Research advances on the mechanism of non-coding RNA regulated diabetic wound healing / 中华烧伤杂志

Diabetic wounds are a common complication of diabetic patients, and the incidence has been increasing in recent years. In addition, its poor clinical prognosis seriously affects the quality of life of patients, which has become the focus and difficulty of diabetes treatment. As the RNA regulating gene expression, non-coding RNA can regulate the pathophysiological process of diseases, and play an important role in the healing process of diabetic wounds. In this paper, we reviewed the regulatory role, diagnostic value, and therapeutic potential of three common non-coding RNA in diabetic wounds, in order to provide a new solution for the diagnosis and treatment of diabetic wounds at the genetic and molecular level.

Clinical and genetic analysis of an infant with permanent neonatal diabetes mellitus due to novel variant of insulin gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for an infant with permanent neonatal diabetes mellitus (PNDM).@*METHODS@#Clinical data of the child was collected. Targeted capture-next generation sequencing was carried out to identify the potential variants. Candidate variant was verified by Sanger sequencing of her family members.@*RESULTS@#The child was a 4-month-and-26-day female featuring onset of ketoacidosis accompanied with fasting blood glucose of 24.4 mmol/L, positive urine glucose, decreased serum C-peptide, HbA1c of 9.58%, and negative diabetes autoantibody. Genetic testing revealed that she has carried a heterozygous c.314T>G (p.L105R) variant of the INS gene. Sanger sequencing verified that neither of her parents has carried the same variant, which was also unreported in the literature. The variant was classified as likely pathogenic based on the ACMG guidelines.@*CONCLUSION@#The c.314T>G (P.L105R) variant of the INS gene probably underlay the genetic etiology in this child. Genetic testing should be conducted for children with suspected PNDM for early diagnosis and appropriate treatment.

Research progress in role of autophagy in diabetic wound healing and traditional Chinese medicine intervention / 中国中药杂志

Diabetic ulcer(DU) is a chronic and refractory ulcer which often occurs in the foot or lower limbs. It is a diabetic complication with high morbidity and mortality. The pathogenesis of DU is complex, and the therapies(such as debridement, flap transplantation, and application of antibiotics) are also complex and have long cycles. DU patients suffer from great economic and psychological pressure while enduring pain. Therefore, it is particularly important to promote rapid wound healing, reduce disability and mortality, protect limb function, and improve the quality of life of DU patients. By reviewing the relevant literatures, we have found that autophagy can remove DU wound pathogens, reduce wound inflammation, and accelerate ulcer wound healing and tissue repair. The main autophagy-related factors microtubule-binding light chain protein 3(LC3), autophagy-specific gene Beclin-1, and ubiquitin-binding protein p62 mediate autophagy. The traditional Chinese medicine(TCM) treatment of DU mitigates clinical symptoms, accelerates ulcer wound healing, reduces ulcer recurrence, and delays further deterioration of DU. Furthermore, under the guidance of syndrome differentiation and treatment and the overall concept, TCM treatment harmonizes yin and yang, ameliorates TCM syndrome, and treats underlying diseases, thereby curing DU from the root. Therefore, this article reviews the role of autophagy and major related factors LC3, Beclin-1, and p62 in the healing of DU wounds and the intervention of TCM, aiming to provide reference for the clinical treatment of DU wounds and subsequent in-depth studies.

Role of TGF-β/Smad signaling pathway in diabetic kidney disease and research progress of traditional Chinese medicine intervention / 中国中药杂志

Diabetic kidney disease is an important microvascular complication of diabetes and the leading cause of end-stage renal disease. Its pathological characteristics mainly include epithelial mesenchymal transition(EMT) in glomerulus, podocyte apoptosis and autophagy, and damage of glomerular filtration barrier. Transforming growth factor-β(TGF-β)/Smad signaling pathway is specifically regulated by a variety of mechanisms, and is a classic pathway involved in physiological activities such as apoptosis, proliferation and differentiation. At present, many studies have found that TGF-β/Smad signaling pathway plays a key role in the pathogenesis of diabetic kidney disease. Traditional Chinese medicine has significant advantages in the treatment of diabetic kidney disease for its multi-component, multi-target and multi-pathway characteristics, and some traditional Chinese medicine extracts, traditional Chinese medicines and traditional Chinese medicine compound prescription improve the renal injury of diabetic kidney disease by regulating TGF-β/Smad signaling pathway. This study clarified the mechanism of TGF-β/Smad signaling pathway in diabetic kidney disease by expounding the relationship between the key targets of the pathway and diabetic kidney disease, and summarized the research progress of traditional Chinese medicine in the treatment of diabetic kidney disease by interfering with TGF-β/Smad signaling pathway in recent years, to provide reference for drug research and clinical treatment of diabetic kidney disease in the future.

tiRNA-Val promotes angiogenesis via Sirt1-Hif-1α axis in mice with diabetic retinopathy

BACKGROUND: Diabetic retinopathy (DR) is a specific microvascular complication arising from diabetes, and its pathogenesis is not completely understood. tRNA-derived stress-induced RNAs (tiRNAs), a new type of small noncoding RNA generated by specific cleavage of tRNAs, has become a promising target for several diseases. However, the regulatory function of tiRNAs in DR and its detailed mechanism remain unknown. RESULTS: Here, we analyzed the tiRNA profiles of normal and DR retinal tissues. The expression level of tiRNA-Val was significantly upregulated in DR retinal tissues. Consistently, tiRNA-Val was upregulated in human retinal microvascular endothelial cells (HRMECs) under high glucose conditions. The overexpression of tiRNA-Val enhanced cell proliferation and inhibited cell apoptosis in HRMECs, but the knockdown of tiRNA-Val decreased cell proliferation and promoted cell apoptosis. Mechanistically, tiRNA-Val, derived from mature tRNA-Val with Ang cleavage, decreased Sirt1 expression level by interacting with sirt1 3'UTR, leading to the accumulation of Hif-1α, a key target for DR. In addition, subretinal injection of adeno-associated virus to knock down tiRNA-Val in DR mice ameliorated the symptoms of DR. CONCLUSION: tiRNA-Val enhance cell proliferation and inhibited cell apoptosis via Sirt1/Hif-1α pathway in HRMECs of DR retinal tissues.

Influence of Family History of Diabetes on Cardiac Autonomic Dysfunction of Adolescents

Abstract Background To evaluate cardiac autonomic modulation of adolescents with a family history of diabetic parents. Objective This study aims to evaluate the influence of a family history of diabetes on cardiac autonomic modulation. Methods This is an analytical and cross-sectional study on adolescents between 11 and 18 years of age, of both genders, who were divided into group with a family history of diabetes and a control group without a family history of diabetes. The study protocol consisted of the analysis of heart rate variability, blood pressure, anthropometric measurements, and body composition. Also, by using questionnaires, level of physical activity, sexual maturation, and sleep quality were evaluated. Normality of data distribution was tested using the Kolmogorov-Smirnov test. Then, statistical significance was evaluated using the Student's t-test, and the Cohen's teste was used for calculation of the effect size. The level of significance adopted in the statistical analysis was 5%. Results When the group of individuals with a family history of diabetes was compared with the control group, statistically significant differences were observed in the variables the standard deviation of the NN time series interval (SDNN) (43.9 ± 2.2 vs. 53.5 ± 2.6 ms), the square root of the quadratic differences (RMSSD) (41.9 ± 3.3 vs. 52.4 ± 3.2 ms), standard deviation of beat-to-beat instantaneous variability (SD1) (29.7 ± 2.3 vs. 37.1 ± 2.3 ms), long-term standard deviation of continuous RR intervals (SD2) (. 54.1 ± 2.6 vs. 66.66 ± 3.5 ms), and in low frequency (LF) (496.0 ± 49.5 vs. 728 ± 71.6 ms2) and high frequency (HF) (1050.0 ± 120.4 vs. 737.4 ± 98.5 ms2) in the frequency domain. Conclusions Global autonomic modulation is decreased in adolescents with a family history of diabetes. We also observed a decrease in vagal activity in this group. So, sympathetic autonomic modulation is predominant in this population. (Int J Cardiovasc Sci. 2020; [online].ahead print, PP.0-0)

Gene variant analysis of a child presented with neonatal diabetes and multiple organ malformations / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for an infant with neonatal diabetes (NDM) and multiple malformations.@*METHODS@#Genetic variants were detected by next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing.@*RESULTS@#A de novo heterozygous variant, c.1454_1455del(p.K485Rfs), was detected in exon 5 of the GATA6 gene. The variant was undetected in his parents and unreported previously. Bioinformatic analysis predicted the variant to be pathogenic.@*CONCLUSION@#The heterozygous variant of c.1454_1455del(p.K485Rfs) of the GATA6 gene probably underlies the disease in this child. Genetic testing can facilitate diagnosis and genetic counseling for NDM.

Asociación entre diabetes mellitus tipo 2, historia familiar de diabetes y deterioro cognitivo en adultos mayores chilenos / Risk of cognitive impairment among older people with diabetes or family history of the disease

Background: Although cardiovascular risk factors are associated with an impaired cognitive function, the impact of diabetes on cognitive function in Chilean adults is unknown. Aim: To investigate the association of diabetes or family history of the disease with cognitive impairment in older adults. Materials and Methods: Data from the 2009-2010 Chilean National Health Survey including 1,384 participants aged ≥ 60 years were included in this study. A score below 13 points for the Mini Mental State Examination (MMSE) was considered an indication of cognitive impairment. Logistic regression analyses were performed to assess the association between MMSE, diabetes and family history of the disease. Results: Cognitive impairment increased with age (Odds ratio (OR): 1.83 [95% confidence intervals (CI): 1.53; 2.19], p < 0.01, per 5 years increment in age). This trend was greater in individuals with diabetes (OR: 2.37 [95% CI: 1.68; 3.35], p < 0.01) compared to those without the disease. A similar trend was identified among individuals with a family history of diabetes compared to those without. Conclusions: Older adults with diabetes are more susceptible to develop cognitive impairment.

Enfermedad de Gaucher / Gaucher´s disease

Las enfermedades por depósito, representan un amplio espectro clínico de enfermedades. Una de las más frecuentes es la enfermedad de Gaucher, cuyo defecto primordial radica en el almacenamiento de glucosilceramida. Su prevalencia es 1/100.000 habitantes en países del Medio Oriente. En Suramérica es tan infrecuente que no se cuenta con estadísticas claras. Presentamos un paciente de 21 años de edad con antecedentes de diabetes mellitus tipo 1, quien inicia clínica 6 meses previos a su ingreso caracterizado por dolor en hipocondrio derecho, difuso, de moderada intensidad, intermitente, con periodos de acalmia de hasta 10 días, acompañado de náuseas, astenia, hiporexia y adinamia. Durante su hospitalización se realizan estudios de imagen que muestran hepatoesplenomegalia (homogénea) y en el laboratorio se encontraron transaminasas elevadas, anemia persistente y niveles de glucemia variables. Se realizan biopsias hepática y de medula ósea, compatibles con enfermedad por depósito tipo Gaucher. . Esta enfermedad es poco conocida en nuestro país, siendo la de mayor incidencia la enfermedad de Fabry. Se debe considerar la coexistencia con otras enfermedades metabólicas como diabetes tipo 1, que pudieran condicionar su aparición(AU)

Storage diseases represent a broad clinical spectrum. Gaucher´s disease, in which the primary defect lies in the storage of glucosylceramide has a prevalence of 1/100.000 in countries of the Middle East. In South America this disease is so infrequent, that there is no clear information about the prevalence. We present the case a 21-year old patient, with diabetes mellitus type 1 and a history of intermittent abdominal pain in the right hypochondrium, moderate intensity, nausea, asthenia, and hyporexia. The image studies showed homogeneous hepatosplenomegaly. The laboratory workup reported elevated transaminases, persistent anemia and fluctuating blood glucose levels. Hepatic and bone marrow biopsies were compatible with Gaucher type III disease. This disease is little known in our country, were Fabry´s disease is more common. Coexistence with other metabolic diseases such as diabetes should be considered(AU)

Diabetes mellitus e doença cardiovascular. panorama do problema no brasil e no mundo / Diabetes mellitus and cardiovascular disease. overview of the problem in brazil and worldwide

Os dados atuais estimam que em todo o mundo a presença do diabetes é de aproximadamente 425 milhões, sendo que um em cada 11 adultos tem diabetes, dois terços dos quais vivem em áreas urbanas e estão em idade produtiva. As taxas do diabetes estão aumentando em todo o mundo. A Federação Internacional de Diabetes estima que o número de pessoas com diabetes subirá de 366 milhões em 2011 para 552 milhões em 2030, e é provável que atinja 629 milhões em 2045. A população de diabéticos no Brasil, no final dos anos 80, tinha uma prevalência estimada de 7,6% na população adulta, com uma estimativa atual de aproximadamente 12 milhões de adultos. Estudos realizados em seis capitais brasileiras com servidores de universidades públicas na faixa etária de 35 a 74 anos e com medidas laboratoriais mais abrangentes encontraram prevalência de aproximadamente 20%, sendo que aproximadamente metade dos casos não possui diagnóstico prévio. Em 2014, estimou-se que haveria 11,9 milhões de indivíduos, na faixa etária entre 20 e 79 anos, com diabetes no Brasil, podendo chegar a 19,2 milhões em 2035. Portanto, as perspectivas quanto ao desenvolvimento do diabetes em nosso país e no mundo compõem um cenário bastante desfavorável, pois a prevalência dos fatores desencadeantes como obesidade e sedentarismo tende a aumentar, sendo necessárias medidas de orientação populacional para modificação dos hábitos e hábitos alimentares.

Current data estimate that the presence of diabetes worldwide is around 425 million, with one in every 11 adults having diabetes, two thirds of whom live in urban areas and are of productive age. The rates of diabetes are increasing all over the world. The International Diabetes Federation estimates that the number of people living with diabetes will rise from 366 million in 2011 to 552 million in 2030, and is likely to reach 629 million in 2045. The population of diabetics in Brazil at the end of the 1980s had an estimated prevalence of 7.6% in the adult population, with a current estimate of around 12 million adults. Studies conducted in six Brazilian capitals, with civil servants working at public universities, in the age group 35 to 74 years, and using more comprehensive laboratory measures, found a prevalence of about 20%, with approximately half of the cases having no previous diagnosis. In 2014, it was estimated that there were 11.9 million individuals aged between 20 and 79 years with diabetes in Brazil, with this figure reaching as high as 19.2 million by 2035. Therefore, the prospects regarding the development of diabetes, in our country and worldwide, present a very unfavorable scenario, given that the prevalence of triggering factors, such as obesity and a sedentary lifestyle, are tending to increase, requiring measures to guide the population and modify lifestyle and dietary habits.

More than kin, less than kind: one family and the many faces of diabetes in youth

SUMMARY Identification of the correct etiology of diabetes brings important implications for clinical management. In this report, we describe a case of a 4-year old asymptomatic girl with diabetes since age 2, along with several individuals in her family with different etiologies for hyperglycemia identified in youth. Genetic analyses were made by Sanger sequencing, laboratory measurements included HbA1c, lipid profile, fasting C-peptide, pancreatic auto-antibodies (glutamic acid decarboxylase [GAD], Islet Antigen 2 [IA-2], and anti-insulin). We found a Gly178Ala substitution in exon 5 of GCK gene in three individuals co-segregating with diabetes, and type 1 diabetes was identified in two other individuals based on clinical and laboratory data. One individual with previous gestational diabetes and other with prediabetes were also described. We discuss difficulties in defining etiology of hyperglycemia in youth in clinical practice, especially monogenic forms of diabetes, in spite of the availability of several genetic, laboratory, and clinical tools.

Tratamiento de las repercusiones sinérgicas en presencia de enfermedad periodontal en el paciente con diabetes: revisión de la literatura / Treatment of the synergistic effects of periodontaldisease in patients with diabetes. literature review

Introducción: La interacción de las enfermedades periodontales serelacionan con el medio ambiente, huésped, factores microbianos ysusceptibilidad genética. En esta patología la interacción de las bacteriasy el sistema inmunológico dan como resultado una producción elevada de mediadores infl amatorios como las interleucinas IL-1, IL-6 y el TNF-α que destruirán el tejido conectivo y óseo. La diabetes por sí misma ya sea tipo 1 o 2 va a tener repercusiones a nivel de los diferentes órganos de la economía como los riñones, sistema nervioso,ojos, sistema circulatorio y de ahí al periodonto. Cuando el paciente nose encuentra en control sistémico, los efectos adversos van aumentandoy se provoca una sinergia entre la alteración glucémica y la afectaciónperiodontal. Se ha descrito la relación del efecto benéfi co del tratamientoperiodontal en el control glucémico en pacientes diabéticos y no diabéticos. Conclusión: El tratamiento periodontal no quirúrgico demostró reducir los valores de los parámetros periodontales así como los valores séricos de glucosa en ayuno y hemoglobina glucosilada y coadyuvar en el control glucémico.

Introduction: The interaction of periodontal disease is related to theenvironment, host, microbial factors and genetic susceptibility. In thiscondition, the interaction of bacteria and the immune system result inincreased production of infl ammatory mediators such as IL-1, IL-6interleukins, and TNF-α that will destroy connective tissue and bone.Diabetes itself either type 1 or 2 will have repercussions at the levelof the diff erent organs of the economy as it is kidneys, nervous system,eyes, circulatory system and hence the periodontium. When the patientis not in controlling systemic adverse eff ects are increased and synergybetween periodontal health and glycemic involvement provoked. It hasbeen reported regarding the benefi cial eff ect of periodontal treatmenton glycemic control in diabetic and non-diabetic patients. Conclusion:The non-surgical periodontal treatment was shown to reduce the valuesof periodontal parameters and serum fasting glucose and glycatedhemoglobin and assist in glycemic control.

Síndrome de anemia megaloblástica sensible a la tiamina de aparición en la niñez, con mutación en el genSLC19A2: caso clínico / Infantile-onset thiamine responsive megaloblastic anemia syndrome with SLC19A2 mutation: a case report

Antecedentes. El síndrome de anemia megaloblástica sensible a la tiamina (TRMA, por sus siglas en inglés), también conocido como síndrome de Rogers, se caracteriza por presentar anemia megaloblástica, hipoacusia neurosensorial y diabetes mellitus. Las alteraciones en el transporte de la tiamina hacia las células se deben a mutaciones homocigotas o heterocigotas compuestas en el gen SLC19A2. Presentación de un caso. Presentamos el caso de una niña que manifestaba sordera neurosensorial tratada con una prótesis auditiva, diabetes con necesidad de insulina y anemia macrocítica, tratada con tiamina (100 mg/día). El nivel de hemoglobina mejoró hasta alcanzar 12,1 g/dl después de aumentar la dosis terapéutica de tiamina hasta 200 mg/día. Conclusión. Se debe evaluar a los pacientes con TRMA para detectar anemia megaloblástica, hipoacusia neurosensorial y diabetes mellitus. Se les debe dar seguimiento para determinar la respuesta de la enfermedad hematológica y de la diabetes después de la terapia con tiamina. La dosis terapéutica de tiamina puede aumentarse según la respuesta clínica. Debe proporcionarse asesoramiento genético.

Background. Thiamine-responsive megaloblastic anemia syndrome (TRMA), also known as Rogers syndrome, is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Disturbances of the thiamine transport into the cells results from homozygous or compound heterozygous mutations in the SLC19A2 gene. Case presentation. We report a girl which presented with sensorineural deafness treated with a hearing prosthesis, insulin requiring diabetes, macrocytic anemia, treated with thiamine (100 mg/day). Hemoglobin level improved to 12.1 g/dl after dose of thiamine therapy increased up to 200 mg/day. Conclusion. Patients with TRMA must be evaluated for megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. They must be followed for response of hematologic and diabetic after thiamine therapy. It should be kept in mind that dose of thiamine therapy may be increased according to the clinical response. Genetic counseling should be given.

Revisión sobre el uso de microRNA en la detección temprana de diabetes mellitus en caninos / Review on the use of microRNA in the early detection of diabetes mellitus in canines

Diabetes mellitus in canines corresponds to a pathology whose etiopathogenesis has not yet been fully understood, since it has a great similarity with human type 1 diabetes mellitus, but the same risk factors have not been found. New diagnostic methods have been investigated in recent years in diabetic murine models, among which microRNAs have been studied as early markers of type 1 and type 2 diabetes mellitus. In canines a homology has been found between microRNAs 21, microRNA 34, microRNA 29, and microRNA 146a with those studied in human and murine diabetics. This would imply that the study of these microRNAs may have a great impact on the early detection of diabetes in canines and be a model for the study of new microRNAs that may be implicated in the development of diabetes in humans.

Potential mechanisms linking probiotics to diabetes: a narrative review of the literature / Mecanismos potenciais ligando probióticos a diabetes: uma revisão narrativa da literatura

ABSTRACT CONTEXT AND OBJECTIVE: Some studies have suggested a wide range of possible mechanisms through which probiotics may play a role in diabetes prevention and treatment. However, the underlying mechanisms are not fully understood. We conducted this study to review the potential mechanisms suggested for the effect of probiotics in diabetes. DESIGN AND SETTING: Narrative review conducted at the Food Security Research Center of Isfahan. METHODS: A search in the electronic databases MEDLINE (PubMed), Cochrane Library, Web of Science and Google scholar was performed up to October 2016. RESULTS: The initial search yielded 1214 reports. After removing duplicates, 704 titles and abstracts were screened. Finally, out of 83 full-text articles that were reviewed for eligibility, 30 articles were included in the final analysis. The anti-diabetic mechanisms for probiotics reported encompass intraluminal and direct effects on the intestinal mucosa and microbiota (n = 13), anti-inflammatory and immunomodulatory effects (n = 10), antioxidative effects (n = 5), effects on endoplasmic reticulum (ER) stress and expression of genes involved in glucose homeostasis and insulin resistance (n = 6), with some studies pointing to more than one mechanism. CONCLUSION: The results may throw some light on the capacity of probiotics as a novel approach towards controlling diabetes. However, further human studies are warranted to elucidate and confirm the potential role of probiotics in diabetes prevention and treatment. Also, it needs to be ascertained whether the effectiveness of probiotics in diabetes prevention and treatment is dependent on the strain of the microorganisms.

RESUMO CONTEXTO E OBJETIVO: Alguns estudos têm sugerido ampla gama de possíveis mecanismos, pelos quais os probióticos podem desempenhar um papel na prevenção e tratamento do diabetes. No entanto, os mecanismos subjacentes não são totalmente compreendidos. Realizamos este estudo para revisar os possíveis mecanismos sugeridos para o efeito dos probióticos na diabetes. TIPO DE ESTUDO E LOCAL: Revisão narrativa conduzida no Food Security Research Centro de Isfahan. MÉTODOS: Busca sistemática nas bases de dados eletrônicas MEDLINE (PubMed), Cochrane Library, Web of Science e Google scholar até outubro de 2016. RESULTADOS: A busca inicial resultou em 1.214 artigos. Após a remoção de duplicatas, foram pesquisados 704 títulos e resumos. Finalmente, de 83 artigos completos revisados para elegibilidade, 30 foram incluídos na análise final. Os mecanismos antidiabéticos relatados dos probióticos abrangem efeitos intraluminais e diretos na mucosa e microbiota intestinal (n = 13), efeitos anti-inflamatórios e imunomoduladores (n = 10), efeitos antioxidativos (n = 5), efeitos sobre o estresse de retículo endoplasmático (RE) e expressão de genes envolvidos na homeostase da glicose e resistência à insulina (n = 6), com alguns estudos apontando para mais de um mecanismo. CONCLUSÃO: Os resultados podem lançar alguma luz sobre os probióticos como uma nova abordagem no controle do diabetes, no entanto, mais estudos em humanos são justificados para elucidar e confirmar o papel potencial dos probióticos na prevenção e tratamento do diabetes. Além disso, deverá ser determinado se a eficácia dos probióticos na prevenção e tratamento do diabetes é dependente da cepa dos microrganismos.

Asociación bidireccional entre enfermedad periodontal y diabetes / Two-way association between periodontal disease and diabetes

El propósito de esta presentación es marcar el concepto de que la asociación entre enfermedad periodontal y diabetes es una vía bidireccional; la primera puede determinar el inicio o agravamiento de la diabetes, en tanto que ésta es uno de los factores de riesgo más estudiados que puede aumentar la gravedad de las enfermedades periodontales que son siempre iniciadas por los microorganismos patógenos.

A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging / Uma orientação diagnóstica para neurodegeneração com acúmulo cerebral de ferro: aspectos clínicos, genéticos e de neuroimagem

ABSTRACT Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.

RESUMO A neurodegeneração com acúmulo cerebral de ferro (sigla em inglês NBIA) representa um grupo heterogêneo e complexo de doenças neurodegenerativas hereditárias, caracterizada pelo acúmulo cerebral de ferro, especialmente nos núcleos da base. O quadro clínico das NBIAs em geral inclui distúrbios do movimento, particularmente parkinsonismo e distonia, disfunção cognitiva, sinais piramidais e anormalidades da retina. As formas de NBIA descritas até o momento incluem neurodegeneração associada a pantothenase kinase (PKAN), neurodegeneração associada a phospholipase A2 (PLAN), neuroferritinopatia, aceruloplasminemia, neurodegeneração associada a beta-propeller protein (BPAN), síndrome de Kufor-Rakeb, neurodegeneração associada a mitochondrial membrane protein (MPAN), neurodegeneração associada a “fatty acid hydroxylase” (FAHN), neurodegeneração associada a coenzyme A synthase protein (CoPAN) e síndrome de Woodhouse-Sakati. Esta revisão é uma orientação para o diagnóstico das NBIAs, partindo das características clínicas e achados de neuroimagem, até a etiologia genética.

Permanent neonatal diabetes by a new mutation in KCNJ11: unsuccessful switch to sulfonylurea

Permanent neonatal diabetes (PNDM) can result from activating heterozygous mutations in KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channels (KATP). Sulfonylureas promote KATP closure and stimulate insulin secretion, being an alternative therapy in PNDM, instead of insulin. Male, 20 years old, diagnosed with diabetes at 3 months of age. The genetic study identified a novel heterozygous mutation in exon 1 of the KCNJ11 gene – KCNJ11:c1001G>7 (p.Gly334Val) – and confirmed the diagnosis of PNDM. Therefore it was attempted to switch from insulin therapy to sulfonylurea. During glibenclamide institution C-peptide levels increased, however the suboptimal glycemic control lead us to restart an intensive insulin scheme. This new variant of KCNJ11 mutation had a phenotypic lack of response to sulfonylurea therapy. Age, prior poor metabolic control and functional change of KATP channel induced by this specific mutation may explain the observed unsuccessful switch to sulfonylurea. Interestingly, C-peptide levels raise during glibenclamide administration support some degree of improvement in insulin secretory capacity induced by the treatment. Understanding the response to sulfonylurea is crucial as successful treatment may be life-changing in these patients.