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Pigmentary pallidal degeneration(NBIA1)

MedGen UID:
6708
Concept ID:
C0018523
Disease or Syndrome
Synonyms: Hallervorden-Spatz disease; NBIA1; Neuroaxonal dystrophy, late infantile; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; Pantothenate Kinase-Associated Neurodegeneration; PKAN NEUROAXONAL DYSTROPHY, JUVENILE-ONSET
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Pigmentary pallidal degeneration (2992000); Pigmentary pallidal atrophy (2992000); Hallervorden-Spatz disease (2992000)
 
Gene (location): PANK2 (20p13)
OMIM®: 234200
Orphanet: ORPHA157850

Definition

Pantothenate kinase-associated neurodegeneration (PKAN) is a type of neurodegeneration with brain iron accumulation (NBIA). The phenotypic spectrum of PKAN includes classic PKAN and atypical PKAN. Classic PKAN is characterized by early childhood onset of progressive dystonia, dysarthria, rigidity, and choreoathetosis. Pigmentary retinal degeneration is common. Atypical PKAN is characterized by later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease. [from GTR]

Additional descriptions

From GeneReviews
Pantothenate kinase-associated neurodegeneration (PKAN) is a type of neurodegeneration with brain iron accumulation (NBIA). The phenotypic spectrum of PKAN includes classic PKAN and atypical PKAN. Classic PKAN is characterized by early childhood onset of progressive dystonia, dysarthria, rigidity, and choreoathetosis. Pigmentary retinal degeneration is common. Atypical PKAN is characterized by later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease.  https://www.ncbi.nlm.nih.gov/books/NBK1490
From OMIM
Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, severity, and cognitive involvement are variable (review by Gregory et al., 2009). PKAN has been classified clinically as 'classic,' 'atypical,' or 'intermediate.' In the classic form, patients present within the first decade of life with rapidly progressing disease and loss of ambulation approximately 15 years later. In the atypical form, patients have onset in the second decade with slow progression and maintain independent ambulation after 15 years. In the intermediate form, patients have early onset and slow progression or later onset and rapid progression. Patients with early onset tend to develop pigmentary retinopathy, whereas those with later onset tend to have speech disorders and psychiatric features. All patients have the 'eye of the tiger' sign on brain MRI (Hayflick et al., 2003; Pellecchia et al., 2005). Kumar et al. (2006) noted that the 'eye of the tiger' sign is not pathognomonic for PANK2 mutations. They reported 2 unrelated adult patients with cognitive dysfunction who had the characteristic sign on MRI but did not have mutations in the PANK2 gene. Gregory et al. (2009) provided a detailed review of the different forms of neurodegeneration with brain iron accumulation. In addition, some patients with Kufor-Rakeb syndrome (606693), also known as Parkinson disease-9 (PARK9), have iron deposition in the basal ganglia. Genetic Heterogeneity of Neurodegeneration with Brain Iron Accumulation Neurodegeneration with brain iron accumulation is an umbrella term that encompasses a group of genetically heterogeneous disorders. See also NBIA2A (256600) and NBIA2B (610217), both caused by mutation in the PLA2G6 gene (603604); NBIA3 (606159), caused by mutation in the FTL gene (134790); NBIA4 (614298), caused by mutation in the C19ORF12 gene (614297); NBIA5 (300894), caused by mutation in the WDR45 gene (300526); and NBIA6 (615643), caused by mutation in the COASY gene (609855). See review of Schneider and Bhatia (2012) on syndromes of neurodegeneration with brain iron accumulation, including Kufor-Rakeb disease (606693) and aceruloplasminemia (604290).  http://www.omim.org/entry/234200

Clinical features

Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A deterioration of the retina. This nonspecific term is retained here because of its wide use in the literature, but if possible new annotations should indicate the precise type of retinal abnormality.
Retinitis pigmentosa
MedGen UID:
20551
Concept ID:
C0035334
Disease or Syndrome
Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited ocular diseases that result in a progressive retinal degeneration affecting 1 in 3,000 to 5,000 people (Veltel et al., 2008). Symptoms include night blindness, the development of tunnel vision, and slowly progressive decreased central vision starting at approximately 20 years of age. Upon examination, patients have decreased visual acuity, constricted visual fields, dyschromatopsia (tritanopic; see 190900), and the classic fundus appearance with dark pigmentary clumps in the midperiphery and perivenous areas ('bone spicules'), attenuated retinal vessels, cystoid macular edema, fine pigmented vitreous cells, and waxy optic disc pallor. RP is associated with posterior subcapsular cataracts in 39 to 72% of patients, high myopia, astigmatism, keratoconus, and mild hearing loss in 30% of patients (excluding patients with Usher syndrome; see 276900). Fifty percent of female carriers of X-linked RP have a golden reflex in the posterior pole (summary by Kaiser et al., 2004). Juvenile Retinitis Pigmentosa Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (see 204000), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Autosomal recessive forms of juvenile retinitis pigmentosa can be caused by mutation in the SPATA7 (609868), LRAT (604863), and TULP1 (602280) genes (see LCA3, 604232, LCA14, 613341, and LCA15, 613843, respectively). An autosomal dominant form of juvenile retinitis pigmentosa (see 604393) is caused by mutation in the AIPL1 gene (604392).
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary loss of URINE, such as leaking of urine. It is a symptom of various underlying pathological processes. Major types of incontinence include URINARY URGE INCONTINENCE and URINARY STRESS INCONTINENCE.
Abnormality of the foot
MedGen UID:
8888
Concept ID:
C0016506
Anatomical Abnormality
Alterations or deviations from normal shape or size which result in a disfigurement of the foot.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Behavioral symptoms
MedGen UID:
14048
Concept ID:
C0004941
Sign or Symptom
An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.
Blepharospasm
MedGen UID:
599
Concept ID:
C0005747
Disease or Syndrome
A focal dystonia that affects the muscles of the eyelids and brow, associated with involuntary recurrent spasm of both eyelids.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
A condition characterized by pervasive dysphoric mood, loss of interests, and inability to experience pleasure.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
An involuntary, persistent state of firm, tense muscles with marked resistance to passive movement.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Neurodegeneration
MedGen UID:
17999
Concept ID:
C0027746
Cell or Molecular Dysfunction
Loss of functional activity and trophic degeneration of nerve axons and their terminal arborizations following the destruction of their cells of origin or interruption of their continuity with these cells. The pathology is characteristic of neurodegenerative diseases. Often the process of nerve degeneration is studied in research on neuroanatomical localization and correlation of the neurophysiology of neural pathways.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Akinesia
MedGen UID:
43218
Concept ID:
C0085623
Disease or Syndrome
Inability to initiate changes in activity or movement and to perform ordinary volitional movements rapidly and easily.
Orofacial dyskinesia
MedGen UID:
57747
Concept ID:
C0152115
Disease or Syndrome
Cerebral degeneration
MedGen UID:
56343
Concept ID:
C0154671
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Abnormal pyramidal signs
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Choreoathetosis
MedGen UID:
66712
Concept ID:
C0234967
Finding
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Global brain atrophy
MedGen UID:
66840
Concept ID:
C0241816
Pathologic Function
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
A group of disorders which feature impaired motor control characterized by bradykinesia, MUSCLE RIGIDITY; TREMOR; and postural instability. Parkinsonian diseases are generally divided into primary parkinsonism (see PARKINSON DISEASE), secondary parkinsonism (see PARKINSON DISEASE, SECONDARY) and inherited forms. These conditions are associated with dysfunction of dopaminergic or closely related motor integration neuronal pathways in the BASAL GANGLIA.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Excessive movement of muscles of the body as a whole, which may be associated with organic or psychological disorders.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Motor tics
MedGen UID:
199761
Concept ID:
C0751900
Sign or Symptom
A tic affecting muscle movement.
Eyelid apraxia
MedGen UID:
222979
Concept ID:
C1142448
Finding
Dysphonia
MedGen UID:
282893
Concept ID:
C1527344
Mental or Behavioral Dysfunction
A speech disorder resulting in impaired utterance of sounds by the vocal folds.
Obsessive-compulsive trait
MedGen UID:
322417
Concept ID:
C1834433
Finding
The presence of one or more obsessive-compulsive personality traits. Obsessions refer to persistent intrusive thoughts, and compulsions to intrusive behaviors, which the affected person experiences as involuntary, senseless, or repugnant.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Eye of the tiger anomaly of globus pallidus
MedGen UID:
871224
Concept ID:
C4025705
Finding
The presence, on T2-weighted magnetic resonance imaging, of markedly low signal intensity if the globus pallidus that surrounds a central region of high signal intensity in the anteromedial globus pallidus, producing an eye-of-the-tiger appearance.
Acanthocytosis
MedGen UID:
195801
Concept ID:
C0687751
Disease or Syndrome
Acanthocytosis is a type of poikilocytosis characterized by the presence of spikes on the cell surface. The cells have an irregular shape resembling many-pointed stars.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary loss of URINE, such as leaking of urine. It is a symptom of various underlying pathological processes. Major types of incontinence include URINARY URGE INCONTINENCE and URINARY STRESS INCONTINENCE.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Decreased muscle mass
MedGen UID:
373256
Concept ID:
C1837108
Finding
Dysphonia
MedGen UID:
282893
Concept ID:
C1527344
Mental or Behavioral Dysfunction
A speech disorder resulting in impaired utterance of sounds by the vocal folds.
Blepharospasm
MedGen UID:
599
Concept ID:
C0005747
Disease or Syndrome
A focal dystonia that affects the muscles of the eyelids and brow, associated with involuntary recurrent spasm of both eyelids.
Facial grimacing
MedGen UID:
65891
Concept ID:
C0234853
Finding
Eyelid apraxia
MedGen UID:
222979
Concept ID:
C1142448
Finding
Hyperpigmentation of the skin
MedGen UID:
57992
Concept ID:
C0162834
Pathologic Function
A darkening of the skin related to an increase in melanin production and deposition.

Recent clinical studies

Etiology

Trachoo O, Satirapod C, Panthan B, Sukprasert M, Charoenyingwattana A, Chantratita W, Choktanasiri W, Hongeng S
J Assist Reprod Genet 2017 Jan;34(1):109-116. Epub 2016 Nov 4 doi: 10.1007/s10815-016-0833-y. PMID: 27815806Free PMC Article
Woltjer RL, Reese LC, Richardson BE, Tran H, Green S, Pham T, Chalupsky M, Gabriel I, Light T, Sanford L, Jeong SY, Hamada J, Schwanemann LK, Rogers C, Gregory A, Hogarth P, Hayflick SJ
Mol Genet Metab 2015 Dec;116(4):289-97. Epub 2015 Oct 31 doi: 10.1016/j.ymgme.2015.10.012. PMID: 26547561Free PMC Article
Tomić A, Petrović I, Svetel M, Dobričić V, Dragašević Mišković N, Kostić VS
Parkinsonism Relat Disord 2015 May;21(5):521-4. Epub 2015 Feb 17 doi: 10.1016/j.parkreldis.2015.02.006. PMID: 25724846
Rodriguez-Raecke R, Roa-Sanchez P, Speckter H, Fermin-Delgado R, Perez-Then E, Oviedo J, Stoeter P
Parkinsonism Relat Disord 2014 Sep;20(9):975-9. Epub 2014 Jun 13 doi: 10.1016/j.parkreldis.2014.06.005. PMID: 24965278
Tanteles GA, Spanou-Aristidou E, Antoniou C, Christophidou-Anastasiadou V, Kleopa KA
J Neurol Sci 2014 May 15;340(1-2):233-6. Epub 2014 Mar 11 doi: 10.1016/j.jns.2014.03.001. PMID: 24655737

Diagnosis

Trachoo O, Satirapod C, Panthan B, Sukprasert M, Charoenyingwattana A, Chantratita W, Choktanasiri W, Hongeng S
J Assist Reprod Genet 2017 Jan;34(1):109-116. Epub 2016 Nov 4 doi: 10.1007/s10815-016-0833-y. PMID: 27815806Free PMC Article
Han J, Kim do W, Lee CH, Han SH
J Neuroophthalmol 2016 Jun;36(2):182-6. doi: 10.1097/WNO.0000000000000335. PMID: 26828840
Tomić A, Petrović I, Svetel M, Dobričić V, Dragašević Mišković N, Kostić VS
Parkinsonism Relat Disord 2015 May;21(5):521-4. Epub 2015 Feb 17 doi: 10.1016/j.parkreldis.2015.02.006. PMID: 25724846
Tanteles GA, Spanou-Aristidou E, Antoniou C, Christophidou-Anastasiadou V, Kleopa KA
J Neurol Sci 2014 May 15;340(1-2):233-6. Epub 2014 Mar 11 doi: 10.1016/j.jns.2014.03.001. PMID: 24655737
Lee CH, Lu CS, Chuang WL, Yeh TH, Jung SM, Huang CL, Lai SC
ScientificWorldJournal 2013;2013:860539. Epub 2013 Nov 19 doi: 10.1155/2013/860539. PMID: 24348190Free PMC Article

Therapy

Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, Galanello R, Barella S, Origa R, Balocco M, Pelosin E, Marchese R, Ruffinengo U, Forni GL
Parkinsonism Relat Disord 2014 Jun;20(6):651-4. Epub 2014 Mar 12 doi: 10.1016/j.parkreldis.2014.03.002. PMID: 24661465
Pratini NR, Sweeters N, Vichinsky E, Neufeld JA
Am J Phys Med Rehabil 2013 Aug;92(8):728-33. doi: 10.1097/PHM.0b013e318282d209. PMID: 23370589Free PMC Article
Parmar A, Khare S, Srivastav V
J Assoc Physicians India 2012 Apr;60:74-6. PMID: 23029753
Awasthi R, Gupta RK, Trivedi R, Singh JK, Paliwal VK, Rathore RK
AJNR Am J Neuroradiol 2010 Mar;31(3):442-7. Epub 2009 Oct 22 doi: 10.3174/ajnr.A1849. PMID: 19850762
Lyoo CH, Prokisch H, Meitinger T, Lee SY, Kim DH, Lee MS
Mov Disord 2008 Jan 30;23(2):283-4. doi: 10.1002/mds.21799. PMID: 17999425

Prognosis

Tomić A, Petrović I, Svetel M, Dobričić V, Dragašević Mišković N, Kostić VS
Parkinsonism Relat Disord 2015 May;21(5):521-4. Epub 2015 Feb 17 doi: 10.1016/j.parkreldis.2015.02.006. PMID: 25724846
Morales-Briceño H, Chacón-Camacho OF, Pérez-González EA, Arteaga-Vázquez J, Rodríguez-Violante M, Cervantes-Arriaga A, Pérez-Rodríguez L, Zenteno JC, Mutchinick OM
Clin Genet 2015 Mar;87(3):259-65. Epub 2014 Jun 6 doi: 10.1111/cge.12400. PMID: 24712887
Rodriguez-Raecke R, Roa-Sanchez P, Speckter H, Fermin-Delgado R, Perez-Then E, Oviedo J, Stoeter P
Parkinsonism Relat Disord 2014 Sep;20(9):975-9. Epub 2014 Jun 13 doi: 10.1016/j.parkreldis.2014.06.005. PMID: 24965278
Lee CH, Lu CS, Chuang WL, Yeh TH, Jung SM, Huang CL, Lai SC
ScientificWorldJournal 2013;2013:860539. Epub 2013 Nov 19 doi: 10.1155/2013/860539. PMID: 24348190Free PMC Article
Shan J, Wen B, Zhu J, Lin P, Zheng J, Yan C
Neurol Sci 2013 Apr;34(4):561-3. Epub 2012 Aug 29 doi: 10.1007/s10072-012-1177-8. PMID: 22930366

Clinical prediction guides

Stoeter P, Roa-Sanchez P, Speckter H, Perez-Then E, Foerster B, Vilchez C, Oviedo J, Rodriguez-Raecke R
Parkinsonism Relat Disord 2015 Jun;21(6):577-81. Epub 2015 Mar 14 doi: 10.1016/j.parkreldis.2015.03.009. PMID: 25819806
Morales-Briceño H, Chacón-Camacho OF, Pérez-González EA, Arteaga-Vázquez J, Rodríguez-Violante M, Cervantes-Arriaga A, Pérez-Rodríguez L, Zenteno JC, Mutchinick OM
Clin Genet 2015 Mar;87(3):259-65. Epub 2014 Jun 6 doi: 10.1111/cge.12400. PMID: 24712887
Rodriguez-Raecke R, Roa-Sanchez P, Speckter H, Fermin-Delgado R, Perez-Then E, Oviedo J, Stoeter P
Parkinsonism Relat Disord 2014 Sep;20(9):975-9. Epub 2014 Jun 13 doi: 10.1016/j.parkreldis.2014.06.005. PMID: 24965278
Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, Galanello R, Barella S, Origa R, Balocco M, Pelosin E, Marchese R, Ruffinengo U, Forni GL
Parkinsonism Relat Disord 2014 Jun;20(6):651-4. Epub 2014 Mar 12 doi: 10.1016/j.parkreldis.2014.03.002. PMID: 24661465
Williams S, Gregory A, Hogarth P, Hayflick SJ, Gillingham MB
Mol Genet Metab 2013 Nov;110(3):336-41. Epub 2013 Jul 1 doi: 10.1016/j.ymgme.2013.06.017. PMID: 23891537

Recent systematic reviews

Dusek P, Schneider SA, Aaseth J
J Trace Elem Med Biol 2016 Dec;38:81-92. Epub 2016 Mar 24 doi: 10.1016/j.jtemb.2016.03.010. PMID: 27033472
Walker RH, Jung HH, Dobson-Stone C, Rampoldi L, Sano A, Tison F, Danek A
Neurology 2007 Jan 9;68(2):92-8. doi: 10.1212/01.wnl.0000250356.78092.cc. PMID: 17210889

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