This document provides an overview of neurodegeneration due to brain iron accumulation (NBIA). It defines NBIA as a heterogeneous group of inherited neurodegenerative disorders characterized by extrapyramidal movement disorders and abnormal iron accumulation in the basal ganglia. It then describes several specific disorders that fall under the NBIA classification, including their typical clinical presentations, imaging features, pathology findings, and treatment approaches. Key disorders discussed include PKAN, PLAN, MPAN, and BPAN. The document provides detailed information on the genetic causes and characteristic signs of each condition.

1. Neurodegeneration
due to
brain iron accumulation
Presented by : Dr. Sachin Adukia Moderator: Dr. Kuldeep Shetty

2. Content
 Definition
 Shared features
 Classification
 Disorders
 Clinical features
 Imaging
 Treatment
 Prognosis

3. Introduction
 NBIA - a heterogeneous group of inherited neurodegenerative disorders characterized by
extrapyramidal movement disorders and abnormal iron accumulation in the deep basal
ganglia nuclei of the brain.
 ultra-rare” with less than 1/1000000 affected
 Prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic
deposition of iron in BG
 Areas rich in iron appear hypointense on T2-weighted sequences, and isointense on T1
 Blooming on GRE, SWI
 symmetric distribution of iron in key gray matter nuclei intrinsically enriched in their iron
content (GP, SN, red nucleus, dentate nucleus, putamen, and thalamus)
 Iron deposition can also be s/i: HIV dementia, FA, AD, PD but to a lesser degree

6. PANTOTHENATE KINASE-
ASSOCIATED NEURODEGENERATION (PKAN)
 Historically “Hallervorden-Spatz disease”
 approx 50% of all cases
 Defect is in PANK 2 gene which catalyses biosynthesis of CoA required for FA and
intermediary metabolism

7. Classic Atypical
Age early-onset, rapidly progressive Later onset, slowly-progressive
Presentation change in gait and falls, h/o DD, poor
night vision
change in speech patterns; stutter,
Parkinsonian-type palilalia or
hypophonia, spasmodic dysphonia
Cortico
Spinal
spasticity, brisk reflexes and extensor
plantar
Varying degrees of spasticity
Extra
Pyramidal
System
LL dystonia: striatal toe, foot
dystonia,
Action induced dystonia, OMD
Teenage: dystonia > parkinsonism
20’s: parkinsonism > dystonia
Occular bilateral Adie’s pupil, RP, abnormal
pursuit and saccades
EOM abormalities +, but RP is rare
Tics - new tic disorder or worsening of
earlier tics
Neuropsych - Mood lability, impulsivity, non-specific
behavioral changes, OCD
Course of
illness
Younger onset = more severe
congnitive dysfunction
Stepwise deterioration: trunk, limb,
bulbar
rate of decline is steeper following the
onset of symptoms, but then tends to
stabilize and change only minimally
over years

9. --- On T2 : - GP is hypointense with an anteromedially-placed region of
hyperintensity: “eye of the tiger” sign
--- It is not absolutely sensitive or specific: the central HI can consolidate or fade
over time, thus these cases do nit have Eye of the Tiger
--- mimics s/i MPAN, CO poisoning survivors, MSA, CBGD, neuroferritinopathy
PATHOLOGICALLY:
---- Iron is seen as frankly rusty discoloration of GP but not other structures
iron-specific stains that reveal the iron to have a perivascular distribution
---- A central area of neuronal depletion and tissue rarefaction surrounded by
relatively more preserved iron-laden neuropil, neurons, and astrocytes corresponds
to the “eye of the tiger” seen on MRI

13. Treatment
 treatment is symptomatic
 anticholinergics, benzodiazepines,
 baclofen, which may be delivered intrathecally.
 Botulinum toxin for targeted relief of dystonia and spasticity
 ?? DBS
 OT/PT
 Deferiprone, an iron chelator - ?? role– no measurable clinucal improvement

14. PHOSPHOLIPASE A2-ASSOCIATED
NEURODEGENERATION (PLAN)
 Mutations in the calcium-independent phospholipase A2 gene PLA2G6
 critical role in cell membrane phospholipid homeostasis,
 INAD and aNAD
 infantile neuroaxonal dystrophy (INAD), a term that originates from the hallmark
pathologic finding of dystrophic axons found on nerve or conjunctival biopsy
 aNAD: if onset is later in childhood or those with INAD but slower rate of progress

15. INAD aNAD
Age 6 to 36 months Later in childhood
Presentation slowing or cessation of development,
followed by progressive loss of
previously acquired milestones
CST Truncal hypotnia
Hypotonia and areflexia is replaced by
spastic tetraplegia as the disease
advances
Hypotonia and areflexia tend to
predominate likely due to peripheral
neuropathy
EPS dystonia
Occular Optic atrophy, strabismus and nystagmus
EEG frontal-predominant fast rhythms and
sometimes overt epileptiform discharges.
Cerebellar Walk and talk is impaired early on, thus
cerebellar dysfunction cannot be
assessed
cerebellar dysfunction with gait
ataxia, dysmetria and dysarthria
Course of
illness
Progressive dementia, +/- Sz
Most die before age 10 y

17. Imaging
 MRI
 Cerebellar atrophy is the most common in both INAD and aNAD
 diffuse T2 white matter hyperintensities, and thinning of the corpus callosum and optic
chiasma
 iron accumulation, manifesting as T2 hypointensity, may be absent or subtle
 PATHOLOGY
 cerebellar and cortical atrophy may be observed on gross pathology
 Dystrophic axonal spheroids (hallmark diagnostic finding) are seen as eosinophilc
swellings in peripheral nerves, spinal cord, brainstem and basal ganglia
 prominent Lewy body pathology involving the basal ganglia and neocortex
 Tau pathology hyperphosphorylated neurofibrillary tangles and neuropil threads

20. Treatment
 Symptomatic
 Standard medications to treat seizures, spasticity, dystonia, and parkinsonism
 levodopa in adult-onset dystonia-parkinsonism is complicated by early motor
fluctuations and exacerbation of neuropsychiatric symptoms.
 Physiotherapy early to delay or prevent contractures
 Gastrostomy tube - nutritional support

21. MITOCHONDRIAL MEMBRANE PROTEIN-ASSOCIATED
NEURODEGENERATION (MPAN)
 Mutations in c19orf12
 ? role in cellular energetics and fatty acid metabolism
 Clinical features
 Onset is in first decade or early adulthood

22.  Childhood presentation
 Earliest sign: spastic gait with extensor plantar
 optic atrophy, learning difficulties, dysarthria, and sometimes behavioral and psychiatric
features
 Dystonia, when present, tends to be limited to the feet and hands
 As the disease progresses
 LMN signs may emerge: Loss of DTR, atrophy, weakness
 Cognitive decline
 Dysphagia +/- aspiration pneumonia
 Adulthood presentation :
 cognitive and behavioral changes, parkinsonism and mixed gait disorders.

23. Imaging
 Pallidal and nigral iron accumulation is s/I T2 and GRE
 hyperintense streaking of the globus pallidus in the region of the medial medullary lamina
 Cortical and cerebellar atrophy : more advanced disease
 PATHOLOGY:
 a remarkable burden of Lewy bodies and Lewy neurites in BG and also neocortex
 Cortical Lewy body pathology in MPAN exceeds that seen in sporadic Parkinson disease
by 40-fold
 Even more than in LBD
 Axonal spheroids, thought to represent dying neurons: seen peripherally and centrally
 Iron deposits are seen in GP > substantia nigra; little or no iron is seen in the cortex

24. Treatment
 Similar to PLAN

25. BETA-PROPELLER PROTEIN-ASSOCIATED
NEURODEGENERATION (BPAN)
 Historically “static encephalopathy with neurodegeneration in childhood” (SENDA)
 The only X-linked form; X linked dominant; mostly female
 mutations in WDR45
 two distinct phases to its course,
 syndrome of global development delay with seizures, pyramidal signs and disordered
sleep in childhood,
 followed by a decline in adulthood with the development of parkinsonism, dystonia
and dementia

26.  Motor milestones are delayed: the child may exhibit toe walking or a broad-based, ataxic
gait.
 Intellectual disability is marked:
 little expressive language is acquired, with most children attaining only a few spoken
words.
 Seizures: uncommon/febrile or syndromic epilpesy with multiple refractory Sz types
 sleep disorders, including hypersomnolence, hyposomnolence, shortened sleep latency,
and abnormal rapid eye movement sleep
 hand stereotypies

27. Adulthood and clinical course
 During the teenage years or early adulthood, signs of parkinsonism emerge: stooping,
bradykinesia, gait changes, freezing,
 May respond to levodopa but soon develop brittle levodopa-induced dyskinesias or
dystonia
 progressive decline in cognitive function : previously-learned skills are lost
 eventually all patients lose ambulatory ability and become profoundly demented

28. Imaging
 in early childhood is typically unremarkable
 Later T2 hypointensities consistent with iron accumulation in GP > SN, cerebral
peduncles
 most pronounced in the substantia nigra where it appears as a discrete linear streak
 This same area on T1 is surrounded by a hyperintense “halo” extending to the
cerebral peduncles, thought to represent neuromelanin release from degenerating
neurons
 Others :
 thinning of the corpus callosum,
 cerebellar atrophy and more global atrophy as the disease advances.

31. Pathology of BPAN
 iron-specific stains such as Prussian blue.shows iron accumulation in GP, SN
 tau positive neurofibrillary tangles are seen in the cortex, putamen, hippocampus and
hypothalamus
 Axonal spheroids are s/i GP, SN, pons, medulla, thalmus

32. Treatment
 Childhood: Rx of refractory Sz
 Adulthood: Rx of PD with monitoring for medication related side effects

33. Fatty acid hydroxylase-associated
neurodegeneration (FAHN)
 FA2H gene product is responsible for hydroxylating FA and plays a key role in myelin
production
 presents in the first decade of life with gait difficulties and falling.
 Progressive spasticity, dystonia and cerebellar dysfunction
 leading to loss of ambulation in many cases due to spastic quadriparesis,
 dysarthria and dysphagia.
 Optic atrophy with variable degrees of visual impairment.
 progressive cognitive decline
 seizures less consistent
 MR imaging
 iron accumulation in GP (not always), sometimes in SN
 T2-bright white matter lesions, thinning of the corpus callosum, and progressive atrophy of
cerebellum, pons, medulla and cord

36. COASY protein-associated neurodegeneration (CoPAN)
 Presents in first decade of life with gait difficulties and mild cognitive
impairment.
 Oromandibular dystonia, dysarthria, and progressive spasticity follow,
 Later axonal neuropathy
 Emergence of parkinsonism further adds to disability.
 MRI demonstrates non-homogenous T2 pallidal hypointensity with a region of
medial hyperintensity : reminiscent of “eye of the tiger”

37. Neuroferritinopathy
 Autosomal dominant
 mutant protein disrupts the structure and iron-carrying capacity of ferritin, resulting in
abnormal iron deposition in the brain.Presents in mid life as a syndrome of chorea,
dystonia, parkinsonism, cognitive decline – frontal lobe or subcortical dmentia and low
serum ferritin
 MRI : patchy abnormal iron accumulation in CN, putamen, thalamus, GP, SN and red
nucleus. Later cavitations may develop in GP, putamen.
 distinguished from Huntington disease by its prominent action-induced orofacial
dystonia, asymmetric presentation, late cognitive decline
 differs from other NBIA by its dominant inheritance pattern, uncommon in childhood,
and distinctive pattern of iron accumulation

39. PKAN vs NFT

40. Aceruloplasminemia
 is a disorder of iron metabolism : mutations in CP gene cause an absence of or reduction
in the copper-carrying ceruloplasmin protein  abnormal iron trafficking and deposition
throughout the body, including CNS
 presents in adulthood ,
 c/b retinal disease, liver disease, diabetes
 and a movement disorder consisting of blepharospasm, facial dystonia, chorea, tremor,
parkinsonism, ataxia, and cognitive decline
 Lab studies:
 low or absent serum ceruloplasmin, elevated ferritin, low iron, microcytic anemia, and
low serum copper but normal urinary copper
 Iron chelation has not shown any significant clinical benefit

42. Woodhouse-Sakati syndrome
 s/i Saudi Arabian population MC
 syndrome of endocrine and neurologic abnormalities.
 Clinical features:
 extrapyramidal movement disorders- dystonia, choreoathetosis,
 intellectual disability,
 sensorineural hearing loss, keratoconus
 Facial dysmorphia, hypogonadism, diabetes mellitus, polyendocrine dysfynction
alopecia,
 abnormalities on electrocardiogram- Flattened T wave
 MRI: basal ganglia T2 hypointensities and extensive confluent white matter T2 P/V HI

44. Kufor-Rakeb syndrome
 originally described in a Jordanian family
 Clinically
 syndrome of juvenile-onset parkinsonism, spasticity, and cognitive decline
 supranuclear gaze palsy, facial-finger-faucial mini myoclonus, and tremor
 Aggression and episodes of psychosis, including frank hallucinations
 MRI:
 Globus pallidus, caudate, and putamen T2 hypointensity
 Generalized cerebral, cerebellar, brain stem atrophy and progressive pyramid atrophy
 basal ganglia iron may not be evident
 Rx :
 Parkinsonism is levodopa-responsive but, like MPAN and BPAN, management is
complicated by the early development of motor fluctuations and dyskinesias.

48. References
 Kruer MC, Boddaert N, Schneider SA, Houlden H, Bhatia KP, Gregory A,
Anderson JC, Rooney WD, Hogarth P, Hayflick SJ. Neuroimaging features of
neurodegeneration with brain iron accumulation. American Journal of
Neuroradiology. 2012 Mar 1;33(3):407-14.
 Hogarth P. Neurodegeneration with brain iron accumulation: diagnosis and
management. Journal of movement disorders. 2015 Jan;8(1):1.

49. Thank You