statdx/docs_md/articles/pkan_aa473236-a733-4f9b-8d92-267ab8d4bcd9.md

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PKAN	aa473236-a733-4f9b-8d92-267ab8d4bcd9	key value 99e1aff7-f42c-43a0-95ae-d89c8551aa01 Kevin R. Moore, MD key value b2e6dabb-ee1c-42a4-a332-9f0814c1c607 Surjith Vattoth, MD, FRCR	name slug treeNodeId Brain brain 6d8829f1-14d7-45af-8675-255189aa526a name slug treeNodeId Diagnosis diagnosis 51c00394-446e-4a38-94af-d3b1d14d34e8 name slug treeNodeId Pathology-Based Diagnoses pathology-based-diagnoses d9d3a8ed-f21b-4831-8c77-591a3500ef77 name slug treeNodeId Inherited Metabolic/Degenerative Disorders inherited-metabolicdegenerative-di- 84bf5d29-d01f-4001-8f6b-51ceefdbf32d name slug treeNodeId Miscellaneous miscellaneous d463e98a-acd6-436d-9bc5-1ef8c667dd95 name slug treeNodeId PKAN pkan null	Brain	a7d8f640-eee8-4b62-b1b8-ee5b300be451	2a300f30-c8a6-45d2-83ae-397a03bd87b8	18	08/10/20	PKAN	Brain, Diagnosis, Pathology-Based Diagnoses, Inherited Metabolic/Degenerative Disorders, Miscellaneous, PKAN	PKAN | STATdx	PKAN	DX	true	Brain Diagnosis Pathology-Based Diagnoses Inherited Metabolic/Degenerative Disorders Miscellaneous PKAN

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title: "PKAN" docid: "aa473236-a733-4f9b-8d92-267ab8d4bcd9" authors:

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• "Diagnosis"
• "Pathology-Based Diagnoses"
• "Inherited Metabolic/Degenerative Disorders"
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• "PKAN"

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KEY FACTS

• Terminology

  • Pantothenate kinase-associated neurodegeneration (PKAN) - Pantothenate kinase 2 (PANK2) mutation - Most common form of neurodegeneration with brain iron accumulation (NBIA)

• Imaging

  • Best diagnostic clue: Eye of tiger sign = diffuse pallidal T2 hypointensity with medial foci ↑ T2 signal - Highly suggestive of PKAN
  • Hyperintense "eye" may predate surrounding pallidal hypointensity

• Top Differential Diagnoses

  • Disorders with ↑ T2 signal globus pallidus (GP) - Metabolic: Methylmalonic acidemia (MMA), Kearns-Sayre, L-2-hydroxyglutaric aciduria, Canavan, neuroferritinopathy - Ischemic/toxic: Anoxic encephalopathy, carbon monoxide/cyanide poisoning, kernicterus

• Pathology

  • PANK2 gene encodes mitochondrial-targeted pantothenate kinase 2, key enzyme in biosynthesis of coenzyme A (CoA)
  • Progressive, physiologic brain iron accumulation occurs in GP, substantia nigra (SN) > red and dentate nuclei
  • Basal ganglia and retina vulnerable to oxidative damage secondary to high metabolic demand
  • Autosomal recessive (50% sporadic)
  • PANK2 mutation → CoA deficiency → energy and lipid dyshomeostasis → production of oxygen free radicals → phospholipid membrane destruction
  • Iron accumulation likely secondary phenomenon in PKAN

• Clinical Issues

  • Classic PKAN: Dystonia, dysarthria, rigidity, choreoathetosis in young child
  • Atypical PKAN: Psychiatric, speech, pyramidal/extrapyramidal disturbances in older child/teenager
  • Epidemiology - Rare; incidence unknown
  • Prognosis - Classic PKAN: Fatal; mean disease duration after symptom onset is 11 years - Atypical PKAN: Eventual severe impairment/death
  • No curative treatment

• Diagnostic Checklist

  • Eye of tiger sign highly suggestive of PKAN
  • Physiologic GP hypointensity difficult to distinguish from pathologic hypointensity in teenager/adult

TERMINOLOGY

• Abbreviations

  • Pantothenate kinase-associated neurodegeneration (PKAN)

• Synonyms

  • Neurodegeneration with brain iron accumulation type 1 (NBIA-1)
  • Hallervorden-Spatz syndrome (obsolete term) - PKAN and NBIA-1 = preferred terms

• Definitions

  • Neurodegeneration with brain iron accumulation (NBIA) = umbrella term for neurodegenerative disorders characterized by brain iron accumulation - Known causes include PKAN (most common), aceruloplasminemia, neuroferritinopathy, and infantile neuroaxonal dystrophy
  • PKAN caused by mutation pantothenate kinase 2 gene (PANK2)

IMAGING

• General Features

  • Best diagnostic clue: Eye of tiger sign = diffuse pallidal T2 hypointensity with medial foci ↑ T2 signal - Highly suggestive of PKAN - Hyperintense "eye" may predate surrounding pallidal hypointensity - "Eye" caliber and intensity ↓ as disease progresses - Pallidal hypointensity increases as disease progresses - Eye of tiger sign has been described in neuroferritinopathy
  • Variable ↓ T2 signal substantia nigra (SN) > > dentate nuclei (DN)
  • Atrophy in advanced diseases
  • Location: Globus pallidus (GP), SN, DN
  • Morphology: Signal alteration of GP resembles tiger eyes
  • Iron deposition (ferritin bound) responsible for T2-hypointense imaging appearance

• CT Findings

  • NECT: Variable; hypodense, hyperdense, normal GP
  • CECT: No abnormal enhancement

• MR Findings

  • T1WI: Variable (ferritin-bound iron has > T1 shortening than hemosiderin bound)
  • T2WI - Eye of tiger sign = diffuse pallidal hypointensity with medial foci ↑ signal - Variable ↓ signal SN; more common in older patients
  • FLAIR: "Eye" persists
  • T2* GRE: ↓ T2 signal GP, SN "blooms" due to paramagnetic effect iron
  • Susceptibility-weighted imaging (SWI): Greater blooming artifact than T2* GRE
  • T1WI C+: No abnormal enhancement
  • MRS: ↓ NAA GP (neuronal loss)

• Nuclear Medicine Findings

  • Tc-99m SPECT: ↑ activity in medial GP - Possible chelation Tc-99m by pallidal cysteine

• Imaging Recommendations

  • Best imaging tool

    - Multiplanar MR with SWI
    

  • Protocol advice

    - Consider SWI or T2* GRE sequence for mineralization
    - T2 hypointensity more conspicuous on spin-echo (vs. fast spin-echo) and high-field strength magnets
    

DIFFERENTIAL DIAGNOSIS

• Disorders With ↑ T2 Signal Globus Pallidus

  • Metabolic - Methylmalonic acidemia (MMA): ↑ T2 signal GP ± periventricular white matter (WM) - Kearns-Sayre/L-2-hydroxyglutaric aciduria: ↑ T2 GP (> than other deep gray) and peripheral WM - Canavan: ↑ T2 GP (> than other deep gray) and subcortical WM; macrocephaly; ↑ NAA - Neuroferritinopathy: Variable-sized foci ↑ T2 signal GP, putamen, caudate heads with ↓ T2 SN, DN; disease of adults - Guanidinoacetate methyltransferase deficiency (impairs creatine synthesis)
  • Ischemic/toxic - Anoxic encephalopathy: ↑ T2 GP (and other deep gray) and cortex - Carbon monoxide poisoning: ↑ T2 GP (± other deep gray, cortex, WM) - Cyanide poisoning: ↑ T2 basal ganglia followed by hemorrhagic necrosis - Kernicterus: ↑ T2/T1 GP in neonate

PATHOLOGY

• General Features

  • Iron accumulation likely secondary phenomenon in PKAN - Serial MRs in patients with PKAN show hyperintense foci in GP predating surrounding hypointensity
  • Embryology, anatomy - Progressive, physiologic brain iron accumulation occurs in GP, SN > red and DN - ↓ T2 signal GP identified in majority of normal patients by age ≥ 25, but never before age 10
  • Genetics - Autosomal recessive (50% sporadic) - > 100 PANK2 mutations Chr 20p12.3-p13 identified - MR eye of tiger sign highly correlative with PANK2 mutation - PANK2 gene encodes mitochondrial-targeted pantothenate kinase 2, key enzyme in biosynthesis of coenzyme A (CoA) - CoA essential to energy and fatty acid metabolism, among other functions - Null mutations are more common in early onset, rapidly progressive disease - Missense mutations more common in late onset, more slowly progressive disease - Suggests residual pantothenate kinase 2 activity in late-onset (less severe) disease - HARP: Hypoprebetalipoproteinemia, acanthocytosis,retinitis pigmentosa, and pallidal degeneration - Allelic with PKAN - Prominent orofacial dystonia; early-onset parkinsonism
  • Etiology - Leading theory - PANK2 mutation → CoA deficiency → energy and lipid dyshomeostasis → production of oxygen free radicals → phospholipid membrane destruction - Basal ganglia and retina vulnerable to oxidative damage secondary to high metabolic demand - Additional factors - Cysteine accumulation in GP secondary to ↓ phosphopantothenate causes iron chelation and peroxidative cell membrane damage - Axonal spheroids further compromise glial and neuronal function

• Gross Pathologic & Surgical Features

  • Symmetric, rust-brown pigmentation GP (interna > externa), and pars reticulata SN - In addition to iron, intra-/extraneuronal ceroid lipofuscin and melanin contribute to pigmentation
  • Variable atrophy

• Microscopic Features

  • Classic features - ↑ iron GP interna and pars reticulata SN - Iron located in astrocytes, microglial cells, neurons, and around vessels - Neuronal loss, gliosis, and glial inclusions primarily involving GP interna and pars reticulata SN - Round or oval, nonnucleated, axonal swellings ("spheroids") in GP, SN, cortex, and brainstem
  • Loose tissue (consisting of reactive astrocytes, dystrophic axons, and vacuoles in anteromedial GP) corresponds to "eye" in eye of tiger sign on MR
  • Variably present acanthocytes (on blood smear)

CLINICAL ISSUES

• Presentation

  • Clinical classification into classic and atypical disease - Classic PKAN: Early onset, more rapidly progressive disease, uniform phenotype - Atypical PKAN: Late onset, more slowly progressive disease, heterogeneous phenotype
  • Most common signs/symptoms - Classic PKAN: Dystonia - Other extrapyramidal signs/symptoms: Dysarthria, rigidity, choreoathetosis - Upper motor neuron signs/symptoms and cognitive decline are frequent - Pigmentary retinopathy (66%) - Atypical PKAN: Psychiatric and speech disturbances - Other signs/symptoms: Pyramidal/extrapyramidal disturbances (including freezing), dementia
  • Clinical profile - Classic PKAN: Young child with gait, postural deficits - Atypical PKAN: Teenager with speech, psychiatric disturbance
  • Normal serum and CSF iron levels
  • Confirmatory PANK2 mutation analysis should be performed in all suspected cases of PKAN

• Demographics

  • Age

    - Classic PKAN: Majority present before 6 years of age
    - Atypical PKAN: Mean age at presentation is 13 years
    

  • Epidemiology: Rare; incidence unknown

• Natural History & Prognosis

  • Natural History - Classic PKAN: Rapid, nonuniform progression with periods of deterioration interspersed with stability, leading to early adulthood death - Atypical PKAN: More slowly progressive with loss of ambulation 15-40 years after disease onset
  • Prognosis - Classic PKAN: Fatal; mean disease duration after symptom onset is 11 years - Atypical PKAN: Eventual severe impairment, ± death, adulthood

• Treatment

  • No curative treatment; iron chelation ineffective
  • Palliative therapy - Baclofen, trihexyphenidyl frequently ineffective - Stereotactic pallidotomy - Promising initial results with pallidal deep brain stimulation

DIAGNOSTIC CHECKLIST

• Image Interpretation Pearls

  • Eye of tiger sign highly suggestive of PKAN
  • Physiologic GP hypointensity difficult to distinguish from pathologic hypointensity in teenager/adult

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References

Selected References

1. Chang X et al: Natural history and genotype-phenotype correlation of pantothenate kinase-associated neurodegeneration. CNS Neurosci Ther. ePub, 2020
2. Dangel T et al: Palliative care in 9 children with neurodegeneration with brain iron accumulation. Neurol Sci. 41(3):653-60, 2020
3. Zeng J et al: Magnetic resonance imaging, susceptibility weighted imaging and quantitative susceptibility mapping findings of pantothenate kinase-associated neurodegeneration. J Clin Neurosci. 59:20-8, 2019
4. Razmeh S et al: Pantothenate kinase-associated neurodegeneration: clinical aspects, diagnosis and treatments. Neurol Int. 10(1):7516, 2018
5. Sharma LK et al: A therapeutic approach to pantothenate kinase associated neurodegeneration. Nat Commun. 9(1):4399, 2018
6. Darling A et al: Clinical rating scale for pantothenate kinase-associated neurodegeneration: a pilot study. Mov Disord. 32(11):1620-30, 2017
7. Liu Z et al: Subthalamic nuclei stimulation in patients with pantothenate kinase-associated neurodegeneration (PKAN). Neuromodulation. 20(5):484-91, 2017
8. Arber C et al: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation; unifying theories. Neuropathol Appl Neurobiol. 42(3):220-41, 2016
9. Amaral LL et al: Neurodegeneration with brain iron accumulation: clinicoradiological approach to diagnosis. J Neuroimaging. 25(4):539-51, 2015
10. Dusek P et al: The neurotoxicity of iron, copper and manganese in Parkinson's and Wilson's diseases. J Trace Elem Med Biol. 31:193-203, 2015
11. Dusek P et al: Wilson disease and other neurodegenerations with metal accumulations. Neurol Clin. 33(1):175-204, 2015
12. Hogarth P: Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord. 8(1):1-13, 2015
13. Ma LY et al: Novel gene mutations and clinical features in patients with pantothenate kinase-associated neurodegeneration. Clin Genet. 87(1):93-5, 2015
14. Stoeter P et al: Changes of cerebral white matter in patients suffering from pantothenate kinase-associated neurodegeneration (PKaN): a diffusion tensor imaging (DTI) study. Parkinsonism Relat Disord. 21(6):577-81, 2015
15. Bosemani T et al: Susceptibility-weighted imaging in pantothenate kinase-associated neurodegeneration. J Pediatr. 164(1):212, 2014
16. Dezfouli MA et al: PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation. Mov Disord. 28(2):228-32, 2013
17. Schipper HM: Neurodegeneration with brain iron accumulation - clinical syndromes and neuroimaging. Biochim Biophys Acta. 1822(3):350-60, 2012
18. Shah SO et al: Late-onset neurodegeneration with brain iron accumulation with diffusion tensor magnetic resonance imaging. Case Rep Neurol. 4(3):216-23, 2012
19. Kurian MA et al: Childhood disorders of neurodegeneration with brain iron accumulation (NBIA). Dev Med Child Neurol. 53(5):394-404, 2011
20. Gregory A et al: Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet. 46(2):73-80, 2009
21. Mikati MA et al: Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration. Eur J Paediatr Neurol. 13(1):61-4, 2009
22. Mylius V et al: Low-frequency rTMS of the premotor cortex reduces complex movement patterns in a patient with pantothenate kinase-associated neurodegenerative disease (PKAN). Neurophysiol Clin. 39(1):27-30, 2009
23. Sachin S et al: Clinical spectrum of Hallervorden-Spatz syndrome in India. J Clin Neurosci. 16(2):253-8, 2009
24. Schneider SA et al: Iron accumulation in syndromes of neurodegeneration with brain iron accumulation 1 and 2 - causative or consequential? J Neurol Neurosurg Psychiatry. 80(6):589-90, 2009
25. Wu YR et al: Pantothenate kinase-associated neurodegeneration in two Taiwanese siblings: identification of a novel PANK2 gene mutation. Mov Disord. 24(6):940-1, 2009
26. Chan KY et al: Pantothenate kinase-associated neurodegeneration in two Chinese children: identification of a novel PANK2 gene mutation. Hong Kong Med J. 14(1):70-3, 2008
27. Isaac C et al: Pallidal stimulation for pantothenate kinase-associated neurodegeneration dystonia. Arch Dis Child. 93(3):239-40, 2008
28. Lyoo CH et al: Anticholinergic-responsive gait freezing in a patient with pantothenate kinase-associated neurodegeneration. Mov Disord. 23(2):283-4, 2008
29. McNeill A et al: T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology. 70(18):1614-9, 2008
30. Surguchov A: Molecular and cellular biology of synucleins. Int Rev Cell Mol Biol. 270:225-317, 2008
31. Gupta R et al: Autopsy always teach and tell: neurodegeneration with brain iron accumulation: a case report. Indian J Pathol Microbiol. 50(4):792-4, 2007
32. Hamani C et al: Surgery for other movement disorders: dystonia, tics. Curr Opin Neurol. 20(4):470-6, 2007
33. Kazek B et al: A novel PANK2 gene mutation: clinical and molecular characteristics of patients short communication. J Child Neurol. 22(11):1256-9, 2007
34. Saleheen D et al: Novel mutation in the PANK2 gene leads to pantothenate kinase-associated neurodegeneration in a Pakistani family. Pediatr Neurol. 37(4):296-8, 2007
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Images

Selected Images

Axial T2WI MR in a 5 year old with cerebral palsy demonstrates eye of the tiger sign typical of pantothenate kinase-associated neurodegeneration (PKAN): Symmetric areas of high T2 signal within the medial globus pallidus with surrounding pallidal hypointensity.

Axial T2WI MR in a 5 year old with cerebral palsy demonstrates eye of the tiger sign typical of pantothenate kinase-associated neurodegeneration (PKAN): Symmetric areas of high T2 signal within the medial globus pallidus with surrounding pallidal hypointensity.

Axial T2WI MR in a 5 year old with cerebral palsy demonstrates eye of the tiger sign typical of pantothenate kinase-associated neurodegeneration (PKAN): Symmetric areas of high T2 signal within the medial globus pallidus with surrounding pallidal hypointensity.

Axial T2WI MR in a 5 year old with cerebral palsy demonstrates eye of the tiger sign typical of pantothenate kinase-associated neurodegeneration (PKAN): Symmetric areas of high T2 signal within the medial globus pallidus with surrounding pallidal hypointensity.

Dystonia prompted repeat MR 4 years later. Axial T2WI MR shows that the "eyes" have diminished in size and intensity with greater surrounding pallidal hypointensity. Volume loss is now evident, particularly frontal.

Coronal T2WI MR of the same patient at 9 years of age shows abnormal hypointense signal in the globus pallidus and substantia nigra .

Axial T2 GRE MR in the same patient at 9 years of age shows blooming of the hypointense signal in the globus pallidus secondary to the paramagnetic effect of iron. The findings in this patient are typical of the evolution of classic PKAN: Diminishing caliber of the "eye," increasing surrounding pallidal hypointensity, and progressive volume loss.*

Axial T1WI MR in a 5 year old with classic PKAN shows that the "eye" in the eye of the tiger is hypointense with few punctate areas of surrounding hyperintensity .

Axial T1WI MR in the same patient at 9 years old shows the "eye" as mostly hyperintense. The appearance of the "eye" in eye of the tiger is variable depending on the stage of the disease. Progressive iron deposition within the globus pallidus likely accounts for greater T1 shortening seen in later disease.

Coronal T2WI MR in a patient with classic PKAN shows the classic eye of the tiger sign with small foci of ↑ T2 signal in the medial globi pallidi surrounded by abnormal pallidal hypointensity.

Axial T2 GRE MR in a patient with classic PKAN shows blooming of hypointense signal in the inferior globus pallidus and substantia nigra . Abnormal iron accumulation within the substantia nigra is more conspicuous on imaging as the disease progresses.*

Axial T2WI MR in a 12 year old with advanced classic PKAN undergoing preoperative imaging for pallidotomies shows globi pallidi hypointense and atrophic with subtle eye of the tiger signs . Note also the diffuse volume loss.

Axial SWI in the same patient shows blooming of hypointense signal within the globi pallidi. The eyes of the tiger are no longer seen, obscured by the blooming effect. SWI is more sensitive than T2 GRE due to magnetic susceptibility effects.*

Additional Images

Axial T2WI MR shows the classic eye of the tiger appearance of PKAN. The globus pallidi are abnormally hypointense with central foci of hyperintensity , resembling a tiger's eyes.

Coronal T2WI MR captures all the main imaging features of PKAN: Eye of the tiger sign in the globus pallidi with symmetric hypointensity in the surrounding globus pallidi and substantia nigra .

Axial T1WI MR shows no apparent abnormal signal intensity in the substantia nigra in a patient with PKAN.

Axial T1WI MR in a patient with PKAN shows hyperintensity of the substantia nigra . The T1 appearance of the globus pallidi and substantia nigra in PKAN is variable.

Axial T2 GRE MR shows focal hypointense signal ("blooming") in the bilateral globus pallidus secondary to the paramagnetic effect of iron.*

Axial NECT shows focal globus pallidus calcification bilaterally. The CT appearance of PKAN is variable. Globus pallidus may be hypodense or hyperdense secondary to dystrophic calcification, as seen in this case.

Axial T2WI MR shows diffusely hypointense globus pallidus in a 15 year old with spastic gait. Lack of eye of the tiger indicates lack of PANK2 mutation. These patients have other forms of neurodegeneration with brain iron accumulation (NBIA(, not PKAN.

Axial T2WI MR in the same patient shows hypointense substantia nigra . Nigral hypointensity is usually greater in patients with NBIA other than PKAN.