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1.
Neurology ; 102(7): e209174, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38513194

RESUMEN

BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Mutación de Línea Germinal , Femenino , Humanos , Masculino , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Vaina de Mielina/patología , Nervios Periféricos/diagnóstico por imagen , Fenotipo , Estudios Transversales , Estudios Retrospectivos , Linaje , Adulto Joven , Persona de Mediana Edad , Anciano
2.
Eur J Intern Med ; 101: 86-92, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35487805

RESUMEN

OBJECTIVE: To characterize the demographic, genetic, clinical, and serological features of patients with anti-3­hydroxy-3-methylglutaryl-CoA reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) in a region of northern Spain. METHODS: Study of all patients diagnosed with anti-HMGCR IMNM during a 5-year period at a reference hospital in northern Spain. Besides clinical and laboratory data, we analyzed the genetic influence of HLA genes and the rs4149056 (c.521T>C) single nucleotide polymorphism (SNP) in the SLCO1B1 gene. RESULTS: 8 patients (5 women, 3 men) with a mean ± SD age of 64.9 ± 7.3 years, fulfilled the criteria for anti-HMGCR IMNM. The incidence rate was 0.6 per 100.000 person-years and the prevalence 3 per 100.000 population. All patients had been exposed to statins. All of them had predominant lower limb proximal and symmetric muscle weakness that was severe in 2 and had elevated serum CK levels with a median [IQR] of 4488 [2538-9194] IU/L. Serum 25­hydroxy vitamin D levels were decreased in all patients in whom it was determined. The 3 patients with a previous diagnosis of hypothyroidism had abnormal levels of TSH at the time of diagnosis. All patients experienced improvement with different schemes of immunosuppressive therapy. Noteworthy, 7 of 8 patients carried the HLA-DRB1*11 allele. The frequency of the rs4149056 C allele in the SLCO1B1 gene (12.5%) was similar to that of the general population. CONCLUSION: In northern Spain, anti-HMGCR IMNM preferentially affects people over 50 years of age who are carriers of the HLA-DRB1*11 allele and take statins. Both low vitamin D levels and hypothyroidism may play a potential predisposing role in the development of this disease.


Asunto(s)
Enfermedades Autoinmunes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipotiroidismo , Enfermedades Musculares , Miositis , Anciano , Autoanticuerpos , Femenino , Cadenas HLA-DRB1 , Humanos , Hidroximetilglutaril-CoA Reductasas , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Persona de Mediana Edad , Músculo Esquelético , Enfermedades Musculares/epidemiología , Enfermedades Musculares/genética , Miositis/epidemiología , Miositis/genética , Necrosis , Vitamina D
4.
Eur J Neurol ; 28(6): 2083-2091, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33721382

RESUMEN

BACKGROUND AND PURPOSE: Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG. METHODS: This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18 years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed. RESULTS: We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6 years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95-4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15-2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43-3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47-4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up. CONCLUSIONS: Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.


Asunto(s)
Miastenia Gravis , Timoma , Neoplasias del Timo , Humanos , Miastenia Gravis/complicaciones , Miastenia Gravis/epidemiología , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Timectomía , Timoma/complicaciones , Timoma/epidemiología , Neoplasias del Timo/complicaciones , Neoplasias del Timo/epidemiología
5.
Neurol Sci ; 42(1): 215-223, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32617742

RESUMEN

INTRODUCTION: The aim of this study is to describe the normal cross-sectional area (CSA) and appearance of cervical nerve roots in ultrasound, correlating it to age and other patient somatic parameters. METHODS: One hundred healthy volunteers were included. We aimed to achieve uniform representation throughout all age groups. Ultrasound of the cervical nerve roots was performed bilaterally. CSA and margins description were obtained. RESULTS: C5 nerve, 8.32 ± 2.30; C6 nerve, 11.88 ± 3.36; C7 nerve, 12.79 ± 3.85; C8 nerve, 11.20 ± 3.45. Significant correlation between CSA and age was demonstrated, but not for body mass index. Blurred margins were present in up to 23.71% cervical nerves, more frequently in older individuals and in C7 nerve. DISCUSSION: If ultrasound morphology of cervical nerve roots is used as a diagnostic parameter, the normal range of CSA values and percentage of blurred margins according to age should be considered.


Asunto(s)
Vértebras Cervicales , Raíces Nerviosas Espinales , Anciano , Índice de Masa Corporal , Vértebras Cervicales/diagnóstico por imagen , Voluntarios Sanos , Humanos , Valores de Referencia , Raíces Nerviosas Espinales/diagnóstico por imagen , Ultrasonografía
6.
Artículo en Inglés | MEDLINE | ID: mdl-31886449

RESUMEN

Objectives: Using recent optimized electrodiagnostic criteria sets, we primarily aimed at verifying the accuracy of the initial electrophysiological test in very early Guillain-Barré syndrome (VEGBS), ≤4 days of onset, compared with the results of serial electrophysiology. Our secondary objective was to correlate early electrophysiological results with sonographic nerve changes. Methods: This is a retrospective study based on consecutive VEGBS patients admitted to the hospital. Each patient had serial nerve conduction studies (NCS) in at least 4 nerves. Initial NCS were done within 4 days after onset, and serial ones from the second week onwards. Electrophysiological recordings of each case were re-evaluated, GBS subtype being established accordingly. Nerve ultrasonography was almost always performed within 2 weeks after onset. Results: Fifteen adult VEGBS patients were identified with a mean age of 57.8 years. At first NCS, VEGBS sub-typing was only possible in 3 (20%) cases that showed an axonal pattern, the remaining patterns being mixed (combining axonal and demyelinating features) in 6 (40%), equivocal in 5 (33.3%), and normal in 1 (6.7%). Upon serial NCS, 7 (46.7%) cases were categorized as acute demyelinating polyneuropathy, 7 (46.7%) as axonal GBS, and 1 (6.6%) as unclassified syndrome. Antiganglioside reactivity was detected in 5 out of the 7 axonal cases. Nerve US showed that lesions mainly involved the ventral rami of scanned cervical nerves. Conclusions: Serial electrophysiological evaluation is necessary for accurate VEGBS subtype classification. Ultrasonography helps delineate the topography of nerve changes. Significance: We provide new VEGBS pathophysiological insights into nerve conduction alterations within the first 4 days of the clinical course.

7.
Acta Neurol Scand ; 139(6): 546-554, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30929269

RESUMEN

OBJECTIVE: We report a prospective study analysing clinical characteristics, subtyping and prognosis in Guillain-Barré syndrome (GBS). METHOD: The study was based on consecutive GBS patients admitted between 2009 and 2017. Disability was serially assessed using the GBS disability scale. RESULTS: Fifty-six GBS patients were identified with an average age of 55 years (range, 5-86 years) and a male/female ratio of 2.1. The interval to nadir was <7 days in 59% of cases, and 7 to 28 days in the remainder; at nadir, 35.5% of patients were able to walk unaided, and 64.5% did not. Mechanical ventilation was needed in 20% of cases. There were two fatal cases. Clinical variants included paraparetic GBS seven cases, Miller Fisher syndrome one case, and acute sensory ataxic neuropathy (ASAN) one case. Serial electrophysiology showed a demyelinating pattern in 62.5% of cases, axonal in 28.5%, inexcitable in 1.8%, equivocal in 1.8%, and normal in 5.4%. Very early (1 to 4 days after onset) electrophysiology was done in 18 patients; equivocal or normal features in six of them evolved into an axonal pattern in four. Reversible conduction failure of sensitive nerves occurred in ASAN. Antiganglioside antibodies were only detected in axonal GBS. At 24-month follow-up, functional outcome did not differ between demyelinating and axonal GBS. Clinico-pathological correlation in an early fatal case is reported. CONCLUSIONS: This GBS study demonstrates comparable clinical features to previous investigations from well-defined populations. There was a relatively high prevalence of axonal GBS. We provide new pathophysiological insights on nerve conduction alterations.


Asunto(s)
Síndrome de Guillain-Barré/epidemiología , Síndrome de Guillain-Barré/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , España/epidemiología , Adulto Joven
8.
J Neurol Neurosurg Psychiatry ; 88(11): 941-952, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28860329

RESUMEN

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. METHODS: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. RESULTS: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. CONCLUSIONS: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/terapia , Progresión de la Enfermedad , Marcadores Genéticos/genética , Piel/patología , Resultado del Tratamiento , Adulto , Anciano , Biopsia , Catepsina A/genética , Enfermedad de Charcot-Marie-Tooth/sangre , Enfermedad de Charcot-Marie-Tooth/genética , Femenino , Glutatión Transferasa/genética , Glicoproteínas/genética , Humanos , Masculino , Persona de Mediana Edad , Neurregulina-1/genética , Proteínas Nucleares , PPAR gamma/genética , Hidrolasas Diéster Fosfóricas/genética , Pronóstico , Pirofosfatasas/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción Genética/genética
9.
J Neurol ; 264(8): 1655-1677, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28364294

RESUMEN

Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy with great variety of phenotypes, inheritance patterns, and causative genes. According to median motor nerve conduction velocity (MNCV), CMT is divided into demyelinating (CMT1) with MNCV below 38 m/s, axonal (CMT2) with MNCV above 38 m/s, and intermediate CMT with MNCV between 25 and 45 m/s. In each category, transmission may be autosomal dominant, autosomal recessive, or X-linked. The nosology of intermediate CMT is controversial because of concerns about electrophysiological delimitation. A systematic computer-based literature search was conducted on PubMed, using the following MeSH: (1) intermediate Charcot-Marie-Tooth; (2) X-linked intermediate Charcot-Marie-Tooth; and (3) X-linked Charcot-Marie-Tooth and electrophysiology. We retrieved 225 articles reporting X-linked CMT or intermediate CMT with electrophysiological information. After eligibility, 156 papers were used for this review. In assessing median MNCV, compound muscle action potential (CMAP) amplitudes were taken into account. In cases with attenuated CMAP and wherever possible, proximal median MNCV was used for accurate definition of conduction slowing in the intermediate range. In the vast majority of males with X-linked CMT associated with GJB1 mutation (CMTX1), median MNCV was intermediate. CMT associated with DRP2 mutation is another well-documented X-linked intermediate disorder. Autosomal dominant intermediate CMT (DI-CMT) encompasses 11 different types; six of them with assigned phenotype MIM number and the remaining five being unnumbered. Based on available electrophysiological information, we wonder if DI-CMTA should be reclassified within CMT2. Autosomal recessive intermediate CMT (RI-CMT) covers four numbered MIM phenotypes though, in accordance with reported electrophysiology, two of them (RI-CMTB and RI-CMTD) should probably be reclassified within AR-CMT2. We conclude that intermediate CMT is a complex inherited syndrome, whose characterization requires a specific electrophysiological protocol comprising evaluation of upper limb proximal nerve trunks when distal CMAP amplitudes are reduced, and that an updated version of MIM phenotype numbering is needed.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Animales , Enfermedad de Charcot-Marie-Tooth/patología , Humanos , Nervio Mediano/fisiopatología , Conducción Nerviosa
10.
J Neurol ; 264(2): 221-236, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27314967

RESUMEN

Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disorder of the peripheral nervous system. In early GBS, arbitrarily established up to 10 days of disease onset, patients could exhibit selective manifestations due to involvement of the proximal nerves, including nerve roots, spinal nerves and plexuses. Such manifestations are proximal weakness, inaugural nerve trunk pain, and atypical electrophysiological patterns, which may lead to delayed diagnosis. The aim of this paper was to analyze the nosology of early GBS reviewing electrophysiological, autopsy and imaging studies, both in acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor/motor-sensory axonal neuropathy (AMAN/AMSAN). Early electrophysiology showed either well-defined demyelinating or axonal patterns, or a non-diagnostic pattern with abnormal late responses; there may be attenuated M responses upon lumbar root stimulation as the only finding. Pathological changes predominated in proximal nerves, in some studies, most prominent at the sides where the spinal roots unite to form the spinal nerves; on very early GBS endoneurial inflammatory edema was the outstanding feature. In the far majority of cases, spinal magnetic resonance imaging showed contrast enhancement of cauda equina, selectively involving anterior roots in AMAN. Both in AIDP and AMAN/AMSAN, ultrasonography has demonstrated frequent enlargement of ventral rami of C5-C7 nerves with blurred boundaries, whereas sonograms of upper and lower extremity peripheral nerves exhibited variable and less frequent abnormalities. We provide new insights into the pathogenesis and classification of early GBS.


Asunto(s)
Síndrome de Guillain-Barré/clasificación , Síndrome de Guillain-Barré/fisiopatología , Nervios Periféricos/fisiopatología , Animales , Síndrome de Guillain-Barré/patología , Síndrome de Guillain-Barré/terapia , Humanos , Nervios Periféricos/diagnóstico por imagen , Nervios Periféricos/patología
12.
Ann Neurol ; 80(6): 823-833, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27686364

RESUMEN

OBJECTIVE: To identify the unknown genetic cause in a large pedigree previously classified with a distinct form of axonal Charcot-Marie-Tooth disease type 2G (CMT2G) and to explore its transcriptional consequences. METHODS: Clinical reevaluation of the pedigree was performed, followed by linkage analysis with the redefined disease statuses, and whole genome and exome sequencing. The impact of the mutation was investigated by immunoblotting and transcriptome sequencing. RESULTS: Thirteen affected individuals over 3 generations displayed mild and quiescent lower-limb axonal sensorimotor neuropathy. Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers. We redefined the disease-linked region to chr9q31.3-q34.2 and subsequently identified a novel missense variant in the E3 ubiquitin-protein ligase LRSAM1 (p.Cys694Tyr). Unlike previous reports, we demonstrated in patients' lymphoblasts that the mutation does not influence overall protein levels of LRSAM1, nor of its ubiquitylation target TSG101. The mutation is associated with several transcriptional changes, including a significant upregulation of another E3 ubiquitin-protein ligase, NEDD4L, and of TNFRSF21, a key regulator of axonal degeneration. INTERPRETATION: Our findings demonstrate that the isolated genetic entity CMT2G is caused by a missense mutation in LRSAM1 and should be reclassified as CMT2P. MRI of lower-limb musculature can be used to detect minimal signs of the disease. Transcriptome analysis of patients' cells highlights novel molecular players associated with LRSAM1 dysfunction, and reveals pathways and therapeutic targets shared with amyotrophic lateral sclerosis and Alzheimer disease. Ann Neurol 2016;80:823-833.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación Missense , Ubiquitina-Proteína Ligasas Nedd4 , Conducción Nerviosa/genética , Conducción Nerviosa/fisiología , Linaje , Regulación hacia Arriba
13.
J Neurol ; 263(2): 361-369, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26645395

RESUMEN

The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.


Asunto(s)
Ataxia Cerebelosa/genética , Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de Neurofilamentos/genética , Adulto , Edad de Inicio , Atrofia , Ataxia Cerebelosa/patología , Cerebelo/patología , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/patología , Preescolar , Análisis Mutacional de ADN , Electromiografía , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patología , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa
16.
J Peripher Nerv Syst ; 20(2): 67-71, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26114802

RESUMEN

Mitofusin 2 (MFN2) mutations are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). The majority are inherited in an autosomal dominant manner but recessive and semi-dominant kindreds have also been described. We previously reported a deletion of exons 7 and 8 resulting in nonsense-mediated decay, segregating with disease when present in trans with another pathogenic MFN2 mutation. Detailed clinical and electrophysiological data on a series of five affected patients from four kindreds and, when available, their parents and relatives were collected. MFN2 Sanger sequencing, multiplex ligation probe amplification, and haplotype analysis were performed. A severe early-onset CMT phenotype was seen in all cases: progressive distal weakness, wasting, and sensory loss from infancy or early childhood. Optic atrophy (four of five) and wheelchair dependency in childhood were common (four of five). All were compound heterozygous for a deletion of exons 7 and 8 in MFN2 with another previously reported pathogenic mutation (Phe216Ser, Thr362Met, and Arg707Trp). Carrier parents and relatives were unaffected (age range: 24-82 years). Haplotype analysis confirmed that the deletion had a common founder in all families.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , GTP Fosfohidrolasas/genética , Proteínas Mitocondriales/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Inglaterra , Exones , Humanos , Persona de Mediana Edad , Linaje , Gales , Adulto Joven
17.
J Neurol ; 262(5): 1289-300, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25877835

RESUMEN

The purpose of the study was to describe a pedigree with NEFL E396K mutation associated with a novel dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) phenotype. The pedigree comprised four patients over two generations, aged between 35 and 59 years, who have been serially evaluated since 1993. Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait. Both older patients showed ascending leg weakness to involve pelvic musculature. CMT neuropathy score ranged from 14 to 26 (moderate to severe disease). Electrophysiology showed uniform nerve conduction slowing in the intermediate range, both in distal and proximal nerve segments. Multimodal evoked potential and blink reflex studies revealed abnormalities indicative of central sensorimotor pathway dysfunction. On imaging studies of lower-limb musculature, there was massive atrophy of intrinsic foot muscles and to a lesser degree of calves and thighs predominating in muscles innervated by tibial and sciatic nerves. In both patients exhibiting waddling gait, there was atrophy of pelvic muscles mainly involving gluteus medius, gluteus minimus and piriformis. We conclude that NEFL E396K mutation may manifest with a novel DI-CMT phenotype, characterized by simultaneous involvement of the peripheral and central nervous system.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Glutamina/genética , Lisina/genética , Mutación/genética , Proteínas de Neurofilamentos/genética , Potenciales de Acción/genética , Adulto , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Creatina Quinasa/sangre , Análisis Mutacional de ADN , Electrofisiología , Potenciales Evocados/genética , Salud de la Familia , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Conducción Nerviosa/genética , Tomografía Computarizada por Rayos X
19.
Muscle Nerve ; 52(1): 39-44, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25363904

RESUMEN

INTRODUCTION: We analyzed the utility of tendon reflex (T-reflex) testing in Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: A total of 82 subjects from 27 unrelated CMT1A pedigrees were evaluated prospectively. The series also comprised 28 adult healthy controls. Electrophysiology included evaluation of biceps T-reflex and soleus T-reflex. RESULTS: Seventy-one individuals (62 adults and 9 children) had clinical and electrophysiological features of CMT1A. The remaining 11 (8 adults and 3 children) were unaffected. On electrophysiological testing, the biceps T-reflex was elicited in 58 of 62 (93%) adult CMT1A patients and in all 9 affected children. Latencies of the biceps T-reflex were always markedly prolonged, and a cut-off limit of 16.25 ms clearly separated adult patients and controls or unaffected kin adult individuals. In affected children, the soleus T-reflex latency was also prolonged when compared with age and height normative data. CONCLUSION: T-reflex testing is an accurate diagnostic technique for CMT1A patients.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Electromiografía , Reflejo/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Charcot-Marie-Tooth/genética , Niño , Preescolar , Femenino , Humanos , Masculino , Metalotioneína/genética , Persona de Mediana Edad , Conducción Nerviosa , Curva ROC , Estadísticas no Paramétricas , Adulto Joven
20.
Neuromuscul Disord ; 24(11): 1003-17, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25085517

RESUMEN

This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. We then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures - the 10m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry - further improved discrimination between severely and mildly affected patients. From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials.


Asunto(s)
Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Factores de Edad , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/terapia , Análisis por Conglomerados , Estudios de Cohortes , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular , Dimensión del Dolor , Desempeño Psicomotor/fisiología , Caminata , Adulto Joven
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