Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a 20-year-old female with Hallervorden-Spatz syndrome (HSS). This patient is the product of consanguineous parents. She developed genu valgum, tendency to fall and mental deterioration at the age of 6, decrease of the number of spoken words at the age of 14, dysarthria, unsteady gait, postural tremor of the upper extremities, dystonic posture of hands and double incontinence at the age of 16. Her disease progressed slowly. Neurological examination on admission revealed severe mental retardation, optic atrophy, forced grasping, hyperactive tendon reflexes in the upper extremities and bilateral Babinski sign. An extensive laboratory investigation including the leukocyte lysosomal enzymes, serum amino acid analyses, copper studies and ceruloplasmin were almost within normal limits. MRI, T2 weighted images, showed markedly decreased signal intensity in the globus pallidus but substantia nigra and increased signal intensity in diffuse cerebral white matter. T1 weighted images showed marked atrophy of the brainstem and cerebellum. She met the diagnostic criteria for HSS by Swaiman; we diagnosed her as HSS group II. HSS is characterized by the presence of many spheroids in the central nervous system which is similar to neuroaxonal dystrophy (ND). However, clinical and pathological differences exist between HSS and ND, the precise classification of the two conditions has remained controversial. Although there are many reported cases in which both conditions overlap, this is the first reported case that simultaneously demonstrates increased iron deposition in the globus pallidus, marked atrophy of the brainstem and cerebellum and typical clinical course compatible with HSS.
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PMID:[A case of Hallervorden-Spatz syndrome with marked atrophy of the brainstem and cerebellum]. 836 59

Hallervorden-Spatz syndrome (HSS) (OMIM #234200) is a rare, autosomal recessive neurode-generative disorder with brain iron accumulation as a prominent finding. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals massive iron deposits in the basal ganglia. Systemic and cerebrospinal fluid iron levels are normal, as are plasma levels of ferritin, transferrin and ceruloplasmin. Conversely, in disorders of systemic iron overload, such as haemochromatosis, brain iron is not increased, which suggests that fundamental differences exist between brain and systemic iron metabolism and transport. In normal brain, non-haem iron accumulates regionally and is highest in basal ganglia. Pathologic brain iron accumulation is seen in common disorders, including Parkinson's disease, Alzheimer's disease and Huntington disease. In order to gain insight into normal and abnormal brain iron transport, metabolism and function, our approach was to map the gene for HSS. A primary genome scan was performed using samples from a large, consanguineous family (HS1) (see Fig. 1). While this family was immensely powerful for mapping, the region demonstrating homozygosity in all affected members spans only 4 cM, requiring very close markers in order to detect linkage. The HSS gene maps to an interval flanked by D20S906 and D20S116 on chromosome 20p12.3-p13. Linkage was confirmed in nine additional families of diverse ethnic backgrounds.
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PMID:Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. 894 32

The Hallervorden-Spatz syndrome (HSS) is a rare condition characterized by extrapyramidal and pyramidal signs, dystonia, dysarthria, retinal degeneration, dementia and a progressive course. The development of magnetic resonance imaging (MRI) has increased the number of clinical and pathological reports of HSS. MRI pallidal abnormalities are called "eye of the tiger" signs. The combination of clinical features and MRI findings can be considered as highly suggestive of a diagnosis of HSS. Patient 1 was a 28 year old man who had been well until the age of 25 years. He developed dysarthria, difficulty with his gait and dystonia in his arms at the age of 28 years. Patient 2 was a 33 year old man who was the older brother of the first patient. He developed gait difficulty, tongue dystonia and dystonia of both arms at the age of 25 years. Each patient had spastic gait, dysarthria, dystonic posturing of both arms and generalized hyperreflexia, but no Kayser-Fleischer rings or retinitis pigmentosa. Blood chemistry, urine copper, serum copper and serum ceruloplasmin were all normal. MRI of the brain showed the "eye of the tiger" sign in the globus pallidus on T2 weighted images. These siblings had clinical features and MRI findings consistent with HSS. They are the first to be reported in Thailand.
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PMID:Hallervorden-Spatz syndrome in two siblings diagnosed by clinical features and magnetic resonance imaging. 1125 96

Iron is essential for oxidation-reduction catalysis and bioenergetics; however, unless appropriately shielded, this metal plays a crucial role in the formation of toxic oxygen radicals that can attack all biological molecules. Organisms are equipped with specific proteins designed for iron acquisition, export and transport, and storage, as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. Despite these homeostatic mechanisms, organisms often face the threat of either iron deficiency or iron overload. This review describes several hereditary iron-overloading conditions that are confined to the brain. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich's ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron-sulfur cluster formation, and the neurologic and cardiac manifestations of Friedreich's ataxia are due to iron-mediated mitochondrial toxicity. Patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus. Finally, aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by loss-of-function mutations in ceruloplasmin gene that leads to misregulation of both systemic and central nervous system iron trafficking. Affected individuals suffer from extrapyramidal signs, cerebellar ataxia, progressive neurodegeneration of retina, and diabetes mellitus. Excessive iron depositions are found in the brain, liver, pancreas, and other parenchymal cells, but plasma iron concentrations are decreased. These conditions are not common, but awareness about them is important for differential diagnosis of various neurodegenerative disorders.
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PMID:Hereditary causes of disturbed iron homeostasis in the central nervous system. 1510 72

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.
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PMID:Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms. 2062 44

Neurodegenerative disorders with brain iron accumulation (NBIA) are a clinically and genetically heterogeneous group of conditions in which there is neurodegeneration accompanied by elevated levels of brain iron. NBIA is frequently of genetic etiology, but may be secondary to an acquired systemic or neurological disease. Mutations in the ferritin light chain cause an adult-onset autosomal-dominant choreiform movement disorder termed neuroferritinopathy. Homozygous mutations in the ceruloplasmin gene cause aceruloplasminemia, which is characterized by the triad of diabetes, retinopathy, and a neurological disorder in mid adulthood. Mutations in pantothenate kinase 2 (PANK2) and phospholipase A2 (PLA2G6) cause recessive, childhood-onset extrapyramidal disorders termed pantothenate kinase-associated neurodegeneration (PKAN) and infantile neuroaxonal dystrophy (INAD), respectively. There is considerable phenotypic overlap between these conditions. The most useful investigation in suspected NBIA is brain magnetic resonance imaging, which can identify pathological iron deposition and distinguish between genotypes. Iron depletion therapy has been demonstrated to be successful in aceruloplasminemia, but not neuroferritinopathy, PKAN, or INAD. The presentation of NBIA overlaps with the more common adult movement disorders and pediatric neurometabolic conditions, and a high index of suspicion is required to make a correct diagnosis.
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PMID:Neurodegeneration with brain iron accumulation. 2149 76