The Experts below are selected from a list of 240 Experts worldwide ranked by ideXlab platform
D. Ghezzi - 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
C. Yilmaz - One of the best experts on this subject based on the ideXlab platform.
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Kept in Mind Infantile Neuroaxonal Dystrophy.
Genetic counseling (Geneva Switzerland), 2016Co-Authors: Zeynep Selen Karalok, B.d. Taskin, U. Aydogmus, S. Ceylaner, Kadri Karaer, C. YilmazAbstract:Infantile Neuroaxonal Dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder usually presenting between the ages of six months and two years, characterized by rapidly regression of cognitive and motor functions, axial hypotonia, gait disturbance, limb spasticity, cerebellar signs, optic atrophy and confirmed by PLA2G6 gene. PLA2G6 is causative of PL^Gd-associated neurodegeneration (PLAN), which is a subgroup of neurodegeneration with brain iron accumulation (NBIA). This group includes: 1) Infantile Neuroaxonal Dystrophy (INAD); 2) Atypical later-onset NAD; 3) Karak syndrome; 4) early onset dystonia-parkinsonism with cognitive impairment (2,5). INAD patients' progression is rapid and death occurs often at the end of the first decade (3,5).We would like to share a case experience of a 20 month-boy who was admitted to our clinic for difficulty in walking and frequent falls. He started walking and talking at the age of one. He couldn't make two words sentences. He had three siblings of whom one of them had similar findings. His sister' early psychomotor development was normal till 1 year of age. From age one, she stopped making progress and subsequently she developed seizures, mental regression, became bedridden and died. His other sister was at the age of 16 and brother was at the age of 6, their medical histories was unremarkable. The parents have a third-degree consanguinity. Neurological examination of ornease showed hypotonia and had areflexia. His initial MRI revealed insignificant vermin hypoplasia, whereas the following MRI after nine months revealed cerebellar vermian hypoplasia and apparent claval hypertrophy (Fig. 1). Metabolic screening tests were normal (tandem mass spectroscopy, very long chain fatty acid, plasma and urine aminoacids, transferrin isoelectric focusing for CDG). Electromyography (EMG) showed distal axonal type sensory-motor neuropathy. His visual examination was normal at the beginning. But control visual examination showed optic atrophy without strabismus and nystagmus. Delayed visual evoked potentials (VEP) was seen. By these findings, a genetic evaluation was initiated after obtaining appropriate parental consent. To make a precise diagnosis, we then performed targeted Next Generation Sequencing (NGS) of related PLA2G6 gene. PLA2G6 gene sequencing analysis was performed using the MiSeq next generation sequencing (NGS) platform (Illumina, San Diego, CA, USA). Exons 1 to 17 of the PLA2G6 gene and their flanking splice site junctions were amplified using primers and protocols from PRIMER® - Primer Designer v.2.0 (Scientific & Educational Software Program). Obtained sequences were compared with the reference sequences deposited in the public database (NM_003560). Sequencing analysis showed missense mutation in exon 14 of PLA2G6 gene (c,1756G>A, p.G586R). The proband was homozygous whereas both parents were heterozygous mutant allele. Detected mutation occurred at highly conserved sites in the multi-sequence alignment and is predicted by three different in silico analyses: the SIFT (Sorting Intolerant From Tolerant) program (http://sift.jcvi.org/), Mutation Taster program (http://www.mutationtaster.org) and the PolyPhen2 program (http://genetics.bwh. harvard.edu/pph2/) approaches to be non-tolerated changes that affect protein function. Molecular analysis of PLA2G6 (gene sequencing) gene demonstrated a novel homozygous p.G586R (c.1756G>A) mutation. By now he is 38 months and unable to walk, can sit without support only a few minutes. He only says a word and has bulbar dysfunction (drooling).Infantile Neuroaxonal Dystrophy is RL42G6-associated neurodegeneration (PLAN) which comprises a continuum of four phenotypes with overlapping clinical and radiologic features (2,5). PLA2G6 is located at chromosome 22ql3.1. and encodes IPLA2-VI, calcium independent phospholipase and dysfunction of it causes neurodegeneration and brain-iron dyshomeostasis (7, 8). Pathological features are axonal swelling and storage of spheroids throughout the central nervous system and peripheral tissues. …
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p109 2442 Infantile Neuroaxonal Dystrophy a new mutation
European Journal of Paediatric Neurology, 2015Co-Authors: Zeynep Selen Karalok, B.d. Taskin, U. Aydogmus, S. Ceylaner, Kadri Karaer, C. YilmazAbstract:Objective Infantile Neuroaxonal Dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder characterised by rapid cognitive and motor regression, axial hypotonia, gait disturbance, limb spasticity, cerebellar signs, and optic atrophy. Although magnetic resonance imaging (MRI) can sometimes contribute towards the diagnosis, the confirmation of INAD is by Pla2G6 gene analysis. Methods A patient is presented with motor retardation, hypotonia and diagnosed as INAD with a new mutation. Results We report a two years old boy who was referred with difficulty in walking and frequent falls. He has started walking and talking at the age of one. He couldn't make two words sentence. He has two siblings of whom one of them had similar findings. He Her early psychomotor development was normal till 1 year of age. From age 1, she stopped making progress and subsequently she developed seizures, mental regression and became bedridden. Her MRI revelaed cerebellar atrophy. She died at the age of six without diagnosis. His other sister was at the age of 16 and her medical history was unremarkable. The parents have a third-degree consanguinity. Neurological examination of our case showed hypotonia and had areflexia. His initial MRI was normal whereas the following MRI after nine months revealed cerebellar vermian hypoplasia. Metabolic screening tests were normal (Tandem mass spectroscopy, very long chain fatty acid, plasma and urine aminoacids, transferin isoelectric focusing for CDG). Electromyography showed motor axonal neuropathy. His visual examination was normal. Molecular analysis of PLA2G6 gene demonstrated a novel homozygous P.G586R (c.1756G>A) mutation. Conclusion Our case indicates that INAD should be kept in mind in the differential diagnosis of patients with hypotonia and psychomotor regression.
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P109 – 2442: Infantile Neuroaxonal Dystrophy: A new mutation
European Journal of Paediatric Neurology, 2015Co-Authors: Zeynep Selen Karalok, B.d. Taskin, U. Aydogmus, S. Ceylaner, Kadri Karaer, C. YilmazAbstract:Objective Infantile Neuroaxonal Dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder characterised by rapid cognitive and motor regression, axial hypotonia, gait disturbance, limb spasticity, cerebellar signs, and optic atrophy. Although magnetic resonance imaging (MRI) can sometimes contribute towards the diagnosis, the confirmation of INAD is by Pla2G6 gene analysis. Methods A patient is presented with motor retardation, hypotonia and diagnosed as INAD with a new mutation. Results We report a two years old boy who was referred with difficulty in walking and frequent falls. He has started walking and talking at the age of one. He couldn't make two words sentence. He has two siblings of whom one of them had similar findings. He Her early psychomotor development was normal till 1 year of age. From age 1, she stopped making progress and subsequently she developed seizures, mental regression and became bedridden. Her MRI revelaed cerebellar atrophy. She died at the age of six without diagnosis. His other sister was at the age of 16 and her medical history was unremarkable. The parents have a third-degree consanguinity. Neurological examination of our case showed hypotonia and had areflexia. His initial MRI was normal whereas the following MRI after nine months revealed cerebellar vermian hypoplasia. Metabolic screening tests were normal (Tandem mass spectroscopy, very long chain fatty acid, plasma and urine aminoacids, transferin isoelectric focusing for CDG). Electromyography showed motor axonal neuropathy. His visual examination was normal. Molecular analysis of PLA2G6 gene demonstrated a novel homozygous P.G586R (c.1756G>A) mutation. Conclusion Our case indicates that INAD should be kept in mind in the differential diagnosis of patients with hypotonia and psychomotor regression.
G. Zorzi - 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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Infantile Neuroaxonal Dystrophy: neuroradiological studies in 11 patients.
Neuroradiology, 1999Co-Authors: Laura Farina, Nardo 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.
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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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.
Shunzo Chiba - One of the best experts on this subject based on the ideXlab platform.
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ictal video eeg analysis of Infantile Neuroaxonal Dystrophy
Epilepsia, 1994Co-Authors: Shuji Wakai, Hideomi Asanuma, Hiroyuki Hayasaka, Yoshitaka Kawamoto, Hirofumi Sueoka, Yukitoshi Ishikawa, Ryoji Minami, Shunzo ChibaAbstract:A 4-year-old boy with Infantile Neuroaxonal Dystrophy (INAD) showed gradual deterioration from age 9 months with seizure development at age approximately 36 months. Sural nerve biopsy performed at age 42 months confirmed INAD. The seizure, recorded by video-EEG, consisted of a series of symmetrical tonic spasms of both upper extremities after a prodrome period of staring and akinesis. Each spasm had phonation, and episodic autonomic symptoms such as hypertension and flushing of the face occurred throughout the seizure. Ictal EEG with each tonic spasm, showed diffuse 1-s, irregular sharp and high-voltage slow wave complexes followed by desynchronization.
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Ictal Video‐EEG Analysis of Infantile Neuroaxonal Dystrophy
Epilepsia, 1994Co-Authors: Shuji Wakai, Hideomi Asanuma, Hiroyuki Hayasaka, Yoshitaka Kawamoto, Hirofumi Sueoka, Yukitoshi Ishikawa, Ryoji Minami, Shunzo ChibaAbstract:A 4-year-old boy with Infantile Neuroaxonal Dystrophy (INAD) showed gradual deterioration from age 9 months with seizure development at age approximately 36 months. Sural nerve biopsy performed at age 42 months confirmed INAD. The seizure, recorded by video-EEG, consisted of a series of symmetrical tonic spasms of both upper extremities after a prodrome period of staring and akinesis. Each spasm had phonation, and episodic autonomic symptoms such as hypertension and flushing of the face occurred throughout the seizure. Ictal EEG with each tonic spasm, showed diffuse 1-s, irregular sharp and high-voltage slow wave complexes followed by desynchronization.