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1.
Am J Hum Genet ; 106(3): 412-421, 2020 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-32142645

RESUMEN

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.


Asunto(s)
Edad de Inicio , Alelos , Encefalopatías/genética , Calcinosis/genética , Moléculas de Adhesión Celular/genética , Genes Recesivos , Adolescente , Adulto , Animales , Encefalopatías/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Niño , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Linaje
2.
Am J Hum Genet ; 92(2): 245-51, 2013 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-23332917

RESUMEN

Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid ß-glucosidase 1. ß-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding ß-glucosidase 2, GBA2. Two nonsense mutations (c.363C>A [p.Tyr121(∗)] and c.1018C>T [p.Arg340(∗)]) and a substitution (c.2618G>A [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans.


Asunto(s)
Ataxia Cerebelosa/complicaciones , Ataxia Cerebelosa/genética , Genes Recesivos/genética , Espasticidad Muscular/complicaciones , Espasticidad Muscular/genética , Mutación/genética , beta-Glucosidasa/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Familia , Femenino , Glucosilceramidasa , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Túnez , beta-Glucosidasa/química
3.
Clin Auton Res ; 25(1): 19-36, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25687905

RESUMEN

Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies.


Asunto(s)
Ligamiento Genético , Estudio de Asociación del Genoma Completo , Atrofia de Múltiples Sistemas/genética , Mutación/genética , Transferasas Alquil y Aril/genética , Animales , Modelos Animales de Enfermedad , Humanos , Enfermedad por Cuerpos de Lewy/genética , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética
4.
Nat Commun ; 15(1): 2269, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38480682

RESUMEN

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.


Asunto(s)
Encefalopatías , Humanos , Acetilación , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encefalopatías/genética , Patrón de Herencia , Mutación , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismo
5.
Stroke ; 43(3): 670-6, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22223244

RESUMEN

BACKGROUND AND PURPOSE: Postpartum angiopathy (PPA), a rare cause of stroke in the puerperium, is heralded by severe headaches within 1-2 weeks after delivery. Angiography demonstrates segmental vasoconstriction that often resolves spontaneously. PPA is generally regarded as benign. We aimed to define clinical presentations, radiological findings, and outcomes of patients with PPA. METHODS: We retrospectively reviewed patients from 3 centers with acute neurological symptoms and angiography showing vasoconstriction in the postpartum period. Patients without neuroimaging and with diagnoses of cerebral venous sinus thrombosis and aneurysmal hemorrhage were excluded. Patient characteristics, clinical symptoms, neuroimaging findings, and clinical condition at hospital discharge were collected. RESULTS: Eighteen patients (mean age, 31 years; range, 15-41) were identified. Median gestation was 38 weeks. Twelve (67%) had a history of prior uneventful pregnancy. Neurological symptoms began on median day 5 postpartum and included headache (n=16, 89%), focal deficit (n=9, 50%), visual disturbance (n=8, 44%), encephalopathy (n=6, 33%), and seizure (n=5, 28%), often in combination. Brain imaging was abnormal in most (n=13, 72%). The most common abnormalities were intracranial hemorrhage (n=7, 39%), vasogenic edema (n=6, 35%), and infarction (n=6, 35%). Clinical outcomes were markedly variable with full recovery seen in 9 (50%), death after a fulminant course in 4 (22%), and residual deficits in 5 (28%). CONCLUSIONS: In contrast to prior reports, this group of patients with PPA had a higher proportion of nonbenign outcomes. Most patients who undergo neuroimaging have parenchymal abnormalities, which are most often stroke (hemorrhagic or ischemic) or reversible vasogenic edema.


Asunto(s)
Trastornos Cerebrovasculares/diagnóstico , Periodo Posparto , Accidente Cerebrovascular/diagnóstico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Angiografía Cerebral , Arterias Cerebrales/patología , Hemorragia Cerebral/etiología , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/terapia , Bases de Datos Factuales , Femenino , Humanos , Angiografía por Resonancia Magnética , Enfermedades del Sistema Nervioso/etiología , Examen Neurológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Embarazo , Complicaciones del Embarazo/epidemiología , Estudios Retrospectivos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/terapia , Terminología como Asunto , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Vasoconstricción/fisiología , Adulto Joven
7.
PLoS One ; 11(2): e0149557, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26894433

RESUMEN

BACKGROUND: The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases. METHODS: Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography. RESULTS: We detected a statistically significant decrease (by 3-5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)]. CONCLUSION: Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated.


Asunto(s)
Cerebelo/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Ubiquinona/metabolismo , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/metabolismo
8.
J Neurol Sci ; 348(1-2): 266-8, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25560911

RESUMEN

Mutations in the fukutin-related protein (FKRP) gene are a known cause of autosomal recessive limb-girdle muscular dystrophy. Clinically, patients resemble Becker's muscular dystrophy and generally present in the first two decades of life with a mild, progressive phenotype. Cardiac involvement is variable. Heterozygous carriers are usually clinically unaffected. We report a patient presenting later in life with life-threatening cardiac failure and we describe for the first time clinically manifesting carriers in the family.


Asunto(s)
Insuficiencia Cardíaca/etiología , Proteínas de la Membrana/genética , Distrofia Muscular de Cinturas , Anciano , Femenino , Heterocigoto , Humanos , Distrofia Muscular de Cinturas/complicaciones , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/fisiopatología , Linaje
9.
Neurobiol Aging ; 36(2): 1221.e1-6, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25308964

RESUMEN

A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in 3 patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found 1 patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuropathologically confirmed samples with MSA (n = 96), PSP (n = 177), and CBD (n = 18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS and/or CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP, or CBD in a large series of cases.


Asunto(s)
Expansión de las Repeticiones de ADN , Trastornos Parkinsonianos/genética , Proteínas/genética , Adulto , Anciano , Ganglios Basales/patología , Enfermedades de los Ganglios Basales/genética , Proteína C9orf72 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/genética , Enfermedades Neurodegenerativas/genética , Parálisis Supranuclear Progresiva/genética , Síndrome
10.
Mult Scler Relat Disord ; 2(4): 349-54, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25877845

RESUMEN

Susac's syndrome is a treatable microangiopathy of unknown etiology affecting arterioles of the brain, retina, and cochlea. The typical clinical manifestation is the triad of encephalopathy, visual loss, and sensorineural hearing loss. One or more of these features may not be present at onset and therefore Susac's syndrome's diagnosis may be difficult. We describe the clinical presentation, diagnostic tests, and treatment of three cases diagnosed and treated at our institution.

11.
Neurobiol Aging ; 33(8): 1851.e1-5, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22445326

RESUMEN

An intronic expansion of a hexanucleotide GGGGCC repeat in the C9ORF72 gene has recently been shown to be an important cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in familial and sporadic cases. The frequency has only been defined in a small number of populations where the highest sporadic rate was identified in Finland (21.1%) and the lowest in mainland Italy (4.1%). We examined the C9ORF72 expansion in a series of 146 Greek ALS cases, 10.95% (n = 16) of cases carried the pathological expansion defined as greater than 30 repeats. In the 10 familial ALS probands, 50% (n = 5) of them carried a pathologically large expansion. In the remaining 136 sporadic ALS cases, 11 were carriers (8.2%). None of the 228 Greek controls carried an expanded repeat. The phenotype of our cases was spinal (13/16) or bulbar (3/16) ALS, the familial cases were all spinal ALS and none of our cases had behavioral frontotemporal dementia. Expansions in the C9ORF72 gene therefore represent a common cause of ALS in Greece and this test will be diagnostically very important to implement in the Greek population. The frequency is higher than other populations with the exception of Finland and this may be due to Greece being a relatively isolated population.


Asunto(s)
Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Esclerosis Amiotrófica Lateral/congénito , Proteína C9orf72 , Femenino , Marcadores Genéticos/genética , Variación Genética/genética , Grecia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo
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