A Complex Phenotype of a Patient with Spastic Paraplegia Type 4 Caused by a Novel Pathogenic Variant in the SPAST Gene

Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by degeneration of the corticospinal tract. Among the 79 causative genes involved in HSPs, variants in SPAST on chromosome 2p22, which encodes the microtubule-severing protein spastin, are responsible for spastic paraplegia type 4 (SPG4), the most common form of HSPs. SPG4 is characterized by a clinically pure phenotype that is associated with restricted involvement of the corticospinal tract; however, it is often accompanied by additional neurological symptoms such as epilepsy and cognitive impairment. There are few reports regarding the clinical course and treatment of epilepsy associated with SPG4. We describe a 21-year-old male patient with progressive weakness and spasticity of the lower limbs since infancy, which was complicated by epilepsy and cognitive impairment. Magnetic resonance imaging of the brain showed right hippocampal atrophy before the onset of epilepsy. Genetic analysis revealed a novel missense variant (NM_014946.4:c.1330G>C, p.Asp444His) in the SPAST gene. At the age of 13, the patient developed focal epilepsy, characterized by focal onset seizures that were preceded by a sensation of chest tightness. Carbamazepine, levetiracetam, and zonisamide were ineffective in controlling the seizures; however, the use of lacosamide in combination with lamotrigine and valproate was highly effective in improving the seizure symptoms and led to the patient being seizure free for at least 2 years. In conclusion, the missense variant in SPAST may cause a complex SPG4 phenotype accompanied by epilepsy and cognitive impairment, suggesting that the clinical manifestations of this condition do not confine to the motor system.

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Hereditary spastic paraplegia: An “ears of the lynx” magnetic resonance imaging sign in a patient with recessive genetic type 11

The Neuroradiology Journal ◽

10.1177/1971400920953820 ◽

2020 ◽

pp. 197140092095382

Author(s):

Emiliano Ruiz Romagnoli ◽

Manuel Perez Akly ◽

Luis A Miquelini ◽

Jorge A Funes ◽

Cristina H Besada

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Corpus Callosum ◽

Hereditary Spastic Paraplegia ◽

Brain Magnetic Resonance Imaging ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Resonance Imaging ◽

Hereditary Spastic Paraplegias ◽

Monogenic Diseases

Hereditary spastic paraplegias are an uncommon group of monogenic diseases that include 79 types of genetic disorders. The most frequent cause of recessive hereditary spastic paraplegia is a mutation in the spastic paraplegia gene type 11 followed by type 15. This group is usually associated with non-specific clinical features like cognitive decline and may precede the progressive weakness and spasticity of lower limbs. The magnetic resonance imaging hallmark of hereditary spastic paraplegia is thinning of the spinal cord. However, brain magnetic resonance imaging may provide relevant clues for specific hereditary spastic paraplegia subtypes, and thinning of the corpus callosum has been described as the most frequent abnormality in almost one-third of recessive hereditary spastic paraplegias. Moreover, a characteristic abnormality affecting the forceps minor of the corpus callosum has been recently reported as the “ears of the lynx” sign and is highly suggestive of type 11 and 15 hereditary spastic paraplegias. We report a patient who was diagnosed with hereditary spastic paraplegia type 11 by exome genetic testing, presenting the ears of the lynx sign in the first magnetic resonance imaging assessment.

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Chinese patients with hereditary spastic paraplegias (HSPs): a protocol for a hospital-based cohort study

BMJ Open ◽

10.1136/bmjopen-2021-054011 ◽

2022 ◽

Vol 12 (1) ◽

pp. e054011

Author(s):

Yu-Sen Qiu ◽

Yi-Heng Zeng ◽

Ru-Ying Yuan ◽

Zhi-Xian Ye ◽

Jin Bi ◽

...

Keyword(s):

Cohort Study ◽

Disease Progression ◽

Molecular Mechanisms ◽

Cholesterol Metabolism ◽

Clinical Signs ◽

Clinical Manifestations ◽

Lower Limbs ◽

Chinese Patients ◽

Hereditary Spastic Paraplegias ◽

Mri Features

IntroductionHereditary spastic paraplegias (HSPs) are uncommon but not rare neurodegenerative diseases. More than 100 pathogenic genes and loci related to spastic paraplegia symptoms have been reported. HSPs have the same core clinical features, including progressive spasticity in the lower limbs, though HSPs are heterogeneous (eg, clinical signs, MRI features, gene mutation). The age of onset varies greatly, from infant to adulthood. In addition, the slow and variable rates of disease progression in patients with HSP represent a substantial challenge for informative assessment of therapeutic efficacy. To address this, we are undertaking a prospective cohort study to investigate genetic–clinical characteristics, find surrogates for monitoring disease progress and identify clinical readouts for treatment.Methods and analysisIn this case-control cohort study, we will enrol 200 patients with HSP and 200 healthy individuals in parallel. Participants will be continuously assessed for 3 years at 12-month intervals. Six aspects, including clinical signs, genetic spectrum, cognitive competence, MRI features, potential biochemical indicators and nerve electrophysiological factors, will be assessed in detail. This study will observe clinical manifestations and disease severity based on different molecular mechanisms, including oxidative stress, cholesterol metabolism and microtubule dynamics, all of which have been proposed as potential treatment targets or modalities. The analysis will also assess disease progression in different types of HSPs and cellular pathways with a longitudinal study using t tests and χ2 tests.Ethics and disseminationThe study was granted ethics committee approval by the first affiliated hospital of Fujian Medical University (MRCTA, ECFAH of FMU (2019)194) in 2019. Findings will be disseminated via presentations and peer-reviewed publications. Dissemination will target different audiences, including national stakeholders, researchers from different disciplines and the general public.Trial registration numberNCT04006418.

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Hereditary Spastic Paraplegia Mimicking Cerebral Palsy-Heterozygous Mutation in ALDH18A1

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2021/49813.15390 ◽

2021 ◽

Author(s):

Amit S Vatkar ◽

Nisha Dolas ◽

Vedashree Deshpande ◽

Pallavi Wadhawan ◽

Mumtaz Sharif

Keyword(s):

Cerebral Palsy ◽

Neurodegenerative Disorders ◽

Birth Asphyxia ◽

Lower Limbs ◽

Heterozygous Mutation ◽

Spastic Diplegia ◽

Spastic Paraplegia ◽

Hereditary Spastic Paraplegias ◽

History Of ◽

One Year

Spastic paraplegias are characterised by progressive rigidity and weakness of the lower limbs. Spastic paraplegia is a standard differential diagnosis for spastic diplegic cerebral palsy. Hereditary Spastic Paraplegias (HSP) are genetically and clinically heterogeneous group of neurodegenerative disorders causing paraplegias. Eighty forms of HSP have been noted and 64 genes have been identified. The Aldehyde Dehydrogenase 18 family member A1 (ALDH18A1) gene is located at 10q24.1 and it encodes delta-1-Pyrroline-5-Carboxylate Synthetase (P5CS), a mitochondrial bifunctional enzyme which is used for catalysing various amino acids. Mutations in this gene causes P5CS deficiency, which is responsible for neurodegenerative diseases. One should suspect neurometabolic conditions when no definite history of birth asphyxia is present in a case of cerebral palsy. Hereby, the authors report a case of a one-year-old male child with heterozygous mutation in ALDH18A1 gene resulting in spastic diplegia.

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Hereditary spastic paraplegia-a differential for spastic paraplegia in children

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20205526 ◽

2020 ◽

Vol 8 (1) ◽

pp. 182

Author(s):

Niharika Shetty ◽

Sahana Devadas ◽

Mallesh Kariappa

Keyword(s):

Genetic Analysis ◽

Clinical Examination ◽

Neurodegenerative Disorders ◽

Hereditary Spastic Paraplegia ◽

Adult Life ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Mri Brain ◽

Progressive Weakness ◽

Rule Out

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders with familial origin mainly affecting the lower limbs. It has a prevalence of 3-10/100,000. The diagnosis is by symptomatology, clinical examination and neuroimaging to rule out other causes of spastic paraplegia. The diagnosis is confirmed by genetic analysis. Since this disorder is slowly progressive with nonspecific MRI brain findings the diagnosis can be delayed with delay in the start of rehabilitation measures. This disorder is usually diagnosed in the adult life and the literature has very few cases of paediatric HSP and hence we are reporting a case of HSP. Here we present the case of two siblings who presented to us with progressive weakness of both the lower limbs.

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Clinical-anamnestic analysis of the course and treatment of benign and borderline epithelial ovarian tumors

HEALTH OF WOMAN ◽

10.15574/hw.2016.115.86 ◽

2016 ◽

pp. 86-93

Author(s):

M.Yu. Yegorov ◽

◽

A.A. Sukhanova ◽

Keyword(s):

Varicose Veins ◽

Clinical Manifestations ◽

Abnormal Uterine Bleeding ◽

Abdominal Distension ◽

Ovarian Tumors ◽

Lower Limbs ◽

Benign Tumors ◽

Age Group ◽

Venous Disorders ◽

Serous Tumors

The objective: study the features of gynecological, physical history, diagnosis and treatment of patients with benign epithelial ovarian tumors (BeEOT) and borderline epithelial ovarian tumors (BEOT), determining the frequency of recurrence of ovarian tumors in the postoperative period. Patients and methods. According to a retrospective analysis of case histories of 112 women with epithelial ovarian tumors (EOT) underwent conservative or radical surgical treatment in a hospital, two groups were formed: I group – patients with benign epithelial ovarian tumors (BeEOT), which amounted to 85 (75.9%) women, and group II – patients with borderline epithelial ovarian tumors (BEOT), which amounted to 27 (24.1%) women. It was found that the main complaints of patients with EOT were pain (49.1%), abdominal distension (17%), and abnormal uterine bleeding (12.5%). The highest incidence of BeEOT (31.8%) observed in the age group of 41–50 years, while the peak incidence of BEOT (44.4%) corresponds to the age group of 51–60 years. Results. In BEOT endocrine pathology occurs significantly more frequently (p<0.05) than in BeEOT – 25.9% vs. 9.4%, respectively. Pathology of pancreatic-hepatobiliary system occurs significantly more frequently (p<0.05) in patients with BEOT compared with BeEOT – 81.5% versus 57.6%, respectively. Venous disorders (varicose veins of the pelvic organs, lower limbs, haemorrhoids) observed in BEOT significantly more frequently (p<0.05) than in BeEOT – 18.5% vs. 5.9%, respectively. EOT most often diagnosed in the period from 1 to 6 months after the first clinical manifestations with an average uptake of medical care 4.6±0.57 months. In assessing of peritoneal exudate cytogram the mesothelium cells are significantly more common for BeEOT (p<0.01) than BEOT – 79.4% versus 40.9%, respectively. Cervicitis is more likely significantly to occur in BeEOT (p<0.01) than in BEOT – 29.4% vs. 7.4%, respectively. The most common histological type among the benign tumors of the ovaries are endometriomas, which occurred in 48.2% of all BeEOT cases, and among the borderline tumors – serous tumors, which accounted for 59.3% of all BEOTs. Conclusion. The use of organ sparing surgery in EOT increases the risk of recurrence, especially in the case of endometrial histology or borderline variant of tumor. Key words: benign and borderline epithelial ovarian tumors, clinical-anamnestic analysis, diagnosis, treatment.

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Vitiligo: An Updated Narrative Review

Current Pediatric Reviews ◽

10.2174/1573396316666201210125858 ◽

2020 ◽

Vol 16 ◽

Author(s):

Alexander K. C. Leung ◽

Joseph M. Lam ◽

Kin Fon Leong ◽

Kam Lun Hon

Keyword(s):

Present Article ◽

English Literature ◽

Disease Onset ◽

Clinical Manifestations ◽

Calcineurin Inhibitors ◽

Ultraviolet B ◽

Lower Limbs ◽

Treatment Modalities ◽

Topical Corticosteroids ◽

Topical Calcineurin Inhibitors

Background: Vitiligo is a relatively common acquired pigmentation disorder that can cause significant psychological stress and stigmatism. Objective: This article aims to familiarize physicians with the clinical manifestations, evaluation, diagnosis, and management of vitiligo. Methods: A Pubmed search was conducted in Clinical Queries using the key term "vitiligo". The search included metaanalyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to the English literature. The information retrieved from the above search was used in the compilation of the present article. The information retrieved from the above search was used in the compilation of the present article. Results: Approximately one quarter of patients with vitiligo have the onset before 10 years of age. Genetic, immunological, neurogenic and environmental factors may have a role to play in the pathogenesis. Vitiligo typically presents as acquired depigmented, well-demarcated macules/patches that appear milk- or chalk-white in color. Lesions tend to increase in number and enlarge centrifugally in size with time. Sites of predilection include the face, followed by the neck, lower limbs, trunk, and upper limbs. The clinical course is generally unpredictable. In children with fair skin, no active treatment is usually necessary other than the use of sunscreens and camouflage cosmetics. If treatment is preferred for cosmesis, topical corticosteroids, topical calcineurin inhibitors, and narrowband ultraviolet B phototherapy are the mainstays of treatment. Conclusion: The therapeutic effect of all the treatment modalities varies considerably from individual to individual. As such, treatment must be individualized. In general, the best treatment response is seen in younger patients, recent disease onset, darker skin types, and head and neck lesions. Topical corticosteroids and calcineurin inhibitors are the treatment of choice for those with localized disease. Topical calcineurin inhibitors are generally preferred for lesions on genitalia, intertriginous areas, face, and neck. Narrowband ultraviolet B phototherapy should be considered in patients who have widespread vitiligo or those with localized vitiligo associated with a significant impact on the quality of life who do not respond to treatment with topical corticosteroids and calcineurin inhibitors.

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

Human Genome Variation ◽

10.1038/s41439-021-00153-x ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Takuya Morikawa ◽

Shiroh Miura ◽

Takahisa Tateishi ◽

Kazuhito Noda ◽

Hiroki Shibata

Keyword(s):

Molecular Diagnosis ◽

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Family Members ◽

Pathogenic Variant ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Nonsynonymous Variant ◽

Japanese Family ◽

Functional Variants

AbstractSpastic 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.

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Regional abnormality of functional connectivity is associated with clinical manifestations in individuals with intractable focal epilepsy

Scientific Reports ◽

10.1038/s41598-021-81207-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yasuo Nakai ◽

Hiroki Nishibayashi ◽

Tomohiro Donishi ◽

Masaki Terada ◽

Naoyuki Nakao ◽

...

Keyword(s):

Functional Connectivity ◽

Focal Epilepsy ◽

Clinical Manifestations ◽

Eigenvector Centrality ◽

Functional Connections ◽

Duration Of Illness ◽

Healthy Control ◽

Matched Data ◽

Clinical Conditions ◽

Age And Sex

AbstractWe explored regional functional connectivity alterations in intractable focal epilepsy brains using resting-state functional MRI. Distributions of the network parameters (corresponding to degree and eigenvector centrality) measured at each brain region for all 25 patients were significantly different from age- and sex-matched control data that were estimated by a healthy control dataset (n = 582, 18–84 years old). The number of abnormal regions whose parameters exceeded the mean + 2 SD of age- and sex-matched data for each patient were associated with various clinical parameters such as the duration of illness and seizure severity. Furthermore, abnormal regions for each patient tended to have functional connections with each other (mean ± SD = 58.6 ± 20.2%), the magnitude of which was negatively related to the quality of life. The abnormal regions distributed within the default mode network with significantly higher probability (p < 0.05) in 7 of 25 patients. We consider that the detection of abnormal regions by functional connectivity analysis using a large number of control datasets is useful for the numerical assessment of each patient’s clinical conditions, although further study is necessary to elucidate etiology-specific abnormalities.

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Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Current Neurology and Neuroscience Reports ◽

10.1007/s11910-021-01099-x ◽

2021 ◽

Vol 21 (4) ◽

Author(s):

Lydia Saputra ◽

Kishore Raj Kumar

Keyword(s):

Genetic Diagnosis ◽

Spastic Paraplegia ◽

Limb Weakness ◽

Hereditary Spastic Paraplegias ◽

Gene Testing ◽

Testing Strategies ◽

Whole Exome ◽

The Right ◽

Gene Panels ◽

High Degree

Abstract Purpose of Review The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP. Recent Findings There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Summary Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

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Anxiety prevalence in coexisting alzheimer’s and thyroid pathology

European Psychiatry ◽

10.1016/s0924-9338(11)71869-7 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 158-158

Author(s):

I. Ioancio ◽

R. Trascu ◽

I. Turcu ◽

L. Spiru

Keyword(s):

Cognitive Impairment ◽

Anxiety Disorder ◽

Alzheimer Disease ◽

Thyroid Function ◽

Thyroid Disease ◽

Clinical Manifestations ◽

Cognitive Disorders ◽

Thyroid Disorder ◽

Thyroid Pathology ◽

Normal Thyroid Function

BackgroundAlzheimer disease (AD) is one of the most common neurodegenerative disorders (prevalence boosts from 0.2% in patients aged 55-65 up to 27% in patients aged 85+ years. Clinical manifestations of psychiatric disorders accompanying hypo- and hyper-thyroid function can mimic cognitive impairment.ObjectivesOur study aimed at studying the relationship between thyroid pathology, anxiety disorder and Alzheimer disease (AD).MethodsOur longitudinal, prospective research followed 49 patients with thyroid disorders (aged 50-85 years, 93.5 females); 63.3% (n = 31) had coexisting dementia and thyroid disease while 36.7% (n = 18) were dementia-cleared (10 had mild cognitive impairment (MCI) and 8 - anxiety and/or depression); we cross/analyzed control (n = 18) and target (n = 31) groups.ResultsIn the target group, 64.5% (n = 20) had hypothyroidism, 22.6% (n = 7) had euthyroid function and 12.9% (n = 4) had hyperthyroidism. The prevalence of anxiety and depression was higher in the hypothyroidism + dementia group (55.5%, n = 11) than in the hypothyroidism-only group (44.4%, n = 8). Most controls (77.8%, n = 14) had hypothyroidism while 22% (n = 4) had normal thyroid function.ConclusionsAnxiety disorder had a greater prevalence both in the group with dementia + thyroid disease and in the MCI group. Hypothyroidism was the dominant thyroid disorder in both groups. The early diagnostic and treatment of thyroid disease is expected to improve prognosis and evolution of future cognitive disorders (MCI & AD).

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