Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The arguments over the nomenclature of the syndrome are reviewed. Ethical considerations favour replacing the present eponyms with the title of panthothenate kinase-associated neurodegeneration (PKAN), now that more is known about the cause of the condition. The symptoms and signs of the syndrome are described, and these can present from infancy to adult life. Dystonia, involuntary movements and spasticity are prominent causes of disability. If the onset is delayed the presentation can be unusual. Tests that can help in diagnosis are reviewed, especially the "eye of the tiger" revealed by magnetic resonance imaging scanning. Death usually occurs about 10 years after the onset, but the course may be more prolonged. The findings on autopsy are also considered, with the typical findings of iron pigment deposits and axonal spheroids. Then the causes are discussed. Once the responsible gene PANK2 had been discovered on chromosome 20 it was found that this encoded for pantothenate kinase which is essential for the synthesis of coenzyme A from pantothenate; and this is integral to fatty acid synthesis and energy metabolism. Also this can lead to a concentration of cysteine in the basal ganglia, and then to an accumulation of iron in these areas. The cysteine-iron complex will result in tissue damage by promoting oxidative stress, as in some other neurodegenerative diseases. The syndrome of PKAN can therefore be identified as a disorder of pantothanate, vitamin B5, metabolism. Infantile neuroaxonal dystrophy is briefly described as there have been suggestions that it is a variety of PKAN, but the evidence is in favour of the two diseases being separate entities. There may as yet be no specific treatment for this syndrome, but much can be done to help these children. Drugs may be needed to control epilepsy, and when dystonia is severe it may be possible to alleviate this by medical or surgical means. Also there will be other problems needing expert management, such as the provision of alternative means of communication if dysarthria is marked. The hope for the future is that now the cause has been found it will be possible to use methods such as antioxidative therapy and gene induction procedures.
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PMID:Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome). 1237 76

Pantothenate kinase-associated neurodegeneration (PKAN) (MIM 234200; Hallervorden-Spatz syndrome) is a degenerative, autosomal recessive disorder in childhood, currently without specific treatment. In contrast to variable clinical features, T2-weighted magnetic resonance images show a characteristic 'eye-of-the-tiger sign' in the globus pallidus due to excess iron deposition. Recently a defect in pantothenate kinase, the key regulatory enzyme in the synthesis of coenzyme A from pantothenate, has been identified as the cause of the disease. We report a 12-year-old boy with progressive rigidity, dystonia, impaired voluntary movement, dysarthria, and mental deterioration. Over 10 years the boy had been misdiagnosed with clumsiness, emotional and behavioural deficits, and attention deficit disorder, before neuroimaging was performed showing the characteristic 'eye-of-the-tiger sign'. Molecular analyses confirmed two mutations in the PANK2 gene [coding sequence of a gene that has homology to murine pantothenate kinase-1]. We conclude that in progressive childhood dystonia, PKAN should be considered and magnetic resonance imaging performed early. The newly described defect of the pantothenate kinase enzyme enables a novel therapeutic approach to be considered, based on the mutation analyses of the PANK2 gene, as well as the prenatal diagnosis of this disorder.
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PMID:Progressive dystonia in a 12-year-old boy. 1269 33

Hallervorden-Spatz syndrome (HSS) is a neurodegenerative disorder characterized by progressive dementia, dystonia, ataxia, and rigidity. An atypical form of adult-onset HSS was observed in a 36-year-old man presenting with progressive dysarthria. Markedly dysarthric speech and a weak atrophic tongue associated with a neurogenic pattern of motor unit recruitment in bulbar-supplied muscles on electromyography led to an initial impression of bulbar amyotrophic lateral sclerosis (ALS). Lack of expected progression of symptoms, however, prompted reinvestigation. Repeat brain magnetic resonance imaging demonstrated an "eye-of-the-tiger" pattern in the basal ganglia, characteristic of HSS, thus requiring genetic studies. DNA analyses of the pantothenate kinase gene (PANK2) was conducted and revealed two novel, disease-causing exon 3 missense mutations (Cys231Ser and Tyr251Cys). This case broadens the genotypic and phenotypic spectrum of HSS to include a late-onset syndrome resembling bulbar-onset ALS.
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PMID:Adult Hallervorden-Spatz syndrome simulating amyotrophic lateral sclerosis. 1281 83

Neurological abnormalities associated with spiculated, "acanthocytic" red cells in blood have been summarized as neuroacanthocytosis. This is a heterogeneous group of conditions that can now be clearly subdivided on the basis of genetic discoveries. The core neuroacanthocytosis syndromes are autosomal recessive chorea-acanthocytosis (ChAc) and the X-linked McLeod syndrome (MLS). Huntington's disease-like 2 (HLD2) and pantothenate kinase associated neurodegeneration (PKAN) can now also be included. All of these share dyskinesias, cognitive deterioration and progressive neurodegeneration mainly of the basal ganglia, but they are sufficiently distinct to permit a specific working diagnosis on the basis of clinical, laboratory and imaging findings. In addition, the VPS13A (formerly called CHAC), XK, JPH3 and PANK2 genes, respectively, may be examined for mutations. Unfortunately, little is yet known about the normal and abnormal physiology of the protein products of these genes, but they appear to be involved in membrane function and intracellular protein sorting. Since no cures are yet available, development and study of disease models in experimental animals (mouse, C. elegans) is a priority for current research. From a clinical point of view, the common occurrence of cardiomyopathy in MLS, the transfusion hazards due to the McLeod Kell phenotype and the possibility of improving the violent trunk spasms and orofacial dyskinesias typical for ChAc (with subsequent lip or tongue mutilations and feeding dystonia) by deep brain surgery or stimulation should be considered in patient management.
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PMID:Neuroacanthocytosis: new developments in a neglected group of dementing disorders. 1576 Jun 37

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.
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PMID:Neurodegeneration with brain iron accumulation. 1641 93

We describe an atypical case of pantothenate kinase-associated neurodegeneration (PKAN) in which slowly progressive arm tremor was the predominant symptom beginning at the age of 25, with late-onset dystonia and dysarthria developing at the age of 50. Compound heterozygous mutations resulting in missense amino acid substitutions G521R and I529V were identified in the pantothenate kinase (PANK2) gene. We demonstrate that while the G521R mutation results in an unstable and inactive protein, the previously unreported I529V substitution has no apparent effect on the stability or catalytic activity of PanK2. The phenotype that results from this combination of mutations suggests that atypical presentations of PKAN may arise from partial deficits in PanK2 catalytic activity.
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PMID:Partial deficit of pantothenate kinase 2 catalytic activity in a case of tremor-predominant neurodegeneration with brain iron accumulation. 1645 Mar 44

Pantothenate kinase-associated neurodegeneration is an autosomal-recessive disorder associated with the accumulation of iron in the basal ganglia. The disease presents with dystonia, rigidity, and gait impairment, leading to restriction of activities and loss of ambulation. The disorder is caused by defective iron metabolism associated with mutations in the PANK2 gene, which codes for the pantothenate kinase enzyme. We report on a mutation screen conducted in two siblings to establish a molecular diagnosis of the disease and a genetic test for the family.
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PMID:Novel mutation in the PANK2 gene leads to pantothenate kinase-associated neurodegeneration in a Pakistani family. 1790 78

We report a case of a young girl with early onset pantothenate kinase-kssociated neurodegeneration (PKAN) whose initial clinical manifestation was ataxia at the age of 2.5 years. Subsequently the patient presented to us with refractory severe dystonia resulting in essentially complete loss of motor control. She had a mutation in PANK2 gene consisting of an aminoacid change of Alanine to Valine in exon 5 (A382V). After Globus Pallidus deep brain stimulation (DBS) at the age of 11 years, the patient regained useful motor function and speech with a marked decrease in the severity of the dystonia. The patient's condition gradually returned to her pre-DBS status when the device had to be removed 3 months later due to infection. Our case is the sixth case with classical PKAN that was treated by Globus Pallidus stimulation, the fifth one to have a favorable response to it and the only one in whom response was proven by the inadvertent removal of the DBS device due to infection. In addition, our case had a novel mutation and novel clinical features (onset with ataxia, occurrence of early seizure activity) on top of her other symptoms that were otherwise typical of early onset disease.
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PMID:Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration. 1970 16

In addition to pure PD and pure dystonic syndromes, there are a group of disorders with overlapping features. The differential diagnosis of these dystonia parkinsonism syndromes can be complex. In view of the growing list of recognized disorders and recent advances in genetics, we review the autosomal recessive forms of dystonia parkinsonism, summarizing clinical presentations, results of investigations, and response to treatment of gene-proven cases. We concentrate on PANK2-, PLA2G6-, ATP13A2-, FBX07, TAF1-, and PRKRA-associated neurodegeneration. Parkin, PINK1, and DJ-1 are also briefly reviewed.
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PMID:Complicated recessive dystonia parkinsonism syndromes. 1918 14

Here we report the clinical, neuroimaging, and molecular findings of a classic pantothenate kinase-associated neurodegeneration (PKAN) patient of Turkish origin. Our patient is the first reported case of PKAN in Turkey with molecular genetic confirmation of the diagnosis. The frameshift mutation c.821_822delCT of the PANK2 gene detected in our patient has only been described in such classic patients to date, and our case provides further evidence of the association of this mutation with the classic PKAN phenotype. Since this mutation is a rare disease-causing mutation in other populations, further studies of more Turkish PKAN patients will show if it is the result of a founder effect in this population. In our case, molecular diagnosis allowed accurate prenatal genetic testing and counseling for this family. This case report highlights the importance of magnetic resonance imaging and molecular investigation in children who have progressive neurodegenerative symptoms of parkinsonism, dystonia, pyramidal features, and dementia.
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PMID:Pantothenate kinase-associated neurodegeneration (PKAN): molecular confirmation of a Turkish patient with a rare frameshift mutation in the coding region of the PANK2 gene. 1948 Mar 28


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