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1.
Invest Ophthalmol Vis Sci ; 65(2): 38, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38411969

RESUMO

Purpose: To investigate the molecular effect of the variant PHYH:c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency of 0.0045 in the South Asian population in gnomAD. Methods: We recruited patients from Moorfields Eye Hospital (London, UK) and Buenos Aires, Argentina, who were diagnosed with retinitis pigmentosa and found to have biallelic variants in PHYH, with at least one being c.678+5G>T. Total RNA was purified from PaxGene RNA-stabilized whole-blood samples, followed by reverse transcription to cDNA, PCR amplification of the canonical PHYH transcript, Oxford Nanopore Technologies library preparation, and single-molecule amplicon sequencing. Results: Four patients provided a blood sample. One patient had isolated retinitis pigmentosa and three had mild extraocular findings. Blood phytanic acid levels were normal in two patients, mildly elevated in one, and markedly high in the fourth. Retinal evaluation showed an intact ellipsoid zone as well as preserved autofluorescence in the macular region in three of the four patients. In all patients, we observed in-frame skipping of exons 5 and 6 in 31.1% to 88.4% of the amplicons and a smaller proportion (0% to 11.3% of amplicons) skipping exon 6 only. Conclusions: We demonstrate a significant effect of PHYH:c.678+5G>T on splicing of the canonical transcript. The in-frame nature of this may be in keeping with a mild presentation and higher prevalence in the general population. These data support the classification of the variant as pathogenic, and patients harboring a biallelic genotype should undergo phytanic acid testing.


Assuntos
Doença de Refsum , Retinite Pigmentosa , Humanos , Ácido Fitânico , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/genética , Éxons/genética , RNA/genética , Oxigenases de Função Mista
2.
Nutrients ; 15(11)2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37299514

RESUMO

Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. Many patients with ARD require diet modification, psychosocial support, and various specialist visits to manage their symptoms. In this study, we explored the quality of life in individuals with ARD by analyzing retrospective survey data collected by the Coordination of Rare Diseases at Sanford (CoRDS) Registry and Global Defeat Adult Refsum Everywhere (DARE) Foundation. Statistical tests used were frequencies, mean, and median. There were 32 respondents, ranging between 11 and 32 responses for each question. The mean age at diagnosis was 35.5 ± 14.5 years (range 6-64) with 36.4% male and 63.6% female respondents. The average age for retinitis pigmentosa diagnosis was 22.8 ± 15.7 years (range 2-61). Dieticians were the most frequently seen (41.7%) for management of low-phytanic-acid diets. Most participants exercise at least once per week (92.5%). Depression symptoms were reported in 86.2% of the participants. Early diagnosis of ARD is important for managing symptoms and preventing progression of visual impairment due to phytanic acid buildup. Interdisciplinary approach should be used for patients to address physical and psychosocial impairments of ARD.


Assuntos
Doença de Refsum , Retinite Pigmentosa , Adulto , Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Doença de Refsum/diagnóstico , Ácido Fitânico , Estudos Retrospectivos , Qualidade de Vida , Estilo de Vida
3.
J Food Sci ; 88(6): 2385-2396, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37122139

RESUMO

Phytol is a diterpene alcohol found abundantly in nature as the phytyl side chain of chlorophylls. Free form of phytol and its metabolites have been attracting attention because they have a potential to improve the lipid and glucose metabolism. On the other hand, phytol is unfavorable for those who suffering from Refsum's disease. However, there is little information on the phytol contents in leafy vegetables rich in chlorophylls. This study indicated that raw spinach leaves contain phytol of 0.4-1.5 mg/100 g fresh weight. Furthermore, crude enzyme extracted from the leaves showed the enzyme activities involved in dephytylation of chlorophyll derivatives and they were high at mild alkaline pH and around 45°C, and lowered at 55°C or above. Under the optimum pH and temperature for such enzymes determined in the model reaction using the crude enzyme, phytol content in the smoothie made from raw spinach leaves increased with an increase of chlorophyllide, another reaction product. Comparison between the increased amounts of phytol and chlorophyllide showed that the enzymatic dephytylation of chlorophylls was critically responsible for the increase of phytol in the smoothie. PRACTICAL APPLICATION: Phytol, which is released by the enzymes related to chlorophyll metabolism in plants, has been investigated because of its potential abilities to improve the lipid metabolism and blood glucose level. In contrast to such health benefits, they are known to be toxic for patients suffering from Refsum's disease. This research for the first time reports the phytol content in raw spinach leaves and that phytol can be increased in the smoothie made from spinach leaves by the action of endogenous enzymes on chlorophyll derivatives under a certain condition. These results help control phytol content in the smoothies.


Assuntos
Clorofilídeos , Doença de Refsum , Humanos , Clorofilídeos/metabolismo , Spinacia oleracea/metabolismo , Doença de Refsum/metabolismo , Fitol/metabolismo , Clorofila
5.
Biochim Biophys Acta Bioenerg ; 1864(2): 148961, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36812958

RESUMO

Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid (Phyt) concentrations are highly increased in tissues of individuals with this disease, it is conceivable that this branched-chain fatty acid is cardiotoxic. The present study investigated whether Phyt (10-30 µM) could disturb important mitochondrial functions in rat heart mitochondria. We also determined the influence of Phyt (50-100 µM) on cell viability (MTT reduction) in cardiac cells (H9C2). Phyt markedly increased mitochondrial state 4 (resting) and decreased state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respirations, besides reducing the respiratory control ratio, ATP synthesis and the activities of the respiratory chain complexes I-III, II, and II-III. This fatty acid also reduced mitochondrial membrane potential and induced swelling in mitochondria supplemented by exogenous Ca2+, which were prevented by cyclosporin A alone or combined with ADP, suggesting the involvement of the mitochondrial permeability transition (MPT) pore opening. Mitochondrial NAD(P)H content and Ca2+ retention capacity were also decreased by Phyt in the presence of Ca2+. Finally, Phyt significantly reduced cellular viability (MTT reduction) in cultured cardiomyocytes. The present data indicate that Phyt, at concentrations found in the plasma of patients with Refsum disease, disrupts by multiple mechanisms mitochondrial bioenergetics and Ca2+ homeostasis, which could presumably be involved in the cardiomyopathy of this disease.


Assuntos
Cardiomiopatias , Doença de Refsum , Ratos , Animais , Doença de Refsum/metabolismo , Ácido Fitânico/farmacologia , Ácido Fitânico/metabolismo , Cálcio/metabolismo , Ratos Wistar , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Metabolismo Energético , Mitocôndrias Cardíacas/metabolismo , Ácidos Graxos/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Homeostase
6.
Commun Biol ; 5(1): 1216, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357486

RESUMO

Peripheral tolerance prevents the initiation of damaging immune responses by autoreactive lymphocytes. While tolerogenic mechanisms are tightly regulated by antigen-dependent and independent signals, downstream pathways are incompletely understood. N-myc downstream-regulated gene 1 (NDRG1), an anti-cancer therapeutic target, has previously been implicated as a CD4+ T cell clonal anergy factor. By RNA-sequencing, we identified Ndrg1 as the third most upregulated gene in anergic, compared to naïve follicular, B cells. Ndrg1 is upregulated by B cell receptor activation (signal one) and suppressed by co-stimulation (signal two), suggesting that NDRG1 may be important in B cell tolerance. However, though Ndrg1-/- mice have a neurological defect mimicking NDRG1-associated Charcot-Marie-Tooth (CMT4d) disease, primary and secondary immune responses were normal. We find that B cell tolerance is maintained, and NDRG1 does not play a role in downstream responses during re-stimulation of in vivo antigen-experienced CD4+ T cells, demonstrating that NDGR1 is functionally redundant for lymphocyte anergy.


Assuntos
Doença de Charcot-Marie-Tooth , Doença de Refsum , Camundongos , Animais , Linfócitos T , Doença de Refsum/genética , Doença de Refsum/metabolismo , Doença de Charcot-Marie-Tooth/genética , Tolerância Imunológica , Ativação Linfocitária
7.
Mol Cell Biol ; 42(7): e0055921, 2022 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-35708320

RESUMO

Charcot-Marie-Tooth type 4D (CMT4D) is an autosomal recessive demyelinating form of CMT characterized by progressive motor and sensory neuropathy. N-myc downstream regulated gene 1 (NDRG1) is the causative gene for CMT4D. Although more CMT4D cases have been reported, the comprehensive molecular mechanism underlying CMT4D remains elusive. Here, we generated a novel knockout mouse model in which the fourth and fifth exons of the Ndrg1 gene were removed. Ndrg1-deficient mice develop early progressive demyelinating neuropathy and limb muscle weakness. The expression pattern of myelination-related transcriptional factors, including SOX10, OCT6, and EGR2, was abnormal in Ndrg1-deficient mice. We further investigated the activation of the ErbB2/3 receptor tyrosine kinases in Ndrg1-deficient sciatic nerves, as these proteins play essential roles in Schwann cell myelination. In the absence of NDRG1, although the total ErbB2/3 receptors expressed by Schwann cells were significantly increased, levels of the phosphorylated forms of ErbB2/3 and their downstream signaling cascades were decreased. This change was not associated with the level of the neuregulin 1 ligand, which was increased in Ndrg1-deficient mice. In addition, the integrin ß4 receptor, which interacts with ErbB2/3 and positively regulates neuregulin 1/ErbB signaling, was significantly reduced in the Ndrg1-deficient nerve. In conclusion, our data suggest that the demyelinating phenotype of CMT4D disease is at least in part a consequence of molecular defects in neuregulin 1/ErbB signaling.


Assuntos
Doença de Charcot-Marie-Tooth , Doença de Refsum , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/metabolismo , Receptores ErbB , Camundongos , Neuregulina-1/genética , Neuregulina-1/metabolismo , Fenótipo , Doença de Refsum/genética , Doença de Refsum/metabolismo , Células de Schwann/metabolismo
8.
Neurol Sci ; 43(7): 4463-4472, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35149926

RESUMO

Charcot-Marie-Tooth disease, type 4D (CMT4D) is a progressive, autosomal recessive form of CMT, characterized by distal muscle weakness and atrophy, foot deformities, severe motor sensory neuropathy, and sensorineural hearing impairment. Mutations in NDRG1 gene cause neuropathy in humans, dogs, and rodents. Here, we describe clinical and genetic features of a 17-year-old male with wasting of hand muscle and foot and severe motor neuropathy. Whole exome sequencing was carried out on the patient and his unaffected parents. We identified a novel deletion of nine nucleotides (c.537 + 2_537 + 10del) on the splice donor site of intron 8 in NDRG1 gene. The Sanger sequencing confirmed the segregation of this mutation in autosomal recessive inheritance. Furthermore, transcript analysis confirmed a splice defect and reveals using of an alternate cryptic splice donor site on the downstream intronic region. It resulted in an insertion of 42 nucleotides to exon 8 of NDRG1. Translation of the resulting transcript sequence revealed an insertion of 14 amino acids in-frame to the existing NDRG1 protein. This insertion is predicted to disrupt an alpha helix which is involved in protein-protein interactions in homologous proteins. Our study expands the clinical and genetic spectrum of CMT4D. The splice defect we found in this patient reveals a novel splice isoform of NDRG1 as the potential cause for the neuropathy observed in this patient.


Assuntos
Doença de Charcot-Marie-Tooth , Sítios de Splice de RNA , Adolescente , Doença de Charcot-Marie-Tooth/genética , Humanos , Masculino , Mutação/genética , Nucleotídeos , Sítios de Splice de RNA/genética , Doença de Refsum
10.
FEBS J ; 287(23): 5096-5113, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32160399

RESUMO

Refsum disease (RD) is an inborn error of metabolism that is characterised by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanate in plasma and tissues of patients. To date, no cure exists for RD, but phytanate levels in patients can be reduced by plasmapheresis and a strict diet. In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics and proteomics (available via ProteomeXchange with identifier PXD015518) data, which we obtained from healthy controls and RD patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanate and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of RD at the genome scale, and we studied the effect of phytanate on cell metabolism. We identified 53 metabolites that were predicted to discriminate between healthy and RD patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy. DATABASES: Transcriptomics data are available via GEO database with identifier GSE138379, and proteomics data are available via ProteomeXchange with identifier PXD015518.


Assuntos
Aminoácidos/metabolismo , Biomarcadores/análise , Fibroblastos/patologia , Metaboloma , Proteoma , Doença de Refsum/patologia , Transcriptoma , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Doença de Refsum/genética , Doença de Refsum/metabolismo
12.
Adv Exp Med Biol ; 1085: 191-192, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30578512

RESUMO

Patient with Refsum disease present with nyctalopia, and the fundus shows progressive panretinal degeneration. Vision gradually decreases, with progressive peripheral constriction. The pupil usually does not dilate well.


Assuntos
Erros Inatos do Metabolismo/fisiopatologia , Doença de Refsum/fisiopatologia , Fundo de Olho , Humanos , Cegueira Noturna/patologia
13.
J Clin Neurosci ; 53: 231-234, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29724652

RESUMO

Charcot-Marie-Tooth disease 4D (CMT4D) is characterized by severe peripheral neuropathy and deafness. It is caused by mutations in the N-myc downstream-regulated gene 1 (NDRG1). We report a Chinese man with a homozygous mutation c.675C > T of NDRG1 that resulted in Q185X, representing the third known CMT4D patient of non-European ancestry. The patient presented with a 15-year-long history of progressive limb weakness accompanied by hearing loss and dysarthria. There was abnormal differentiation and increased interpeak latencies in brainstem auditory evoked potentials. Compound muscle action potentials (CMAP) of the peripheral nerves were not elicited in distal segments, while prolonged distal latencies and decreased CMAP were present in proximal nerves. A mild enlargement of the lateral ventricles showed in brain magnetic resonance imaging studies. Q185X of NDRG1 is a novel mutation with CMT4D, which are demonstrated in Asian population. Q185X of the NDRG1 expands the clinical and mutational spectrum of CMT4D.


Assuntos
Proteínas de Ciclo Celular/genética , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Doença de Refsum/genética , Doença de Refsum/fisiopatologia , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Adulto Jovem
15.
PLoS One ; 12(11): e0188035, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29131855

RESUMO

Patients suffering from Refsum's disease show mutations in the enzyme necessary for the degradation of phytanic acid. Accumulation of this tetramethyl-branched fatty acid in inner organs leads to severe neurological and cardiac dysfunctions which can even result in death. Thus, patients with Refsum's disease have to follow a specific diet resigning foods with high levels of phytanic acid and trans-phytol like products from ruminant animals with a tolerable daily intake (TDI) of ≤ 10 mg/d. We recently reported the occurrence of phytyl fatty acid esters (PFAE, trans-phytol esterified with a fatty acid) in bell pepper with trans-phytol amounts of up to 5.4 mg/100 g fresh weight (FW). In this study we carried out in vitro-digestion experiments of PFAE with artificial digestion fluids. Our results demonstrate that PFAE actually are a source for bioavailable trans-phytol and thus add to the TDI. Eating only one portion of bell pepper (∼150 g) could therefore lead to exploitation of the TDI of up to 81%. Analysis of additional vegetable matrices showed that also rocket salad with up to 4.2 mg/100 g FW trans-phytol bound in PFAE represents a risk-relevant food for patients with Refsum's disease and should therefore be taken into account.


Assuntos
Ácidos Graxos/metabolismo , Ácido Fitânico/metabolismo , Doença de Refsum/metabolismo , Verduras/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Fatores de Risco
16.
Hum Mutat ; 38(11): 1569-1578, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28776325

RESUMO

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln), in two Chinese CMT families with consanguineous histories. Further functional studies were performed to characterize the biological effects of these variants. Cell culture transfection studies showed that mutant NDRG1 carrying p.Leu146Pro, p.Arg148*, or p.Arg234Gln variant degraded faster than wild-type NDRG1, resulting in lower protein levels. Live cell confocal microscopy and coimmunoprecipitation analysis indicated that these variants did not disrupt the interaction between NDRG1 and Rab4a protein. However, NDRG1-knockdown cells expressing mutant NDRG1 displayed enlarged Rab4a-positive compartments. Moreover, mutant NDRG1 could not enhance the uptake of DiI-LDL or increase the fraction of low-density lipoprotein receptor on the cell surface. Taken together, our study described two missense mutations in NDRG1 and emphasized the important role of NDRG1 in intracellular protein trafficking.


Assuntos
Proteínas de Ciclo Celular/genética , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Estudos de Associação Genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação de Sentido Incorreto , Doença de Refsum/diagnóstico , Doença de Refsum/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Proteínas de Ciclo Celular/metabolismo , Doença de Charcot-Marie-Tooth/metabolismo , Feminino , Duplicação Gênica , Técnicas de Silenciamento de Genes , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Fenótipo , Ligação Proteica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Doença de Refsum/metabolismo , Análise de Sequência de DNA , Deleção de Sequência , Adulto Jovem , Proteínas rab4 de Ligação ao GTP/metabolismo
17.
Ann Otol Rhinol Laryngol ; 126(8): 611-614, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28681609

RESUMO

OBJECTIVES: Whether the origin of severe hearing loss in Refsum's syndrome is caused by cochlear impairment or retrocochlear degeneration remains unclear. This case report aims to investigate hearing performance before and after cochlear implantation to shed light on this question. Also, identification of new mutations causing Refsum's syndrome would be helpful in generating additional means of diagnosis. METHODS: A family of 4 individuals was subjected to genetic testing. Two siblings (56 and 61 years old) suffered from severe hearing and vision loss and received bilateral cochlear implants. Genetic analysis, audiological outcome, and clinical examinations were performed. RESULTS: One new mutation in the PHYH gene (c.768del63bp) causing Refsum's disease was found. Preoperative distortion product otoacoustic emissions (DPAOEs) were absent. Postoperative speech perception in Freiburger speech test was 100% for bisyllabic words and 85% (patient No. 1) and 65% (patient No. 2), respectively, for monosyllabic words. Five years after implantation, speech perception remained stable for bisyllabic words but showed decreasing capabilities for monosyllabic words. DISCUSSION: A new mutation causing Refsum's disease is presented. Cochlear implantation in case of severe hearing loss leads to an improvement in speech perception and should be recommended for patients with Refsum's disease, especially when the hearing loss is combined with a severe loss of vision. Decrease of speech perception in the long-term follow-up could indicate an additional retrocochlear degeneration.


Assuntos
Implante Coclear , Perda Auditiva Neurossensorial/cirurgia , Oxigenases de Função Mista/genética , Doença de Refsum/genética , Audiometria de Resposta Evocada , Audiometria de Tons Puros , Feminino , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Emissões Otoacústicas Espontâneas , Doença de Refsum/complicações , Irmãos , Percepção da Fala
18.
Mol Genet Metab ; 121(3): 279-282, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28566232

RESUMO

Phytanic acid is a branched-chain fatty acid, the level of which is elevated in patients with a variety of peroxisomal disorders, including Refsum disease, and Rhizomelic chondrodysplasia punctata type 1 and 5. Elevated levels of both phytanic and pristanic acid are found in patients with Zellweger Spectrum Disorders, and pristanic acid is elevated in patients with α-methylacyl-CoA racemase deficiency. For the diagnosis of peroxisomal disorders, a variety of metabolites can be measured in blood samples from suspected patients, including very long-chain fatty acids, phytanic and pristanic acid. Based on the fact that very long-chain fatty acylcarnitines are elevated in tissues and plasma from patients with certain peroxisomal disorders, we investigated whether phytanoyl- and pristanoyl-carnitine are also present in plasma from patients with different peroxisomal disorders. Our study shows that phytanoyl- and pristanoyl-carnitine are indeed present in plasma samples from patients with different types of peroxisomal disorders, but only when the total plasma levels of their corresponding fatty acids, phytanic acid and pristanic acid, are markedly elevated. We conclude that the measurement of phytanoyl- and pristanoyl-carnitine is not sensitive and specific enough to use these acylcarnitines as conclusive diagnostic markers for peroxisomal disorders.


Assuntos
Carnitina/sangue , Diterpenos/sangue , Ácidos Graxos/sangue , Transtornos Peroxissômicos/diagnóstico , Carnitina/análogos & derivados , Células Cultivadas , Ácidos Graxos/química , Humanos , Oxirredução , Transtornos Peroxissômicos/sangue , Ácido Fitânico/sangue , Doença de Refsum/sangue
20.
J Peripher Nerv Syst ; 22(1): 47-50, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27982524

RESUMO

Charcot-Marie-Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N-Myc downstream-regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38-year-old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT.


Assuntos
Proteínas de Ciclo Celular/genética , Doença de Charcot-Marie-Tooth/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Doença de Refsum/genética , Adulto , Cerebelo/diagnóstico por imagem , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Humanos , Imageamento por Ressonância Magnética , Bulbo/diagnóstico por imagem , Doença de Refsum/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem
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