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Pigmentary pallidal degeneration(NBIA1)

MedGen UID:
6708
Concept ID:
C0018523
Disease or Syndrome
Synonyms: 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
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
SNOMED CT: Pigmentary pallidal degeneration (2992000); Pigmentary pallidal atrophy (2992000); Hallervorden-Spatz disease (2992000)
 
Gene: PANK2
Cytogenetic location: 20p13
OMIM®: 234200
Orphanet: ORPHA157850

Definition

Pantothenate kinase-associated neurodegeneration (PKAN) is a form of neurodegeneration with brain iron accumulation, or NBIA (formerly called Hallervorden-Spatz syndrome). PKAN is characterized by progressive dystonia and basal ganglia iron deposition with onset that usually occurs before age ten years. Commonly associated features include dysarthria, rigidity, and pigmentary retinopathy. Approximately 25% of affected individuals have an 'atypical' presentation with later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease. [from GeneReviews]

Additional description

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

Weight loss
MedGen UID:
504965
Concept ID:
CN001653
Finding
Reduction inexisting body weight.
Urinary incontinence
MedGen UID:
776587
Concept ID:
C2712331
Finding
Eyelid apraxia
MedGen UID:
222979
Concept ID:
C1142448
Finding
Facial grimacing
MedGen UID:
504415
Concept ID:
CN000259
Finding
Blepharospasm
MedGen UID:
504534
Concept ID:
CN000604
Finding
A focal dystonia that affects the muscles of the eyelids and brow, associated with involuntary recurrent spasm of both eyelids.
Visual impairment
MedGen UID:
22663
Concept ID:
C0042798
Finding
Vision considered to be inferior to normal vision as represented by accepted standards of acuity, field of vision, or motility. Low vision generally refers to visual disorders that are caused by diseases that cannot be corrected by refraction (e.g., MACULAR DEGENERATION; RETINITIS PIGMENTOSA; DIABETIC RETINOPATHY, etc.).
Abnormal retinal pigmentation
MedGen UID:
350681
Concept ID:
C1862475
Finding
Retinal degeneration
MedGen UID:
504488
Concept ID:
CN000512
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.
Pigmentary retinopathy
MedGen UID:
504507
Concept ID:
CN000544
Finding
Optic atrophy
MedGen UID:
504537
Concept ID:
CN000609
Finding
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Choreoathetosis
MedGen UID:
66712
Concept ID:
C0234967
Finding
Hypertonia
MedGen UID:
115988
Concept ID:
C0235396
Finding
Depression
MedGen UID:
137999
Concept ID:
C0344315
Finding
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Sign or Symptom
A finding referring to walking difficulties.
Eyelid apraxia
MedGen UID:
222979
Concept ID:
C1142448
Finding
Dysphonia
MedGen UID:
282893
Concept ID:
C1527344
Disease or Syndrome
Trouble with the voice when trying to talk, including hoarseness and change in pitch or quality or voice.
Obsessive-compulsive trait
MedGen UID:
322417
Concept ID:
C1834433
Finding
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Dysarthria
MedGen UID:
333395
Concept ID:
C1839743
Finding
Dysphagia
MedGen UID:
342867
Concept ID:
C1853381
Finding
Cerebral degeneration
MedGen UID:
383859
Concept ID:
C1856209
Finding
Seizures
MedGen UID:
409523
Concept ID:
C1959629
Finding
Tremor
MedGen UID:
776582
Concept ID:
C2364114
Finding
Blepharospasm
MedGen UID:
504534
Concept ID:
CN000604
Finding
A focal dystonia that affects the muscles of the eyelids and brow, associated with involuntary recurrent spasm of both eyelids.
Behavioral abnormality
MedGen UID:
425007
Concept ID:
CN000665
Finding
An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.
Dementia
MedGen UID:
504574
Concept ID:
CN000683
Finding
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.
Hyperactivity
MedGen UID:
504585
Concept ID:
CN000708
Finding
Ataxia
MedGen UID:
504767
Concept ID:
CN001146
Finding
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).
Spasticity
MedGen UID:
504771
Concept ID:
CN001152
Finding
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Global developmental delay
MedGen UID:
504774
Concept ID:
CN001157
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.
Abnormality of the cranial nerves
MedGen UID:
428251
Concept ID:
CN001183
Finding
Abnormality affecting one or more of the cranial nerves, which emerge directly from the brain stem.
Parkinsonism
MedGen UID:
504793
Concept ID:
CN001191
Finding
Characteristic neurologic anomaly resulting form degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Rigidity
MedGen UID:
505075
Concept ID:
CN001866
Finding
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Bradykinesia
MedGen UID:
505077
Concept ID:
CN001869
Finding
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).
Chorea
MedGen UID:
505081
Concept ID:
CN001874
Finding
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion.
Neurological speech impairment
MedGen UID:
446437
Concept ID:
CN001964
Finding
Neurodegeneration
MedGen UID:
505144
Concept ID:
CN001976
Finding
Progressive loss of neural cells and tissue.
Global brain atrophy
MedGen UID:
505182
Concept ID:
CN002073
Finding
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
Akinesia
MedGen UID:
505189
Concept ID:
CN002092
Finding
Inability to initiate changes in activity or movement and to perform ordinary volitional movements rapidly and easily.
Orofacial dyskinesia
MedGen UID:
505193
Concept ID:
CN002098
Finding
Eye of the tiger anomaly of globus pallidus
MedGen UID:
505241
Concept ID:
CN002228
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.
Motor tics
MedGen UID:
506450
Concept ID:
CN116932
Finding
Movement-based tics affecting discrete muscle groups.
Abnormal joint morphology
MedGen UID:
446404
Concept ID:
CN001252
Finding
An abnormal structure or form of the joints, i.e., one or more of the articulations where two bones join.
Dysphagia
MedGen UID:
342867
Concept ID:
C1853381
Finding
Constipation
MedGen UID:
368096
Concept ID:
C1963087
Finding
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Hyperpigmentation of the skin
MedGen UID:
504657
Concept ID:
CN000892
Finding
A darkening of the skin related to an increase in melanin production and deposition.
Dysphonia
MedGen UID:
282893
Concept ID:
C1527344
Disease or Syndrome
Trouble with the voice when trying to talk, including hoarseness and change in pitch or quality or voice.
Acanthocytosis
MedGen UID:
350717
Concept ID:
C1862626
Finding
Recurrent respiratory infections
MedGen UID:
400943
Concept ID:
C1866203
Finding
Recurrent respiratory infections
MedGen UID:
400943
Concept ID:
C1866203
Finding
Hypertonia
MedGen UID:
115988
Concept ID:
C0235396
Finding
Decreased muscle mass
MedGen UID:
324803
Concept ID:
C1837466
Finding
Spasticity
MedGen UID:
504771
Concept ID:
CN001152
Finding
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Myopathy
MedGen UID:
505479
Concept ID:
CN002886
Finding
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Abnormality of the foot
MedGen UID:
427893
Concept ID:
CN001600
Finding
An abnormality of the skeleton of foot.

Recent clinical studies

Etiology

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. [Epub ahead of print] 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
Kurian MA, Hayflick SJ
Int Rev Neurobiol 2013;110:49-71. doi: 10.1016/B978-0-12-410502-7.00003-X. PMID: 24209433
Pérez-González EA, Chacón-Camacho OF, Arteaga-Vázquez J, Zenteno JC, Mutchinick OM
Eur J Med Genet 2013 Nov;56(11):606-8. Epub 2013 Sep 25 doi: 10.1016/j.ejmg.2013.08.007. [Epub ahead of print] PMID: 24075960
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. [Epub ahead of print] PMID: 22930366

Diagnosis

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. [Epub ahead of print] PMID: 24655737
Bosemani T, Meoded A, Poretti A
J Pediatr 2014 Jan;164(1):212. Epub 2013 Oct 7 doi: 10.1016/j.jpeds.2013.08.050. [Epub ahead of print] PMID: 24112863
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
Pérez-González EA, Chacón-Camacho OF, Arteaga-Vázquez J, Zenteno JC, Mutchinick OM
Eur J Med Genet 2013 Nov;56(11):606-8. Epub 2013 Sep 25 doi: 10.1016/j.ejmg.2013.08.007. [Epub ahead of print] PMID: 24075960
Fermin-Delgado R, Roa-Sanchez P, Speckter H, Perez-Then E, Rivera-Mejia D, Foerster B, Stoeter P
Clin Neuroradiol 2013 Mar;23(1):11-5. Epub 2012 Jan 19 doi: 10.1007/s00062-011-0127-9. [Epub ahead of print] PMID: 22258188

Therapy

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
Hartig MB, Prokisch H, Meitinger T, Klopstock T
Curr Drug Targets 2012 Aug;13(9):1182-9. PMID: 22515741
Crisci C, Esposito M
BMJ Case Rep 2011 May 16;2011 doi: 10.1136/bcr.07.2011.4514. PMID: 22689279Free PMC Article
Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, Longo F, Garavaglia B, Aquino D, Savoiardo M, Solari A, Nardocci N
Mov Disord 2011 Aug 1;26(9):1756-9. Epub 2011 May 6 doi: 10.1002/mds.23751. [Epub ahead of print] PMID: 21557313

Prognosis

Verhoeven WM, Egger JI, Koolen DA, Yntema H, Olgiati S, Breedveld GJ, Bonifati V, van de Warrenburg BP
Parkinsonism Relat Disord 2014 Mar;20(3):332-6. Epub 2013 Dec 10 doi: 10.1016/j.parkreldis.2013.11.019. [Epub ahead of print] PMID: 24368176
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
Nardocci N, Zorzi G
Handb Clin Neurol 2013;113:1919-24. doi: 10.1016/B978-0-444-59565-2.00062-9. PMID: 23622415
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. [Epub ahead of print] PMID: 22930366
Leoni V, Strittmatter L, Zorzi G, Zibordi F, Dusi S, Garavaglia B, Venco P, Caccia C, Souza AL, Deik A, Clish CB, Rimoldi M, Ciusani E, Bertini E, Nardocci N, Mootha VK, Tiranti V
Mol Genet Metab 2012 Mar;105(3):463-71. Epub 2011 Dec 14 doi: 10.1016/j.ymgme.2011.12.005. [Epub ahead of print] PMID: 22221393Free PMC Article

Clinical prediction guides

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. [Epub ahead of print] PMID: 23891537
Brunetti D, Dusi S, Morbin M, Uggetti A, Moda F, D'Amato I, Giordano C, d'Amati G, Cozzi A, Levi S, Hayflick S, Tiranti V
Hum Mol Genet 2012 Dec 15;21(24):5294-305. Epub 2012 Sep 13 doi: 10.1093/hmg/dds380. [Epub ahead of print] PMID: 22983956Free PMC Article
Siudeja K, Srinivasan B, Xu L, Rana A, de Jong J, Nollen EA, Jackowski S, Sanford L, Hayflick S, Sibon OC
EMBO Mol Med 2011 Dec;3(12):755-66. Epub 2011 Oct 14 doi: 10.1002/emmm.201100180. [Epub ahead of print] PMID: 21998097Free PMC Article
Chiapparini L, Savoiardo M, D'Arrigo S, Reale C, Zorzi G, Zibordi F, Cordelli DM, Franzoni E, Garavaglia B, Nardocci N
Neuropediatrics 2011 Aug;42(4):159-62. Epub 2011 Aug 29 doi: 10.1055/s-0031-1285925. [Epub ahead of print] PMID: 21877312
Mahoney R, Selway R, Lin JP
Dev Med Child Neurol 2011 Mar;53(3):275-9. Epub 2010 Dec 17 doi: 10.1111/j.1469-8749.2010.03815.x. [Epub ahead of print] PMID: 21166667

Recent systematic reviews

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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