RESUMO
Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder affecting 1:1,000,000 children. It results from pathogenic variants in the PLA2G6 gene located on chromosome 22q13.1. The onset of symptoms usually occurs between 6 and 18 months, causing developmental regression leading to debilitating symptoms such as muscle weakness, dementia, and loss of basic skills. Eventually, it progresses to life-threatening symptoms, including breathing difficulties, which limit the life expectancy to 5-10 years. While potential genetic therapies for treatment are being developed, they are yet to be approved for use, and management remains essentially supportive. This case report is about a nine-year-old Pakistani girl with INAD. She presented with recurrent chest infections, developmental regression, loss of speech, paralysis, hypertension, and eventually breathing difficulties. Brain magnetic resonance imaging and genetic testing confirmed the diagnosis. This case posed diagnostic challenges in view of its overlapping clinical presentation. Through this report, we aim to raise awareness about this condition among practitioners, outline the importance of genetic counseling in susceptible couples, and suggest potential areas of further research.
Assuntos
Distrofias Neuroaxonais , Humanos , Feminino , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/fisiopatologia , Criança , Imageamento por Ressonância Magnética , Fosfolipases A2 do Grupo VI/genéticaRESUMO
Background: Despite being the second most common type of neurodegeneration with brain iron accumulation, there is limited literature on PLA2G6-associated neurodegeneration (PLAN) within the Asian ethnicity, particularly in the Indian context. Methods: We conducted a retrospective observational study on patients with pathogenic/likely pathogenic PLA2G6 variants based on exome sequencing. Results: We identified 26 patients (22 families, 15 males) of genetically-confirmed PLAN with a median age of 22.5 years and age at onset of 13.0 years, encompassing various subtypes: infantile neuroaxonal dystrophy (5/26;19.2%), atypical neuroaxonal dystrophy (3/26;11.5%), dystonia-parkinsonism (5/26;19.2%), dystonia-parkinsonism-myoclonus (n = 4, 15.38%), early-onset Parkinson's disease (2/26;7.7%), complex dystonia (2/26;7.7%), and complicated hereditary spastic paraparesis (cHSP; 5/26;19.2%). The common initial symptoms included walking difficulty (7/26;26.9%), developmental regression (6/26;23.1%), and slowness (4/26;15.4%). Dystonia (14/26;53.8%), followed by parkinsonism (11/26; 42.3%), was the most common motor symptom. Non-motor symptoms included cognitive decline (12/26;46.2%) and behavioral changes (6/26;23.1%). Neuroimaging revealed cerebellar atrophy in 23/26 (88.5%) patients and claval hypertrophy in 80% (4/5) of INAD patients. Levodopa responsiveness was noted in 12 of 14 patients with parkinsonism/dystonia who received levodopa, and dyskinesia was noted in 10/11 patients. Genetic analysis revealed a total of 19 unique variants in PLA2G6 gene, of which 11 were novel. Twelve patients harbored the c.2222G>A variant, which is predominantly seen in Asian subpopulations. Conclusions: The study introduces 26 new patients of PLAN and 12 patients associated with the c.2222G>A variant, potentially forming the most extensive single center series to date. It also expands the phenotypic, neuroimaging, and genotypic spectrum of PLAN.
Assuntos
Fosfolipases A2 do Grupo VI , Distrofias Neuroaxonais , Humanos , Fosfolipases A2 do Grupo VI/genética , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Estudos Retrospectivos , Criança , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/fisiopatologia , Pré-Escolar , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Índia , Pessoa de Meia-Idade , Centros de Atenção TerciáriaRESUMO
INTRODUCTION: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurological syndrome caused by pathogenic variants in the C19orf12 and is characterized by iron deposition in the basal ganglia and substantia nigra. Only a limited number of cohort studies were published to date and the prevalence of MPAN remains uncertain. METHODS: Recruited subjects with MPAN in Russia were diagnosed by whole-exome sequencing or Sanger sequencing of the C19orf12 gene. Data of over 14000 whole exome sequencing analyses was used to calculate the estimated disease frequency. RNA analysis was performed by RT-PCR. QSVanalyzer software was used to quantify the allelic disbalance. RESULTS: We describe the clinical and molecular characterizations of 17 patients with MPAN. DNA analysis detected three previously undescribed pathogenic/likely pathogenic variants in the C19orf12 gene. The estimated disease frequency was calculated to be 1:619150. We describe unusual clinical observations in several cases. One patient showed severe neurogenic muscle weakness along with a lack of marked spasticity or optic nerve atrophy. In another mild clinical case with the NM_001031726.3:c.204_214del (p.(Gly69Argfs*10)) variant in a heterozygous state, a marked allelic disbalance was observed on the RNA level with reduced expression level of the wild-type allele. Thus, this case became the first one of a possible regulatory variant causing MPAN. CONCLUSION: We reported a detailed clinical and molecular characterization of the third-largest MPAN cohort. We expanded the mutational and clinical spectrum of MPAN. Moreover, we calculated the estimated MPAN frequency in the Russian population for the first time.
Assuntos
Globo Pálido/patologia , Distúrbios do Metabolismo do Ferro , Proteínas de Membrana , Membranas Mitocondriais , Proteínas Mitocondriais , Distrofias Neuroaxonais , Substância Negra/patologia , Adolescente , Adulto , Criança , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Distúrbios do Metabolismo do Ferro/epidemiologia , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Imageamento por Ressonância Magnética , Distrofias Neuroaxonais/epidemiologia , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Estudos Retrospectivos , Federação Russa/epidemiologia , Substância Negra/diagnóstico por imagem , Sequenciamento do ExomaRESUMO
Mitochondria membrane protein-associated neurodegeneration (MPAN) neurodegenerative disorder is typically associated with biallelic C19orf12 variants. Here we describe a new and review candidate previous monoallelic de novo C19orf12 variants to define loss of function mutations located in the putative non-membrane spanning C19orf12 isoform as the potential basis of monoallelic MPAN.
Assuntos
Distúrbios do Metabolismo do Ferro/genética , Proteínas de Membrana/genética , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Distrofias Neuroaxonais/genética , Amish , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/patologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Mutação com Perda de Função , Imageamento por Ressonância Magnética , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Linhagem , Isoformas de ProteínasAssuntos
Fosfatase Alcalina/genética , Gânglios da Base/patologia , Distúrbios Distônicos , Hipofosfatasia , Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Transtornos Parkinsonianos , Adulto , Gânglios da Base/diagnóstico por imagem , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Distúrbios Distônicos/patologia , Distúrbios Distônicos/fisiopatologia , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologiaRESUMO
FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). METHODS: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. RESULTS: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. CONCLUSION: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.
Assuntos
Proteínas F-Box/genética , Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Transtornos Parkinsonianos , Complexo de Endopeptidases do Proteassoma/metabolismo , Adulto , Consanguinidade , Epilepsia/enzimologia , Epilepsia/genética , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/enzimologia , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Distrofias Neuroaxonais/enzimologia , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Paraplegia/enzimologia , Paraplegia/genética , Paraplegia/patologia , Paraplegia/fisiopatologia , Transtornos Parkinsonianos/enzimologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Degenerações Espinocerebelares/enzimologia , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/patologia , Degenerações Espinocerebelares/fisiopatologia , Síndrome , Adulto JovemRESUMO
BACKGROUND: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain. METHODS: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected. RESULTS: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age. CONCLUSIONS: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.
Assuntos
Proteínas de Transporte/genética , Doenças Desmielinizantes , Deficiências do Desenvolvimento , Epilepsia , Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/diagnóstico , Epilepsia/etiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Pessoa de Meia-Idade , Distrofias Neuroaxonais/complicações , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/fisiopatologia , Fenótipo , Sequenciamento do Exoma , Adulto JovemRESUMO
Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic disorders characterized by progressive extrapyramidal and other neurological symptoms due to focal iron accumulation in the basal ganglia (Adidi et al., 2016). ß-Propeller protein-associated neurodegeneration (BPAN) is the most recently identified subtype of NBIA caused by heterozygous variants in WDR45 (OMIM: *300526) at Xp11.23. We report the clinical neurophysiological and neuro-imaging findings of a new subtype of BPAN in a 6 year-old female patient, who was identified to have a large de novo WDR45 deletion who presented in the first year of life with early onset global developmental delay, severe cognitive impairment, generalized hypotonia and a corticosteroid responsive epileptic encephalopathy.
Assuntos
Proteínas de Transporte/genética , Distúrbios do Metabolismo do Ferro/diagnóstico , Distrofias Neuroaxonais/diagnóstico , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Síndromes Epilépticas/genética , Feminino , Heterozigoto , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Imageamento por Ressonância Magnética , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/fisiopatologia , Deleção de SequênciaRESUMO
BACKGROUND AND AIM: Neurodegeneration with brain iron accumulation (NBIA) and Wilson's disease (WD) is considered the prototype of neurodegenerative disorders characterised by the overloading of iron and copper in the central nervous system. Growing evidence has unveiled the involvement of these metals in brain cortical neurotransmission. Aim of this study was to assess cortical excitability profile due to copper and iron overload. METHODS: Three patients affected by NBIA, namely two patients with a recessive hereditary parkinsonism (PARK9) and one patient with aceruloplasminemia and 7 patients with neurological WD underwent transcranial magnetic stimulation (TMS) protocols to assess cortical excitability. Specifically, we evaluated the motor thresholds that reflect membrane excitability related to the voltage-gated sodium channels in the neurons of the motor system and the ease of activation of motor cortex via glutamatergic networks, and ad hoc TMS protocols to probe inhibitory-GABAergic (short interval intracortical inhibition, SICI; short-latency afferent inhibition, SAI; cortical silent period, CSP) and excitatory intracortical circuitry (intracortical facilitation, ICF). RESULTS: Patients with NBIA exhibited an abnormal prolongation of CSP respect to HC and WD patients. On the contrary, neurological WD displayed higher motor thresholds and reduced CSP and SICI. CONCLUSION: Hereditary conditions due to overload of copper and iron exhibited peculiar cortical excitability profiles that can help during differential diagnosis between these conditions. Moreover, such results can give us more clues about the role of metals in acquired neurodegenerative disorders, such as Parkinson disease, Alzheimer disease, and multiple sclerosis.
Assuntos
Ceruloplasmina/deficiência , Excitabilidade Cortical/fisiologia , Degeneração Hepatolenticular/fisiopatologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Distrofias Neuroaxonais/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Magnética Transcraniana , Adulto JovemAssuntos
Distúrbios do Metabolismo do Ferro , Proteínas Mitocondriais/genética , Distrofias Neuroaxonais , Adolescente , Alelos , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/patologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/metabolismo , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , LinhagemAssuntos
Distúrbios do Metabolismo do Ferro/diagnóstico , Distrofias Neuroaxonais/diagnóstico , Adulto , Proteínas de Transporte/genética , Feminino , Humanos , Irã (Geográfico) , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Imageamento por Ressonância Magnética , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Ultrassonografia Doppler Transcraniana , Adulto JovemAssuntos
Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Adulto , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Masculino , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologiaRESUMO
INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.
Assuntos
Cerebelo/patologia , Globo Pálido/metabolismo , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Substância Negra/metabolismo , Adolescente , Adulto , Idade de Início , Atrofia/patologia , Cerebelo/diagnóstico por imagem , Criança , Pré-Escolar , Estudos Transversais , Globo Pálido/diagnóstico por imagem , Fosfolipases A2 do Grupo VI/genética , Humanos , Imageamento por Ressonância Magnética , Distrofias Neuroaxonais/diagnóstico por imagem , Fenótipo , Índice de Gravidade de Doença , Substância Negra/diagnóstico por imagem , Adulto JovemAssuntos
Proteínas de Transporte/genética , Distúrbios do Metabolismo do Ferro/genética , Mutação , Distrofias Neuroaxonais/genética , Espasmos Infantis/genética , Potenciais Evocados Auditivos do Tronco Encefálico , Humanos , Lactente , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Distrofias Neuroaxonais/fisiopatologia , Espasmos Infantis/fisiopatologiaRESUMO
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.
Assuntos
Interleucinas/genética , Distúrbios do Metabolismo do Ferro , Proteínas de Transporte da Membrana Mitocondrial , Distrofias Neuroaxonais , Adulto , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/fisiopatologia , Adulto JovemRESUMO
BACKGROUND AND AIMS: Phospholipase A2 associated neurodegeneration (PLAN) is a heterogeneous autosomal recessive disorder caused by mutations in the ubiquitously expressed PLA2G6 gene. It is responsible for delayed brain iron accumulation and induces progressive psychomotor regression. We report the concomitant clinical, radiological and neurophysiological findings in PLAN patients in an attempt to determine the contribution of each test to guide diagnosis. METHODS: Concomitant clinical, radiological, electroencephalographic (EEG) and electrodiagnostic testing (EDX) findings in a series of 8 consecutive genetically confirmed PLAN patients were collected. RESULTS: All patients presented marked motor axonal loss, with decreased or absent distal compound muscle action potentials, acute and chronic denervation at needle electromyography, in contrast with preservation of sensory conduction. EEG showed high-amplitude fast activity in all patients aged above 15 months. Two patients showing severe neonatal hypotonia displayed atypical hypsarhythmia and epileptic spasms. Iron deposition in globus pallidus was observed in only two patients aged above 6 years. CONCLUSIONS: Peripheral involvement is an early feature in PLAN recognizable by EDX at an earlier stage than typical iron accumulation in the brain. Furthermore, the association of West syndrome and axonal motor neuropathy may represent positive clues in favor of PLAN. This results emphasize the interest of early and repeated EDX.
Assuntos
Distrofias Neuroaxonais/fisiopatologia , Criança , Eletroencefalografia , Eletromiografia , Feminino , Fosfolipases A2 do Grupo VI/genética , Humanos , Lactente , Masculino , Mutação , Distrofias Neuroaxonais/genéticaAssuntos
Distonia/diagnóstico , Fosfolipases A2 do Grupo VI/genética , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Distúrbios do Metabolismo do Ferro/diagnóstico , Distrofias Neuroaxonais/diagnóstico , Adulto , Consanguinidade , Distonia/etiologia , Distonia/genética , Distonia/fisiopatologia , Olho/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/complicações , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Distrofias Neuroaxonais/complicações , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/fisiopatologia , Torcicolo/fisiopatologia , Adulto JovemRESUMO
INTRODUCTION: Phospholipase A2-associated neurodegeneration (PLAN) is an autosomal recessive movement disorder with abnormal iron deposition in basal ganglia, substantial nigra and adjacent areas, and cerebellar atrophy. It is caused by PLA2G6 mutations and comprises three phenotypes. We aimed to investigate genetic mutations in patients with predominantly extrapyramidal symptoms. METHODS: Eighteen Chinese patients with early onset of extrapyramidal symptoms were identified and underwent targeted next-generation sequencing, followed by Sanger sequencing. Detailed clinical and radiological features are presented. Prediction software was used to evaluate the pathogenicity of the identified variants. RESULTS: We identified 7 PLA2G6 variants including five known variants (c.668Câ¯>â¯T, c.991Gâ¯>â¯T, c.1117Gâ¯>â¯A, c.1982Câ¯>â¯T, and c.2218Gâ¯>â¯A) and two novel variants (c.1511Câ¯>â¯T, and c.1915Gâ¯>â¯A) in four index cases. Among them, three cases had initial symptoms of difficulty walking or gait disturbance around the age of 30, and one case and his sibling developed mental handicap at age 7. Two cases exhibited a phenotype of "early parkinsonism" and the other two cases mimicked a phenotype of "hereditary spastic paraplegia (HSP)". Iron deposition in globus pallidus and substantia nigra was seen in three cases. Cerebellar atrophy was present in all four cases. CONCLUSIONS: Our study expands the mutation spectrum of the PLA2G6 gene and further supports the hypothesis that PLA2G6 mutations are associated with a continuous clinical spectrum from PLAN to HSP.
Assuntos
Fosfolipases A2 do Grupo VI/genética , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/fisiopatologia , Adulto , China , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Transtornos Parkinsonianos/fisiopatologia , Fenótipo , Análise de Sequência de DNA , Paraplegia Espástica Hereditária/fisiopatologiaRESUMO
BACKGROUND/AIMS: Neurodegeneration with brain iron accumulation (NBIA) type I is a rare disease that can be divided into a classical or atypical variant, according to age of onset and clinical pattern. Neuro-ophthalmological involvement has been documented in the classical variant but only anecdotically in the atypical variant. We sought to describe the visual and ocular motor function in patients with atypical form of NBIA type I. METHODS: Cross-sectional study, including patients with genetically confirmed NBIA type I and classified as atypical variant, who underwent ophthalmological examination with best corrected visual acuity (BCVA), optical coherence tomography (OCT), fundus autofluorescence (FAF), electroretinography (ERG), visual evoked potentials (VEP) and video-oculography. RESULTS: Seven patients with a mean BCVA of 0.12±0.14 logMAR were included. Only two patients showed structural evidence of advanced retinopathy in OCT and FAF, and there were no cases of optic atrophy. ERG data, however, showed abnormal scotopic and/or photopic responses in all patients. VEP were normal in all three patients. Ocular fixation was markedly unstable (eg, increased rate of saccadic pulses) in the majority of patients (5). Additional mild ocular motor disturbances included low gain pursuit (2), hypermetric saccades (1), low gain optokinetic (2) and caloric and rotatory responses (3). CONCLUSION: Functional retinal changes associated with marked instability of ocular fixation should be included in the clinical spectrum of NBIA, particularly in the atypical form.
Assuntos
Potenciais Evocados Visuais/fisiologia , Movimentos Oculares/fisiologia , Distúrbios do Metabolismo do Ferro/complicações , Distrofias Neuroaxonais/complicações , Transtornos da Motilidade Ocular/fisiopatologia , Retina/fisiopatologia , Doenças Retinianas/fisiopatologia , Acuidade Visual , Adulto , Estudos Transversais , Eletrorretinografia , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Pessoa de Meia-Idade , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/fisiopatologia , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/etiologia , Retina/diagnóstico por imagem , Doenças Retinianas/diagnóstico , Doenças Retinianas/etiologia , Tomografia de Coerência Óptica , Adulto JovemRESUMO
Phospholipase A2-associated neurodegeneration (PLAN), a syndrome of Neurodegeneration with Brain Iron Accumulation (NBIA), is an autosomal recessive disorder caused by mutations in PLA2G6 gene. This gene encodes a calcium-independent group VI phospholipase A2 (iPLA-VI) critical in cell membrane homeostasis. PLAN syndrome encompasses a group of phenotypes with a different age of onset: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy of childhood-onset (atypical NAD) and adult-onset PLA2G6-related dystonia-parkinsonism (PARK14). INAD is a severe progressive psychomotor disorder characterized by the presence of axonal spheroids throughout the central and peripheral nervous system. Here we report clinical, genetic and histopathological findings of an INAD consanguineous-family from Senegal. Sanger sequencing analysis revealed a new homozygous PLA2G6-mutation in the proband (c.1483C>T) and the co-segregation of the mutation in this family. Electron microscopy on skin biopsy showed degenerated axons confirming the phenotype. This study contributes to enrich the landscape of PLA2G6-associated INAD mutations and enforce the genotype-phenotype correlation.