BPAN manifesting with febrile seizures and language delay: a case report from Brazil

Neurodegeneration with brain iron accumulation (NBIA) is a complex group of hereditary progressive neurodegenerative diseases characterized by deposition of iron in the basal ganglia. Twelve genetic forms of this disorder have been identified in previous studies. Though they have different inheritance mechanisms all are usually associated with abnormal brain MRI findings. One of NBIA types is an X-linked disorder known as Beta-propeller Protein Associated Neurodegeneration (BPAN). Herein we describe the case of a 4-year-old girl with 2 episodes of febrile seizures, a brain MRI showing nonspecific hyperintense signal in the dentate nucleus area, and delays in language and communication development. Her diagnosis was made based on a genetic evaluation where exome sequencing revealed a mutation in the position chrX:48.933.022 region of the WDR45 gene. The literature describes different clinical presentations for BPAN, each with a different prognosis, suggesting a wide range of possible symptoms of BPAN, including mild cognitive delay and even epileptic encephalopathy (EE). (AU)

Hepcidina: la llave del metabolismo del hierro / Hepcidin: the key of iron metabolism / Hepcidina: a chave do metabolismo do ferro

En las últimas décadas se ha avanzado en el conocimiento de la regulación del metabolismo del Hierro (Fe). La Hepcidina (Hp), producida por los hepatocitos, regula la absorción de hierro desde el tubo digestivo y la liberación desde los depósitos del sistema macrofágico y del hígado. En caso de deficiencia de Fe, la Hp está disminuida entregando Fe a la transferrina (Tf). El aumento de Fe y de las citoquinas de la inflamación estimulan la producción de Hp. El ejecutor de la Hp es la Ferroportina (FP), único exportador de Fe. Hay reguladores naturales de la Hp, como la Matriptasa 2. Las mutaciones que limitan su expresión inducen dificultades en la disponibilidad de Fe (IRIDA, sobrecarga de Fe). En los últimos años se ha identificado la Eritroferrona, producida por los eritroblastos activos en la eritropoyesis. Inhibe la síntesis de Hp, permitiendo la liberación del hierro de los depósitos y su absorción por el tubo digestivo, para facilitar la disponibilidad de Fe para la eritropoyesis. Aún no está definido cómo se podrán utilizar estos elementos en el campo diagnóstico, su estandarización y su aplicación terapéutica, pero es probable que resulten de gran utilidad.

In the last decades, a lot of progress has been made on the knowledge of iron (Fe) metabolism regulation. Hepcidin (Hp) is produced by hepatocytes and it regulates the iron absorption from the duodenum and the liberation from macrophages and from the liver. When there is iron deficiency, Hp, which delivers iron to transferrin (Tf), is low. Iron overload and inflammation cytokines stimulate Hp production. The Hp natural executor is Ferroportin (FP), which is the only iron exporter from the cells. One of the natural regulators of Hp is Matriptasa 2, which down regulates Hp. Mutations that limit their expression induce iron overload and anemia (IRIDA). In the last few years, Erythroferrone (ERFE) was discovered. ERFE is produced by active erythroblasts: it inhibits Hp synthesis, allowing the iron liberation from deposits and its duodenal absorption, and also the iron release from macrophages facilitating the erythroid production. The erythroblastic activity, even ineffective, acts as a stimulus of ERFE synthesis. Until now, it has not been defined yethow these different variables could be used for diagnosis, its standardization, or for therapeutic applications, but it is highly probable that they will improve our knowledge and managements kills in this field.

Nas últimas décadas háavanços no conhecimento da regulação do metabolismo do Ferro (Fe). A Hepcidina (Hp), produzida pelos hepatócitos, regula a absorção do ferro desde o tubo digestivo e a liberação desde os depósitos do sistema macrofágico e do fígado. Em caso de deficiência de Fe, a Hp está diminuída entregando Fe à transferrina (Tf). O aumento de Fe e as citoquinas da inflamação estimulam a produção de Hp. O executor da Hp é a Ferroportina (Fp), único exportador de Fe. Há reguladores naturais da Hp, como a Matriptase 2. As mutações que limitam sua expressão induzem dificultades na disponibilidade de Fe (IRIDA, sobrecarga de Fe). Nos últimos anos se identificou que a Eritroferrona, produzida pelos eritroblastosativos na eritropoiese inibe a síntese de Hp, permitindo a liberação de ferro dos depósitos e a absorção pelo tubo digestivo, para facilitar a disponibilidade de Fe para a eritropoiese. Ain da não sedefiniu como poderãoser utilizadosestes elementos no campo diagnóstico, sua padronização e sua aplicação terapêutica, mas é provável que sejam de grande utilidade.

Valor utilitario específico de la técnica modificada de Perls para el diagnóstico anatomopatológico / Specific utilitarian value of the modified technique of Perls for the pathological diagnosis

Se modificó la técnica de Perls para disponer de un medio que pudiera revelar la presencia del pigmento férrico y poder utilizarlo en el diagnóstico histopatológico; para ello se elevó a 58 grados centígrados la temperatura en los reactivos, lo cual no se hace en el procedimiento habitual, y el citado pigmento se tiñó de verde o azul, de manera que fue posible identificarlo en los núcleos grises de la base en un paciente con síndrome de Hallervordem - Spatz, que falleció en esta institución.

The technique of Perls was modified to have a mean that could reveal the presence of the ferric pigment and to be able to use it in the histopathological diagnosis; for this purpose the temperature was rised to 58º centigrades in the reagents, which is not done in the habitual procedure, and the mentioned pigment was stained of green or blue, so that it was possible to identify it in the gray nuclei of the base in a patient with syndrome of Hallervordem - Spatz, who died in this institution.

Non haematological effects of iron deficiency - a perspective.

Iron deficiency is a continuum beginning from lowering of tissue stores to the phase of exhausted tissue stores, interference with iron driven biochemical reactions in the body, microcytosis, hypochromia, increasing severity of anaemia with all its attendant consequences. Iron deficiency anaemia is a very well known concept but what is often not appreciated is the effect of broad canvas of iron deficiency on various tissues, organs and systems in our body in addition to iron deficiency anaemia leading to concept of "Iron deficiency disease". In this condition not only tissue delivery of oxygen is compromised but proliferation, growth, differentiation, myelinogenesis, immunofunction, energy metabolism, absorption and biotransformation are compromised leading to abnormal growth and behaviour, mental retardation, reduced cardiac performance and work efficiency, infection etc which ultimately leads to the concept that "iron deficiency not only breaks the machine but also wrecks the machinery."

Hemocromatosis

En la hemocromatosis hay sobrecarga de hierro por incremento en el ingreso. La hemocromatosis hereditaria es un trastorno autosómico recesivo frecuente. hay mayor absorción del hierro a nivel intestinal y el hierro de depósito, normalmente de 1 g, puede ascender a 20 g o más, ocacionando alteraciones funcionales y daño de estructuras de órganos como el hígado, páncreas, corazón e hipófisis. Suele manifestarse clínicamente después de los 40 años por cirrosis, diabetes, insuficiencia cardíaca e hipogonadismo. El tamiz diagnóstico se efectúa con saturación de la transferrina(>50 por ciento en mujeres y <60 por ciento en hombres)y la ferritina (>200 g/dL). El diagnóstico se comprueba con labiopsia hepática. La terapia de elección son las flebotomías semanales hasta la normalización de los depósitos de hierro. Debe estudiarse la familia y establecer la vigilancia y/o el tratamiento periódico de los pacientes sintomáticos y asintomáticos. La sobrecarga de hierro transfunsional se presenta en pacientes con anemia aplástica, talasemia mayor y anemia falciforme, que reciben transfunsiones sanguíneas repetidas. El exceso de hierro se remueve con agentes quelantes como la desferroxamina en infusiones parenterales, que promueven la eliminación urinaria del hierro. En formas raras de hemocromatosis, la terapia quelante y las flebotomías ayudan en su manejo.