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The paper is concerned with a description of an atypical clinical picture of Charcot-Marie-Tooth neuronal amyotrophy in 2 eight-year old monozygotic twins. The traits of the disease were characterized by a deformation of the feet, mild cerebellar symptoms, development of ptosis and other myopathical symptoms, an enlargement of the transversal nerve of the neck and a distribution of the process to the proximal parts. The diagnosis was confirmed by EMG studies. The authors detected a large amount of abortive signs in many members of the family both along the mothers, as well as fathers line. This observation demonstrates clinical and genetical polymorphism of neuronal amyotraphy.
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PMID:[Polymorphism of Charcot-Marie-Tooth neural amyotrophy in uniovular twins]. 56 55

We present a kindred with a previously undescribed combination of neuronal Charcot-Marie-Tooth disease, ptosis, parkinsonism, and mild dementia. The propositus, a 72-year-old man, had pes cavus, peripheral neuropathy, ptosis, parkinsonism, hyperreflexia, orthostatic hypotension, central hypoventilation, and mild dementia. Peripheral electrophysiologic studies showed features of an axonal neuropathy. The electroencephalogram showed intermittent 2 to 4 Hz activity symmetrically in the hemispheres. Several family members in 3 generations had pes cavus, neuropathy, ptosis, parkinsonism, and dementia although not all of the features were consistently present. Survival past the 7th decade was common. Autopsy in 2 affected members revealed the neuropathy to be axonal in type and showed mild to moderate loss of anterior horn cells in the spinal cord and pigmentary loss with gliosis in the substantia nigra. This is a unique, benign, autosomal dominant syndrome which shows complete penetrance, variable expression, and both central and peripheral nervous system involvement.
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PMID:Benign autosomal dominant syndrome of neuronal Charcot-Marie-Tooth disease, ptosis, parkinsonism, and dementia. 218 81

Peroneal muscular atrophy (PMA) may be occasionally associated with other neurodegenerative features including parkinsonism. We report the association of PMA of neuronal type with parkinsonism, ptosis and congenital strabismus in a 62-year-old Sicilian woman. The complete syndrome was present only in the proband, but variously combined features were present in ten other family members over four generations, with likely autosomal dominant inheritance. Although a similar syndrome of PMA, ptosis, parkinsonism and dementia was already reported, this family showed a previously undescribed combination of features in view of the presence of congenital strabismus.
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PMID:Peroneal muscular atrophy with parkinsonism, ptosis, and congenital strabismus. 825 67

Centronuclear myopathy (CNM) is a slowly progressive congenital myopathy characterized by abnormal centrally located nuclei in a large number of muscle fibres. Recently, different missense mutations affecting the middle domain of the dynamin 2 (DNM2) have been shown to cause autosomal dominant CNM. In order to better define the phenotype of DNM2-related CNM, we report here on the clinical and muscle imaging findings of 10 patients harbouring DNM2 mutations. DNM2-CNM is characterized by slowly progressive muscular weakness usually beginning in adolescence or early adulthood. In addition to bilateral ptosis, our data show that distal muscle weakness often exceeds proximal involvement. Furthermore, electrophysiological investigations frequently demonstrated signs of mild axonal peripheral nerve involvement, and electromyographical examination may show neuropathic changes in addition to the predominant myopathic changes. These features overlap with findings seen in the phenotype of DNM2-related autosomal dominant Charcot-Marie-Tooth disease type 2B. In all 10 DNM2-CNM patients, muscle computer tomography assessment showed a consistent pattern of muscular involvement and a characteristic temporal course with early and predominant distal muscle involvement, and later affection of the posterior thigh compartment and gluteus minimus muscles. The recognition of this specific imaging pattern of muscle involvement--distinct to the reported patterns in other congenital myopathies--may enable a better selection for direct genetic testing.
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PMID:Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy. 1723 17

Mutations in dynamin 2 (DNM2) have been associated with autosomal dominant centronuclear myopathy, dominant intermediate Charcot-Marie-Tooth (CMT) type B and CMT2. Here, we report a novel DNM2 mutation in the Pleckstrin homology domain of DNM2 (p.K559del) in a patient with an axonal length-dependent sensorimotor polyneuropathy predominantly affecting the lower limbs. Neuropathy is associated with congenital cataracts, ophthalmoparesis, ptosis and neutropenia. There was no evidence of a skeletal myopathy on EMG or muscle biopsy. We suggest that this constellation of clinical features can help the diagnosis and selection of patients for direct DNM2 genetic analysis.
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PMID:A novel mutation in the dynamin 2 gene in a Charcot-Marie-Tooth type 2 patient: clinical and pathological findings. 1839 88

By homologous EST searching and nested PCR a new human geneGJB5 encoding gap junction protein beta-5 was identified.GJB5 was genetically mapped to human chromosome 1p33-p35 by FISH. RT-PCR revealed that it was expressed in skin, placenta and fetal skin. DNA sequencing ofGJB5 was carried out in 142 patients with sensorineural hearing impairment and probands of 36 families with genetic diseases, including erythrokeratodermia (5 families), Charcot-Marie-Tooth disease (13), ptosis (4), and retinitis pigmentosa and deafness (14). Two missense mutations (686A-->G, H229R; 25C-->T, L9F) were detected in two sensorineural hearing impairment families. A heterologous deletion of 18 bp within intron was found in 3 families with heredity hearing impairment, and in one of the 3 families, a missense mutation (R265P) was identified also. But the deletion and missense mutation seemed not segregating with hearing impairment in the family. No abnormal mRNA or mRNA expression was detected in deletion carriers by RT-PCR analysis in skin tissue. Mutation analysis in 199 unaffected individuals revealed that two of them were carriers with the same 18 bp deletion.
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PMID:Cloning, mapping and mutation analysis of human geneGJB5 encoding gap junction protein beta-5. 1876 93

Dynamin 2 (DNM2)-related dominant centronuclear myopathy is usually a mild disorder, but more severe variants have been associated with mutations affecting the pleckstrin homology (PH) domain of the protein, mainly implicated in different forms of Charcot-Marie-Tooth Disease (CMT). Whilst DNM2-related CMT may feature non-neurological findings including cataracts, this has not been reported in DNM2-related centronuclear myopathy. We report a girl presenting from birth with hypotonia, respiratory and feeding difficulties. Motor development was delayed and at 9years she lost the ability to walk. She had ptosis, external ophthalmoplegia and bilateral cataracts. Muscle biopsy showed increase in central nuclei with type 1 hypotrophy and fibrosis. DNM2 screening revealed a novel heterozygous substitution (c.1862T>C; p.Leu621Pro) affecting the PH domain of the protein. Her further course was progressive and at 14years she died from respiratory failure. Our findings expand the phenotypical spectrum associated with DNM2 mutations and provide a new clinical indicator for involvement of this gene in patients with centronuclear myopathy.
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PMID:Centronuclear myopathy with cataracts due to a novel dynamin 2 (DNM2) mutation. 1993 20

We report the case of a 62-year-old man with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO). He developed gait disturbance at 54 years of age, muscle weakness at 56 years, and difficulty hearing at 58 years. His brother had muscle weakness in both legs from age 20 years, and was diagnosed with Charcot-Marie-Tooth disease because he had muscle weakness of the four extremities, decreased CMAP and SNAP amplitudes on peripheral nerve conduction tests, and loss of large myelinated fibers and onion-bulb formations on sural nerve biopsy. His brother died aged 46 years, but no accurate cause of death was identified. Neurological examination of the present patient revealed bilateral ptosis, external ophthalmoparesis, dysarthria, dysphagia, sensorineural hearing loss, mild weakness and atrophy of proximal muscles in all four limbs, severe sensory ataxia, and disturbance of deep sensation in his legs. He showed elevation of lactate and pyruvate levels in cerebrospinal fluid and serum. An aerobic exercise test disclosed a marked increase in lactate and pyruvate levels in serum. On nerve conduction study, amplitudes of CMAP and SNAP, and F wave-evoked frequency were decreased. Needle electromyography showed chronic neurogenic patterns with fibrillation potentials in the extremity muscles. Head MRI demonstrated T2 prolonged lesions in the bilateral basal ganglia, while brain MRS revealed a small lactate peak. Biopsy of his left lateral vastus muscle showed ragged-red fibers and group atrophy, and some muscle fibers had decreased cytochrome c activity. Left sural nerve biopsy revealed a marked loss of large myelinated fibers, and some onion-bulb formations. Genetic testing disclosed a large mtDNA deletion in the biopsied muscle. Among nuclear genes, we found point mutations in ANT-1 (exon 1 c.105G>A, 5' untranslated region) and POLG-1 (exon 4, c.1218G>A, p. and exon 23 c.3920C>T, p.A1217V). We diagnosed SANDO. This is the first case of SANDO with large mitochondrial DNA deletions in Japanese.
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PMID:[A case of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis with multiple mitochondrial DNA deletions]. 2352

Dynamin2 (DNM2) gene mutations may result in Charcot-Marie-Tooth disease and centronuclear myopathy. Here, we present a patient suffering from cardiomyopathy and centronuclear myopathy with repetitive discharges and mild axonal neuropathy due to DNM2 mutation. Detailed cardiological and neurological examinations, electrophysiological tests, muscle biopsy, and molecular genetic analysis were performed. The patient developed left bundle branch block at age 40 and was fitted with a pacemaker at the age of 43. The patient has severe heart failure, ptosis, strabism, facial and proximal muscle weakness. Electrophysiological investigations found myopathy, complex repetitive discharges, and axonal neuropathy. Skeletal muscle biopsy detected centronuclear myopathy and cytochrome C oxidase (COX) negative fibers. Genetic analysis detected a pathogenic c.1105C>T (p.R369W) DNM2 gene mutation and heteroplasmic multiple mitochondrial DNA (mtDNA) deletion. Our data broadens the phenotypic spectrum of DNM2 mutations. The presence of the multiple mtDNA deletions may provide new aspects to understanding the pathogenesis of multisystemic symptoms in patients with DNM2 mutations.
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PMID:The coexistence of dynamin 2 mutation and multiple mitochondrial DNA (mtDNA) deletions in the background of severe cardiomyopathy and centronuclear myopathy. 2549 87

Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases, and with a complex phenotype with immunodeficiency, skin changes and myelodysplasia. MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication. In this study, we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause. The affected individuals were homozygous for a missense MCM3AP variant, located at the Sac3 domain, which was predicted to affect conserved amino acid likely important for the function of the germinal-centre associated nuclear protein. Our data support further expansion of the clinical spectrum linked to MCM3AP variant and highlight that MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis.
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PMID:Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP. 3295 58


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