The Experts below are selected from a list of 516 Experts worldwide ranked by ideXlab platform
Paula S. Henthorn - One of the best experts on this subject based on the ideXlab platform.
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A novel mitofusin 2 mutation causes canine fetal-onset Neuroaxonal Dystrophy
neurogenetics, 2011Co-Authors: John C. Fyfe, Rabá A. Al-tamimi, Junlong Liu, Alejandro A. Schäffer, Richa Agarwala, Paula S. HenthornAbstract:We recently reported autosomal recessive fetal-onset Neuroaxonal Dystrophy (FNAD) in a large family of dogs that is not caused by mutation in the PLA2G6 locus (Fyfe et al., J Comp Neurol 518:3771–3784, 2010 ). Here, we report a genome-wide linkage analysis using 333 microsatellite markers to map canine FNAD to the telomeric end of chromosome 2. The interval of zero recombination was refined by single-nucleotide polymorphism (SNP) haplotype analysis to ~200 kb, and the included genes were sequenced. We found a homozygous 3-nucleotide deletion in exon 14 of mitofusin 2 ( MFN2 ), predicting loss of a glutamate residue at position 539 in the protein of affected dogs. RT-PCR demonstrated near normal expression of the mutant mRNA, but MFN2 expression was undetectable to very low on western blots of affected dog brainstem, cerebrum, kidney, and cultured fibroblasts and by immunohistochemistry on brainstem sections. MFN2 is a multifunctional, membrane-bound GTPase of mitochondria and endoplasmic reticulum most commonly associated with human Charcot–Marie–Tooth disease type 2A2. The canine disorder extends the range of MFN2 -associated phenotypes and suggests MFN2 as a candidate gene for rare cases of human FNAD.
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inherited Neuroaxonal Dystrophy in dogs causing lethal fetal onset motor system dysfunction and cerebellar hypoplasia
The Journal of Comparative Neurology, 2010Co-Authors: John C. Fyfe, Raba A Altamimi, Rudy J Castellani, Diana S Rosenstein, Dan Goldowitz, Paula S. HenthornAbstract:Neuroaxonal Dystrophy in brainstem, spinal cord tracts, and spinal nerves accompanied by cerebellar hypoplasia was observed in a colony of laboratory dogs. Fetal akinesia was documented by ultrasonographic examination. At birth, affected puppies exhibited stereotypical positioning of limbs, scoliosis, arthrogryposis, pulmonary hypoplasia, and respiratory failure. Regional hypoplasia in the central nervous system was apparent grossly, most strikingly as underdeveloped cerebellum and spinal cord. Histopathologic abnormalities included swollen axons and spheroids in brainstem and spinal cord tracts; reduced cerebellar foliation, patchy loss of Purkinje cells, multifocal thinning of the external granular cell layer, and loss of neurons in the deep cerebellar nuclei; spheroids and loss of myelinated axons in spinal roots and peripheral nerves; increased myocyte apoptosis in skeletal muscle; and fibrofatty connective tissue proliferation around joints. Breeding studies demonstrated that the canine disorder is a fully penetrant, simple autosomal recessive trait. The disorder demonstrated a type and distribution of lesions homologous to that of human infantile Neuroaxonal Dystrophy (INAD), most commonly caused by mutations of phospholipase A2 group VI gene (PLA2G6), but alleles of informative markers flanking the canine PLA2G6 locus did not associate with the canine disorder. Thus, fetal-onset Neuroaxonal Dystrophy in dogs, a species with well-developed genome mapping resources, provides a unique opportunity for additional disease gene discovery and understanding of this pathology.
Carlo Fusco - One of the best experts on this subject based on the ideXlab platform.
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Infantile Neuroaxonal Dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis.
Brain & development, 2016Co-Authors: Alessandro Iodice, Daniele Frattini, Carlotta Spagnoli, Grazia Gabriella Salerno, Gianna Bertani, Patrizia Bergonzini, Francesco Pisani, Carlo FuscoAbstract:Infantile Neuroaxonal Dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile Neuroaxonal Dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical Neuroaxonal Dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.
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Brief Communication A Case of Infantile Neuroaxonal Dystrophy of Neonatal Onset
2016Co-Authors: Carlo Fusco, Daniele Frattini, Celeste Panteghini, Rosario Pascarella, Barbara GaravagliaAbstract:Infantile Neuroaxonal Dystrophy is a rare neurodegenerative disorder, with onset in the first or second year of life. Mutations in the PLA2G6 gene encoding iPLA2-VI, a calcium-independent phospholipase, have been identified in these children. In classic infan-tile Neuroaxonal Dystrophy–affected children, psychomotor regression is the most frequent presentation, usually with ataxia and optic atrophy, followed by the development of tetraparesis. We report a child carrying a homozygous mutation in the PLA2G6 gene with neonatal onset of disease and somewhat different clinical phenotype such as severe congenital hypotonia, marked weakness, and bulbar signs suggesting that infantile Neuroaxonal Dystrophy can start at birth with atypical phenotype
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A Case of Infantile Neuroaxonal Dystrophy of Neonatal Onset
Journal of child neurology, 2014Co-Authors: Carlo Fusco, Daniele Frattini, Celeste Panteghini, Rosario Pascarella, Barbara GaravagliaAbstract:Infantile Neuroaxonal Dystrophy is a rare neurodegenerative disorder, with onset in the first or second year of life. Mutations in the PLA2G6 gene encoding iPLA2-VI, a calcium-independent phospholipase, have been identified in these children. In classic infantile Neuroaxonal Dystrophy–affected children, psychomotor regression is the most frequent presentation, usually with ataxia and optic atrophy, followed by the development of tetraparesis. We report a child carrying a homozygous mutation in the PLA2G6 gene with neonatal onset of disease and somewhat different clinical phenotype such as severe congenital hypotonia, marked weakness, and bulbar signs suggesting that infantile Neuroaxonal Dystrophy can start at birth with atypical phenotype.
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Downbeat nystagmus as the presenting symptom of infantile Neuroaxonal Dystrophy: a case report.
Brain & development, 2014Co-Authors: Daniele Frattini, N. Nardocci, Barbara Garavaglia, Celeste Panteghini, Rosario Pascarella, Carlo FuscoAbstract:Abstract Infantile Neuroaxonal Dystrophy is a rare neurodegenerative disorder characterized by infantile onset and rapid progression of psychomotor regression and hypotonia evolving into spasticity and dementia. Although nystagmus is a well-established neurological sign in infantile Neuroaxonal Dystrophy, it is mainly described as pendular and noticed in later stages of the disease. We report a 13-month-old girl with infantile Neuroaxonal Dystrophy harboring a compound heterozygous mutation in the PLA2G6 gene with downbeat nystagmus as the only presenting symptom. Our case indicates that downbeat nystagmus can be a rare but very early onset sign of cerebellar involvement in infantile Neuroaxonal Dystrophy and can anticipate the appearance of psychomotor regression and neuroradiological abnormalities.
N. Nardocci - One of the best experts on this subject based on the ideXlab platform.
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R106C TFG variant causes infantile Neuroaxonal Dystrophy “plus” syndrome
neurogenetics, 2018Co-Authors: A. Catania, N. Nardocci, B. Garavaglia, G. Zorzi, R. Battini, T. Pippucci, R. Pasquariello, M. L. Chiapparini, M. Seri, D. GhezziAbstract:TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile Neuroaxonal Dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient’s fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.
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R106C TFG variant causes infantile Neuroaxonal Dystrophy “plus” syndrome
'Springer Science and Business Media LLC', 2018Co-Authors: A. Catania, N. Nardocci, B. Garavaglia, G. Zorzi, R. Battini, T. Pippucci, R. Pasquariello, M. L. Chiapparini, M. Seri, D. GhezziAbstract:TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile Neuroaxonal Dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient\u2019s fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking
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Downbeat nystagmus as the presenting symptom of infantile Neuroaxonal Dystrophy: a case report.
Brain & development, 2014Co-Authors: Daniele Frattini, N. Nardocci, Barbara Garavaglia, Celeste Panteghini, Rosario Pascarella, Carlo FuscoAbstract:Abstract Infantile Neuroaxonal Dystrophy is a rare neurodegenerative disorder characterized by infantile onset and rapid progression of psychomotor regression and hypotonia evolving into spasticity and dementia. Although nystagmus is a well-established neurological sign in infantile Neuroaxonal Dystrophy, it is mainly described as pendular and noticed in later stages of the disease. We report a 13-month-old girl with infantile Neuroaxonal Dystrophy harboring a compound heterozygous mutation in the PLA2G6 gene with downbeat nystagmus as the only presenting symptom. Our case indicates that downbeat nystagmus can be a rare but very early onset sign of cerebellar involvement in infantile Neuroaxonal Dystrophy and can anticipate the appearance of psychomotor regression and neuroradiological abnormalities.
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Infantile Neuroaxonal Dystrophy and pantothenate-kinase-associated neurodegeneration: locus heterogeneity.
Neurology, 2004Co-Authors: Konstanze Hörtnagel, Thomas Meitinger, Evelyn Botz, N. Nardocci, Giovanna Zorzi, Barbara Garavaglia, Thomas KlopstockAbstract:Common clinical, radiologic, and pathologic features in infantile Neuroaxonal Dystrophy (INAD) and pantothenate kinase-associated neurodegeneration (PKAN) have led to the hypothesis of an allelic relationship. With the discovery of the gene defect in PKAN, this can now be tested directly. The authors excluded linkage in one consanguineous INAD family by haplotype analysis. Moreover, sequencing in seven INAD families revealed no mutations in PANK2 or in other genes of CoA biogenesis. Thus, INAD and PKAN are genetically heterogeneous disorders.
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Infantile Neuroaxonal Dystrophy: neuroradiological studies in 11 patients.
Neuroradiology, 1999Co-Authors: Laura Farina, N. Nardocci, Maria Grazia Bruzzone, Ludovico D'incerti, G. Zorzi, L. Verga, M. Morbin, Mario SavoiardoAbstract: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.
John C. Fyfe - One of the best experts on this subject based on the ideXlab platform.
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A novel mitofusin 2 mutation causes canine fetal-onset Neuroaxonal Dystrophy
neurogenetics, 2011Co-Authors: John C. Fyfe, Rabá A. Al-tamimi, Junlong Liu, Alejandro A. Schäffer, Richa Agarwala, Paula S. HenthornAbstract:We recently reported autosomal recessive fetal-onset Neuroaxonal Dystrophy (FNAD) in a large family of dogs that is not caused by mutation in the PLA2G6 locus (Fyfe et al., J Comp Neurol 518:3771–3784, 2010 ). Here, we report a genome-wide linkage analysis using 333 microsatellite markers to map canine FNAD to the telomeric end of chromosome 2. The interval of zero recombination was refined by single-nucleotide polymorphism (SNP) haplotype analysis to ~200 kb, and the included genes were sequenced. We found a homozygous 3-nucleotide deletion in exon 14 of mitofusin 2 ( MFN2 ), predicting loss of a glutamate residue at position 539 in the protein of affected dogs. RT-PCR demonstrated near normal expression of the mutant mRNA, but MFN2 expression was undetectable to very low on western blots of affected dog brainstem, cerebrum, kidney, and cultured fibroblasts and by immunohistochemistry on brainstem sections. MFN2 is a multifunctional, membrane-bound GTPase of mitochondria and endoplasmic reticulum most commonly associated with human Charcot–Marie–Tooth disease type 2A2. The canine disorder extends the range of MFN2 -associated phenotypes and suggests MFN2 as a candidate gene for rare cases of human FNAD.
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inherited Neuroaxonal Dystrophy in dogs causing lethal fetal onset motor system dysfunction and cerebellar hypoplasia
The Journal of Comparative Neurology, 2010Co-Authors: John C. Fyfe, Raba A Altamimi, Rudy J Castellani, Diana S Rosenstein, Dan Goldowitz, Paula S. HenthornAbstract:Neuroaxonal Dystrophy in brainstem, spinal cord tracts, and spinal nerves accompanied by cerebellar hypoplasia was observed in a colony of laboratory dogs. Fetal akinesia was documented by ultrasonographic examination. At birth, affected puppies exhibited stereotypical positioning of limbs, scoliosis, arthrogryposis, pulmonary hypoplasia, and respiratory failure. Regional hypoplasia in the central nervous system was apparent grossly, most strikingly as underdeveloped cerebellum and spinal cord. Histopathologic abnormalities included swollen axons and spheroids in brainstem and spinal cord tracts; reduced cerebellar foliation, patchy loss of Purkinje cells, multifocal thinning of the external granular cell layer, and loss of neurons in the deep cerebellar nuclei; spheroids and loss of myelinated axons in spinal roots and peripheral nerves; increased myocyte apoptosis in skeletal muscle; and fibrofatty connective tissue proliferation around joints. Breeding studies demonstrated that the canine disorder is a fully penetrant, simple autosomal recessive trait. The disorder demonstrated a type and distribution of lesions homologous to that of human infantile Neuroaxonal Dystrophy (INAD), most commonly caused by mutations of phospholipase A2 group VI gene (PLA2G6), but alleles of informative markers flanking the canine PLA2G6 locus did not associate with the canine disorder. Thus, fetal-onset Neuroaxonal Dystrophy in dogs, a species with well-developed genome mapping resources, provides a unique opportunity for additional disease gene discovery and understanding of this pathology.
John W. Finnie - One of the best experts on this subject based on the ideXlab platform.
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primary congenital Neuroaxonal Dystrophy with peripheral nerve demyelination in merino border leicester polled dorset lambs
Australian Veterinary Journal, 2017Co-Authors: M C Hawes, John W. Finnie, I V Jerrett, R Badman, M ScottAbstract:CASE REPORT: Clinicopathological features of Neuroaxonal Dystrophy (NAD) in newborn, Merino-Border Leicester × Polled Dorset lambs are described. The affected lambs were unable to walk at birth and microscopic examination of brainstem and spinal cord sections revealed bilaterally symmetrical accumulations of axonal swellings (spheroids), the histological hallmark of primary NAD. The neurological deficit was also exacerbated by myelin loss and secondary axonal degeneration, particularly in the spinal cord and sciatic nerves, but also, to a more limited extent, in brainstem and spinal nerves. CONCLUSIONS: Although lambs previously diagnosed with NAD have ranged in age from 2 days to 7 months, this is believed to be the first report of congenital NAD in this species. Moreover, the present cases are the only ones in which peripheral nerve demyelination has been found.
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Neuroaxonal Dystrophy in merino border leicester polled dorset lambs
Australian Veterinary Journal, 2014Co-Authors: John W. Finnie, I V Jerrett, Jim Manavis, J CaveAbstract:Case report The clinicopathological features of Neuroaxonal Dystrophy (NAD) in 2 lambs are described. Of 40 Merino-Border Leicester × Polled Dorset lambs on a property in north-eastern Victoria, 4 presented with marked ataxia and listlessness, and 2 affected animals (2 days and 2 weeks of age, respectively) of both sexes were necropsied. Numerous axonal swellings (spheroids) were found in the central nervous system, particularly in brainstem nuclei and spinal cord grey matter, and there was severe spinal cord demyelination. Conclusions This is the first report of NAD in such crossbred lambs; the affected animals were much younger than in previously described cases of ovine NAD and myelin loss was of much greater magnitude than previously reported.
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Neuroaxonal Dystrophy in australian merino lambs
Journal of Comparative Pathology, 2012Co-Authors: Allan Kessell, John W. Finnie, Jim Manavis, P C Blumbergs, I V JerrettAbstract:Neuroaxonal Dystrophy (NAD) is a morphological abnormality in man and animals that is characterized by the occurrence of numerous axonal swellings (spheroids) in the nervous system. NAD has been described in Suffolk lambs in the USA, Merino lambs in Australia and several breeds of sheep in New Zealand. This paper describes the clinicopathological changes of only the second occurrence of NAD reported in Merino lambs. There were some features (myelin loss, gliosis and visual impairment) in these Australian cases that have not been reported previously in ovine NAD. Application of immunohistochemical markers of axonal transport suggested that disruption of this transport mechanism contributed to spheroid development.