RESUMEN
Juvenile neuronal-ceroid-lipofuscinosis (JNCL) is a lysosomal storage disease caused by mutations in CLN3. The most frequent mutation is a 1.02-kb deletion that, when homozygous, causes the classical clinical presentation. Patients harboring mutations different than the major deletion show a marked clinical heterogeneity, including protracted disease course with possible involvement of extraneuronal tissues. Cardiac involvement is relatively rare in JNCL and it is usually due to myocardial storage of ceroid-lipofuscinin. Only recently, histopathological findings of autophagic vacuolar myopathy (AVM) were detected in JNCL patients with severe cardiomyopathy. We describe a 35-year-old male showing a delayed-classic JNCL with visual loss in childhood and neurological manifestations only appearing in adult life. He had an unusual CLN3 genotype with an unreported deletion (p.Ala349_Leu350del) and the known p.His315Glnfs*67 mutation. Autophagic vacuolar myopathy was shown by muscle biopsy. At clinical follow-up, moderately increased CPK levels were detected whereas periodic cardiac assessments have been normal to date. Adult neurologists should be aware of protracted JNCL as cause of progressive neurological decline in adults. The occurrence of autophagic vacuolar myopathy necessitates periodic cardiac surveillance, which is not usually an issue in classic JNCL due to early neurological death.
Asunto(s)
Eliminación de Gen , Enfermedades por Almacenamiento Lisosomal/genética , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Enfermedades Musculares/genética , Lipofuscinosis Ceroideas Neuronales/genética , Adulto , Humanos , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Masculino , Enfermedades Musculares/diagnóstico , Lipofuscinosis Ceroideas Neuronales/diagnóstico , SíndromeRESUMEN
We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 µm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, αvß3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Melanoma/metabolismo , Modelos Biológicos , Animales , Barrera Hematoencefálica/patología , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Melanoma/patología , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Ratas , Células Tumorales CultivadasRESUMEN
Adult polyglucosan body disease is a rare autosomal recessive disease, caused by glycogen branching enzyme gene mutations, characterised by urinary dysfunction, spastic paraplegia with vibration sense loss, peripheral neuropathy, and cognitive impairment. Fabry's disease is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations; neurological manifestations include cerebrovascular accidents, small-fibre neuropathy and autonomic dysfunction. Here, we report the case of a 44-year-old Sicilian male with stroke-like episodes, hypohidrosis and mild proteinuria, which led to the diagnosis of Fabry's disease after a hemizygous mutation (p.Ala143Thr) in α-galactosidase A gene was detected. Subsequently, he developed progressive walking difficulties and dementia, which were considered atypical for Fabry's disease. Therefore, we performed additional investigations that eventually led to the diagnosis of adult polyglucosan body disease caused by two novel missense mutations (p.Asp413His and p.Gly534Val) in the glycogen branching enzyme gene. Recently, the pathogenic role of the p.Ala143Thr mutation in causing Fabry's disease has been questioned. This case underlines the importance of performing further investigations when facing with atypical features even in the presence of a genetic diagnosis of a rare disease.
Asunto(s)
Errores Diagnósticos , Enfermedad de Fabry/diagnóstico , Enfermedad del Almacenamiento de Glucógeno/diagnóstico , Enfermedades del Sistema Nervioso/diagnóstico , Adulto , Enfermedad de Fabry/genética , Enfermedad del Almacenamiento de Glucógeno/genética , Humanos , Masculino , Enfermedades del Sistema Nervioso/genéticaRESUMEN
OBJECTIVE: To report 4 cases of autosomal recessive hereditary neuropathy associated with novel mutations in the periaxin gene (PRX) with a review of the literature. Periaxin protein is required for the maintenance of peripheral nerve myelin. Patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4F) or Déjèrine-Sottas neuropathy (DSN). Only 12 different mutations have been described thus far. METHODS: Case reports and literature review. RESULTS: Four patients from 3 unrelated families (2 siblings and 2 unrelated patients) were affected by an early-onset, slowly progressive demyelinating neuropathy with relevant sensory involvement. All carried novel frameshift or nonsense mutations in the PRX gene. The 2 siblings were compound heterozygotes for 2 PRX null mutations (p.Q547X and p.K808SfsX2), the third patient harbored a homozygous nonsense mutation (p.E682X), and the last patient had a homozygous 2-nt insertion predicting a premature protein truncation (p.S259PfsX55). Electrophysiologic analysis showed a severe slowing of motor nerve conduction velocities (MNCVs, between 3 and 15.3 m/s) with undetectable sensory nerve action potentials (SNAPs). Sural nerve biopsy, performed in 2 patients, demonstrated a severe demyelinating neuropathy and onion bulb formations. Interestingly, we observed some variability of disease severity within the same family. CONCLUSIONS: These cases and review of the literature indicate that PRX-related neuropathies have early onset but overall slow progression. Typical features are prominent sensory involvement, often with sensory ataxia; a moderate-to-dramatic reduction of MNCVs and almost invariable absence of SNAPs; and pathologic demyelination with classic onion bulbs, and less commonly myelin folding and basal lamina onion bulbs.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Proteínas de la Membrana/fisiología , Adulto , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/fisiopatología , Progresión de la Enfermedad , Femenino , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Mutación , Vaina de Mielina/metabolismo , Estudios Retrospectivos , Nervio Sural/patologíaAsunto(s)
Enfermedades del Sistema Nervioso Periférico/patología , Nervio Sural/patología , Autoanticuerpos/análisis , Autoanticuerpos/sangre , Biomarcadores/análisis , Biomarcadores/sangre , Biopsia/métodos , Biopsia/normas , Técnicas Citológicas/métodos , Técnicas Citológicas/normas , Técnicas Citológicas/tendencias , Humanos , Microscopía Electrónica de Transmisión , Países Bajos , Selección de Paciente , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Guías de Práctica Clínica como Asunto/normas , Valor Predictivo de las Pruebas , Nervio Sural/fisiopatologíaRESUMEN
Neuronal ceroid lipofuscinoses (NCLs) are relatively common storage diseases of childhood and early adolescence. Ultrastructural shape of storage cytosomes, type of disease gene, and age of onset serve to classify the different NCLs, some of which appear to cluster in Scandinavian countries. The CLN5 form usually presents as a classical epileptiform encephalopathy of late infancy but a more aggressive cognitive impairment has been described in a single family. We report two sibs harbouring a novel mutation (p.Tyr258Asp) in the CLN5 gene and displaying behaviour disturbances and mental deterioration, rather than epilepsy, as the dominant disease manifestation at onset.
Asunto(s)
Trastornos de la Conducta Infantil/etiología , Discapacidades para el Aprendizaje/etiología , Proteínas de la Membrana/genética , Mutación Missense/genética , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/psicología , Adolescente , Niño , Trastornos de la Conducta Infantil/patología , Humanos , Italia , Discapacidades para el Aprendizaje/patología , Proteínas de Membrana de los Lisosomas , Masculino , Lipofuscinosis Ceroideas Neuronales/patologíaRESUMEN
CT and MR imaging showed diffuse changes of the frontal white matter and genu of the corpus callosum with minimal atrophy and no contrast enhancement in a 41-year-old woman with progressive dementia. Brain biopsy disclosed axonal spheroids and gliosis in the white matter without macrophage or inflammatory infiltration or vessel abnormalities consistent with neuroaxonal leukodystrophy. This disease can be suspected on CT and MR imaging findings but requires neuropathologic examination to be diagnosed.
Asunto(s)
Axones/patología , Encefalopatías/complicaciones , Encefalopatías/diagnóstico , Demencia/etiología , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Adulto , Femenino , HumanosRESUMEN
Three members of an Italian family with autosomal dominant dementia and multiple strokes had the A713T mutation of the APP gene. The neuropathologic examination of the proband disclosed Alzheimer disease (AD) with severe cerebral amyloid angiopathy and multiple infarcts. This indicates that the A713T mutation of the APP gene, lying at the gamma-secretase cleavage site, can be responsible for AD with symptomatic cerebral amyloid angiopathy.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Angiopatía Amiloide Cerebral/genética , Infarto Cerebral/genética , Mutación Missense , Mutación Puntual , Enfermedad de Alzheimer/patología , Sustitución de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide , Precursor de Proteína beta-Amiloide/química , Ácido Aspártico Endopeptidasas , Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Infarto Cerebral/patología , Codón/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Endopeptidasas/metabolismo , Femenino , Genes Dominantes , Humanos , Italia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , LinajeRESUMEN
OBJECTIVE: To correlate the density of swellings in intraepidermal nerve fibers (IENF) with the longitudinal measurement of the epidermal innervation density in patients with painful neuropathy and to assess the predictive value of IENF swelling to progression of neuropathy. METHODS: Fifteen patients with persistent pain in the feet underwent neurologic examination, nerve conduction studies, quantitative sensory examination, and skin biopsies at proximal thigh and distal leg. In all patients and in 15 healthy subjects, IENF density and swelling ratio (no. swellings/no. IENF) were quantified at distal leg. Follow-up study, including IENF density and swelling ratio quantification, was performed a mean of 19.2 months later. Double staining confocal microscope studies using anti-human protein-gene-product 9.5, anti-tubule, anti-neurofilament, and anti-synaptophysin antibodies were performed to assess specific accumulation within swellings. Ultrastructural investigation of IENF was also carried out. RESULTS: Patients with neuropathy had lower density of IENF and higher swelling ratio than healthy subjects (p < 0.01) at distal leg. At follow-up, patients showed a parallel decrease in both IENF density (p = 0.02) and swelling ratio (p = 0.002). However, swelling ratio remained higher (p = 0.03) than in controls. Progression of neuropathy was confirmed by the decay in sural nerve sensory nerve action potential amplitude. Double immunostaining studies suggest accumulation of tubules and ubiquitin-associated proteins within swellings. Swollen and vacuolated IENF were identified in patients with neuropathy by conventional and immuno-electron microscopy. CONCLUSIONS: Increased swelling ratio predicted the decrease in IENF density in patients with painful neuropathy. Its quantification could support earlier diagnosis of sensory axonopathy.
Asunto(s)
Axones/patología , Epidermis/inervación , Degeneración Nerviosa , Neuralgia/patología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fibras Nerviosas/patología , Fibras Nerviosas/ultraestructura , Neuralgia/diagnóstico , PronósticoAsunto(s)
Cauda Equina/patología , Proteínas del Líquido Cefalorraquídeo/análisis , Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de la Mielina/genética , Enfermedad de Charcot-Marie-Tooth/líquido cefalorraquídeo , Enfermedad de Charcot-Marie-Tooth/patología , Cromosomas Humanos Par 17/genética , Consanguinidad , Progresión de la Enfermedad , Dosificación de Gen , Duplicación de Gen , Homocigoto , Humanos , Hipertrofia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nervio Sural/patologíaRESUMEN
A 7.5-year-old girl, with infantile neuroaxonal dystrophy (INAD), showed a gradual deterioration from 16 months; at age 5 years she was bedridden, with severe tetraplegia, strabismus, nystagmus and optic atrophy, and dementia. From age 5.5 years, she had paroxysmal tonic events. Videopolygraphic recordings disclosed two different kinds of motor events: (a) epileptic tonic seizures, in wakefulness and sleep, associated with autonomic changes and ictal EEG discharges; and (b) nonepileptic prolonged clusters of brief tonic spasms, without ictal modifications of the EEG. Both motor events were characterized by a minimal and clinically similar tonic contraction of the upper extremities. Video-polygraphic studies are mandatory for a correct paroxysmal event classification and treatment in INAD patients.
Asunto(s)
Electroencefalografía/estadística & datos numéricos , Epilepsia/diagnóstico , Monitoreo Fisiológico/estadística & datos numéricos , Distrofias Neuroaxonales/diagnóstico , Brazo/fisiopatología , Niño , Electromiografía/estadística & datos numéricos , Epilepsia/epidemiología , Epilepsia/fisiopatología , Femenino , Humanos , Contracción Muscular/fisiología , Músculo Esquelético/fisiopatología , Distrofias Neuroaxonales/epidemiología , Distrofias Neuroaxonales/fisiopatología , Polisomnografía/estadística & datos numéricos , Sueño/fisiología , Grabación de Cinta de Video , Vigilia/fisiologíaRESUMEN
The neuronal ceroid lipofuscinoses (NCL) are progressive neurodegenerative diseases occurring in infancy and adulthood. Atypical forms of these diseases have been described and are particularly represented in the late-infantile and juvenile onset groups. Recent progress in biochemistry and molecular genetics has identified some of these variants as separate disease entities while disclosing the phenotypic variability of some classic forms. We report the results of a retrospective analysis performed on a series of 27 NCL patients, 15 of which were atypical as to clinical and/or pathological findings. Most of such patients, belonging to the late-infantile onset group and displaying homogeneous clinical-pathological features, were suggestive for CLN6. The two atypical juvenile NCL patients had features which resembled the "protracted form" of the disease. Given their relative frequency, strict clinical and pathological criteria are still the most useful tools for identifying and characterizing atypical forms and for defining phenotype-genotype correlations.
Asunto(s)
Glicoproteínas de Membrana , Chaperonas Moleculares , Lipofuscinosis Ceroideas Neuronales/clasificación , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Adulto , Edad de Inicio , Niño , Preescolar , Electroencefalografía , Epilepsias Mioclónicas/diagnóstico , Epilepsias Mioclónicas/etiología , Potenciales Evocados Somatosensoriales , Potenciales Evocados Visuales , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Lipofuscinosis Ceroideas Neuronales/genética , Fenotipo , Proteínas/genética , Estudios RetrospectivosRESUMEN
Gerstmann-Sträussler-Scheinker disease is a familial neurodegeneration characterized clinically by adult-onset ataxia, postural abnormalities, and cognitive decline, and pathologically by amyloid deposits mostly localized in the cerebral and cerebellar cortices and the basal ganglia. The disease is due to mutations in the prion protein gene. Processing of the mutant proteins originates the amyloidogenic fragments that accumulate in the tissue. PrP-immunoreactive amyloid deposits are the morphological hallmark of the disease. Hypertrophic astrocytes, activated microglia, and nerve cell loss are consistently associated with PrP-amyloid deposits, while spongiosis, diffuse PrP immunoreactivity, neurofibrillary tangles, Lewy bodies, and long fiber tracts degeneration are occasionally associated. The clinical and pathological variability observed in GSS families is related to both mutations and the M/V polymorphism at codon 129 of the mutated gene.
Asunto(s)
Encéfalo/patología , Enfermedad de Gerstmann-Straussler-Scheinker/patología , Amiloide/genética , Animales , Ganglios Basales/patología , Corteza Cerebelosa/patología , Corteza Cerebral/patología , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Gliosis , Humanos , Inmunohistoquímica , Cuerpos de Lewy/patología , Microscopía Electrónica , Mutación , Neuritas/patología , Ovillos Neurofibrilares , Placa Amiloide/química , Placa Amiloide/ultraestructura , Polimorfismo Genético , Proteínas Priónicas , Priones/análisis , Precursores de Proteínas/genéticaRESUMEN
Mutations in the gene coding for the Schwann cell transcription factor early growth response 2 (EGR2), which seems to regulate myelinogenesis and hindbrain development, have been observed in few cases of inherited neuropathy. The authors describe a unique combination of cranial nerve deficits in one member of a Charcot-Marie-Tooth 1 family carrying an EGR2 mutation (Arg381His). This finding further supports the role of EGR2 in cranial nerve development.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedades de los Nervios Craneales/genética , Proteínas de Unión al ADN/genética , Mutación Missense , Factores de Transcripción/genética , Adulto , Anciano , Proteína 2 de la Respuesta de Crecimiento Precoz , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Pérdida Auditiva Sensorineural/etiología , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Fibras Nerviosas Mielínicas/patología , Conducción Nerviosa , Nervio Sural/patologíaRESUMEN
BACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms. OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A. METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0). RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula. CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de la Mielina/genética , Mutación Puntual/genética , Adulto , Niño , Femenino , Humanos , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Vaina de Mielina/ultraestructura , LinajeRESUMEN
We describe a patient with congenital hypomyelination neuropathy. The pathological and morphometrical findings in the sural nerve biopsy were consistent with a defect of myelin formation and maintenance. Direct sequence analysis of the genomic regions coding the peripheral myelin proteins P0 and PMP22 disclosed a heterozygous missense point mutation that leads to a Ser72Leu substitution in the second transmembrane of PMP22. Codon 72 mutations of PMP22 are associated with different phenotypes encompassing the Dejerine-Sottas syndrome and including congenital hypomyelination neuropathy.
Asunto(s)
Sustitución de Aminoácidos/genética , Enfermedades Desmielinizantes/congénito , Enfermedades Desmielinizantes/genética , Mutación Missense/fisiología , Proteínas de la Mielina/genética , Mutación Puntual/fisiología , Sustitución de Aminoácidos/fisiología , ADN/análisis , ADN/genética , Enfermedades Desmielinizantes/patología , Electromiografía , Electrofisiología , Humanos , Lactante , Masculino , Mutación Missense/genética , Mutación Puntual/genética , Nervio Sural/patologíaRESUMEN
The tau gene has been found to be the locus of dementia with rigidity linked to chromosome 17. Exonic and intronic mutations have been described in a number of families. Here we describe a P301S mutation in exon 10 of the tau gene in a new family. Two members of this family were affected. One individual presented with frontotemporal dementia, whereas his son has corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to 2 distinct clinical phenotypes. Both individuals developed rapidly progressive disease in the third decade. Neuropathologically, the father presented with an extensive filamentous pathology made of hyperphosphorylated tau protein. Biochemically, recombinant tau protein with the P301S mutation showed a greatly reduced ability to promote microtubule assembly.
Asunto(s)
Enfermedades de los Ganglios Basales/patología , Corteza Cerebral/patología , Demencia/genética , Lóbulo Frontal/patología , Degeneración Nerviosa , Lóbulo Temporal/patología , Adulto , ADN/genética , Demencia/patología , Salud de la Familia , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Microtúbulos/ultraestructura , Persona de Mediana Edad , Mutación , Linaje , Proteínas tau/genéticaRESUMEN
We report the imaging findings in 11 patients with infantile neuroaxonal dystrophy. Ten patients underwent 15 MRI examinations; one patient had only CT. Of the ten patients who underwent MRI, eight had cerebellar atrophy and mildly increased signal from the cerebellar cortex on T2-weighted images. With T2 weighting there was slightly increased signal from the dentate nuclei in two patients and from the posterior periventricular white matter in three. We saw four patients with a thin optic chiasm. The only two brothers in the series had markedly low signal from the globus pallidus and substantia nigra on 1.5 T T2-weighted images, as seen in Hallervorden-Spatz disease (HSD). Abnormalities of the globus pallidus may be related to a protracted course of the disease. However, an overlap with HSD should be considered.