Hereditary Spastic Paraparesis Research Articles

Biotinidase deficiency: A treatable cause of hereditary spastic paraparesis.

ObjectiveTo expand the genetic spectrum of hereditary spastic paraparesis by a treatable condition and to evaluate the therapeutic effects of biotin supplementation in an adult patient with biotinidase deficiency (BD).MethodsWe performed exome sequencing (ES) in a patient with the clinical diagnosis of complex hereditary spastic paraparesis. The patient was examined neurologically, including functional rating scales. We performed ophthalmologic examinations and metabolic testing.ResultsA 41-year-old patient presented with slowly progressive lower limb spasticity combined with optic atrophy. He was clinically diagnosed with complex hereditary spastic paraparesis. The initial panel diagnostics did not reveal the disease-causing variant; therefore, ES was performed. ES revealed biallelic pathogenic variants in the BTD gene leading to the genetic diagnosis of BD. BD is an autosomal recessive metabolic disorder causing a broad spectrum of neurologic symptoms, optic atrophy, and dermatologic abnormalities. When treatment is initiated in time, symptoms can be prevented or reversed by biotin supplementation. After diagnosis in our patient, biotin supplementation was started. One year after the onset of therapy, symptoms remained stable with slight improvement of sensory deficits.ConclusionsThese findings expand the genetic spectrum of the clinical diagnosis of complex hereditary spastic paraparesis by a treatable disease. Today, most children with BD should have been identified via newborn screening to start biotin supplementation before the onset of symptoms. However, adult patients and those born in countries without newborn screening programs for BD are at risk of being missed. Therapeutic success depends on early diagnosis and presymptomatic treatment.

Clinical and genetic features of five Czech patients with SPG11

Backround: Hereditary spastic paraparesis (HSP) is an umbrella denomination for a group of hereditary neurodegenerative diseases with very heterogenous clinical manifestation.

Health service experiences among adults with hereditary spastic paraparesis or neurofibromatosis type 1

BackgroundPersons with rare disorders may experience poorer health services due to limited knowledge about rare disorders among health professionals. Knowledge about how persons with rare disorders perceive health services can help inform service providers to enhance their practices.MethodsWe conducted a self‐report survey among adults with the rare disorders hereditary spastic paraparesis (HSP; n = 108; mean age 57.7 years; 54.2% females) and neurofibromatosis type 1 (NF1, n = 142; mean age = 50.3 years; 62.0% females). Their responses concerning perceived health experiences were compared to healthy controls from the population study HUNT‐3 (n = 7,312).ResultsBoth rare disorder groups reported lower satisfaction, trust, and participation in meetings with their general practitioner and specialist health services. More reported health problems were overall associated with poorer health service experiences.ConclusionThere is a need to identify predictors of health service experiences at the patient and health service provider levels with the aim to tighten the gap between the health experiences of patients with and without rare disorders.

Clinical and genetic update of hereditary spastic paraparesis.

Hereditary spastic paraparesis is a group of inherited neurological diseases characterized by underlying wide genetic heterogeneity. It should be suspected if there is a positive familial history, a common genetic alteration (i.e. SPG4, the most overall frequent form), or association with other signs, such as cerebellar ataxia (i.e. SPG7), early cognitive impairment or even cognitive deficit (i.e. SPG11), or peripheral neuropathy (i.e. SACS). The natural history is known for certain genetic subgroups, with genotype-phenotype correlations partially explaining childhood or late onset. However, the search for genetic modifying factors, in addition to the causal pathogenic variant or environmental influencers, is still needed. Novel approaches to provide etiological treatment are in the pipeline for SPG11. Symptomatic treatments are available but would benefit from randomized controlled trials.

Management of rare movement disorders in Europe: outcome of surveys of the European Reference Network for Rare Neurological Diseases.

Background and purposeThe diagnosis of rare movement disorders is difficult and specific management programmes are not well defined. Thus, in order to capture and assess care needs, the European Reference Network for Rare Neurological Diseases has performed an explorative care need survey across all European Union (EU) countries.MethodsThis is a multicentre, cross‐sectional study. A survey about the management of different rare movement disorders (group 1, dystonia, paroxysmal dyskinesia and neurodegeneration with brain iron accumulation; group 2, ataxias and hereditary spastic paraparesis; group 3, atypical parkinsonism; group 4, choreas) was sent to an expert in each group of disorders from each EU country.ResultsSome EU countries claimed for an increase of teaching courses. Genetic testing was not readily available in a significant number of countries. Regarding management, patients’ accessibility to tertiary hospitals, to experts and to multidisciplinary teams was unequal between countries and groups of diseases. The availability of therapeutic options, such as botulinum toxin or more invasive treatments like deep brain stimulation, was limited in some countries.ConclusionsThe management of these conditions in EU countries is unequal. The survey provides evidence that a European care‐focused network that is able to address the unmet rare neurological disease care needs and inequalities is highly warranted.

Multimodal MRI Longitudinal Assessment of White and Gray Matter in Different SPG Types of Hereditary Spastic Paraparesis.

Hereditary spastic paraplegias (HSP) are a group of genetically and clinically heterogeneous neurologic disorders. Hereby we describe a relatively large group of patients (pts) affected by HSP studied at baseline (31 pts) and at follow-up (mean period 28.9 ± 8.4 months; 23 pts) with multimodal advanced MRI: high-resolution T1 images for voxel-based morphometry (VBM) analysis, magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI). An age-matched healthy control (HC) group underwent the same neuroimaging protocol in a time schedule matched with the HSP patients. At baseline, VBM showed gray matter (GM) reduction in HSP in the right pre-frontal cortex and bilaterally in the thalami. MRS at baseline depicted in HSP patients compared to the HC group reduction of NAA/Cr ratio in the right pre-frontal region, increase of Cho/Cr ratio in the right pre-central regions, and increase of mI/Cr ratio on the left pre-central area. At cross-sectional follow-up analysis and longitudinal evaluation, no VBM and MRS statistically significant results were obtained. Tract-based spatial statistics (TBSS) analysis showed widespread DTI brain white matter (WM) alterations in patients compared to HC at baseline, which are characterized by reduction of fractional anisotropy (FA) and increase of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity, as confirmed on cross-analysis of the follow-up dataset. A longitudinal analysis with TBSS in HSP patients did not show significant variations, while upon applying region-based analysis we found increased FA and decreased MD and AD in specific brain WM fiber complex during follow-up. The changes were not correlated with the clinical presentation (pure vs complicated HSP), motor function, and motility indexes or history of specific treatments (botulinum toxin). In conclusion, the cross-sectional analysis of the multiparametric MRI data in our HSP patients confirmed the non-prominent involvement of the cortex in the primary motor regions but rather of other more associative areas. On the contrary, DTI demonstrated a widespread involvement of the brain WM, including the primary motor regions, which was confirmed at follow-up. The longitudinal analysis revealed an apparent inversion of tendency when considering the expected evolution of a neurodegenerative process: we detected an increase of FA and a decrease of MD and AD. These time-related modifications may suggest a repair attempt by the residual central WM fibers, which requires confirmation with a larger group of patients and with a longer time interval.

An Irish family with autosomal recessive SPG7-associated hereditary spastic paraparesis with a wide clinical spectre (426)

An Irish family with autosomal recessive SPG7-associated hereditary spastic paraparesis with a wide clinical spectre (426)

Mutations in heat shock protein beta-1 (HSPB1) are associated with a range of clinical phenotypes related to different patterns of motor neuron dysfunction: A case series

BackgroundHeat shock protein beta-1 (HSPB1) is a ubiquitously expressed molecular chaperone that is important in protecting cells against cellular injury. Mutations in this protein are known to cause autosomal dominant hereditary distal axonal neuropathies, including Charcot Marie Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). However, patients with HSPB1 mutations have also been described with upper motor neuron signs.We present five patients with mutations in HSPB1 who presented with a range of clinical phenotypes related to different patterns of motor neuron dysfunction. Three of these mutations have not been previously reported. MethodsPatients were seen at our neuromuscular or amyotrophic lateral sclerosis (ALS) clinics. Gene sequencing was carried out as part of diagnostic investigations. Detailed clinical and electrophysiologic data was collected. ResultsFive patients had variants of HSPB1. Three patients had a hereditary length-dependent sensori-motor axonal neuropathy consistent with Charcot Marie Tooth type 2 (CMT2); two of these patients carried novel mutations in the C-terminal region (p.Glu186* and p.Pro170Thr). One patient had the clinical picture of ALS and a novel missense mutation (p.Arg27Leu) in the N-terminal region. Another patient had the phenotype of hereditary spastic paraparesis (HSP) associated with a missense mutation (p.Gly84Arg) already described in families with CMT or dHMN. ConclusionThis study describes three novel mutations of HSPB1 and describes two patients with upper motor neurone signs associated with HSPB1 mutations.

Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

BackgroundPhospholipase A2 group VI (PLA2G6) mutations associated with neurodegeneration (PLAN) manifest as heterogeneous neurodegenerative disorders with variable ages of onset. The genotype-phenotype correlation is not well-established. We aim to describe three adult patients with PLAN and combined these data with results from previous studies to elucidate adult-onset PLA2G6 phenotype-genotype correlations.Case presentationsThe first index patient presented with dystonia-parkinsonism starting at age 31 years, accompanied by major depression and cognitive decline. Genetic analysis using targeted next generation sequencing (NGS) panel, Sanger sequencing, and segregation analyses revealed a compound heterozygous mutation, c.991G > T (p.D331Y)/c.1077G > A (M358IfsX), in PLA2G6. The other two patients had levodopa-responsive, early-onset parkinsonism, starting in their late twenties. Both patients had homozygous c.991G > T (p.D331Y) mutations in PLA2G6. Patient characteristics of our reported 3 cases were compared to those of 32 previously described (2008 to 2019) patients with adult-onset PLAN. Among the combined cohort of 35 patients with adult-onset PLAN, 14 had dystonia-parkinsonism, 17 had early-onset Parkinson’s disease, 3 had hereditary spastic paraparesis, and one had ataxia. The c.991G > T (p. D331Y) mutation was almost exclusively found in Chinese patients, suggesting a common founder effect. All patients with homozygous p.D331Y mutations had levodopa-responsive, early-onset PD (100%); while other mutations mostly led to dystonia-parkinsonism, ataxia, spasticity, and combine psychiatric comorbidities.ConclusionsWe showed that adult-onset PLAN could present as purely parkinsonism features, without brain iron accumulation, particularly patients with homozygous p.D331Y mutations. Compound heterozygous mutations, including heterozygous p.D331Y, produced heterogeneous phenotypes, without obvious levodopa responsiveness.

Primary progressive multiple sclerosis presenting under the age of 18 years: Fact or fiction?

Previous cohort studies on paediatric multiple sclerosis (MS) have reported very low frequencies for a primary progressive MS (PPMS) course ranging from 0% to 7%. We identified six patients presenting prior to the age of 18 years and fulfilling the 2017 McDonald Criteria for PPMS. Presentation with progressive neurological symptoms and signs in young people should prompt evaluation for genetic causes such as leukodystrophies, hereditary spastic paraparesis and mitochondrial diseases given the rarity of primary progressive course in paediatric MS. In the absence of an alternative diagnosis, with new therapeutic options becoming available for PPMS, this diagnosis should then be considered.

SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)

SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)

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.

Intrathecal Baclofen in Hereditary Spastic Paraparesis.

Introduction: Treatment with intrathecal baclofen (ITB) is a therapeutic option in the management of severe spasticity in patients with hereditary spastic paraparesis (HSP). However, information on the impact of ITB on the natural course of disease, especially the effect of ITB on functional parameters over time is limited.Materials and Methods: We evaluated seven patients with HSP retrospectively who were treated with an ITB device. The following parameters were measured before (pre-implantation) and after implantation (post-implantation) of the ITB device at steady state dosage of ITB and annually until last follow-up: modified Ashworth Scale, Reflex Scale, modified Rankin Scale, and Rivermead Mobility Index. The ITB dosages were assessed after reaching steady state as well as annually until last follow-up.Results: The ITB device was implanted 13 ± 6 (range 9–16) years after diagnosis of HSP on average. Severe spasticity was controlled in all patients by a mean baclofen dosage of 188 ± 60 (range 145–230) μg per day at steady state post-implantation. The modified Ashworth Scale improved significantly from 3 (interquartile range [IQR] 3–3.25) to 1 (IQR 1–1.25; p = 0.046), as did the Reflex Scale from 5 (IQR 4.75–5) to 3 (IQR 2.75–3; p = 0.046) at steady state dosage of ITB. The modified Rankin Scale improved from 2 (IQR 2–2) to 1 (IQR 1–1.5; p = 0.083) and the Rivermead Mobility Index remained 14 (IQR 13.5–14 pre-implantation, IQR 14–14 post-implantation; p = 0.18). Post-implantation, spasticity improved for 2–3 years, followed by a stable phase of ambulatory and other mobility functions for 4–5 years. Thereafter, the maintenance or progressive loss of mobility depended on individual courses of the disease. No ITB-related severe side effects occurred.Discussion: Our data further support the role of ITB in the treatment of severe spasticity in patients with deteriorated walking performance suffering HSP. ITB therapy may initially improve spasticity and stabilize mobility functions for the first 6–8 years in patients with HSP.

A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy.

Autophagy (self-eating) is a conserved cellular degradation process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Autophagy dysfunction can have various pathological consequences, including tumor progression, pathogen hyper-virulence, and neurodegeneration. This review describes the mechanisms of autophagy and its associations with other cell death mechanisms, including apoptosis, necrosis, necroptosis, and autosis. Autophagy has both positive and negative roles in infection, cancer, neural development, metabolism, cardiovascular health, immunity, and iron homeostasis. Genetic defects in autophagy can have pathological consequences, such as static childhood encephalopathy with neurodegeneration in adulthood, Crohn’s disease, hereditary spastic paraparesis, Danon disease, X-linked myopathy with excessive autophagy, and sporadic inclusion body myositis. Further studies on the process of autophagy in different microbial infections could help to design and develop novel therapeutic strategies against important pathogenic microbes. This review on the progress and prospects of autophagy research describes various activators and suppressors, which could be used to design novel intervention strategies against numerous diseases and develop therapeutic drugs to protect human and animal health.

Altered CSF levels of monoamines in hereditary spastic paraparesis 10: A case series.

ObjectiveTo perform a comprehensive clinical characterization and biochemical CSF profile analyses in 2 Swedish families with hereditary spastic paraparesis (HSP) 10 (SPG10) caused by 2 different mutations in the neuronal kinesin heavy chain gene (KIF5A).MethodsStructured clinical assessment, genetic studies, and neuroradiologic and electrophysiological evaluations were performed in 4 patients from 2 families with SPG10. Additional CSF analysis was conducted in 3 patients with regard to levels of neurodegenerative markers and monoamine metabolism.ResultsAll patients exhibited a complex form of HSP with a mild to moderate concurrent axonal polyneuropathy. The heterozygous missense mutations c.767A>G and c.967C>T in KIF5A were found. Wide intrafamilial phenotype variability was evident in both families. CSF analysis demonstrated a mild elevation of neurofilament light (NFL) chain in the patient with longest disease duration. Unexpectedly, all patients exhibited increased levels of the dopamine metabolite, homovanillic acid, whereas decreased levels of the noradrenergic metabolite, 3-methoxy-4-hydroxyphenylglycol, were found in 2 of 3 patients.ConclusionsWe report on CSF abnormalities in SPG10, demonstrating that NFL elevation is not a mandatory finding but may appear after long-standing disease. Impaired transportation of synaptic proteins may be a possible explanation for the increased dopaminergic turnover and noradrenergic deficiency identified. The reasons for these selective abnormalities, unrelated to obvious clinical features, remain to be explained. Our findings need further confirmation in larger cohorts of patients harboring KIF5A mutations.

P81-S The effect of repetitive transcranial magnetic stimulation on motor function in hereditary

Background Hereditary spastic paraparesis (HSP) is a group of inherited disorders affecting predominantly the motor cortex and pyramidal tract, which results in slowly progressing gait disorders, as well as spasticity and weakness of lower extremities. Repetitive transcranial magnetic stimulation (rTMS) has been previously investigated as a therapeutic tool for similar motor deficits in various neurologic conditions. The aim of this randomized, controlled trial was to investigate the therapeutic potential of rTMS in HSP. Methods We recruited 15 patients (five women, 10 men, mean age 43.7 ± 10.6 years) with HSP. The intervention included five sessions of bilateral 10 Hz rTMS over primary motor areas of the muscles of lower extremities and five sessions of similar sham stimulation. Results One patient dropped out due to seizure and 14 patients completed the study protocol. After real stimulation the strength of the proximal and distal muscles of lower extremities increased and the spasticity of the proximal muscles decreased. Change in spasticity was still present during follow up assessment. No effect was observed regarding gait velocity. No changes were seen after sham stimulation. Conclusions rTMS may have potential in improving weakness and spasticity of lower extremities in HSP, especially of proximal muscles whose motor areas are located more superficially.

Postural stability during gait for adults with hereditary spastic paraparesis

Individuals with hereditary spastic paraparesis (HSP) are often impaired in their ability to control posture as a result of the neurological and musculoskeletal implications of their condition. This research aimed to assess postural stability during gait in a group of adults with HSP. Ten individuals with HSP and 10 healthy controls underwent computerized gait analysis while walking barefoot along a 10-m track. Two biomechanics methods were used to assess stability: the center of pressure and center of mass separation (COP-COM) method, and the extrapolated center of mass (XCOM) method. Spatiotemporal and kinematic variables were also investigated. The XCOM method identified deficits in mediolateral stability for the HSP group at both heel strike and mid-stance. The group with HSP also had slower walking velocity, lower cadence, more time spent in double stance, larger step widths, and greater lateral trunk flexion than the control group. These results suggest that individuals with HSP adjust characteristics of their gait to minimize the instability arising from their impairments but have residual deficits in mediolateral stability. This may result in an increased risk of falls, particularly in the sideways direction.

Electrophysiological Findings of Subclinical Lower Motor Neuron Involvement in Degenerative Upper Motor Neuron Diseases

The present study is an examination of possible subclinical involvement of lower motor neuron (LMN) in patients with primary lateral sclerosis (PLS) and hereditary spastic paraparesis (HSP) electrophysiologically. Nine PLS patients and 5 HSP patients were prospectively analyzed. Jitter measurement with concentric needle electrode (25 mm, 30 G) (CN-jitter) recorded from right extensor digitorum muscle during voluntary contraction with 1 kHz high-pass frequency filter set. European Myelopathy Score (EMS) was used to evaluate disability. The relationship between disability score and jitter values was investigated. HSP patients had suffered from the disease for longer period of time (p<0.001). Mean jitter values of patients with PLS and HSP were 26.5±12.1 µs and 30.8±34.8 µs, and the number of individual high jitters (>43 microseconds) observed in the PLS and HSP groups was 16/180 and 9/100, respectively without a significant intergroup difference. The ratio of patients with an abnormal jitter study were higher in HSP group (60%) compared to PLS (22%) (p<0.05). Potential pairs with blocking were present in HSP group (7 of 100 potential pairs) but not seen in PLS patients. EMS values were significantly lower in patients having potential pairs with high jitter and blocking compared to those without high jitter and blocking. The present study has demonstrated that early signs of LMN dysfunction can be detected electrophysiologically by CN-jitter in patients with UMN involvement. These electrophysiological findings in these patients with longer disease duration and lower clinical scores may be explained by spreading of the disease to LMNs or transsynaptic degeneration and its contribution in disease progression.

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.

Novel c.C2254T (p.Q752*) mutation in ZFYVE26 (SPG15) gene in a patient with hereditary spastic paraparesis

Hereditary spastic paraplegias are clinically and genetically heterogeneous degenerative disorders, and pathological variants in the autosomal recessive ZFYVE26 gene are considered as very rare causes. We describe a novel mutation in ZFYVE26 gene found in a patient with autosomal recessive spastic paraplegias. The use of a 'target-gene' approach allowed us to expand the clinical spectrum associated with hereditary spastic paraplegias.