Hereditary Spastic Paraplegia Cases Research Articles

Clinical features and genotype in COQ4 associated hereditary spastic paraplegia: a case report and a literature reanalysis.

COQ4 mutation often leads to a fatal multi-system disease in infants. Recently, it was reported that the biallelic COQ4 variants may be a potential cause of hereditary spastic paraplegia (HSP). This study aims to describe the clinical features and genotype of the COQ4 associated hereditary spastic paraplegia (HSP). We reported a case of HSP with COQ4 variants, and a literature reanalysis was performed. Three studies with a total of 1309 patients with HSP of unknown cause were included, and 13 (1%) patients were found to have biallelic COQ4 variants. Seven patients fulfilled pure HSP, and six patients fulfilled complicated HSP. The median age of these patients was 24 years (range 15 to 65 years), and the median year of disease onset was 14 years (range 1 to 55 years). The most common clinical manifestations were lower limb spasticity (100%), hyperreflexia (100%), Babinski sign (77%), reduced muscle strength (53.8%) cerebellar ataxia (23.1%), seizures (23.1%) and dysarthria (23.1%). Including our case, 16 different variants located in exon 2, exon 4, exon 5, exon 6, exon 7 and two introns of the COQ4 gene have been identified in patients with HSP. All started CoQ10 supplementation, but follow-up was reported in only one patient. COQ4 variants were associated with childhood, adolescent, and adult onset HSP, which has a relatively mild course. The efficiency of CoQ10 supplement in patients with COQ4 associated HSP need to be classified in the future study.

From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.

Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST. Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder. We describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4. Biallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene.

Panchakarma Intervention in Heriditary Spastic Paraplegia

Hereditary Spastic Paraplegia (HSP) is a large group of inherited neurological disorders, in which the prominent feature is a progressive spastic paraparesis. it can be Multiple genetic mutations with various inheritance patterns (autosomal dominant, autosomal recessive, X-linked recessive). Direct correlation of Hereditary Spastic Paraplegia (HSP) is not found in Ayurvedic classics. It can be studied within the broad spectrum of Vatavyadhi. In the present cases, based on the symptoms observed in patients, it can be considered under the category of Pangu. Objectives: By considering Pangu is manifested from vitiated Vata dosha in combination with other Dosha and presents with symptoms of reduced strength in bilateral lower limb and abnormal gait. An attempt has been made to evaluate the efficacy of Panchakarma procedures in the conservative management of the disease. Method: Two cases of HSP presented with symptoms of difficulty in walking, weakness in bilateral lower limb along with stiffness managed with Dashamoola Kashaya seka, Shastikashalipinda sweda, Balavarnakara basti in Kalabasti pattern. Results: The patient was assessed based on sign and symptoms of HSP. Conclusion: Panchakarma treatment having encouraging results in improving quality of life of patients.

Adult-onset combined oxidative phosphorylation deficiency type 14 manifests as epileptic status: a new phenotype and literature review

BackgroundCombined oxidative phosphorylation deficiency (COXPD) is a severe disorder with early onset and autosomal recessive inheritance, and has been divided into 51 types (COXPD1–COXPD51). COXPD14 is caused by a mutation in the FARS2 gene, which encodes mitochondrial phenylalanyl-tRNA synthetase (mt-PheRS), an enzyme that transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, an increasing number of FARS2 variations have been subsequently identified, which present three main phenotypic manifestations: early onset epileptic encephalopathy, hereditary spastic paraplegia, and juvenile-onset epilepsy. To our knowledge, no adult cases have been reported in the literature.MethodsWe report in detail a case of genetically confirmed COXPD14 and review the relevant literature.ResultsApproximately 58 subjects with disease-causing variants of FARS2 have been reported, including 31 cases of early onset epileptic encephalopathy, 16 cases of hereditary spastic paraplegia, 3 cases of juvenile-onset epilepsy, and 8 cases of unknown phenotype. We report a case of autosomal recessive COXPD14 in an adult with status epilepticus as the only manifestation with a good prognosis, which is different from that in neonatal or infant patients reported in the literature. c.467C > T (p.T156M) has been previously reported, while c.119_120del (p.E40Vfs*87) is novel, and, both mutations are pathogenic.ConclusionsThis case of autosomal recessive COXPD14 in an adult only presented as status epilepticus, which is different from the patients reported previously. Our study expands the mutation spectrum of FARS2, and we tended to define the phenotypes based on the clinical manifestation rather than the age of onset.

Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review

Introduction: In human genetic disorders, copy number variations (CNVs) are considered a considerable underlying cause. CNVs are generally detected by array-based methods but can also be discovered by read-depth analysis of whole-exome sequencing (WES) data. We performed WES-based CNV identification in a cohort of 35 Iranian families with hereditary spastic paraplegia (HSP) patients. Methods: Thirty-five patients whose routine single-nucleotide variants (SNVs) and insertion/deletion analyses from exome data were unrevealing underwent a pipeline of CNV analysis using the read-depth detection method. Subsequently, a comprehensive search about the existence of CNVs in all 84 known HSP-causing genes was carried out in all reported HSP cases, so far. Results and Discussion: CNV analysis of exome data indicated that 1 patient harbored a heterozygous deletion in exon 17 of the SPAST gene. Multiplex ligation-dependent probe amplification analysis confirmed this deletion in the proband and his affected father. Literature review demonstrated that, to date, pathogenic CNVs have been identified in 30 out of 84 HSP-causing genes (∼36%). However, CNVs in only 17 of these genes were specifically associated with the HSP phenotype. Among them, CNVs were more common in L1CAM, PLP1, SPAST, SPG7, SPG11, and REEP1 genes. The identification of the CNV in 1 of our patients suggests that WES allows the detection of both SNVs and CNVs from a single method without additional costs and execution time. However, because of intrinsic issues of WES in the detection of large rearrangements, it may not yet be exploited to replace the CNV detection methods in standard clinical practice.

Deletion of Transferrin Receptor 1 in Parvalbumin Interneurons Induces a Hereditary Spastic Paraplegia-Like Phenotype.

Hereditary spastic paraplegia (HSP) is a severe neurodegenerative movement disorder, the underlying pathophysiology of which remains poorly understood. Mounting evidence has suggested that iron homeostasis dysregulation can lead to motor function impairment. However, whether deficits in iron homeostasis are involved in the pathophysiology of HSP remains unknown. To address this knowledge gap, we focused on parvalbumin-positive (PV+) interneurons, a large category of inhibitory neurons in the central nervous system, which play a critical role in motor regulation. The PV+ interneuron-specific deletion of the gene encoding transferrin receptor 1 (TFR1), a key component of the neuronal iron uptake machinery, induced severe progressive motor deficits in both male and female mice. In addition, we observed skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of HSP-related proteins in male mice with Tfr1 deletion in the PV+ interneurons. These phenotypes were highly consistent with the core clinical features of HSP cases. Furthermore, the effects on motor function induced by Tfr1 ablation in PV+ interneurons were mostly concentrated in the dorsal spinal cord; however, iron repletion partly rescued the motor defects and axon loss seen in both sexes of conditional Tfr1 mutant mice. Our study describes a new mouse model for mechanistic and therapeutic studies relating to HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons and its role in the regulation of motor functions.SIGNIFICANCE STATEMENT Iron is crucial for neuronal functioning. Mounting evidence suggests that iron homeostasis dysregulation can induce motor function deficits. Transferrin receptor 1 (TFR1) is thought to be the key component in neuronal iron uptake. We found that deletion of Tfr1 in parvalbumin-positive (PV+) interneurons in mice induced severe progressive motor deficits, skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of hereditary spastic paraplegia (HSP)-related proteins. These phenotypes were highly consistent with the core clinical features of HSP cases and partly rescued by iron repletion. This study describes a new mouse model for the study of HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons.

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.

A Rare Case of Hereditary Spastic Paraplegia 46 With Novel Compound Heterozygous GBA2 gene variants (P3-8.013)

<h3>Objective:</h3> To present a case of Hereditary Spastic Paraplegia (HSP) 46 with distinct imaging and clinical findings, with two novel variants in <i>GBA2</i>, previously classified as variants of undetermined significance (VUS). <h3>Background:</h3> HSP is an uncommon cause of lower extremity spasticity and weakness. There have been many genetic etiologies identified with various clinical features. HSP 46 is an autosomal recessive, slowly progressive form of HSP caused by biallelic pathogenic variants in <i>GBA2</i>. <h3>Design/Methods:</h3> NA (Case report) <h3>Results:</h3> A 21-year-old man presented with progressive lower extremity weakness and ambulatory dysfunction. Symptom onset was in second grade, when he was found to have difficulty walking and inversion of the right foot. His ambulatory dysfunction continued to progress. Extensive serologic testing was negative, as was MRI of his spinal cord. Brain MRI demonstrated thinning of the corpus collosum. Examination approximately 12 years after his initial presentation was notable for diffuse hyperreflexia, bilateral lower extremity spasticity, and bilateral Hoffmann and Babinski signs. He had excessive lower extremity circumduction in swing phase, hyperextension at the knees, and internal rotation at the hips; consistent with a scissoring gait. There were no cranial neuropathies, sensory deficits, or cerebellar ataxia. The family history was negative. Genetic testing via whole-exome sequencing demonstrated compound heterozygous <i>GBA2</i> variants, both classified as VUS: c.1820 A&gt;G (p.N607S) and c.472 G&gt;A (p.G158R). <h3>Conclusions:</h3> Considering the distinctive clinical features, MRI finding of dysgenesis of the corpus collosum, and absence of an alternative explanation, we propose that the GBA2 variants found in this patient may be causative. Functional studies and/or messenger ribonucleic acid sequencing may confirm our hypothesis. <b>Disclosure:</b> Dr. Gill has nothing to disclose. Dr. Gill has nothing to disclose. Madeline Williamson has nothing to disclose. Dr. Avila has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam Pharmaceuticals. Dr. Avila has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alnylam Pharmaceuticals. Dr. Avila has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Akcea Therapeutics.

Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia.

NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene-based splicing assay, RT-PCR analysis on the patients' RNA, and cell-based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3' end of NIPA1 exon 3 near the exon-intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent-onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis

BackgroundHereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype–phenotype associations in HSP with a focus on movement disorders.MethodsWe performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder.ResultsThe HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5).ConclusionThis systematic IPD-level meta-analysis provides the largest data on genotype–phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.

Adult-Onset Hereditary Spastic Paraplegia 15 in a Saudi Patient with A Compound Heterozygous Variant in the ZFYVE26Gene.

Hereditary spastic paraplegia (HSP) 15 is an autosomal recessive neurodegenerative disease caused by homozygous or heterozygous point mutations in the ZFYVE26 gene that encodes the spastizin protein, located on chromosome 14q22-q24. Hereditary spastic paraplegia has been rarely reported in Saudi Arabia. In this article, we reported a rare case of adult-onset HSP 15 with a pure form of the disease in a Saudi patient with a compound heterozygous variant in the ZFYVE26 gene. The present case suggests that a compound heterozygous mutation in the ZFYVE26 may be associated with a later-onset disease and a milder phenotype. Given the low prevalence of the disease as well as heterogenicity and variability of its presenting symptoms, HSP 15 may be difficult to diagnose. However, early diagnosis is important to prevent unnecessary extensive investigations, facilitate early symptomatic management and provide genetic counseling for family planning to those affected and their first and second-degree relatives.

Hereditary spastic paraplegia due to NIPA1 gene mutation: Case report

Introduction: Hereditary spastic paraplegia (HSP) is the term for a group of neurological disorders characterized by progressive spasticity and muscle weakness in the lower limbs. Its etiology is genetic and has been associated with mutations in more than 60 genes. HSP is rare and may be useful in the differential diagnosis of cerebral palsy. Case presentation: 16-year-old male with a diagnosis of HSP due to mutation of the NIPA1 gene:c.316G&gt;A (p. Gly106arg), which corresponds to HSP type 6 (SPG6). The patient presented with clinical signs of progressive upper motor neuron syndrome in the lower limbs, such as spasticity, hyperreflexia and paraparesis, associated with focal onset seizures diagnosed at age 11 and successfully treated with valproic acid. Spasticity treatment was complex and included oral baclofen, intraoperative botulinum toxin, physical therapy, and multilevel orthopedic surgery for the management of musculoskeletal deformities. Conclusion: This is a rare case of complex HSP, associated with epilepsy, due to the mutation of the NIPA1 gene (SPG6), the most common pathogenic variant within this type of mutation. The present case demonstrates the importance of making an early diagnosis of GSP6 to perform timely interventions in these patients, prevent complications, and avoid a higher level of disability.

Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature

BackgroundHereditary spastic paraplegia (HSP) encompasses several rare genetic disorders characterized by progressive lower extremity spasticity and weakness caused by corticospinal tract degeneration. Published literature on genetically confirmed pediatric HSP cases is limited. MethodsWe conducted a retrospective review of childhood-onset HSP cases followed in the neuromuscular clinics at Children's and Emory Healthcare in Atlanta. Clinical presentation, family history, examination, electrodiagnostic data, neuroimaging, genetic test results, comorbidities, and treatment were recorded. ResultsSixteen patients with HSP (eight males, eight females) with a mean age 19 years ± 15.7 years were included. Ten patients (66%) presented with gait difficulty. Seven (44%) were ambulatory at the last clinic follow-up visit with an average disease duration of 7.4 years. Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1), SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1). Symptom onset to genetic confirmation on an average was 8.2 years. Sensory motor axonal polyneuropathy was found in seven patients, and two exhibited cerebellar atrophy on magnetic resonance imaging (MRI) of the brain. Neurological comorbidities included developmental delay (n = 9), autism (n = 5), epilepsy (n = 3), and attention-deficit/hyperactivity disorder (n = 2). ConclusionsIn our study, a significant proportion (70%) of subjects with childhood-onset HSP had comorbid neurocognitive deficits, polyneuropathy with or without neuroimaging abnormalities, and rare genetic etiology. Genetic diagnosis was established either through inherited genetic neuropathy panel or whole-exome sequencing, which supports the utility of whole-exome sequencing in aiding in HSP diagnosis.

A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neuropathies affecting upper motor neurons and causing progressive gait disorder. Mutations in the gene SPG3A/atlastin-1 (ATL1), encoding a dynamin superfamily member, which utilizes the energy from GTP hydrolysis for membrane tethering and fusion to promote the formation of a highly branched, smooth endoplasmic reticulum (ER), account for approximately 10% of all HSP cases. The continued discovery and characterization of novel disease mutations are crucial for our understanding of HSP pathogenesis and potential treatments. Here, we report a novel disease-causing, in-frame insertion in the ATL1 gene, leading to inclusion of an additional asparagine residue at position 417 (N417ins). This mutation correlates with complex, early-onset spastic quadriplegia affecting all four extremities, generalized dystonia, and a thinning of the corpus callosum. We show using limited proteolysis and FRET-based studies that this novel insertion affects a region in the protein central to intramolecular interactions and GTPase-driven conformational change, and that this insertion mutation is associated with an aberrant prehydrolysis state. While GTPase activity remains unaffected by the insertion, membrane tethering is increased, indicative of a gain-of-function disease mechanism uncommon for ATL1-associated pathologies. In conclusion, our results identify a novel insertion mutation with altered membrane tethering activity that is associated with spastic quadriplegia, potentially uncovering a broad spectrum of molecular mechanisms that may affect neuronal function.

SPTAN1 variants likely cause autosomal recessive complicated hereditary spastic paraplegia.

Heterozygous mutations in SPTAN1 are associated with a broad phenotypical spectrum ranging from axonal neuropathy phenotypes to neurodevelopmental phenotypes with or without epilepsy. Recently, biallelic mutations in SPTAN1 were reported as a potential cause of autosomal recessive pure hereditary spastic paraplegia (HSP). However, no further HSP cases with biallelic SPTAN1 mutations have been reported. Herein, we report the clinical and genetic findings of a patient with complicated HSP likely caused by a novel homozygous SPTAN1 mutation. A patient with complicated HSP from a consanguineous family was recruited. The proband underwent detailed neurological examinations. Homozygosity mapping was performed in the proband and her healthy sister. Whole exome sequencing was performed in the proband. Our patient had early onset motor symptoms with upper motor neuron paralysis and intellectual disability, which is compatible with complicated HSP. Genetic analysis identified a rare homozygous missense mutation in SPTAN1 (c.4162A>G, p.I1388V), which was predicted to be deleterious by in silico tools. Her healthy parents and sister all carried the heterozygous mutation. Our results provided further support for the association of biallelic SPTAN1 variants with HSP and suggested that screening for the SPTAN1 gene should be considered not only in patients with pure HSP but also in patients with complicated HSP.

A Rare Case of Hereditary Spastic Paraplegia: Case Report and Literature Review

Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disorder presenting as lower limb spasticity having two clinical types and various modes of inheritance. A young male patient presented with bilateral lower limb weakness of one-year duration showing both sensory and motor abnormalities on examination. MRI of brain and spine done as part of workup revealed marked atrophy of anterior corpus callosum with abnormal signal intensity at tips of frontal horns of ventricles mimicking the appearance of the ear of a Eurasian lynx. No other abnormality was encountered in the brain or spinal cord in our case. Other imaging abnormalities which can be encountered in such a case include periventricular and central white matter changes as well as spinal cord atrophy. Pathologically this condition is recognised by degeneration of lateral and posterior columns of the spinal cord. The differential diagnosis includes structural, metabolic, neurodegenerative, motor and nutritional deficiency disorders.

Diagnostic Approach to the Suspected Cases of Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) is a heterogeneous group of monogenic neurodegenerative disorders characterized by progressive spasticity of the lower limbs. The clinical features and imaging abnormalities vary greatly according to the affected genes. HSP is classified clinically as pure and complex forms, depending upon the presence or absence of additional neurological defects other than spastic lower limbs. Despite the recent advances in next-generation sequencing technology and its wide availability, a genetic diagnosis of HSP is still not made in more than half of all suspected cases of HSP. In this review, we summarized the various phenotypes of relatively common HSP in clinical practice according to the inheritance pattern, highlighting their clinical, radiological, and neurophysiological features. We further discussed the practical approach to patients with suspected HSP in the current era of next-generation sequencing. Keywords: Spastic paraplegia, hereditary, Diagnosis

Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia.

ObjectiveDespite the need for diagnostics and research, data on fluid biomarkers in hereditary spastic paraplegia (HSP) are scarce. We, therefore, explore Neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of patients with hereditary spastic paraplegia and provide information on the influence of demographic factors.MethodsThe study recruited 59 HSP cases (33 genetically confirmed) and 59 controls matched in age and sex. Neurofilament light chain levels were assessed by enzyme‐linked immunosorbent assay. The statistical analysis included the effects of age, sex, and genetic status (confirmed vs. not confirmed).ResultsLevels of CSF NfL were significantly increased in patients with hereditary spastic paraplegia compared to controls (median 741 pg/mL vs. 387 pg/mL, p < 0.001). Age (1.4% annual increase) and male sex (81% increase) impacted CSF NfL levels in patients. The age‐dependent increase of CSF NfL levels was steeper in controls (2.6% annual increase). Thus, the CSF NfL ratio of patients and matched controls—expressing patients’ fold increases in CSF NfL—declined considerably with age.InterpretationCSF NfL is a reliable cross‐sectional biomarker in hereditary spastic paraplegia. Sex is a relevant factor to consider, as male patients have remarkably higher CSF NfL levels. While levels also increase with age, the gap between patients and controls is narrowing in older subjects. This indicates distinct temporal dynamics of CSF NfL in patients with hereditary spastic paraplegia, with a rise around phenotypic conversion and comparatively static levels afterward.

Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder, characterized by lower-limb spasticity and weakness. To date, more than 82 loci/genes (SPG1-SPG82) have been identified that contribute to the cause of HSP. Despite the use of next-generation sequencing-based methods, genetic-analysis has failed in the finding of causative genes in more than 50% of HSP patients, indicating a more significant heterogeneity and absence of a given phenotype-genotype correlation. Here, we performed whole-exome sequencing (WES) to identify HSP-causing genes in three unrelated-Iranian probands. Candidate variants were detected and confirmed in the probands and co-segregated in the family members. The phenotypic data gathered and compared with earlier cases with the same sub-types of disease. Three novel homozygous variants, c.978delT; p.Q327Kfs*39, c.A1208G; p.D403G and c.3811delT; p.S1271Lfs*44, in known HSP-causing genes including ENTPD1, CYP7B1, and ZFYVE26 were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in CYP7B1 and ZFYVE26 are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in ENTPD1 are related to SPG64 which is an ultra-rare form of HSP. The research affirmed more complexities of phenotypic manifestations and allelic heterogeneity in HSP. Due to these complexities, it is not feasible to show a clear phenotype-genotype correlation in HSP cases. Identification of more families with mutations in HSP-causing genes may help the establishment of this correlation, further understanding of the molecular basis of the disease, and would provide an opportunity for genetic-counseling in these families.

Autosomal Recessive Hereditary Spastic Paraplegia: A Rare Case of a Family with Phenotypic Variation

Background: Hereditary spastic paraplegia is a neurodegenerative disorder with a pure and complex form. More than 50 genetic types are currently known, with different ages of onset for characteristic symptoms. Data regarding hereditary spastic paraplegia remain scarce, and the rare subtype of spastic paraplegia type 5 is no exception. Objective: This report presents data regarding the case of a single family, from the city of Djerba, with five individuals affected with hereditary spastic paraplegia, the largest number of spastic paraplegia type 5 mutated family members so far reported in current literature. Methods: To emphasize the importance of genetic testing, we retrospectively reviewed a familial confirmed case of hereditary spastic paraplegia. Clinical features of family members were described. Results: The family presents a large phenotypic variation that, in part, differs from the known phenotypic presentations. Age of onset and clinical manifestation showed interfamilial variations. The alteration found in CYP7B1 (c.1081C&gt;T; p.R361*) may help emphasize the importance of genetic testing and the much-needed treatment options already in use in current neurological practice. Conclusion: The understanding of the molecular pathways of hereditary spastic paraplegia, together with the establishment of disease biomarkers, will hopefully lead to better and more personalized treatment.