Ferritin L-subunit gene mutation and hereditary hyperferritinaemia cataract syndrome (HHCS): a case report and literature review.

ABSTRACTObjectives: Hereditary hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominant disease characterized by high serum ferritin levels and juvenile bilateral cataracts. It is often caused by mutations in the iron response element (IRE) of the ferritin L-subunit (FTL) gene. Here, we report a 73-year-old woman who presented to clinic with persistently elevated serum ferritin and family history of juvenile bilateral cataracts in four generations.Methods: Exome sequencing was used to identify the mutation of the FTL gene. Moreover, Sanger sequencing was performed to validate the mutation in the proband. We also reviewed the FLT gene mutations in published HHCS cases to provide experience for accurate diagnosis of similar patients.Results: A heterozygous mutation at position +33 (c.-167C > T, chr19:49468598) of the FTL gene was identified in the patient.Discussion: HHCS should be considered in the differential diagnosis of hyperferritinemia, especially in the presence of normal serum iron concentration and transferrin saturation.Conclusion: For patients with unexplained hyperferritinemia and bilateral cataracts who have experienced early vision loss, the establishment of genetic counseling is essential to diagnose other family members who are at risk in time.Abbreviations: FTL: ferritin L-subunit; HHCS: hereditary hyperferritinaemia cataract syndrome; IDT: integrated DNA technologies; IRE: iron response element; IRP: iron regulatory proteins; MRI: magnetic resonance imaging; SNV: single nucleotide variant; UTR: untranslated region.

[Research advances in the pathogenesis and treatment of neurodegeneration with brain iron accumulation].

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic degenerative diseases caused by genetic mutations and characterized by iron deposition in the central nervous system, especially in the basal ganglia, with an overall incidence rate of 2/1 000 000-3/1 000 000. Major clinical manifestations are extrapyramidal symptoms. This disease is presently classified into 14 different subtypes based on different pathogenic genes, and its pathogenesis and treatment remain unclear. This article summarizes the research advances in the pathogenesis and treatment of NBIA, so as to help pediatricians understand this disease and provide a reference for subsequent research on treatment.

Research advances in the pathogenesis and treatment of neurodegeneration with brain iron accumulation / 中国当代儿科杂志

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic degenerative diseases caused by genetic mutations and characterized by iron deposition in the central nervous system, especially in the basal ganglia, with an overall incidence rate of 2/1 000 000-3/1 000 000. Major clinical manifestations are extrapyramidal symptoms. This disease is presently classified into 14 different subtypes based on different pathogenic genes, and its pathogenesis and treatment remain unclear. This article summarizes the research advances in the pathogenesis and treatment of NBIA, so as to help pediatricians understand this disease and provide a reference for subsequent research on treatment.

[Aceruloplasminemia, a rare condition not to be overlooked]. / L'acéruléoplasminémie héréditaire, une pathologie à ne pas méconnaître.

Aceruloplasminemia is a rare iron-overload disease that should be better known by physicians. It is an autosomal recessive disorder due to mutations in ceruloplasmin gene causing systemic iron overload, including cerebral and liver parenchyma. The impairment of ferroxidase ceruloplasmin activity leads to intracellular iron retention leading aceruloplasminemia symptoms. Neurologic manifestations include cognitive impairment, ataxia, extrapyramidal syndrome, abnormal movements, and psychiatric-like syndromes. Physicians should search for aceruloplasminemia in several situations with high ferritin levels: microcytic anaemia, diabetes mellitus, neurological and psychiatric disorders. Diagnosis approach is based on the study of transferrin saturation and hepatic iron content evaluated by magnetic resonance imaging of the liver. Ceruloplasmin dosage is required in case of low transferrin saturation and high hepatic iron content and genetic testing is mandatory in case of serum ceruloplasmin defect. Neurological manifestations occur in the sixties decade and leads to disability. Iron chelators are widely used. Despite their efficacy on systemic and cerebral iron overload, iron chelators tolerance is poor. Early initiation of iron chelation therapy might prevent or slowdown neurodegeneration, highlighting the need for an early diagnosis but their clinical efficacy remains uncertain.

Palliative care in 9 children with neurodegeneration with brain iron accumulation.

AIM: Evaluation of pediatric palliative home care of families with children suffering from neurodegeneration with brain iron accumulation (NBIA) and their parents. MATERIAL AND METHODS: The children were treated at home by a multidisciplinary team. Densitometry was used to evaluate the condition of the skeletal system. Botulinum toxin was injected into the muscles in doses between 22 and 50 units/kg. The quality of palliative care was assessed on the basis of a specially designed questionnaire for parents. RESULTS: The observations were performed on a group of 9 patients with NBIA. On admission, the median age of patients was 9 years (7-14). The average time of palliative home care was 1569 days (34 days-17 years). The median age at death (6 patients) was 11 years (7-15). The botulinum toxin injections gave the following results: reduction of spasticity and dystonia, reduction of spine and chest deformation, relief of pain and suffering, facilitation of rehabilitation and nursing, prevention of permanent contractures, and reduction of excessive salivation. Bone mineral density and bone strength index were reduced. Two patients experienced pathological fracture of the femur. The body mass index at admission varied between 9.8 and 14.9. In 7 cases, introduction of a ketogenic diet resulted in the increase of body mass and height. The ketogenic diet did not worsen the neurological symptoms. The parents positively evaluated the quality of care. CONCLUSION: Palliative home care is the optimal form of treatment for children with NBIA.

Diagnostics and Treatments of Iron-Related CNS Diseases.

Iron has been proposed to be responsible for neuronal loss in several diseases of the central nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Friedreich's ataxia (FRDA), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS). In many diseases, abnormal accumulation of brain iron in disease-affected area has been observed, without clear knowledge of the contribution of iron overload to pathogenesis. Recent evidences implicate that key proteins involved in the disease pathogenesis may also participate in cellular iron metabolism, suggesting that the imbalance of brain iron homeostasis is associated with the diseases. Considering the complicated regulation of iron homeostasis within the brain, a thorough understanding of the molecular events leading to this phenotype is still to be investigated. However, current understanding has already provided the basis for the diagnosis and treatment of iron-related CNS diseases, which will be reviewed here.

Hyperferritinemia in Nonalcoholic Fatty Liver Disease: Iron Accumulation or Inflammation?

Hyperferritinemia, observed in inflammation, iron overload as well as in combination of both, is found in ∼30% of nonalcoholic fatty liver disease (NAFLD) patients. The authors summarized the evidence regarding the potential cause of hyperferritinemia in NAFLD, as this may affect the indicated therapy. A systematic literature search was conducted in EMBASE, PubMed, MEDLINE, and the Cochrane library. In the majority of NAFLD patients, hyperferritinemia is due to inflammation without hepatic iron overload. In a smaller group, a dysmetabolic iron overload syndrome (DIOS) is found, showing hyperferritinemia in combination with mild iron accumulation in the reticuloendothelial cells. The smallest group consists of NAFLD patients with hemochromatosis. Phlebotomy is only effective with hepatocellular iron overload and should not be the treatment when hyperferritinemia is related to inflammation, whether or not combined with DIOS. Treatment with lifestyle changes is to date probably the more effective way until new medication is becoming available.

Severe Yellow Fever and Extreme Hyperferritinemia Managed with Therapeutic Plasma Exchange.

A 43-year-old man was admitted to the intensive care unit and diagnosed with yellow fever. He presented with refractory bleeding, extreme hyperferritinemia, and multiple organ dysfunction syndrome, requiring renal replacement therapy, mechanical ventilation, and treatment with vasoactive drugs. Because the bleeding did not respond to fresh-frozen plasma administration, the patient received therapeutic plasma exchange, which was accompanied by a marked improvement of the clinical and biochemical parameters, including a significant decline in serum ferritin levels.

Hepcidin-ferroportin axis in health and disease.

Hepcidin is central to regulation of iron metabolism. Its effect on a cellular level involves binding ferroportin, the main iron export protein, resulting in its internalization and degradation and leading to iron sequestration within ferroportin-expressing cells. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we present an overview of and rationale for exploring the development of hepcidin agonists and antagonists in various clinical scenarios.

Current status of iron metabolism: Clinical and therapeutic implications. / Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas.

Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases. The most important inhibitory signals are related to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesised has helped design new pharmacological treatments whose main target is the hepcidin. In the near future, there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders.

Astrocyte Dysfunction in Developmental Neurometabolic Diseases.

Astrocytes play crucial roles in maintaining brain homeostasis and in orchestrating neural development, all through tightly coordinated steps that cooperate to maintain the balance needed for normal development. Here, we review the alterations in astrocyte functions that contribute to a variety of developmental neurometabolic disorders and provide additional data on the predominant role of astrocyte dysfunction in the neurometabolic neurodegenerative disease glutaric acidemia type I. Finally, we describe some of the therapeutical approaches directed to neurometabolic diseases and discuss if astrocytes can be possible therapeutic targets for treating these disorders.

[GENETICALLY DETERMINED DISEASES ASSOCIATED WITH PATHOLOGICAL BRAIN IRON ACCUMULATION AND NEURODEGENERATION]. / GENETIKAILAG MEGHÁTAROZOTT, AGYI VASFELHALMOZÓDÁSSAL ÉS NEURODEGENERÁCIÓVAL JÁRÓ KÓRKÉPEK.

The rare, genetically determined group of diseases characterized by pathological accumulation of iron in the central nervous system and progressive, typically movement disorder's symptoms are called NBIA (neurodegeneration with brain iron accumulation). By the rapid development of molecular genetics, it has become apparent that different mutations in numerous genes can lead to pathological cerebral iron accumulation. Simultaneously, it has also been recognized that the age of onset, the symptoms and the prognosis of NBIA disorders are much more diverse than it was previously perceived. To our knowledge, a review article on the most recent clinical data of NBIA has not been published in Hungarian. In the first part of this publication, we survey the general clinical characteristics and the diagnostic algorithm of NBIA diseases and address some considerations for differential diagnostics. In the second part of this review, the particular NBIA disorders are presented in details. The purpose of this article is to provide a clinical overview that may be useful for neurologists, pediatricians and any other medical practitioners interested in this field.

Hepcidin in the diagnosis of iron disorders.

The discovery of the iron-regulatory hormone hepcidin in 2001 has revolutionized our understanding of iron disorders, and its measurement should advance diagnosis/treatment of these conditions. Although several assays have been developed, a gold standard is still lacking, and efforts toward harmonization are ongoing. Nevertheless, promising applications can already be glimpsed, ranging from the use of hepcidin levels for diagnosing iron-refractory iron deficiency anemia to global health applications such as guiding safe iron supplementation in developing countries with high infection burden.

Modulation of hepcidin to treat iron deregulation: potential clinical applications.

The secreted peptide hormone hepcidin regulates systemic and local iron homeostasis through degradation of the iron exporter ferroportin. Dysregulation of hepcidin leads to altered iron homeostasis and development of pathological disorders including hemochromatosis, and iron loading and iron restrictive anemias. Therapeutic modulation of hepcidin is a promising method to ameliorate these conditions. Several approaches have been taken to enhance or reduce the effects of hepcidin in vitro and in vivo. Based on these approaches, hepcidin modulating drugs have been developed and are undergoing clinical evaluation. In this article we review the rationale for development of these drugs, the data concerning their safety and efficacy, their therapeutic uses, and potential future prospects.

A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1.

The arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but it is complicated by high failure rates and attendant morbidity. This study provides the first description of a murine AVF model that recapitulates two salient features of hemodialysis AVFs, namely, anastomosis of end-vein to side-artery to create the AVF and the presence of chronic kidney disease (CKD). CKD reduced AVF blood flow, observed as early as 3 days after AVF creation, and increased neointimal hyperplasia, venous wall thickness, thrombus formation, and vasculopathic gene expression in the AVF. These adverse effects of CKD could not be ascribed to preexisting alterations in blood pressure or vascular reactivity in this CKD model. In addition to vasculopathic genes, CKD induced potentially vasoprotective genes in the AVF such as heme oxygenase-1 (HO-1) and HO-2. To determine whether prior HO-1 upregulation may protect in this model, we upregulated HO-1 by adeno-associated viral gene delivery, achieving marked venous induction of the HO-1 protein and HO activity. Such HO-1 upregulation improved AVF blood flow and decreased venous wall thickness in the AVF. Finally, we demonstrate that the administration of carbon monoxide, a product of HO, acutely increased AVF blood flow. This study thus demonstrates: 1) the feasibility of a clinically relevant murine AVF model created in the presence of CKD and involving an end-vein to side-artery anastomosis; 2) the exacerbatory effect of CKD on clinically relevant features of this model; and 3) the beneficial effects in this model conferred by HO-1 upregulation by adeno-associated viral gene delivery.

[Iron deficiency in elderly people: clinical presentation and management]. / Carence martiale du sujet âgé Conséquences cliniques et prise en charge.

Iron deficiency (absolute or functional) is commonly observed (frequently without associated anemia) in up to one third of old people. Iron deficiency is the most cause of anemia in adults. Many non hematological consequences of iron deficiency are described like: cardiac failure, mood or cognitive disorders, chronic fatigue or restless leg syndrome. Iron deficiency can be orally or with intravenous iron replacement treates if necessary. Long term compliance of patients orally treated for iron deficiency is poor mainly because of fair tolerability of drugs. New regimen of intravenous iron replacement are now available when orally iron administration can not be achieved. In functional iron deficiency iron intravenous replacement seems especially relevant. However further controlled studies are necessary to assess their clinical benefits.