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INTRODUCTION: Mutations in JAM2 have been linked to ~ 2% of primary familial brain calcification (PFBC) cases. PFBC is a rare neurological disorder characterized by excessive calcium deposition in the brain. It causes movement disorders and psychiatric problems. Six other genes were identified as causing PFBC. However, the genetic basis of ~ 50% of PFBC cases remains unknown. This study presented the results of a comprehensive analysis of five unrelated Iranian PFBC families. METHODS: Clinical and paraclinical features of all patients were recorded. Whole-exome sequencing (WES) was done on the DNAs of probands. Data was analyzed, and haplotypes were determined. RESULTS: WES identified two homozygous variants in JAM2 across four families: a novel variant, c.426dup:p.Ser143Leufs*23, in one family and a known mutation, c.685C > T:p.Arg229*, in the remaining three families. Haplotype analysis using six intragenic single-nucleotide polymorphisms (SNPs) in JAM2 revealed an identical haplotype in probands who carried the same mutation, whereas two other probands presented diverse haplotypes. CONCLUSION: Based on our results, p.Arg229* may be a founder mutation in the Iranian population. The variant has been detected in two out of seven other reported JAM2-related families who may originate from the Middle East and exhibit an identical haplotype. Even though this particular mutation may not be classified as a founder mutation, it does appear to be a hotspot, given that it has been observed in 45% of the 11 JAM2-associated families. Our study expanded the clinical features and mutation spectrum of JAM2 and revealed that mutations in JAM2 may be more common than previously reported.
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Encefalopatias , Calcinose , Linhagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encefalopatias/genética , Calcinose/genética , Moléculas de Adesão Celular/genética , Efeito Fundador , Haplótipos , Irã (Geográfico) , Mutação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course. OBJECTIVES: To estimate the probability of preserving ambulatory ability and survival in NBIA. METHODS: In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods. RESULTS: One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03). CONCLUSIONS: KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death.
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Hemocromatose , Distúrbios do Metabolismo do Ferro , Doenças Neurodegenerativas , Neurodegeneração Associada a Pantotenato-Quinase , Transtornos Parkinsonianos , Humanos , Feminino , Encéfalo , Espasticidade Muscular , Caminhada , FerroRESUMO
BACKGROUND: The unique neurovascular structure of the retina has provided an opportunity to observe brain pathology in many neurological disorders. However, such studies on neurodegeneration with brain iron accumulation (NBIA) disorders are lacking. OBJECTIVES: To investigate NBIA's neurological and ophthalmological manifestations. METHODS: This cross-sectional study was conducted on genetically confirmed NBIA patients and an age-gender-matched control group. The thickness of retinal layers, central choroidal thickness (CCT), and capillary plexus densities were measured by spectral domain-optical coherence tomography (SD-OCT) and OCT angiography, respectively. The patients also underwent funduscopy, electroretinography (ERG), visual evoked potential (VEP), and neurological examination (Pantothenate-Kinase Associated Neurodegeneration-Disease Rating Scale [PKAN-DRS]). The generalized estimating equation model was used to consider inter-eye correlations. RESULTS: Seventy-four patients' and 80 controls' eyes were analyzed. Patients had significantly decreased visual acuity, reduced inner or outer sectors of almost all evaluated layers, increased CCT, and decreased vessel densities, with abnormal VEP and ERG in 32.4% and 45.9%, respectively. There were correlations between visual acuity and temporal peripapillary nerve fiber layer (positive) and between PKAN-DRS score and disease duration (negative), and scotopic b-wave amplitudes (positive). When considering only the PKAN eyes, ONL was among the significantly decreased retinal layers, with no differences in retinal vessel densities. Evidence of pachychoroid was only seen in patients with Kufor Rakeb syndrome. CONCLUSION: Observing pathologic structural and functional neurovascular changes in NBIA patients may provide an opportunity to elucidate the underlying mechanisms and differential retinal biomarkers in NBIA subtypes in further investigations. © 2023 International Parkinson and Movement Disorder Society.
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Doenças Neurodegenerativas , Neurodegeneração Associada a Pantotenato-Quinase , Humanos , Estudos Transversais , Potenciais Evocados Visuais , Retina/diagnóstico por imagem , Retina/patologia , Encéfalo , Doenças Neurodegenerativas/patologia , Tomografia de Coerência Óptica , FerroRESUMO
BACKGROUND: Olfactory dysfunction has been suggested as a diagnostic and discriminative biomarker in some neurodegenerative disorders. However, there are few studies regarding the olfactory status in rare diseases including neurodegeneration with brain iron accumulation (NBIA) disorders. METHODS: Genetically-confirmed NBIA patients were enrolled. Neurological and cognitive examinations were conducted according to the Pantothenate Kinase-Associated Neurodegeneration-Disease Rating Scale (PKAN-DRS) and the Mini-Mental State Examination (MMSE) questionnaire, respectively. Olfaction was assessed in three domains of odor threshold (OT), odor discrimination (OD), odor identification (OI), and total sum (TDI) score by the Sniffin' Sticks test. The olfactory scores were compared to a control group and a normative data set. RESULTS: Thirty-seven patients, including 22 PKAN, 6 Kufor Rakeb syndrome, 4 Mitochondrial membrane Protein-Associated Neurodegeneration (MPAN), 5 cases of other 4 subtypes, and 37 controls were enrolled. The mean PKAN-DRS score was 51.83±24.93. Sixteen patients (55.2%) had normal cognition based on MMSE. NBIA patients had significantly lower olfactory scores compared to the controls in TDI and all three subtests, and 60% of them were hyposmic according to the normative data. Including only the cognitively-normal patients, still, OI and TDI scores were significantly lower compared to the controls. The phospholipase A2-Associated Neurodegeneration (PLAN) and MPAN patients had a significantly lower OI score compared to the cognitively-matched PKAN patients. CONCLUSION: Olfactory impairment as a common finding in various subtypes of NBIA disorder can potentially be considered a discriminative biomarker. Better OI in PKAN compared to PLAN and MPAN patients may be related to the different underlying pathologies.
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Doenças Neurodegenerativas , Transtornos do Olfato , Neurodegeneração Associada a Pantotenato-Quinase , Humanos , Olfato/fisiologia , Neurodegeneração Associada a Pantotenato-Quinase/complicações , Neurodegeneração Associada a Pantotenato-Quinase/diagnóstico , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/etiologia , Encéfalo , Doenças Neurodegenerativas/complicações , Ferro , BiomarcadoresRESUMO
BACKGROUND: Transcranial Sonography is a non-invasive technique that has been used as a diagnostic tool for a variety of neurodegenerative disorders. However, the utility and potential application of this technique in NBIA disorders is scarce and inconclusive. METHODS: In this cross-sectional retrospective case-control study, the echogenicity of Substantia Nigra (SN), Lentiform Nucleus (LN), and Diameter of the Third Ventricle (DTV) were assessed by TCS in genetically confirmed NBIA patients referring to the movement disorder clinic. The normal echogenicity area of SN was defined based on the 90th percentile of an age-and-gender-matched control group. NBIA patients underwent neurologic examination at each visit, but their brain magnetic resonance imaging and demographics were extracted from electronic records. RESULTS: Thirty-five NBIA patients of four subtypes with a mean disease duration of 10.54 years and 35 controls were enrolled. The normally defined SN echogenicity in controls was 0.23 cm2. DTV and SN echogenicity areas were significantly higher in patients compared to the controls (P = 0.002 and < 0.001, respectively). Around 85% and 63% of the patients showed LN and SN hyperechogenicity at least on one side, respectively. Disease duration was positively correlated with DTV (r = 0.422, p = 0.015). Cases with Pantothenate Kinase Associated Neurodegeneration (n = 23) also had significantly higher DTV and SN echogenicity area compared to the controls. CONCLUSION: Despite most NBIA patients displayed increased DVT and higher SN and LN hyperechogenicity than healthy controls, the discriminatory role of TCS on different NBIA subtypes remains to be determined.
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Corpo Estriado , Ultrassonografia Doppler Transcraniana , Humanos , Ultrassonografia Doppler Transcraniana/métodos , Estudos de Casos e Controles , Estudos Transversais , Estudos Retrospectivos , Ultrassonografia , FerroRESUMO
In the NAD biosynthetic network, the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme fuels NAD as a co-substrate for a group of enzymes. Mutations in the nuclear-specific isoform, NMNAT1, have been extensively reported as the cause of Leber congenital amaurosis-type 9 (LCA9). However, there are no reports of NMNAT1 mutations causing neurological disorders by disrupting the maintenance of physiological NAD homeostasis in other types of neurons. In this study, for the first time, the potential association between a NMNAT1 variant and hereditary spastic paraplegia (HSP) is described. Whole-exome sequencing was performed for two affected siblings diagnosed with HSP. Runs of homozygosity (ROH) were detected. The shared variants of the siblings located in the homozygosity blocks were selected. The candidate variant was amplified and Sanger sequenced in the proband and other family members. Homozygous variant c.769G>A:p.(Glu257Lys) in NMNAT1, the most common variant of NMNAT1 in LCA9 patients, located in the ROH of chromosome 1, was detected as a probable disease-causing variant. After detection of the variant in NMNAT1, as a LCA9-causative gene, ophthalmological and neurological re-evaluations were performed. No ophthalmological abnormality was detected and the clinical manifestations of these patients were completely consistent with pure HSP. No NMNAT1 variant had ever been previously reported in HSP patients. However, NMNAT1 variants have been reported in a syndromic form of LCA which is associated with ataxia. In conclusion, our patients expand the clinical spectrum of NMNAT1 variants and represent the first evidence of the probable correlation between NMNAT1 variants and HSP.
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Amaurose Congênita de Leber , Nicotinamida-Nucleotídeo Adenililtransferase , Paraplegia Espástica Hereditária , Humanos , Paraplegia Espástica Hereditária/genética , NAD , Mutação , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/genética , Linhagem , Nicotinamida-Nucleotídeo Adenililtransferase/genéticaRESUMO
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.
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Ataxia Cerebelar , Cistos , Ataxias Espinocerebelares , Humanos , Irã (Geográfico) , Mutação/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/genética , NeuroimagemRESUMO
BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) is a rare genetic disorder. Its clinical manifestations comprise a wide spectrum mainly movement disorders. Seizure as a clinical manifestation is known to occur in some NBIAs, but the exact prevalence of epilepsy in each individual disorder is not well elucidated. The aim of this review was to investigate the frequency of seizures in NBIA disorders as well as to determine the associated features of patients with seizures. METHOD: The electronic bibliographic databases PubMed, Scopus, Embase, and Google Scholar were systematically searched for all cases in any type of article from inception to December 16, 2019. All the reported cases of NBIA (with or without genetic confirmation) were identified. Case reports with an explicit diagnosis of any types of NBIA, which have reported occurrence (or absence) of any type of seizure or epilepsy, in the English language, were included. Seizure incidence rate, type, and age of onset were reported as frequencies and percentages. RESULT: 1698 articles were identified and 51 were included in this review. Of 305 reported cases, 150 (49.2%) had seizures (phospholipase A2-associated neurodegeneration (PLAN) = 64 (50.8%), beta-propeller protein-associated neurodegeneration (BPAN) = 57 (72.1%), pantothenate kinase-associated neurodegeneration (PKAN) = 11 (23.4%), and others = 18 (very variable proportions)). The most frequent seizure type in NBIA patients was generalized tonic-clonic seizure with the mean age of seizure onset between 2 and 36 years. However, most of these papers had been published before the new classification of epilepsy became accessible. Affected patients were more likely to be females. CONCLUSION: Seizures are common in NBIA, particularly in PLAN and BPAN. In PKAN, the most common type of NBIA, around 10% of patients are affected by seizures. BPAN is the most possible NBIA accompanying seizure. Most of the findings regarding the seizure characteristics in the NBIAs are biased due to the huge missing data. Therefore, any conclusions should be made with caution and need further investigations.
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Epilepsia , Neurodegeneração Associada a Pantotenato-Quinase , Feminino , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Masculino , Convulsões , Encéfalo , FerroRESUMO
Background Manganese, as an essential element, has neurotoxic effects on basal ganglia and causes parkinsonism, dystonia, and cognitive symptoms in exposed individuals. Transcranial sonography (TCS) is a noninvasive and easily accessible imaging modality for detecting the accumulation of trace elements in the basal ganglia. Methodology In a cross-sectional study of foundry workers of one of the automobile manufacturing companies in 2019, the prevalence of parkinsonism was assessed through neurological examination and brain parenchymal sonography or TCS. The prevalence of parkinsonism according to age, smoking, work experience, marital status, and exposure to manganese was determined. Results Among 83 male workers, the prevalence of parkinsonism according to neurological examination, substantia nigra hyperechogenicity on TCS, lentiform nucleus hyperechogenicity, and totally was 33.7%, 9.6%, 10.8%, and 42.2%, respectively. The association between the prevalence of parkinsonism and age, smoking, work experience, marital status, and manganese exposure was evaluated. Parkinsonism according to lentiform nucleus hyperechogenicity was associated with smoking (odds ratio [OR] (95% confidence interval [CI]) = 26.63 (2.38-178.71)) and work experience (OR (95% CI) = 7.18 (0.84-61.32)). Conclusions According to this study, the prevalence of parkinsonism based on neurological examination or brain sonography findings was 42.2%. The implementation of this combined screening method might facilitate earlier detection of affected individuals among manganese-exposed workers.
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INTRODUCTION: Lafora disease (LD) is a severe form of progressive myoclonus epilepsy characterized by generalized seizures, myoclonus, intellectual decline, ataxia, spasticity, dysarthria, visual loss, and in later stages, psychosis and dementia. To date, mutations in the EPM2A and EPM2B/NHLRC1 genes have been identified as the common causes of LD. However, a mutation in PRDM8 has been reported only once in a Pakistani family affected with early-onset Lafora disease. In the present study, we report the second family with a PRDM8 mutation. METHODS: Two affected individuals of an Iranian family initially diagnosed as complicated hereditary spastic paraplegia (HSP) underwent careful neurologic examination. Homozygosity mapping and whole-exome sequencing were performed. Based on the results of genetic analysis to detection of Lafora bodies, a skin biopsy was done. RESULTS: The clinical features of the patients were described. Linkage to chromosome 4 and a mutation in the PRDM8 gene were identified, suggesting the patients may be affected with early-onset LD. However, like the Pakistani family, the search for Lafora bodies in their skin biopsies was negative. Their electroencephalograms showed generalized epileptiform discharges in the absence of clinical seizures. CONCLUSIONS: The current study increases the number of PRDM8-related cases and expands the phenotypic spectrum of mutations in the PRDM8 gene. Both reported PRDM8-related families presented intra and inter-familial heterogeneity and they have originated from the Middle East. Thus, it seems the PRDM8 mutations should be considered not only in LD but also in other neurodegenerative disorders such as a complicated HSP-like phenotype, especially in this region.
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Doença de Lafora , Epilepsias Mioclônicas Progressivas , Paraplegia Espástica Hereditária , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Histona Metiltransferases/genética , Humanos , Irã (Geográfico) , Doença de Lafora/diagnóstico , Doença de Lafora/genética , Doença de Lafora/patologia , Mutação/genética , Convulsões , Paraplegia Espástica Hereditária/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Hereditary spastic paraplegia (HSP) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness. Different patterns of inheritance have been identified in HSP. Most autosomal-dominant HSPs (AD-HSPs) are associated with mutations of the SPAST gene (SPG4), leading to a pure form of HSP with variable age-at-onset (AAO). Anticipation, an earlier onset of disease, as well as aggravation of symptoms in successive generations, may be correlated to SPG4. Herein, we suggested that anticipation might be a relatively common finding in SPG4 families. METHODS: Whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands. Data were analyzed, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis. Multiplex ligation-dependent probe amplification (MLPA) was done for seven probands. Clinical features of the probands were recorded, and the probable anticipation was checked in these families. Other previous reported SPG4 families were investigated to anticipation. RESULTS: Our findings showed that SPG4 was the common subtype of HSP; three families carried variants in the KIF5A, ATL1, and MFN2 genes, while five families harbored mutations in the SPAST gene. Clinical features of only SPG4 families indicated decreasing AAO in affected individuals of the successive generations, and this difference was significant (p-value <0.05). CONCLUSION: It seems SPAST will be the first candidate gene in families that manifests a pure form of AD-HSP and anticipation. Therefore, it may be a powerful situation of genotype-phenotype correlation. However, the underlying mechanism of anticipation in these families is not clear yet.
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Paraplegia Espástica Hereditária , Adenosina Trifosfatases/genética , Proteínas de Ligação ao GTP/genética , Humanos , Irã (Geográfico) , Cinesinas/genética , Proteínas de Membrana/genética , Mutação/genética , Fenótipo , Paraplegia Espástica Hereditária/genética , Espastina/genéticaRESUMO
Neurodegeneration with brain iron accumulation (NBIA) is a term used for a group of hereditary neurological disorders with abnormal accumulation of iron in basal ganglia. It is clinically and genetically heterogeneous with symptoms such as dystonia, dysarthria, Parkinsonism, intellectual disability, and spasticity. The age at onset and rate of progression are variable among individuals. Current therapies are exclusively symptomatic and unable to hinder the disease progression. Approximately 16 genes have been identified and affiliated to such condition with different functions such as iron metabolism (only two genes: Ferritin Light Chain (FTL) Ceruloplasmin (CP)), lipid metabolism, lysosomal functions, and autophagy process, but some functions have remained unknown so far. Subgroups of NBIA are categorized based on the mutant genes. Although in the last 10 years, the development of whole-exome sequencing (WES) technology has promoted the identification of disease-causing genes, there seem to be some unknown genes and our knowledge about the molecular aspects and pathogenesis of NBIA is not complete yet. There is currently no comprehensive study about the NBIA in Iran; however, one of the latest discovered NBIA genes, GTP-binding protein 2 (GTPBP2), has been identified in an Iranian family, and there are some patients who have genetically remained unknown.
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Distúrbios do Metabolismo do Ferro , Gânglios da Base , Encéfalo/patologia , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Humanos , Irã (Geográfico) , Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/genética , MutaçãoRESUMO
The possible differential diagnoses for children presenting with kyphoscoliosis, skeletal deformities and ophthalmoplegia are diverse. We present 11-year-old identical twins with these symptoms, with interesting etiological concern for those practicing in the fields of neurology, pediatrics, spine surgery and related specialties. A new presentation for a rare genetic condition was the final diagnosis for our patients. In this movement disorder round we describe our approach to this clinical constellation and discuss clinical significance of this genetic condition.
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Doenças em Gêmeos/genética , Cifose/genética , Transtornos dos Movimentos/genética , Oftalmoplegia/genética , Escoliose/genética , Criança , Humanos , MasculinoRESUMO
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.
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Apirase/genética , Proteínas de Transporte/genética , Família 7 do Citocromo P450/genética , Paraplegia Espástica Hereditária/genética , Esteroide Hidroxilases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/fisiopatologia , Sequenciamento do Exoma , Adulto JovemRESUMO
OBJECTIVES: Primary generalized dystonia (PGD) due to heterozygous torsin 1A (TOR1A) gene mutation (DYT1) is a childhood onset dystonia with rapid deterioration of symptoms, leading to severe disability in adolescence. Globus pallidus interna deep brain stimulation (GPi-DBS) has been shown to provide significant improvement in these cases. METHODS: This was a retrospective study of TOR1A mutation positive dystonia patients, conducted at a university hospital from 2006 to 2018. Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS) was used to evaluate dystonia severity before and after surgery. Emergence of postsurgical parkinsonian symptoms was evaluated using the Unified Parkinson Disease Rating Scale (UPDRS) part III. Montreal Cognitive Assessment (MOCA) was applied to assess cognitive dysfunction. SPSS version 18 was used for data analysis. RESULTS: Eleven patients entered for analysis with an average age of 22.36 (±3.35) years (range: 18-28). Seven patients (63.6 %) were female. Mean follow-up period was 8.72 (±0.87). Difference between baseline and most recent BFM scores was significant (disability: 10.5 ±4.52 versus 2.09 (±3.20), P: 0.001; severity: 48.45 (±17.88) versus 9.36 (±10.47), P<0.001). The mean MOCA and UPDRS III scores after 7-9 years of DBS were 27.18 (±2.99), and 6.09 (±4.15), respectively. CONCLUSION: Our experience confirms that GPi-DBS in pediatric patients with DYT1 dystonia is overall successful, with significant and long-lasting positive effects on motor and cognitive functions. There was no prominent side effect in long-term follow up.
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Estimulação Encefálica Profunda/métodos , Distonia Muscular Deformante/terapia , Globo Pálido/fisiologia , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Masculino , Chaperonas Moleculares/genética , Mutação , Estudos Retrospectivos , Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Opsoclonus-myoclonus-ataxia syndrome is a heterogeneous constellation of symptoms ranging from full combination of these three neurological findings to varying degrees of isolated individual sign. Since the emergence of coronavirus disease 2019 (COVID-19), neurological symptoms, syndromes, and complications associated with this multi-organ viral infection have been reported and the various aspects of neurological involvement are increasingly uncovered. As a neuro-inflammatory disorder, one would expect to observe opsoclonus-myoclonus syndrome after a prevalent viral infection in a pandemic scale, as it has been the case for many other neuro-inflammatory syndromes. We report seven cases of opsoclonus-myoclonus syndrome presumably parainfectious in nature and discuss their phenomenology, their possible pathophysiological relationship to COVID-19, and diagnostic and treatment strategy in each case. Finally, we review the relevant data in the literature regarding the opsoclonus-myoclonus syndrome and possible similar cases associated with COVID-19 and its diagnostic importance for clinicians in various fields of medicine encountering COVID-19 patients and its complications.
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Ataxia/fisiopatologia , COVID-19/fisiopatologia , Tosse/fisiopatologia , Febre/fisiopatologia , Mialgia/fisiopatologia , Síndrome de Opsoclonia-Mioclonia/fisiopatologia , SARS-CoV-2/patogenicidade , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/diagnóstico por imagem , Ataxia/tratamento farmacológico , Ataxia/etiologia , Azitromicina/uso terapêutico , COVID-19/complicações , COVID-19/diagnóstico por imagem , Clonazepam/uso terapêutico , Tosse/diagnóstico por imagem , Tosse/tratamento farmacológico , Tosse/etiologia , Dispneia/diagnóstico por imagem , Dispneia/tratamento farmacológico , Dispneia/etiologia , Dispneia/fisiopatologia , Feminino , Febre/diagnóstico por imagem , Febre/tratamento farmacológico , Febre/etiologia , Humanos , Hidroxicloroquina/uso terapêutico , Levetiracetam/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mialgia/diagnóstico por imagem , Mialgia/tratamento farmacológico , Mialgia/etiologia , Síndrome de Opsoclonia-Mioclonia/diagnóstico por imagem , Síndrome de Opsoclonia-Mioclonia/tratamento farmacológico , Síndrome de Opsoclonia-Mioclonia/etiologia , Oseltamivir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Ácido Valproico/uso terapêutico , Tratamento Farmacológico da COVID-19RESUMO
Coenzyme Q10/ COQ10 , an essential cofactor in the electron-transport chain is involved in ATP production. Primary COQ10 deficiency is clinically and genetically a heterogeneous group of mitochondrial disorders caused by defects in the COQ10 synthesis pathway. Its mode of inheritance is autosomal recessive and it is characterized by metabolic abnormalities and multisystem involvement including neurological features. Mutations in 10 genes have been identified concerning this group of diseases, so far. Among those, variants of the COQ7 gene are very rare and confined to three patients with Asian ancestry. Here, we present the clinical features and results of whole-exome sequencing (WES) of three Iranian unrelated families affected by primary COQ10 deficiency. Three homozygous variants in COQ2, COQ4, and COQ7 genes were identified. Candidate variants of the COQ2 and COQ4 genes were novel and associated with the cerebellar signs and multisystem involvement, whereas, the known variant in COQ7 was associated with a mild phenotype that was initially diagnosed as hereditary spastic paraplegia (HSP). This variant has already been reported in a Canadian girl with similar presentations that also originated from Iran suggesting both patients may share a common ancestor. Due to extensive heterogeneity in this group of disorders, and overlap with other mitochondrial/neurological disorders, WES may be helpful to distinguish primary coenzyme Q10 deficiency from other similar conditions. Given that some features of primary coenzyme Q10 deficiency may improve with exogenous COQ10 , early diagnosis is very important.
Assuntos
Alquil e Aril Transferases/genética , Ataxia/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Oxigenases de Função Mista/genética , Debilidade Muscular/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Ataxia/epidemiologia , Ataxia/patologia , Canadá/epidemiologia , Criança , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Irã (Geográfico)/epidemiologia , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/patologia , Debilidade Muscular/epidemiologia , Debilidade Muscular/patologia , Mutação/genética , Ubiquinona/genética , Sequenciamento do ExomaRESUMO
Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.