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BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. The approximately 50 known ALS-associated genes do not fully explain its heritability, which suggests the existence of yet unidentified causative genes. We report results of studies aimed at identification of the genetic cause of ALS in a pedigree (three patients) without mutations in the common ALS-causative genes. METHODS: Clinical investigations included thorough neurological and non-neurological examinations and testings. Genetic analysis was performed by exome sequencing. Functional studies included identification of altered splicing by PCR and sequencing, and mutated proteins by western blot analysis. Apoptosis in the presence and absence of tunicamycin was assessed in transfected HEK293T cells using an Annexin-PE-7AAD kit in conjunction with flow cytometry. RESULTS: Clinical features are described in detail. Disease progression in the patients of the pedigree was relatively slow and survival was relatively long. An RNF13 mutation was identified as the cause of the recessively inherited ALS in the pedigree. The gene is highly conserved, and its encoded protein (RING finger protein 13) can potentially affect various neurodegenerative-relevant functions, including protein homeostasis. The RNF13 splice site mutation caused expression of two mis-spliced forms of RNF13 mRNA and an aberrant RNF13 protein, and affected apoptosis. CONCLUSION: RNF13 was identified as a novel causative gene of recessively inherited ALS. The gene affects protein homeostasis, which is one of most important components of the pathology of neurodegeneration. The contribution of RNF13 to the aetiology of another neurodegenerative disease is discussed.
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BACKGROUND AND PURPOSE: Spinal-bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (AR). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in AR are reported. METHODS: Clinical investigations included thorough neurological and non-neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. UBA1 mutations were modeled on the crystal structure of UBA1. RESULTS: The clinical features of the patients are described in detail. A missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non-Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin-like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin-proteasome system. Interestingly, UBA1 mutations can also cause infantile-onset X-linked spinal muscular atrophy (XL-SMA). The mutation identified here and the XL-SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes. CONCLUSION: UBA1 was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL-SMA is discussed.
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Artrogriposis , Atrofia Bulboespinal Ligada al X , Enfermedad de la Neurona Motora , Atrofia Muscular Espinal , Enzimas Activadoras de Ubiquitina , Humanos , Artrogriposis/complicaciones , Atrofia Bulboespinal Ligada al X/genética , Enfermedad de la Neurona Motora/complicaciones , Atrofia Muscular/complicaciones , Atrofia Muscular Espinal/genética , Receptores Androgénicos/genética , Ubiquitinas , Enzimas Activadoras de Ubiquitina/genéticaRESUMEN
Charcot-Marie-Tooth (CMT) is a common neuropathy, and hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a recently described rare neuromuscular disease. Although many genes have been implicated for CMT, TFG is the only known HMSN-P-causing gene. Within the framework of diagnostic criteria, clinical variation is evident among CMT-diagnosed and also HMSN-P-diagnosed individuals. Mutations that cause p.(Pro285Leu) and p.(Gly269Val) in TFG were earlier reported as cause of HMSN-P in two Iranian pedigrees. Here, we report the identification of p.(Gly269Val) in TFG as cause of CMT in a large Iranian pedigree. The clinical features of patients of the three pedigrees are presented and critically compared. Similarities between the two HMSN-P-diagnosed pedigrees with different TFG mutations, and differences between the two differentially diagnosed pedigrees with the same p.(Gly269Val) mutation were evident. The clinical features of the HMSN-P pedigree with the p.(Pro285Leu) and the CMT pedigree with the p.(Gly269Val) mutation were clearly congruent with the respective diagnoses, whereas the features of the HMSN-P-diagnosed pedigree with the p.(Gly269Val) were intermediate between the other two pedigrees. It is therefore suggested that the clinical features of the three Iranian pedigrees with TFG mutations and diagnosed with HMSN-P or CMT represent a continuum.
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Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Mutación , Proteínas/genética , Adolescente , Adulto , Anciano , Secuencia de Bases , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Niño , Preescolar , Femenino , Expresión Génica , Heterocigoto , Humanos , Lactante , Irán , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Secuenciación del ExomaRESUMEN
Fazio-Londe disease and Brown-Vialetto-Van Laere syndrome are rare related neurological disorders. Although SLC52A3 and SLC52A2 that encode riboflavin transporters are their only known causative genes, many patients without mutations in these genes have been reported. Clinical and genetic data of a patient with features suggestive of Fazio-Londe disease are presented. Neurological examination revealed significant involvement of cranial nerves and weakness in the lower extremities. Pontobulbar presentations were prominent. EDX study suggested motor neuronopathy. Hearing was normal. She was diagnosed with FL disease. Response to riboflavin supplementation was not favorable. The patient's pedigree suggested recessive inheritance. SLC52A3 and SLC52A2 were screened and mutations were not observed. Results of exome sequencing and segregation analysis suggested that a mutation in TNRC18 is a candidate cause of disease in the patient. The three dimensional structure of the TNRC18 protein was predicted and it was noted that its two conserved domains (BAH and Tudor) interact and that the valine residue affected by the mutation is positioned close to both domains. A mutation in TNRC18 is cautiously reported as the possible cause of FL disease in the patient. The finding warrants further inquiries on TNRC18 about which little is presently known.
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INTRODUCTION: Riboflavin Transporter Deficiency (RTD) is a rare neurological disorder characterized by pontobulbar palsy, hearing loss, and motor cranial nerve involvement. SLC52A3 and SLC52A2 mutations are causes of RTD. SLC52A2 mutations are usually found in childhood onset cases. Fifteen Iranian RTD diagnosed patients without SLC52A2 mutations have been previously described. We aimed to identify causative mutations in two childhood cases. METHODS: We recruited patients with diagnosis of BVVL. Comprehensive clinical evaluations were performed on the patients. SLC52A3 and SLC52A2 genes were PCR-amplified and Sanger sequenced. Candidate disease causing variations were screened for segregation with disease status in the respective families and control individuals. RESULTS: A novel homozygous SLC52A3 mutation (p.Met1Val) and a heterozygous SLC52A2 mutation (p.Ala288Val) were both observed in one proband with typical RTD presentations. The aggregate of presentations in the early stages of disease in the second patient that included weakness in the lower extremities, absence of bulbar or hearing defects, prominent sensory polyneuropathy as evidenced in electrodiagnostic studies, and absence of sensory symptoms including sensory ataxia did not prompt immediate RTD diagnosis. Dysarthria and decreased hearing manifested later in the disease course. A novel homozygous SLC52A2 (p.Val314Met) mutation was identified. CONCLUSION: A literature search found recent reports of other atypical RTD presentations. These include MRI findings, speech understanding difficulties accompanied by normal hearing, anemia, and left ventricular non-compaction. Knowledge of unusual presentations lessens the chance of misdiagnosis or delayed RTD diagnosis which, in light of favorable effects of riboflavin supplementation, is of immense importance.
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Proteínas de Transporte de Membrana , Mutación , Humanos , Masculino , Mutación/genética , Proteínas de Transporte de Membrana/genética , Parálisis Bulbar Progresiva/genética , Parálisis Bulbar Progresiva/diagnóstico , Femenino , Receptores Acoplados a Proteínas G/genética , Niño , Linaje , Enfermedades de los Ganglios Basales , Pérdida Auditiva SensorineuralRESUMEN
We report identification of a homozygous mutation in NPC2 in two Iranian siblings with a neurologic dysfunction whose disease had not been diagnosed prior to our genetic analysis. The mutation was identified by exome sequencing. The finding resulted in diagnosis of Niemann-Pick disease type C (NPC) in the siblings, and initiation of treatment with Miglustat. The clinical features of the patients are presented. It has been suggested that NPC is under diagnosed, particularly when presentations are not very severe, as was the situation in the cases studied here. NPC is a fatal autosomal recessive disorder clinically characterized by hepatosplenomegaly and progressive neurological deterioration. At the cellular level, it causes aberrant cholesterol trafficking and accumulation of unesterified cholesterol in lysosomes. Mutations in NPC1 and NPC2 are cause of disease in respectively, 95% and 5% of NPC patients. The p.Pro120Ser causing mutation in NPC2 observed in the Iranian patients was earlier observed in the only other NPC2 patient reported from the Middle East. The study demonstrates that in addition to greatly facilitating gene discovery, exome sequencing has notable potentials for diagnosis, particularly for diagnosis of atypical cases.
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Proteínas Portadoras/genética , Glicoproteínas/genética , Mutación , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Enfermedad de Niemann-Pick Tipo C/genética , Adolescente , Adulto , Niño , Exoma/genética , Femenino , Pruebas Genéticas , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Irán , Masculino , Enfermedad de Niemann-Pick Tipo C/patología , Linaje , Fenotipo , Proteínas de Transporte VesicularRESUMEN
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegeneration involving motor neurons. The 3-5 years that patients have to live is marked by day-to-day loss of motor and sometimes cognitive abilities. Enormous amounts of healthcare services and resources are necessary to support patients and their caregivers during this relatively short but burdensome journey. Organization and management of these resources need to best meet patients' expectations and health system efficiency mandates. This can only occur in the setting of multidisciplinary ALS clinics which are known as the gold standard of ALS care worldwide. To introduce this standard to the care of Iranian ALS patients, which is an inevitable quality milestone, a national ALS clinical practice guideline is the necessary first step. The National ALS guideline will serve as the knowledge base for the development of local clinical pathways to guide patient journeys in multidisciplinary ALS clinics. To this end, we gathered a team of national neuromuscular experts as well as experts in related specialties necessary for delivering multidisciplinary care to ALS patients to develop the Iranian ALS clinical practice guideline. Clinical questions were prepared in the Patient, Intervention, Comparison, and Outcome (PICO) format to serve as a guide for the literature search. Considering the lack of adequate national/local studies at this time, a consensus-based approach was taken to evaluate the quality of the retrieved evidence and summarize recommendations.
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BACKGROUND: Muscle MRI protocols have been developed to assess muscle involvement in a wide variety of muscular dystrophies. Different muscular dystrophies can involve muscle groups in characteristic patterns. These patterns can be identified in muscle MRI in the form of fatty infiltration. OBJECTIVE: This study was conducted to add the existing knowledge of muscle MRI in GNE myopathy and evaluate the correlation of muscular involvement with different gene mutations. METHODS: The MRI scans of the 18 GNE patients were analyzed retrospectively. Cluster analysis was done for grouping the muscles and patients. RESULTS: The four muscles with the highest fat infiltration were adductor magnus, tibialis anterior, semitendinosus, and semimembranosus. Furthermore, three clusters of muscle involvement were found, including cluster 1, typical muscle involvement indicating muscles with the highest infiltration: extensor digitorum longus, gracilis, biceps femoris, soleus, gastrocnemius medial, adductor longus, tibialis anterior, adductor magnus, semimembranosus, semitendinosus; cluster 2, less typical muscle involvement indicating muscles with intermediate fat infiltration, peroneus longus, gastrocnemius lateral, and minimal fat infiltration in most of the patients, i.e., tibialis posterior; and cluster 3, atypical muscle involvement with low-fat infiltration: rectus femoris, sartorius, vastus intermedius, vastus medialis, and vastus lateralis. CONCLUSIONS: This study found three clusters of muscle involvement and three groups of patients among GNE patients. Hamstring muscles and the anterior compartment of the lower leg were the muscles with the highest fat infiltration. Moreover, a weak genotype-muscle MRI association was found in which tibialis posterior was more involved in patients with the most frequent mutation, i.e., C.2228Tâ>âC (p.M743T) mutation; however, this finding may be related to longer disease duration.
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Miopatías Distales/diagnóstico por imagen , Pierna/diagnóstico por imagen , Músculo Esquelético/diagnóstico por imagen , Muslo/diagnóstico por imagen , Adulto , Femenino , Humanos , Irán , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Sandhoff disease is a rare fatal infantile neurologic disorder. Adult onset Sandhoff is even rarer. Variability of clinical features in adult onset Sandhoff patients and overlaps between these and features of other neurologic diseases have sometimes led to mis-diagnosis. We describe an adult onset Sandhoff disease affected individual whose clinical presentation were also consistent with the Brown-Vialetto-Van Laere syndrome (BVVL) diagnosis. Screening of BVVL-causing genes, SLC52A3 and SLC52A2, did not identify candidate disease-causing mutations, but exome sequencing revealed compound heterozygous mutations in the known Sandhoff disease-causing gene, HEXB. Decreased blood hexosaminidase activity and evidence of cerebellar atrophy confirmed Sandhoff disease diagnosis. To the best of our knowledge, this is the first report of a Sandhoff disease case that mimics BVVL and that presents with prominent cranial nerve involvement. For differential diagnosis, measurement of hexosaminidase activity and MRI should quickly be performed. Genetic analysis can be done for confirmation of diagnosis.
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Parálisis Bulbar Progresiva/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico , Enfermedad de Sandhoff/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Mutación , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a prevalent and heterogeneous peripheral neuropathy. Most patients affected with the axonal form of CMT (CMT2) do not harbor mutations in the approximately 90 known CMT-associated genes. We aimed to identify causative genes in two CMT2 pedigrees. METHODS: Neurologic examination, laboratory tests and brain MRIs were performed. Genetic analysis included exome sequencing of four patients from the two pedigrees. The predicted effect of a deep intronic mutation on splicing was tested by regular and real-time PCR and sequencing. RESULTS: Clinical data were consistent with CMT2 diagnosis. Inheritance patterns were autosomal recessive. Exome data of CMT2-101 did not include mutations in known CMT-associated genes. Sequence data, segregation analysis, bioinformatics analysis, evolutionary conservation, and information in the literature strongly implicated HADHA as the causative gene. An intronic variation positioned 23 nucleotides away from following intron/exon border in GDAP1 was ultimately identified as cause of CMT in CMT2-102. It was shown to affect splicing. CONCLUSION: The finding of a HADHA mutation as a cause of CMT is of interest because its encoded protein is a subunit of the mitochondrial trifunctional protein (MTP) complex, a mitochondrial enzyme involved in long chain fatty acid oxidation. Long chain fatty acid oxidation is an important source of energy for skeletal muscles. The mutation found in CMT2-102 is only the second intronic mutation reported in GDAP1. The mutation in the CMT2-102 pedigree was outside the canonical splice site sequences, emphasizing the importance of careful examination of available intronic sequences in exome sequence data.
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Enfermedad de Charcot-Marie-Tooth , Subunidad alfa de la Proteína Trifuncional Mitocondrial/genética , Enfermedad de Charcot-Marie-Tooth/genética , Consanguinidad , Genotipo , Humanos , Mutación , LinajeRESUMEN
Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.
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Factor Activador de Células B/genética , Parálisis Bulbar Progresiva/genética , Estudios de Asociación Genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Transporte de Membrana/genética , Mutación , Esclerosis Amiotrófica Lateral/genética , Audiometría , Parálisis Bulbar Progresiva/diagnóstico , Parálisis Bulbar Progresiva/patología , Femenino , Pruebas Genéticas , Humanos , Pruebas Inmunológicas , Imagen por Resonancia Magnética , Masculino , Músculos/patología , Examen NeurológicoRESUMEN
BACKGROUND: SPG11 mutations can cause autosomal recessive hereditary spastic paraplegia (ARHSP) and juvenile amyotrophic lateral sclerosis (JALS). Because these diseases share some clinical presentations and both can be caused by SPG11 mutations, it was considered that definitive diagnosis may not be straight forward. METHODS: The DNAs of referred ARHSP and JALS patients were exome sequenced. Clinical data of patients with SPG11 mutations were gathered by interviews and neurological examinations including electrodiagnosis (EDX) and magnetic resonance imaging (MRI). RESULTS: Eight probands with SPG11 mutations were identified. Two mutations are novel. Among seven Iranian probands, six carried the p.Glu1026Argfs*4-causing mutation. All eight patients had features known to be present in both ARHSP and JALS. Additionally and surprisingly, presence of both thin corpus callosum (TCC) on MRI and motor neuronopathy were also observed in seven patients. These presentations are, respectively, key suggestive features of ARHSP and JALS. CONCLUSION: We suggest that rather than ARHSP or JALS, combined ARHSP/JALS is the appropriate description of seven patients studied. Criteria for ARHSP, JALS, and combined ARHSP/JALS designations among patients with SPG11 mutations are suggested. The importance of performing both EDX and MRI is emphasized. Initial screening for p.Glu1026Argfs*4 may facilitate SPG11 screenings in Iranian patients.
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Mutación , Fenotipo , Proteínas/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Cuerpo Calloso/diagnóstico por imagen , Diagnóstico Diferencial , Electrodiagnóstico , Femenino , Pruebas Genéticas , Humanos , Imagen por Resonancia Magnética , Masculino , Paraplejía Espástica Hereditaria/diagnósticoRESUMEN
BACKGROUND AND AIM: Lithium, a widely used drug in bipolar-affective disorders, plays gastro-protective roles. The effects of lithium on several tissues are mediated through nitric oxide (NO), which regulates gastrointestinal motility and mucosal integrity. The aim of this study was to investigate the protective effect of chronic lithium administration on visceral hypersensitivity and to investigate the role of NO as a potential mechanism of lithium in a rat model of irritable bowel syndrome. METHODS: Colitis was induced by the intracolonic administration of acetic acid. After subsidence of inflammation on the seventh experimental day, nociception and defecation parameters were measured. A subgroup of animals had been pretreated with lithium carbonate (600 mg/L) for 35 days. Thereafter, either a non-selective NO synthase (NOS) inhibitor (N-nitro-L-arginine methyl ester [L-NAME], 10 mg/kg), a selective NOS inhibitor (aminoguanidine, 100 mg/kg), or saline were administered intraperitoneally 1 h before measurements. RESULTS: Chronic lithium attenuated the visceral hypersensitivity, increased the nociceptive threshold, and decreased stool frequency. L-NAME and aminoguanidine decreased the nociceptive threshold and reduced the protective effects of lithium on visceral hypersensitivity. Stool frequency was increased in both the lithium-treated and water-treated groups by L-NAME administration, but not aminoguanidine. The form of defecation in the lithium-treated rats shifted toward hard stools rather than being soft and formless, but NOS inhibitors did not change the stool consistency pattern. CONCLUSION: The results indicate the antinociceptive property of chronic lithium on visceral hypersensitivity. As this effect was lowered by NOS inhibitors, NO might play a role in the protective effect of lithium to some extent.
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Analgésicos/administración & dosificación , Colon/efectos de los fármacos , Diarrea/etiología , Hiperalgesia/prevención & control , Síndrome del Colon Irritable/tratamiento farmacológico , Carbonato de Litio/administración & dosificación , Óxido Nítrico/metabolismo , Administración Oral , Animales , Colon/inervación , Colon/metabolismo , Colon/patología , Colon/fisiopatología , Defecación/efectos de los fármacos , Diarrea/metabolismo , Diarrea/fisiopatología , Modelos Animales de Enfermedad , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Guanidinas/administración & dosificación , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Inyecciones Intraperitoneales , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/metabolismo , Síndrome del Colon Irritable/fisiopatología , Masculino , NG-Nitroarginina Metil Éster/administración & dosificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Presión , Ratas , Ratas Wistar , Recto/inervación , Restricción Física , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
Mutations in the same gene are sometimes the cause of different clinically diagnosed neurologic disorders; this emphasizes interrelationships between various neurologic diseases. In this light, we screened SLC52A3, which is the cause of Brown-Vialetto-Van Laere syndrome, and C19orf12, which is the cause of neurodegeneration with brain iron accumulation in 60 Iranian amyotrophic lateral sclerosis (ALS) patients without mutations in the 2 most important ALS-causing genes, SOD1 and C9orf72. To the best of our knowledge, neither SLC52A3 nor C19orf12 has been mutation-screened previously in ALS cohorts. Justification for screening SLC52A3 included notable clinical similarities between Brown-Vialetto-Van Laere syndrome and ALS, and justification for screening C19orf12 was known contribution of mitochondrial dysfunction to ALS etiology. Disease-causing variations in the 2 genes were not found among the ALS patients. TARDBP was screened in 107 patients, and a mutation (p.Gly348Cys) was identified in one. Detailed clinical data on the patient are presented. It appears that mutations in TARDBP in ALS patients of Iran are rare and occur at similar frequencies to European populations.
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Esclerosis Amiotrófica Lateral/genética , Parálisis Bulbar Progresiva/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/genética , Proteínas de Transporte de Membrana/genética , Proteínas Mitocondriales/genética , Anciano , Femenino , Humanos , Irán , Masculino , Persona de Mediana Edad , Mutación/genética , Superóxido Dismutasa-1/genéticaRESUMEN
GNE myopathy is a rare distal myopathy, caused by mutations in the GNE gene, affecting sialic acid synthesis. Clinical presentation varies from asymptomatic early stage patients to severely debilitating forms. This first report describes clinical presentations and severity of the disease, using data of 150 patients collected via the on-line, patient-reported registry component of the GNE Myopathy Disease Monitoring Program (GNEM-DMP). Disease progression was prospectively analysed, over a 2-year period, using the GNE myopathy functional activity scale (GNEM-FAS). The average annual rates of decline in function were estimated at -9.6% and -3.2% in ambulant and non-ambulant patients respectively. 4.3% of participants became non-ambulant within one year. The mean time from onset to required use of a wheelchair was 11.9 years. Mean delay of genetic diagnosis from symptom onset was 5.2 years. Mutation specific analysis demonstrated genotype-phenotype relationships; i.e. p.Ala662Val may be associated with a more severe phenotype, compared to p.Val727Met. Patients with compound heterozygous mutation in epimerase and kinase domain appeared to have a more severe phenotype compared to patients with both mutations located within one domain. Acknowledging the limitations of the study, these findings suggest that the severity of the GNE mutations affects disease severity. The GNEM-DMP is a useful data collection tool, prospectively measuring the progression of GNE myopathy, which could play an important role in translational and clinical research and further understanding of genotype-phenotype correlations.
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Miopatías Distales/epidemiología , Miopatías Distales/genética , Adulto , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Asociación Genética , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Complejos Multienzimáticos/genética , Fenotipo , Sistema de Registros , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
We aimed to identify the genetic cause of neurological disease in an Iranian pedigree whose manifestations suggested hereditary motor and sensory neuropathy with proximal predominance (HMSN-P). Identification of a p.Gly269Val mutation in TFG, the known HMSN-P causative gene, provided supportive evidence. Subjective, biochemical, electrodiagnostic, and imaging data were compared with previously reported HMSN-P patients, including patients of an earlier described Iranian pedigree. Although notable clinical variability was found, comparable involvement of proximal and distal muscles was observed in both Iranian pedigrees. Interestingly, the same p.Gly269Val mutation was recently reported as cause of Charcot-Marie-Tooth disease type 2 in a Taiwanese pedigree. The likelihood that the two pedigrees with the p.Gly269Val mutation are not affected with different diseases is discussed. Identification of a second Iranian HMSN-P pedigree further confirms that HMSN-P is not confined to the Far East. Furthermore, p.Pro285Leu that has been the only TFG mutation thus far reported in HMSN-P patients is not the only mutation that can cause the disease. It is emphasized HMSN-P is a neuronopathy.
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Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/patología , Mutación/genética , Linaje , Proteínas/genética , Adulto , Enfermedad de Charcot-Marie-Tooth/genética , Análisis Mutacional de ADN , Femenino , Ligamiento Genético , Haplotipos , Humanos , Irán , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/diagnóstico por imagen , Adulto JovenRESUMEN
GNE myopathy is an autosomal recessive adult-onset disorder characterized by progressive muscle atrophy and weakness, initially involving the distal muscles, while often sparing the quadriceps. It is caused by variants in the GNE gene that encodes a key bifunctional enzyme in the sialic acid biosynthetic pathway. We investigated the clinical and molecular characteristics of 18 non-Jewish Persian patients from 11 unrelated GNE myopathy families. In addition, we reviewed the previously reported cases and suggest genotype-phenotype correlations for the identified variants. Comprehensive clinical and laboratory evaluations were carried out. Sequencing of the GNE gene was performed using genomic DNA from the patients. Screening of the identified variants was performed in all relevant family members. Molecular analyses identified three causative homozygous GNE variants in 11 families: c.2228T>C (p. M743T) in 7, c.830G>A (p.R277Q) in 2, and one novel variation (c.804G>A) in 2 families that results in a synonymous codon change (p.L268=) and likely creates a novel splice site affecting the protein function. This study confirms that c.2228T>C (p.M743T) is the most prevalent disease-causing variant in the non-Jewish Persian population, but other GNE variants can cause GNE myopathy in this population. The patients with all three different variants had similar ages of onset. The youngest patient was an 18-year-old girl in whom the c.830G>A (p.R277Q) variant was identified, whereas the oldest onset age (31 years) was seen in a male patient with c.804G>A (p.L268=). The results of this investigation expand our knowledge about the genotype-phenotype correlations in GNE myopathy and aid in clinical management and therapeutic interventions.
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Miopatías Distales/genética , Estudios de Asociación Genética , Complejos Multienzimáticos/genética , Músculo Esquelético/patología , Adulto , Miopatías Distales/patología , Femenino , Homocigoto , Humanos , Irán , Judíos/genética , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable progressive neurodegenerative disease and thus the assessment of quality of life (QOL) changes and factors that may influence its course is valuable in the meantime. OBJECTIVES: The present study aimed to assess the deterioration rate of QOL and influencing factors in different subgroups of Iranian ALS patients. METHODS: 132 patients were evaluated in this prospective multicenter observational study. QOL was measured using ALS Assessment Questionnaire (ALSAQ-40) during 1year follow up and its progression rate was assessed in different subgroups of patients according to age, sex, stage of disease, riluzole consumption, onset type. Also physical disability and functional disability were measured using MMT and ALSFRS-R scores respectively and their progression rates were compared with ALSAQ-40 changes. RESULTS: Significant deterioration of the scores of ALSAQ-40 during study was consistent in all of its domains (p=0.000). There was a significant negative correlation between ALSFRS-R and MMT changes and ALSAQ-40 change (p=0.000) and this was consistently observed in all domains of ALSAQ-40 (p=0.00). ALSAQ-40 deterioration rate was shown to be significantly lower in severe/terminal stages compared to mild/moderate stages (p=0.00). Significantly higher deterioration rate was observed in bulbar onset versus limb onset patients [F (1,130)=4.52, p=0.04] but no significant difference was observed among other subgroups according to age, sex and riluzole consumption. CONCLUSION: All domains of QOL significantly deteriorate during ALS course and there is a significant correlation between their changes and progression of physical and functional disabilities. Rate of degradation of QOL may be different at different stages of the disease. QOL worsens independent of factors such as sex, age and consumption of riluzole; but onset type (bulbar versus limb) is an imperative factor in quality of life changes during the disease course.
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Esclerosis Amiotrófica Lateral/fisiopatología , Calidad de Vida , Factores de Edad , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/psicología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Irán , Masculino , Persona de Mediana Edad , Fuerza Muscular , Fármacos Neuroprotectores/uso terapéutico , Estudios Prospectivos , Riluzol/uso terapéutico , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a rare disease so far identified only in individuals of Far East ancestry. Here, genome-wide linkage analysis and exome sequencing in an Iranian pedigree with 16 members affected with a neuromuscular disease led to identification of a mutation in TFG that causes p.Pro285Leu as cause of disease. The very same mutation was reported as cause of HMSN-P during the course of the study. Phenotypic analysis in conjunction with genetic data revealed that the Iranian patients were also affected with HMSN-P. Therefore, HMSN-P is not confined to the Far East and may simply not have been diagnosed in other populations. Haplotype analysis suggests at least 3 independent origins for mutated alleles that cause p.Pro285Leu. The phenotypic data gathered included subjective, biochemical, nerve conduction, electromyography, and muscle magnetic resonance imaging data. Comparison with patients with same disease in previous publications showed that clinical variability exists, sensory nerves are prominently affected, and proximal and distal muscles are involved.
Asunto(s)
Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Neuropatía Hereditaria Motora y Sensorial/genética , Mutación/genética , Proteínas/genética , Adulto , Anciano , Alelos , Exoma/genética , Asia Oriental , Femenino , Haplotipos , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Neuropatía Hereditaria Motora y Sensorial/patología , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Irán , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
This study was designed to evaluate ALS progression among different subgroups of Iranian patients. Three hundred and fifty-eight patients from centres around the country were registered and their progression rate was evaluated using several scores including Manual Muscle Test scoring (MMT) and the revised ALS Functional Rating Scale (ALSFRS-R). Progression rate was analysed separately in subgroups regarding gender, onset site, stage of disease and riluzole consumption. A significant difference in MMT deterioration rate (p = 0.01) was noted between those who used riluzole and those who did not. No significant difference was observed in progression rates between male/female and bulbar-onset/limb-onset groups using riluzole. In conclusion, riluzole has a significant effect on muscle force deterioration rate but not functional scale. Progression rate was not influenced by site of onset or gender.