ABSTRACT
Aceruloplasminemia is a rare form of brain iron overload of autosomal recessive inheritance that results from mutations in the CP gene, encoding the iron oxidase ceruloplasmin. Homozygous aceruloplasminemia causes progressive neurodegenerative disease, anemia, and diabetes, and is usually diagnosed late in life upon investigation of anemia, high ferritin, or movement disorders, but its heterozygous state is less characterized and believed to be silent. Here we report two heterozygotes for new mutations causing aceruloplasminemia from whom peripheral blood samples were collected for complete blood counts, iron studies, and genotyping by automated sequencing. We then performed a systematic review of preview reports of heterozygotes with data on genotype and clinical findings. Heterozygosity for aceruloplasminemia invariably causes reduced ceruloplasmin levels, and similarly to previews reports in the literature, our cases did not present with anemia. Mild hyperferritinemia was found only in two reports. Nevertheless, 5 out of 11 variants have been associated with significant neurological symptoms despite the presence of one wild-type alelle. This review contributes to better genetic counseling of heterozygotes for CP gene variants and supports that measuring ceruloplasmin levels may be useful when investigating patients with movement disorders or rare cases of unexplained high ferritin.
Subject(s)
Ceruloplasmin/deficiency , Iron Metabolism Disorders/genetics , Iron Metabolism Disorders/pathology , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/pathology , Adult , Ceruloplasmin/genetics , Female , Heterozygote , Humans , Male , Mutation/genetics , Young AdultABSTRACT
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.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/therapy , Astrocytes/pathology , Brain Diseases, Metabolic/diagnosis , Brain Diseases, Metabolic/therapy , Brain/pathology , Glutaryl-CoA Dehydrogenase/deficiency , Alexander Disease/diagnosis , Alexander Disease/metabolism , Alexander Disease/pathology , Alexander Disease/therapy , Amino Acid Metabolism, Inborn Errors/metabolism , Amino Acid Metabolism, Inborn Errors/pathology , Antioxidants/therapeutic use , Astrocytes/drug effects , Astrocytes/metabolism , Brain/drug effects , Brain/metabolism , Brain Diseases, Metabolic/metabolism , Brain Diseases, Metabolic/pathology , Ceruloplasmin/deficiency , Ceruloplasmin/metabolism , Diet/methods , Disease Management , Glucose/therapeutic use , Glutamate-Ammonia Ligase/deficiency , Glutamate-Ammonia Ligase/metabolism , Glutaryl-CoA Dehydrogenase/metabolism , Hepatic Encephalopathy/diagnosis , Hepatic Encephalopathy/metabolism , Hepatic Encephalopathy/pathology , Hepatic Encephalopathy/therapy , Homeostasis , Humans , Iron Metabolism Disorders/diagnosis , Iron Metabolism Disorders/metabolism , Iron Metabolism Disorders/pathology , Iron Metabolism Disorders/therapy , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/therapy , Neurogenesis/drug effects , Niemann-Pick Disease, Type C/diagnosis , Niemann-Pick Disease, Type C/metabolism , Niemann-Pick Disease, Type C/pathology , Niemann-Pick Disease, Type C/therapy , Pyruvate Carboxylase Deficiency Disease/diagnosis , Pyruvate Carboxylase Deficiency Disease/metabolism , Pyruvate Carboxylase Deficiency Disease/pathology , Pyruvate Carboxylase Deficiency Disease/therapy , Sorption DetoxificationABSTRACT
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.
Subject(s)
Iron Metabolism Disorders/diagnostic imaging , Iron Metabolism Disorders/genetics , Mutation , Neuroaxonal Dystrophies/diagnostic imaging , Neuroaxonal Dystrophies/genetics , Neuroimaging/methods , Alopecia/diagnostic imaging , Alopecia/genetics , Arrhythmias, Cardiac/diagnostic imaging , Arrhythmias, Cardiac/genetics , Basal Ganglia Diseases/diagnostic imaging , Basal Ganglia Diseases/genetics , Ceruloplasmin/deficiency , Ceruloplasmin/genetics , Coenzyme A Ligases/genetics , Diabetes Mellitus/diagnostic imaging , Diabetes Mellitus/genetics , Heredodegenerative Disorders, Nervous System/diagnostic imaging , Heredodegenerative Disorders, Nervous System/genetics , Humans , Hypogonadism/diagnostic imaging , Hypogonadism/genetics , Intellectual Disability/diagnostic imaging , Intellectual Disability/genetics , Magnetic Resonance Imaging/methods , Membrane Proteins/genetics , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/genetics , Pantothenate Kinase-Associated Neurodegeneration/diagnostic imaging , Pantothenate Kinase-Associated Neurodegeneration/genetics , Parkinsonian Disorders/diagnostic imaging , Parkinsonian Disorders/genetics , Phospholipases A2/geneticsABSTRACT
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.
Subject(s)
Humans , Neuroaxonal Dystrophies/genetics , Neuroaxonal Dystrophies/diagnostic imaging , Iron Metabolism Disorders/genetics , Iron Metabolism Disorders/diagnostic imaging , Neuroimaging/methods , Mutation , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/diagnostic imaging , Basal Ganglia Diseases/genetics , Basal Ganglia Diseases/diagnostic imaging , Ceruloplasmin/deficiency , Ceruloplasmin/genetics , Coenzyme A Ligases/genetics , Heredodegenerative Disorders, Nervous System/genetics , Heredodegenerative Disorders, Nervous System/diagnostic imaging , Diabetes Mellitus/genetics , Diabetes Mellitus/diagnostic imaging , Alopecia/genetics , Alopecia/diagnostic imaging , Hypogonadism/genetics , Hypogonadism/diagnostic imagingABSTRACT
The authors report a 44-year-old man with a history of attention deficit and hyperactivity disorder, obsessive compulsive behaviour, vocal tics, depression, and anxiety, in whom a compound heterozygous ATP7B mutation was found, associated with hypoceruloplasminemia, but without clinical or pathological manifestation of Wilson's disease (WD). Genetic testing revealed a compound heterozygous ATP7B mutation already described in WD, p.Met645Arg (C1934TG/c.51+4AâT). Hypoceruloplasminaemia was detected but no clinical manifestations (hepatic or central nervous system) of WD were present. The authors conclude that patients can carry a heterozygous mutation of the ATP7B gene that is associated with hypoceruloplasminaemia and display no overt clinical hepatic and/or central nervous system manifestations of WD.