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title: "PKAN"
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docid: "aa473236-a733-4f9b-8d92-267ab8d4bcd9"
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breadcrumbs:
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- "Brain"
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- "Diagnosis"
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- "Pathology-Based Diagnoses"
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- "Inherited Metabolic/Degenerative Disorders"
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- "Miscellaneous"
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- "PKAN"
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---
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# KEY FACTS
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- ## Terminology
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- Pantothenate kinase-associated neurodegeneration (PKAN)
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- Pantothenate kinase 2 (*PANK2*) mutation
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- Most common form of neurodegeneration with brain iron accumulation (NBIA)
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- ## Imaging
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- Best diagnostic clue: Eye of tiger sign = diffuse pallidal T2 hypointensity with medial foci ↑ T2 signal
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- Highly suggestive of PKAN
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- Hyperintense "eye" may predate surrounding pallidal hypointensity
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- ## Top Differential Diagnoses
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- Disorders with ↑ T2 signal globus pallidus (GP)
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- Metabolic: Methylmalonic acidemia (MMA), Kearns-Sayre, L-2-hydroxyglutaric aciduria, Canavan, neuroferritinopathy
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- Ischemic/toxic: Anoxic encephalopathy, carbon monoxide/cyanide poisoning, kernicterus
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- ## Pathology
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- *PANK2* gene encodes mitochondrial-targeted pantothenate kinase 2, key enzyme in biosynthesis of coenzyme A (CoA)
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- Progressive, physiologic brain iron accumulation occurs in GP, substantia nigra (SN) > red and dentate nuclei
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- Basal ganglia and retina vulnerable to oxidative damage secondary to high metabolic demand
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- Autosomal recessive (50% sporadic)
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- *PANK2* mutation → CoA deficiency → energy and lipid dyshomeostasis → production of oxygen free radicals → phospholipid membrane destruction
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- Iron accumulation likely secondary phenomenon in PKAN
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- ## Clinical Issues
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- Classic PKAN: Dystonia, dysarthria, rigidity, choreoathetosis in young child
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- Atypical PKAN: Psychiatric, speech, pyramidal/extrapyramidal disturbances in older child/teenager
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- Epidemiology
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- Rare; incidence unknown
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- Prognosis
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- Classic PKAN: Fatal; mean disease duration after symptom onset is 11 years
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- Atypical PKAN: Eventual severe impairment/death
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- No curative treatment
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- ## Diagnostic Checklist
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- Eye of tiger sign highly suggestive of PKAN
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- Physiologic GP hypointensity difficult to distinguish from pathologic hypointensity in teenager/adult
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# TERMINOLOGY
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- ## Abbreviations
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- Pantothenate kinase-associated neurodegeneration (PKAN)
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- ## Synonyms
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- Neurodegeneration with brain iron accumulation type 1 (NBIA-1)
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- Hallervorden-Spatz syndrome (obsolete term)
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- PKAN and NBIA-1 = preferred terms
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- ## Definitions
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- Neurodegeneration with brain iron accumulation (NBIA) = umbrella term for neurodegenerative disorders characterized by brain iron accumulation
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- Known causes include PKAN (most common), aceruloplasminemia, neuroferritinopathy, and infantile neuroaxonal dystrophy
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- PKAN caused by mutation pantothenate kinase 2 gene (*PANK2*)
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# IMAGING
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- ## General Features
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- Best diagnostic clue: Eye of tiger sign = diffuse pallidal T2 hypointensity with medial foci ↑ T2 signal
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- Highly suggestive of PKAN
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- Hyperintense "eye" may predate surrounding pallidal hypointensity
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- "Eye" caliber and intensity ↓ as disease progresses
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- Pallidal hypointensity increases as disease progresses
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- Eye of tiger sign has been described in neuroferritinopathy
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- Variable ↓ T2 signal substantia nigra (SN) > > dentate nuclei (DN)
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- Atrophy in advanced diseases
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- Location: Globus pallidus (GP), SN, DN
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- Morphology: Signal alteration of GP resembles tiger eyes
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- Iron deposition (ferritin bound) responsible for T2-hypointense imaging appearance
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- ## CT Findings
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- NECT: Variable; hypodense, hyperdense, normal GP
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- CECT: No abnormal enhancement
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- ## MR Findings
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- T1WI: Variable (ferritin-bound iron has > T1 shortening than hemosiderin bound)
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- T2WI
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- Eye of tiger sign = diffuse pallidal hypointensity with medial foci ↑ signal
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- Variable ↓ signal SN; more common in older patients
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- FLAIR: "Eye" persists
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- T2* GRE: ↓ T2 signal GP, SN "blooms" due to paramagnetic effect iron
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- Susceptibility-weighted imaging (SWI): Greater blooming artifact than T2* GRE
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- T1WI C+: No abnormal enhancement
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- MRS: ↓ NAA GP (neuronal loss)
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- ## Nuclear Medicine Findings
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- Tc-99m SPECT: ↑ activity in medial GP
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- Possible chelation Tc-99m by pallidal cysteine
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- ## Imaging Recommendations
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- ### Best imaging tool
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- Multiplanar MR with SWI
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- ### Protocol advice
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- Consider SWI or T2* GRE sequence for mineralization
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- T2 hypointensity more conspicuous on spin-echo (vs. fast spin-echo) and high-field strength magnets
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# DIFFERENTIAL DIAGNOSIS
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- ## Disorders With ↑ T2 Signal Globus Pallidus
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- Metabolic
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- Methylmalonic acidemia (MMA): ↑ T2 signal GP ± periventricular white matter (WM)
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- Kearns-Sayre/L-2-hydroxyglutaric aciduria: ↑ T2 GP (> than other deep gray) and peripheral WM
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- Canavan: ↑ T2 GP (> than other deep gray) and subcortical WM; macrocephaly; ↑ NAA
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- Neuroferritinopathy: Variable-sized foci ↑ T2 signal GP, putamen, caudate heads with ↓ T2 SN, DN; disease of adults
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- Guanidinoacetate methyltransferase deficiency (impairs creatine synthesis)
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- Ischemic/toxic
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- Anoxic encephalopathy: ↑ T2 GP (and other deep gray) and cortex
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- Carbon monoxide poisoning: ↑ T2 GP (± other deep gray, cortex, WM)
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- Cyanide poisoning: ↑ T2 basal ganglia followed by hemorrhagic necrosis
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- Kernicterus: ↑ T2/T1 GP in neonate
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# PATHOLOGY
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- ## General Features
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- Iron accumulation likely secondary phenomenon in PKAN
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- Serial MRs in patients with PKAN show hyperintense foci in GP predating surrounding hypointensity
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- Embryology, anatomy
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- Progressive, physiologic brain iron accumulation occurs in GP, SN > red and DN
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- ↓ T2 signal GP identified in majority of normal patients by age ≥ 25, but never before age 10
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- Genetics
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- Autosomal recessive (50% sporadic)
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- > 100 *PANK2* mutations Chr 20p12.3-p13 identified
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- MR eye of tiger sign highly correlative with *PANK2* mutation
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- *PANK2* gene encodes mitochondrial-targeted pantothenate kinase 2, key enzyme in biosynthesis of coenzyme A (CoA)
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- CoA essential to energy and fatty acid metabolism, among other functions
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- Null mutations are more common in early onset, rapidly progressive disease
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- Missense mutations more common in late onset, more slowly progressive disease
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- Suggests residual pantothenate kinase 2 activity in late-onset (less severe) disease
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- HARP: **H**ypoprebetalipoproteinemia, **a**canthocytosis,**r**etinitis pigmentosa, and **p**allidal degeneration
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- Allelic with PKAN
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- Prominent orofacial dystonia; early-onset parkinsonism
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- Etiology
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- Leading theory
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- *PANK2* mutation → CoA deficiency → energy and lipid dyshomeostasis → production of oxygen free radicals → phospholipid membrane destruction
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- Basal ganglia and retina vulnerable to oxidative damage secondary to high metabolic demand
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- Additional factors
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- Cysteine accumulation in GP secondary to ↓ phosphopantothenate causes iron chelation and peroxidative cell membrane damage
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- Axonal spheroids further compromise glial and neuronal function
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- ## Gross Pathologic & Surgical Features
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- Symmetric, rust-brown pigmentation GP (interna > externa), and pars reticulata SN
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- In addition to iron, intra-/extraneuronal ceroid lipofuscin and melanin contribute to pigmentation
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- Variable atrophy
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- ## Microscopic Features
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- Classic features
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- ↑ iron GP interna and pars reticulata SN
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- Iron located in astrocytes, microglial cells, neurons, and around vessels
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- Neuronal loss, gliosis, and glial inclusions primarily involving GP interna and pars reticulata SN
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- Round or oval, nonnucleated, axonal swellings ("spheroids") in GP, SN, cortex, and brainstem
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- Loose tissue (consisting of reactive astrocytes, dystrophic axons, and vacuoles in anteromedial GP) corresponds to "eye" in eye of tiger sign on MR
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- Variably present acanthocytes (on blood smear)
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# CLINICAL ISSUES
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- ## Presentation
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- Clinical classification into classic and atypical disease
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- Classic PKAN: Early onset, more rapidly progressive disease, uniform phenotype
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- Atypical PKAN: Late onset, more slowly progressive disease, heterogeneous phenotype
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- Most common signs/symptoms
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- Classic PKAN: Dystonia
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- Other extrapyramidal signs/symptoms: Dysarthria, rigidity, choreoathetosis
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- Upper motor neuron signs/symptoms and cognitive decline are frequent
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- Pigmentary retinopathy (66%)
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- Atypical PKAN: Psychiatric and speech disturbances
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- Other signs/symptoms: Pyramidal/extrapyramidal disturbances (including freezing), dementia
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- Clinical profile
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- Classic PKAN: Young child with gait, postural deficits
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- Atypical PKAN: Teenager with speech, psychiatric disturbance
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- Normal serum and CSF iron levels
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- Confirmatory *PANK2* mutation analysis should be performed in all suspected cases of PKAN
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- ## Demographics
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- ### Age
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- Classic PKAN: Majority present before 6 years of age
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- Atypical PKAN: Mean age at presentation is 13 years
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- Epidemiology: Rare; incidence unknown
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- ## Natural History & Prognosis
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- Natural History
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- Classic PKAN: Rapid, nonuniform progression with periods of deterioration interspersed with stability, leading to early adulthood death
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- Atypical PKAN: More slowly progressive with loss of ambulation 15-40 years after disease onset
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- Prognosis
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- Classic PKAN: Fatal; mean disease duration after symptom onset is 11 years
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- Atypical PKAN: Eventual severe impairment, ± death, adulthood
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- ## Treatment
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- No curative treatment; iron chelation ineffective
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- Palliative therapy
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- Baclofen, trihexyphenidyl frequently ineffective
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- Stereotactic pallidotomy
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- Promising initial results with pallidal deep brain stimulation
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# DIAGNOSTIC CHECKLIST
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- ## Image Interpretation Pearls
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- Eye of tiger sign highly suggestive of PKAN
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- Physiologic GP hypointensity difficult to distinguish from pathologic hypointensity in teenager/adult
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