (HSP) type35 (SPG35). Targeted massive parallel sequencing (MPS) of the HSP genes panel revealed a novel homozygous variant c.130C > T (p.P44S) in the FA2H gene in the 30-year-old patient presenting with spastic paraplegia. The patient originated form the Czech minority in Romania. The patient manifests typical clinical signs for SPG35 (youth onset gait impairment, progressive spastic paraparesis on lower limbs, dysarthria, white matter changes in MRI).

WED 201 A novel KIF1A mutation causing a neurodevelopmental disorder

The KIF1A gene encodes a protein in the kinesin-3 family which drives movement along microtubules and is important for transport of synaptic vesicles. Biallelic mutations have been identified in autosomal recessive hereditary spastic paraplegia (HSP30) and hereditary sensory and autonomic neuropathy type 1A. More recently dominant heterozygous mutations have been found in people with a more severe phenotype that includes developmental delay, spastic paraplegia, neuropathy, optic nerve hypoplasia and progressive cerebellar hypoplasia.We report a female, now 22 years old, who has severe developmental delay, septo-optic dysplasia (requiring growth hormone and hydrocortisone replacement), sensorimotor axonal neuropathy, optic atrophy (now registered blind), non-progressive cerebellar hypoplasia, periodic limb movements and upper limb spasticity. She is extremely sensitive to gabapentin. A de novoKIF1A variant, c.814A&gt;G, was identified. This is a novel missense variant (p.N272D) in the kinesin-motor domain.This case shows a phenotype consistent with previously described heterozygous KIF1A mutations and we believe represents a unifying diagnosis for her neurological disabilities. No previous cases describe non-progressive cerebellar hypoplasia nor septo-optic dysplasia requiring pituitary hormone replacement. This novel mutation therefore expands the phenotype associated with KIF1A mutations. We hypothesize that her sensitivity to gabapentin may be due to the KIF1A mutation.

Novel Type of Complicated Autosomal Dominant Hereditary Spastic Paraplegia Associated with Congenital Distal Arthrogryposis Type I.

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurological disorders. HSP is classified as pure when only a spastic weakness of the lower extremities is present. Complex HSP comes with additional neurological or systemic abnormalities. Complex HSP with skeletal abnormalities is rare and mostly seen in autosomal recessive HSP. Autosomal dominant (AD) complex HSP with skeletal abnormalities are consistently seen only in SPG9 (spastic gait type 9). In this paper, we report a kindred condition with AD HSP among four living affected individuals who had progressive, adult onset spastic paraparesis that was associated with a distal arthrogryposis (DA) in every affected individual. They also had episodes of rhabdomyolysis without any clinical signs of myopathy. Exhaustive genetic analysis including targeted sequencing of known HSP and DA genes and whole exome sequencing did not identify the disease-causing gene. It excluded all known HSP and DA genes. We propose that this is a novel genetic type of complex AD HSP. Elucidation of a genetic cause of this type of HSP will further contribute to our understanding of axonal degeneration and skeletal abnormalities.

Anterior horn cell (AHC) involvement in autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSPTCC) patients with SPG 11 mutations. (P3.088)

Anterior horn cell (AHC) involvement in autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSPTCC) patients with SPG 11 mutations. (P3.088)