RESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.
Asunto(s)
Antineoplásicos Inmunológicos , Miocarditis , Miositis , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Estudios Retrospectivos , Miocarditis/inducido químicamente , Miocarditis/tratamiento farmacológico , Calidad de Vida , Neoplasias/tratamiento farmacológico , Miositis/inducido químicamente , Miositis/tratamiento farmacológicoRESUMEN
Hereditary transthyretin amyloidosis (ATTRv, v for variant) is a late-onset, autosomal dominant disease caused by progressive extracellular deposition of transthyretin amyloid fibrils, leading to organ damage and death. For other late-onset fatal diseases, as Huntington's disease, protocols for pre-symptomatic genetic testing (PST) are available since decades. For ATTRv, limited experience has been reported to date, mostly gathered before the availability of approved therapies. We aimed at developing recommendations for a safe and feasible PST protocol in ATTRv in the era of emerging treatments, taking also into account Italian patients' characteristics and healthcare system rules. After an initial survey on ongoing approaches to PST for ATTRv in Italy, two roundtable meetings were attended by 24 experts from 16 Italian centers involved in the diagnosis and care of this disease. Minimal requirements for PST offer and potential critical issues were highlighted. By November 2019, 457 families affected by ATTRv with 209 molecularly confirmed pre-symptomatic carriers were counted. The median age at PST was 41.3 years of age, regardless of the specific mutation. Half of the Italian centers had a multidisciplinary team, including a neurologist, an internist, a cardiologist, a medical geneticist and a psychologist, although in most cases not all the specialists were available in the same center. A variable number of visits was performed at each site. Experts agreed that PST should be offered only in the context of genetic counselling to at risk individuals aged 18 or older. Advertised commercial options for DNA testing should be avoided. The protocol should consist of several steps, including a preliminary clinical examination, a pre-test information session, an interval time, the genetic test and a post-test session with the disclosure of the test results, in the context of an experienced multidisciplinary team. Recommendations for best timing were also defined. Protocols for PST in the context of ATTRv can be refined to offer at risk individuals the best chance for early diagnosis and timely treatment start, while respecting autonomous decisions and promoting safe psychological adjustment to the genetic result.
Asunto(s)
Neuropatías Amiloides Familiares , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/genética , Consenso , Pruebas Genéticas , Humanos , ItaliaRESUMEN
Rituximab is efficacious in myelin-associated glycoprotein (MAG) polyneuropathy, but the question on timing of retreatments is open. We studied 21 anti-MAG polyneuropathy patients who responded to a first cycle of rituximab, were followed-up for an average of 11.2â¯years, and were retreated only when relapsing. Baseline serum B-cell-activating factor (BAFF) levels were measured. Clinical improvements lasted on average 6â¯years, and as many as 71% of the patients resulted long-lasting responders. Severity of disease and high serum BAFF levels (cut-off ≥860â¯pg/mL for relapse risk) at onset seemed to predict worse prognosis. Measurements of these variables could help deal with the issue of maintenance rituximab therapy in MAG polyneuropathy.
Asunto(s)
Autoanticuerpos/sangre , Factores Inmunológicos/administración & dosificación , Glicoproteína Asociada a Mielina/sangre , Polineuropatías/sangre , Polineuropatías/tratamiento farmacológico , Rituximab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/inmunología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Glicoproteína Asociada a Mielina/inmunología , Polineuropatías/inmunología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Mutations of myelin protein zero gene (MPZ) are found in 5% of Charcot-Marie-Tooth patients. In 2004, Shy et al. identified two main phenotypes associated with them: an early-onset subtype with mainly demyelinating features and a late-onset subgroup with prominent axonal impairment. We evaluated whether novel MPZ mutations described in literature during the last 14 years could still fit with this classification. We collected and revised reports of 69 novel MPZ mutations. Almost 90% of them could be alternatively classified as responsible for: (a) an early-onset phenotype, with first limitations starting before 3 years (2.5 ± 0.50 years), motor milestones delays, frequently severe course and upper limb MNCVs below 15 m/s; (b) late-onset neuropathy, with mean age of onset of 42.8 ± 1.5 years and mean upper limbs motor nerve conduction velocities (MNCVs) of 47.2 ± 1.4 m/s; (c) a phenotype more similar to typical CMT1A neuropathy, with onset during the 2nd decade, MNCV in the range of 15-30 m/s and slowly progressive course. The present work confirms that P0-related neuropathies may be separated into two main distinct phenotypes, while a third, relatively small, group comprehend patients carrying MPZ mutations and a childhood-onset disease, substantiating the subdivision into three groups proposed by Sanmaneechai et al. (Brain 138:3180-3192, 2015). Interestingly, during the last years, an increasing number of novel MPZ mutations causing a late-onset phenotype has been described, highlighting the clinical relevance of late-onset P0 neuropathies. Since the family history for neuropathy is often uncertain, due to the late disease onset, the number of patients carrying this genotype is probably underestimated.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteína P0 de la Mielina/genética , Edad de Inicio , Humanos , Mutación , FenotipoRESUMEN
OBJECTIVE: Charcot-Marie-Tooth neuropathy affects mainly and early the lower limbs, but hands deformities are a relevant problem, which involves the quality of life of the patients. Unfortunately, there are few studies about the evaluation of the upper limbs and very rare works about the rehabilitation. A treatment study at the moment is missing and it is important to search rehabilitation exercises to improve the dexterity and the quality of life of the patients. METHODS: We recruited 9 patients with clinical and genetic diagnosis of CMT and we proposed a rehabilitation protocol which includes muscle recruitment, stretching and proprioceptive exercises for the hand with the duration of 4 weeks (two sessions for week). We evaluated the patients before and one week after the treatment with Thumb Opposition Test, Sollerman Hand Function Scale, dynamometry (tripod pinch and hand grip). RESULTS: The rehabilitation protocol has been well tolerated and there were not dropouts. We did not observe any worsening in every scale we used. Every parameter tested showed an improvement especially in the right/dominant hand. CONCLUSION: This study demonstrates that this three phases treatment is well tolerated by patients, it is not detrimental for the hands status and perfectly reproducible by professionals. Moreover, this could be the basis for future randomized single blind projects.
RESUMEN
BACKGROUND: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. RESULTS: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. CONCLUSION: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.
Asunto(s)
Miosinas Cardíacas/metabolismo , Enfermedades Musculares/diagnóstico , Cadenas Pesadas de Miosina/metabolismo , Adolescente , Adulto , Anciano , Miosinas Cardíacas/genética , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Extremidad Inferior/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/patología , Mutación/genética , Cadenas Pesadas de Miosina/genética , Linaje , Fenotipo , Adulto JovenRESUMEN
Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non-Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor.
Asunto(s)
Neuropatías Amiloides Familiares/tratamiento farmacológico , Benzoxazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/genética , Benzoxazoles/efectos adversos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Italia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Prealbúmina/genética , Pronóstico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy, usually triggered by an infectious episode, mostly of viral origin. Varicella zoster virus (VZV) is a rare cause of GBS, mainly in the case of latent infection reactivation. We report on three adult patients who developed GBS following chickenpox, after a short period of latency. They were promptly treated with intravenous immunoglobulin, and the first one with plasma exchange additionally. All the patients experienced almost complete clinical recovery. Our experience suggests that primary VZV infection constitutes a GBS triggering event.
Asunto(s)
Varicela/complicaciones , Síndrome de Guillain-Barré/terapia , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Intercambio Plasmático , Adulto , Femenino , Síndrome de Guillain-Barré/tratamiento farmacológico , Síndrome de Guillain-Barré/etiología , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene have been associated with both autosomal recessive (AR) and dominant (AD) Charcot-Marie-Tooth (CMT) axonal neuropathy. The relative frequency of heterozygous, dominant mutations in Italian CMT is unknown. We investigated the frequency of dominant mutations in GDAP1 in a cohort of 109 axonal Italian patients by sequencing genomic DNA and search for copy number variations. We also explored correlations with clinical features. All cases had already been tested for variants in common axonal AD genes. Eight patients (7.3%) harbored five already reported heterozygous mutations in GDAP1 (p.Arg120Gly, p.Arg120Trp, p.His123Arg, p.Gln218Glu, p.Arg226Ser). Mutations had different penetrances in the families; the onset of symptoms is in the first decade and progression is slower than usually seen in GDAP1-related AR-CMT. We show that the relative frequency of mutations in GDAP was slightly higher than those observed in MFN2 and MPZ (7.3% vs 6.3% and 5.0%). The relatively milder clinical features and the quite indolent course observed are relevant for prognostic assessment. On the basis of our experience and the data reported here, we suggest GDAP1 as the first gene that should be analysed in Italian patients affected by CMT2.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Vías Autónomas/patología , Vías Autónomas/fisiopatología , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Conducción Nerviosa/genética , Fenotipo , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease type 1X (CMT1X) is an X-linked dominant hereditary motor-sensory peripheral neuropathy, which results from mutations in the Gap Junction B1 (GJB1) gene. In a few cases, gene deletions have been linked to the disease, but their relative contribution in the pathogenesis of CMT1X has not been assessed yet. Herein a retrospective study to establish the incidence of gene deletions is described. METHODS: Copy number variation analysis was performed by multiplex ligation-dependent probe amplification, whilst the breakpoints were defined by Sanger sequencing. RESULTS: A novel GJB1 deletion was identified in a family presenting with a classical CMT1X phenotype. The rearrangement includes the coding and the regulatory regions of GJB1. CONCLUSIONS: GJB1 deletions appear to be a rare but not insignificant cause of CMT1X and are associated with a typical disease phenotype. Accordingly, patients negative for point mutations whose pedigree and clinical records strongly suggest the possibility of CMT1X should be tested for GJB1 copy number variations.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , Variaciones en el Número de Copia de ADN , Eliminación de Gen , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Proteína beta1 de Unión ComunicanteRESUMEN
BACKGROUND: The combination of distal muscle weakness, sensory defects and feet deformities leads to disequilibrium in patients affected by Charcot-Marie-Tooth (CMT) neuropathy. Studies relating the outcome of balance scales and clinical severity of CMT are lacking. AIM: To evaluate the accuracy of the Tinetti Balance scale (TBS) and Berg Balance scale (BBS) in identifying balance disorders and quantifying disease severity in CMT patients. DESIGN: Observational study. SETTING: University of Genoa-IRCCS AOU San Martino IST-Department of Neurology, Italy. POPULATION: Nineteen individuals with a diagnosis of CMT (12 females, 7 males, age 41.26±12.42). METHODS: All subjects underwent an evaluation with both TBS and BBS. Disability was quantified with CMT neuropathy score (CMTNS). Moreover, a complete neurophysiological study was performed. Distal lower limbs strength was evaluated with MRC scale. Pearson rank order correlation was used to determine the correlation between the scores on the two tests and to identify an eventual correlation between TBS or BBS and the CMTNS. RESULTS: Both scales showed a highly significant negative correlation with the CMTNS (r=-0.78, P<0.0005 and r=-0.77, P<0.001, respectively) and distal weakness on the anterior tibial muscles (AT) (TBS: AT left: r=0.65, P<0.005 and AT right: 0.59, P<0.01; BBS: AT left r=+0.71, P<0.001 and AT right r=+0.66, P<0.005). We found also a highly significant, positive correlation between the two different balance scales (r=+0.9, P<0.0001). CONCLUSION: TBS and BBS strongly correlate with disease disability and distal muscular weakness. CLINICAL REHABILITATION IMPACT: Both TBS and BBS may play a relevant role in the assessment of disability in patients affected by CMT. Further studies are needed to validate our results in a larger population.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/rehabilitación , Evaluación de la Discapacidad , Personas con Discapacidad/rehabilitación , Equilibrio Postural/fisiología , Adulto , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Femenino , Humanos , Masculino , Examen Neurológico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Education is the core activity of academic anaesthesia departments. One of the main difficulties appears to be the development of realistic high-quality 'training' practices that are safe for patients. The aim of this study was to determine the incidence of complications occurring after epidural catheter placement by inexperienced anaesthesia trainees and their possible relationship with the experience of the operator. METHODS: In a period covering 16 months, we performed a survey of 1,000 consecutive epidural placements performed by inexperienced anaesthesia residents under the direction of staff members in Padoa University Hospital, Italy. Neurological and cardiovascular complications as well as side effects were assessed and analyzed in terms of the experience levels of the trainees. RESULTS: Complications during epidural catheter placement included dural puncture (2.2%), epidural vascular damage (1.7%), and paresthesias (0.9%). Postoperative complications and side effects comprised local bleeding at the catheter insertion point (0.7%), catheter malfunction (0.4%), cardiovascular side effects (2.0%) and persistent postoperative paresthesias not caused by local anaesthetic infusion (1.7%). One patient suffered a transient radiculopathy. The overall incidence of complications was similar for each experience level examined. CONCLUSION: Epidural catheterization performed under supervision by inexperienced anaesthesia residents is not associated with a significantly greater number of complications than reported in the literature. Moreover, at the early stage of training, we could not demonstrate any correlation between the experience of the operator and the incidence of complications incidence.
Asunto(s)
Anestesia Epidural , Anestesiología/educación , Adulto , Anciano , Anciano de 80 o más Años , Cateterismo , Femenino , Humanos , Internado y Residencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant hereditary disease whose clinical expression is a stepwise subcortical vascular dementia. Initial presentation of the disease involves transient or stabilized focal neurological deficits, migraine and mood changes. Recently, a high prevalence of right-to-left shunt (RLS) due to patent foramen ovale has been reported in subjects with migraine. The aim of our study was to determine the prevalence of RLS in CADASIL with and without migraine. METHODS: We performed transcranial Doppler with gaseous contrast in 5 members of an Italian family with CADASIL, diagnosed by means of genetic and skin biopsy criteria. We then compared the prevalence of RLS in 40 consecutive subjects with juvenile stroke, 80 asymptomatic subjects affected by migraine with aura and 50 normal controls. RESULTS: A very high prevalence of RLS was found in CADASIL patients (4/5, 80%), as opposed to young subjects with ischemic stroke (15/40, 37%), asymptomatic subjects with migraine (32/80, 40%) and normal controls (8/50, 16%). All the subjects with CADASIL and migraine (4/4) showed RLS. The difference between CADASIL patients and controls was highly significant (p = 0.006). CONCLUSIONS: We suggest an association between CADASIL and RLS, possibly due to the abnormal development of the endocardial cushion influenced by Notch 3 mutation. Our hypothesis needs to be tested in larger samples.
Asunto(s)
Aberraciones Cromosómicas , Demencia por Múltiples Infartos/genética , Genes Dominantes , Defectos del Tabique Interatrial/genética , Ultrasonografía Doppler Transcraneal , Adulto , Biopsia , Encéfalo/patología , Demencia por Múltiples Infartos/diagnóstico por imagen , Femenino , Defectos del Tabique Interatrial/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/genética , Examen Neurológico , Fenotipo , Piel/patologíaRESUMEN
Mutations in the early growth response 2 (EGR2) gene are associated with some forms of Charcot--Marie--Tooth disease (CMT) and other demyelinating neuropathies. These mutations modify the EGR2 binding to specific DNA sequences suggesting a role in the transcriptional control of myelination-specific genes. Here we show that the D355V mutation, associated with a CMT case combining axonal and demyelinating abnormalities, reduces three times the affinity of EGR2 to its consensus sequence and ten times its affinity to a sequence in the human Cx32 promoter. These findings could indicate that this EGR2 mutation leads to the development of CMT1 through the transcriptional deregulation of Cx32 gene.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , Proteínas de Unión al ADN/metabolismo , Mutación Puntual , Regiones Promotoras Genéticas/fisiología , Factores de Transcripción/metabolismo , Adolescente , Unión Competitiva/fisiología , Enfermedad de Charcot-Marie-Tooth/metabolismo , Niño , Proteína 2 de la Respuesta de Crecimiento Precoz , Femenino , Expresión Génica/fisiología , Humanos , Vaina de Mielina/fisiología , Transcripción Genética/fisiología , Proteína beta1 de Unión ComunicanteRESUMEN
Charcot-Marie-Tooth 1A (CMT1A) neuropathy is caused by duplication of the peripheral myelin protein 22 (PMP22) gene, leading to protein overexpression. Although this protein has a role in regulating Schwann cell growth and peripheral myelin compaction, how altered concentrations of PMP22 impair myelination is unknown. We established dorsal root ganglia (DRG) cultures from a transgenic rat overexpressing PMP22 (PMP22tg) to study the behavior of PMP22tg Schwann cells in early stages of development and myelination. We used reverse transcriptase-polymerase chain reaction and light and electron microscopy to study PMP22 expression and myelin formation. Myelin ultrastructure was evaluated in sural nerves from CMT1A patients to compare experimental and human findings. PMP22tg DRG cultures contained a greater number of internodes devoid of myelin, in the absence of remyelination, and increased periodicity of myelin lamellae compared with normal cultures. Widening of myelin lamellae was also observed in CMT1A biopsy specimens. Our results suggest that both functions of PMP22, in regulating Schwann cell differentiation and contributing to peripheral myelin compaction, are affected by its overexpression. The presence of similar myelin abnormalities in PMP22tg cultures and human nerves emphasizes the importance of developing in vitro models of hereditary neuropathies to study their underlying pathomechanisms.
Asunto(s)
Ganglios Espinales/metabolismo , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Vaina de Mielina/metabolismo , Tetraciclina/metabolismo , Animales , Animales Modificados Genéticamente , Técnicas de Cultivo de Célula , Ganglios Espinales/diagnóstico por imagen , Humanos , Masculino , Microscopía Electrónica , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley/genética , Nervio Sural/ultraestructura , UltrasonografíaRESUMEN
We studied the expression of insulin-like growth factor I (IGF-I) and its receptor in sural nerves from 8 diabetic patients divided into insulin-treated (IT) and non-insulin-treated (NIT) groups, compared with 5 patients with axonal neuropathies and 4 control patients (undergoing biopsies for diagnostic purposes). Insulin-like growth factor I mRNA levels did not differ in diabetic cases compared with control subjects. In sural nerves from IT patients and axonal neuropathies, IGF-I expression was higher than in NIT subjects and diagnostic controls. Changes in IGF-I receptor mRNA levels paralleled those of the ligand. Insulin-like growth factor I immunoreactivity was higher in nerves undergoing axonal degeneration and higher in IT than NIT diabetic patients and diagnostic controls. These findings suggest that insulin treatment increases IGF-I expression in diabetic nerves. Our data do not support the hypothesis of an absolute IGF-I deficiency in human diabetic neuropathy. A Schwann cell's incapacity to increase IGF-I expression after severe nerve damage, as happens in axonal neuropathies, may be a cofactor in the pathogenesis of diabetic neuropathy.