関: Hallervorden-Spatz disease、Hallervorden-Spatz syndrome

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having partial rights and privileges or subordinate status; "an associate member"; "an associate professor"
a person who joins with others in some activity or endeavor; "he had to consult his associate before continuing"
a person with subordinate membership in a society, institution, or commercial enterprise; "associates in the law firm bill at a lower rate than do partners"
any event that usually accompanies or is closely connected with another; "first was the lightning and then its thunderous associate"
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an enzyme that catalyzes the conversion of a proenzyme to an active enzyme
the basic unit of money in Papua New Guinea

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/05/11 14:27:55」(JST)

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Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and formerly called Hallervorden–Spatz syndrome (use of this eponym is discouraged due to Drs. Julius Hallervorden and Hugo Spatz's affiliation with the Nazi regime and the ethically unacceptable manner in which they obtained some autopsy specimens^[1]^[2]), is a degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron that progressively builds up in the brain.

Signs and symptoms [edit]

Symptoms typically begin in childhood and are progressive, often resulting in death by early adulthood. Symptoms of PKAN begin before middle childhood, and most often are noticed before ten years of age. Symptoms include:

dystonia (repetitive uncontrollable muscle contractions that may cause jerking or twisting of certain muscle groups)
dysphagia & dysarthria due to muscle groups involved in speech being involved
rigidity/stiffness of limbs
tremor
writhing movements
dementia
spasticity
Rigidity (neurology)
weakness
seizures (rare)
toe walking
retinitis pigmentosa,

another degenerative disease that affects the individual’s retina, often causing alteration of retinal color and progressive deterioration of the retina at first causing night blindness and later resulting in a complete loss of vision.

25% of individuals experience an uncharacteristic form of PKAN that develops post-10 years of age and follows a slower, more gradual pace of deterioration than those pre-10 years of age. These individuals face significant speech deficits as well as psychiatric and behavioral disturbances.

Being a progressive, degenerative nerve illness, PKAN leads to early immobility and often death by early adulthood. Death occurs prematurely due to infections such as pneumonia, and the disease in itself is technically not life limiting.

Genetics [edit]

PKAN is an autosomal recessive disorder. The parents of an afflicted child must both be heterozygous carriers for the disease and therefore must carry one mutant allele. As it is an autosomal disorder, those heterozygous for the disorder may not display any atypical characteristics that are considered suggestive of the disorder, however there have been reported cases of compound heterozygosity in which heterozygous individuals do develop the classic form of the disease.^[3]^[4]

The disorder is caused by a mutant PANK2 gene located at the chromosomal locus: 20p13-p12.3. PANK2 is responsible in coding for the protein Pantothenate kinase 2, which in turn is responsible for stifling the accumulation of N-pantothenoyl-cysteine and pantetheine. It is believed that when this accumulation is not suppressed, the result is direct cell toxicity or cell toxicity as a result of free radical damage due to the lack of suppression.

PANK2 encodes a 1.85Kb transcript which is derived from seven exons covering a total distance of approximately 3.5Mb of genomic DNA. The PANK2 gene also encodes a 50.5-kDaprotein that is a functional pantothenate kinase, an essential regulatory enzyme in coenzyme A (CoA) biosynthesis, and catalyzing the phosphorylation of pantothenate (vitamin B₅), N-pantothenoyl-cysteine, and pantetheine (OMIM).

Mutant PANK2 gene coded proteins are often caused by null or missense mutations most notably a 7bp deletion in the PANK2 gene coding sequence.

This disorder has been reported in specific communities based on intra-community marriages where both parents of the child are carrying the same mutation. One of the communities reported is Agrawal (Agarwal) Community mainly based in Northern Part of India. ^[5] ^[6]

Diagnosis [edit]

MRI image shows iron deposits in the basal ganglia, the so-called eye-of-the-tiger sign (T2w GRASE sequence).

A neurological examination would show evidence of muscle rigidity; weakness; and abnormal postures, movements, and tremors. If other family members are also affected, this may help determine the diagnosis. Genetic tests can confirm an abnormal gene causing the disease. However, this test is not yet widely available. Other movement disorders and diseases must be ruled out. Individuals exhibiting any of the above listed symptoms are often tested using MRI (Magnetic Resonance Imaging) for a number of neuro-related disorders. As PKAN is a disease prominently evident in the brain, MRIs are very useful in making a sound diagnosis. An MRI usually shows iron deposits in the basal ganglia. Development of diagnostic criteria continues in the hope of further separating PKAN from other forms of neurodegenerative diseases featuring NBIA.

Neuropathology [edit]

Microscopic features of PKAN include:

Iron granules
Spheroid bodies
Lewy bodies within neurons

Treatment [edit]

There have been no major breakthroughs in the treatment of PKAN, with most pharmacologic treatments focusing on the easing or temporary relieving of PKAN’s symptoms. Iron chelating agents have been used somewhat successfully in retarding the disorder, but they have not been a significant success.

Many believe taking certain vitamins may be beneficial, including pantothenate, Coenzyme Q, and other anti-oxidants.^{[citation needed]}

Current research focuses on the future use of high dose pantothenate, the PANK2 enzyme substrate, in possibly alleviating symptoms as well as the further development of iron chelating agents that may be better aimed at reaching the central nervous system and working to better remove excess iron from the individual’s system.

Complications may result from the medication used to treat symptoms. Immobility from the disease can also lead to skin breakdown, respiratory infections, and blood clots, among others.

History & epidemiology [edit]

PKAN was first described by Hallervorden and Spatz (1922). Their discovery was brought about by a diagnosis of a family of 12 in which five sisters exhibited progressively increasing dementia and dysarthria. Autopsies revealed brown discolorations in different areas of the brain (particularly of interest were the globus pallidus and substantia nigra regions). Further investigation and description was brought about by Meyer (1958) who diagnosed 30 separate cases of PKAN. Meyer(1958) was followed by Elejalde et al. (1978) who described 5 affected family members and hypothesized that the disorder originated in central Europe, backing up his hypothesis with clinical and genetic analysis. Further investigation and insights were provided by Malmstrom-Groth and Kristensson (1982)^[7] and Jankovic et al. (1985).^[8]

Diagnosis of PKAN hit a milestone with the availability of MRIs, as well as the in-depth descriptions of those MRIs provided by Littrup and Gebarski (1985),^[9] Tanfani et al. (1987),^[10] Sethi et al. (1988),^[11]Angelini et al. (1992),^[12] Casteels et al. (1994),^[13] and Malandrini et al. (1995).^[14] The gene was localized to chromosome 20p by Taylor et al. (1996) ^[15] who suggested that this disorder should be referred to as neurodegeneration with brain iron accumulation (NBIA1) to avoid the objectionable eponym of Hallervorden-Spatz. The disease was named 'pantothenate kinase-associated neurodegeneration' or PKAN by Zhou et al. (2001)^[3] who suggested the name to avoid misinterpretation and to better reflect the true nature of the disorder. Most recently Pellecchia et al. (2005) published a report of 16 patients afflicted with PKAN, confirmed by genetic analysis.^[16]

Survival rates for those diagnosed with typical PKAN is 11.18 years with a standard deviation of 7.8 years. Prevalence data regarding this disorder remains incomplete, however it is estimated that anywhere between 1 in 1,000,000 to 3 in 1,000,000 individuals will be afflicted with this disorder (based upon observed cases in a population), but once again this is only an estimate as the disease is so rare it is difficult to statistically and accurately ascertain.

Resources for patients [edit]

There are a number of patient advocacy groups for NBIA. There are well established groups in USA, Germany and Italy. There are also developing groups in UK, France and Spain. If your family member is affected you should make contact with one of the following sites for further help and information

http://www.hoffnungsbaum.de/ http://www.nbia.co.uk/ http://www.nbiadisorders.org/ Asociación española

References [edit]

^ doctor/535 at Who Named It?
^ doctor/1063 at Who Named It?
^ ^a ^b Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ (2001). "A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome". Nat. Genet. 28 (4): 345–9. doi:10.1038/ng572. PMID 11479594.
^ Bei-sha, Tang et al (2005). "Novel compound heterozygous mutations in the PANK2 gene in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration". Movement Disorders 20 (7): 819–21. doi:10.1002/mds.20408. PMC 2105744. PMID 15747360.
^ http://www.scribd.com/doc/95164360/PANK2-Agarwal
^ http://www.britannica.com/bps/additionalcontent/18/27764296/Founder-mutation-in-the-PANK-gene-of-Agrawal-children-with-Neurodegeneration-with-Brain-Iron-accumulation-NBIA
^ Malmström-Groth AG, Kristensson K (1982). "Neuroaxonal dystrophy in childhood. Report of two second cousins with PKAN, and a case of Seitelberger's disease". Acta paediatrica Scandinavica 71 (6): 1045–9. doi:10.1111/j.1651-2227.1982.tb09574.x. PMID 7158329.
^ Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ, Bird ED (February 1985). "Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism". Neurology 35 (2): 227–34. doi:10.1159/000153550. PMID 3969211.
^ Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ, Bird ED (1985). "Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism". Neurology 35 (2): 227–34. doi:10.1159/000153550. PMID 3969211.
^ Tanfani G, Mascalchi M, Dal Pozzo GC, Taverni N, Saia A, Trevisan C (1987). "MR imaging in a case of Hallervorden-Spatz disease". Journal of computer assisted tomography 11 (6): 1057–8. doi:10.1097/00004728-198711000-00027. PMID 3680689.
^ Sethi KD, Adams RJ, Loring DW, el Gammal T (1988). "Hallervorden-Spatz syndrome: clinical and magnetic resonance imaging correlations". Ann. Neurol. 24 (5): 692–4. doi:10.1002/ana.410240519. PMID 3202617.
^ Angelini L, Nardocci N, Rumi V, Zorzi C, Strada L, Savoiardo M (1992). "Hallervorden-Spatz disease: clinical and MRI study of 11 cases diagnosed in life". J. Neurol. 239 (8): 417–25. doi:10.1007/BF00856805. PMID 1447570.
^ Casteels I, Spileers W, Swinnen T, et al. (1994). "Optic atrophy as the presenting sign in Hallervorden-Spatz syndrome". Neuropediatrics 25 (5): 265–7. doi:10.1055/s-2008-1073034. PMID 7885538.
^ Malandrini A, Bonuccelli U, Parrotta E, Ceravolo R, Berti G, Guazzi GC (1995). "Myopathic involvement in two cases of Hallervorden-Spatz disease". Brain Dev. 17 (4): 286–90. doi:10.1016/0387-7604(95)00039-E. PMID 7503394.
^ Taylor TD, Litt M, Kramer P, Pandolfo M, Angelini L, Nardocci N, Davis S, Pineda M, Hattori H, Flett PJ, Cilio MR, Bertini E, Hayflick SJ (1996). "Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13". Nat. Genet. 14 (4): 479–81. doi:10.1038/ng1296-479. PMID 8944032.
^ Pellecchia MT, Valente EM, Cif L, et al. (2005). "The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration". Neurology 64 (10): 1810–2. doi:10.1212/01.WNL.0000161843.52641.EC. PMID 15911822.

External links [edit]

http://enachasociacion.blogspot.com.es/ Asociacion Hallervorden Spatz en español
02041 at CHORUS
synd/1082 at Who Named It?
nbia at NINDS
NBIA Disorders Association

UpToDate Contents

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1. 神経有棘赤血球症 neuroacanthocytosis
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3. 小児における運動減少性運動障害 bradykinetic movement disorders in children
4. ジストニアの分類および評価 classification and evaluation of dystonia
5. 小児における運動過多な運動障害 hyperkinetic movement disorders in children

English Journal

Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): Results from a four years follow-up.

Cossu G1, Abbruzzese G2, Matta G3, Murgia D4, Melis M4, Ricchi V4, Galanello R5, Barella S5, Origa R5, Balocco M6, Pelosin E2, Marchese R2, Ruffinengo U7, Forni GL6.
Parkinsonism & related disorders.Parkinsonism Relat Disord.2014 Jun;20(6):651-4. doi: 10.1016/j.parkreldis.2014.03.002. Epub 2014 Mar 12.
OBJECTIVE: To evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA.METHODS: 6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III an
PMID 24661465

Novel homozygous PANK2 mutation causing atypical pantothenate kinase-associated neurodegeneration (PKAN) in a Cypriot family.

Tanteles GA1, Spanou-Aristidou E1, Antoniou C2, Christophidou-Anastasiadou V1, Kleopa KA3.
Journal of the neurological sciences.J Neurol Sci.2014 May 15;340(1-2):233-6. doi: 10.1016/j.jns.2014.03.001. Epub 2014 Mar 11.
Pantothenate kinase-associated neurodegeneration (PKAN) is the commonest, recessively inherited form of neurodegeneration with brain iron accumulation (NBIA) resulting from mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20. PKAN is usually rapidly progressive, presenting in the va
PMID 24655737

Clinical, imaging, and molecular findings in a sample of Mexican families with pantothenate kinase associated neurodegeneration.

Morales-Briceño H1, Chacón-Camacho OF, Pérez-González EA, Arteaga-Vázquez J, Rodríguez-Violante M, Cervantes-Arriaga A, Pérez-Rodríguez L, Zenteno JC, Mutchinick OM.
Clinical genetics.Clin Genet.2014 Apr 9. doi: 10.1111/cge.12400. [Epub ahead of print]
Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by iron accumulation in the brain, due to mutations in the PANK2 gene. Phenotypic and genotypic characteristics of eleven patients from five Mexican families with PKAN disease are reported. Seque
PMID 24712887

Japanese Journal

神経有棘赤血球症

市場美緒,中村雅之,佐野輝
Brain and nerve 60(6), 635-641, 2008-06
NAID 40016092415

Pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome)

HAYFLICK S. J.
J. Neurol. Sci. 207, 106-107, 2003
NAID 30005096952

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リンク元	「Hallervorden-Spatz syndrome」「パントテン酸キナーゼ関連神経変性症」
関連記事	「associate」「kinase」「associated」「pantothenate」

「Hallervorden-Spatz syndrome」

Pantothenate kinase-associated neurodegeneration
	Classification and external resources
	; Pantetheine
ICD-10	G23.0
ICD-9	333.0
OMIM	234200
DiseasesDB	29462
MedlinePlus	001225
eMedicine	neuro/151
MeSH	D006211
GeneReviews	Pantothenate Kinase-Associated Neurodegeneration;

　　[★]

ハラーホルデン・スパッツ症候群、ハラーフォルデン・シュパッツ症候群、Hallervorden-Spatz症候群

関: Hallervorden-Spatz disease、pantothenate kinase-associated neurodegeneration

「パントテン酸キナーゼ関連神経変性症」

　　[★]

英: pantothenate kinase-associated neurodegeneration
関: ハラーフォルデン・シュパッツ病、ハラーフォルデン・シュパッツ症候群

「associate」

　　[★]

vt.

結合する、連合させる。連想によって結びつける。(人を)仲間/友達などとしての関係に置く。(化)会合させる

vi.

仲間/友人などとして交際する(with)。一つにまとめる、連合する

n.

仕事仲間、提携者、同僚。友人、朋友。準会員。従業員、社員
密接な蒸す偽付きのある物、付随する物、つきもの。準国家
連想によって心に浮かぶ言葉/思い、連想物

adj.

仲間の、同僚の。製紙機械員に次ぐ資格の
付随する、連想される

関: accompany、association、associative、attach、bearing、bind、binding、bond、bonding、coassemble、colleague、combine、conjoin、conjugate、conjugation、conjunction、connect、connection、correlate、correlation、couple、dock、engage、engagement、federation、implication、join、joint、ligate、link、linkage、peer、pertinent、reference、relate、relation、relationship、relative、relevance、relevant、symphysial、union

「kinase」

　　[★] キナーゼカイネースリン酸化酵素 phosphoenzyme phosphotransferase 　

「associated」

　　[★]

adj.

随伴の、随伴性の

関: concomitant、erratic、erratically; associate

「pantothenate」

　　[★]

パントテン酸、パントテン酸塩

関: pantothenic acid

[1] doctor/535 at Who Named It?

[2] doctor/1063 at Who Named It?

[Zhou2001-3] Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ (2001). "A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome". Nat. Genet. 28 (4): 345–9. doi:10.1038/ng572. PMID 11479594.

[4] Bei-sha, Tang et al (2005). "Novel compound heterozygous mutations in the PANK2 gene in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration". Movement Disorders 20 (7): 819–21. doi:10.1002/mds.20408. PMC 2105744. PMID 15747360.

[5] ttp://www.scribd.com/doc/95164360/PANK2-Agarwal

[6] ttp://www.britannica.com/bps/additionalcontent/18/27764296/Founder-mutation-in-the-PANK-gene-of-Agrawal-children-with-Neurodegeneration-with-Brain-Iron-accumulation-NBIA

[7] Malmström-Groth AG, Kristensson K (1982). "Neuroaxonal dystrophy in childhood. Report of two second cousins with PKAN, and a case of Seitelberger's disease". Acta paediatrica Scandinavica 71 (6): 1045–9. doi:10.1111/j.1651-2227.1982.tb09574.x. PMID 7158329.

[8] Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ, Bird ED (February 1985). "Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism". Neurology 35 (2): 227–34. doi:10.1159/000153550. PMID 3969211.

[9] Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ, Bird ED (1985). "Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism". Neurology 35 (2): 227–34. doi:10.1159/000153550. PMID 3969211.

[10] Tanfani G, Mascalchi M, Dal Pozzo GC, Taverni N, Saia A, Trevisan C (1987). "MR imaging in a case of Hallervorden-Spatz disease". Journal of computer assisted tomography 11 (6): 1057–8. doi:10.1097/00004728-198711000-00027. PMID 3680689.

[11] Sethi KD, Adams RJ, Loring DW, el Gammal T (1988). "Hallervorden-Spatz syndrome: clinical and magnetic resonance imaging correlations". Ann. Neurol. 24 (5): 692–4. doi:10.1002/ana.410240519. PMID 3202617.

[12] Angelini L, Nardocci N, Rumi V, Zorzi C, Strada L, Savoiardo M (1992). "Hallervorden-Spatz disease: clinical and MRI study of 11 cases diagnosed in life". J. Neurol. 239 (8): 417–25. doi:10.1007/BF00856805. PMID 1447570.

[13] Casteels I, Spileers W, Swinnen T, et al. (1994). "Optic atrophy as the presenting sign in Hallervorden-Spatz syndrome". Neuropediatrics 25 (5): 265–7. doi:10.1055/s-2008-1073034. PMID 7885538.

[14] Malandrini A, Bonuccelli U, Parrotta E, Ceravolo R, Berti G, Guazzi GC (1995). "Myopathic involvement in two cases of Hallervorden-Spatz disease". Brain Dev. 17 (4): 286–90. doi:10.1016/0387-7604(95)00039-E. PMID 7503394.

[Taylor1996-15] Taylor TD, Litt M, Kramer P, Pandolfo M, Angelini L, Nardocci N, Davis S, Pineda M, Hattori H, Flett PJ, Cilio MR, Bertini E, Hayflick SJ (1996). "Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13". Nat. Genet. 14 (4): 479–81. doi:10.1038/ng1296-479. PMID 8944032.

[16] Pellecchia MT, Valente EM, Cif L, et al. (2005). "The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration". Neurology 64 (10): 1810–2. doi:10.1212/01.WNL.0000161843.52641.EC. PMID 15911822.

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pantothenate kinase-associated neurodegeneration