This document discusses iron metabolism in the central nervous system and neurodegeneration with brain iron accumulation (NBIA). It provides details on: 1) Iron's essential roles in the CNS and brain iron homeostasis mechanisms. 2) Diseases associated with abnormal brain iron accumulation like Parkinson's and how imaging can detect this. 3) Specific NBIA disorders like pantothenate kinase-associated neurodegeneration (PKAN) and infantile neuroaxonal dystrophy (INAD). 4) Clinical features, genetics, pathophysiology, imaging and histopathology findings of these disorders. 5) Limitations in treatment and challenges managing dystonia in severe cases.

1. Dr. Raghu ram
Dept of neurology
NIMS, Hyderabad

2. Iron metabolism in the CNS
• Iron is indispensable in mammalian metabolism because it is integral to the formation
of haem and iron–sulphur clusters and functions as a cofactor in numerous metabolic
reactions .
•For transport of oxygen to the tissues and oxitative phosporylation in the mitochondrial
respiratory chain complexes.

3. • Brain imaging techniques such as MRI, have enabled investigators to detect abnormal
brain iron accumulations in several previously known and newly described diseases, and
this has led to the identification of several disease genes.
• It is often not known whether iron
accumulation contributes to disease progression
or whether accumulation of iron occurs only after
widespread neuronal death

4. Holotransferrin = Transferrin + 2 ferric ions

5. Systemic iron metabolism
Iron is stored in cytosolic proteins such as ferritin, which can sequester up to 4,500 iron atoms.
Ferritin sequestration of iron prevents free iron from reaching high concentrations in the
cytosolic and nuclear compartment

6. Iron entry into CNS
FPN--
TFRC

7. Iron metabolism in the brain

8. Brain iron Homeostasis
• Iron is an essential component of Cyt a, b,c oxidase, and iron–sulfur complexes
of the oxidative chain (ATP production), and a cofactor for tyrosine, tryptophan
Hydroxylase , ribonucleotide reductase, SDH.
• Iron is essential for biosynthesis of lipids, cholesterol, and may have a role in
the GABAergic system.
• Specific areas of brain: GP, SN, dentate nucleus, and motor cortex, have high
iron content in normal brain.
• Robust iron staining is seen in the oligodendrocytes and in the microglia (brain
iron capacitor).

9. Brain iron accumulation
•Iron accumulation occurs in the brain in ageing animals, including humans, in areas
primarily associated with motor activity, including the globus pallidus, red nucleus, dentate
nucleus and substantia nigra
•These brain regions become rich with ferritin which tends to accumulate in humans and to
colocalize with iron, as detected by HPE and immunohistochemistry .
•It is not known why so much iron is stored in the globus pallidus and other basal ganglia,
but it is possible that some specialized neurons in the globus pallidus and basal ganglia are
programmed to transcribe high amounts of ferritin and thereby create a ferritin-rich iron
repository in the CNS — analogous to the liver iron repository

10. •The iron accumulation associated with ageing is not generally associated with
pathology (most ageing individuals do not develop neurodegenerative disease).
•This suggests that the iron observed is contained in healthy ferritin-rich cells, which
may include unique types of neurons and/or oligodendrocytes, astroglia and microglia
in the iron-rich brain regions .
•The composition of cells and iron content of a brain region may change when an iron-
rich area begins to degenerate.
•When a cell dies, microglia and/or macrophages that invade from the peripheral
circulation phagocytose debris released by degenerating cells

11. •When many cells die in an iron-rich brain area, these scavenger cells become iron-rich
by virtue of having phagocytosed iron-rich cellular debris
• Some diseases, including Parkinson’s disease, seem to specifically affect iron-rich
areas such as the substantia nigra.
•This makes it difficult to ascertain whether the iron accumulation often observed in
Parkinson’s disease is a cause or a consequence of the degeneration of substantia
nigra neurons associated with this disease.
•Similarly, in Huntington’s disease, and Alzheimer’s disease and freidrichs ataxia

13. Stages of Iron Deposition on MRI
• Initially hyperintense compared with white matter
(stage I)
• Isointense (stage II)
• Hypointense compared with both gray and white
matter (stage III)

15. NBIA Definition
•Syndromes with neurodegeneration with brain iron accumulation (NBIA) are a group of
neurodegenerative disorders characterized by abnormalities in brain iron metabolism
and with excess iron accumulation in the globus pallidus and to a lesser degree in the
substantia nigra and sometimes adjacent areas.
•They clinically present as neurodegenerative diseases with progressive
hypo- and /or hyperkinetic movement disorders and a variable degree of pyramidal,
cerebellar, peripheral nerve, autonomic, cognitive and psychiatric involvement, and
visual dysfunction.
Susanne A. Schneider ;Neurodegeneration with Brain Iron Accumulation , Curr Neurol Neurosci Rep (2016) 16:9

16. History
• Brain iron research began in the late 19th century with quantitative analysis of
human brain by Zaleski (1886).
• The first systematic studies of iron in the human brain were undertaken in the
1920s by Hugo Spatz (1888–1969).
• Around the same time, Julius Hallervorden (1882–1965) encountered a
progressive neurological disorder associated with extrapyramidal features.
• Julius Hallervoden and Hugo Spatz were German neuropathologists whose work
derived from pathological samples obtained under the Nazi program of active
euthanasia of individuals with physical and intellectual disabilities.

17. [Hugo Spatz 1888-1969]

18. • Hallervorden himself selected and examined a no. of living patients
before personally removing their brains at the killing center.
• On the basis of these materials, he published 12 scientific articles (7 as
sole author) in the postwar era on a variety of topics, including the
effect of CO exposure on the fetal brain.
• “I heard that they were going to do that, and so I went up
to them and told them, ‘Look here now, boys. If you are
going to kill all those people, at least take the brains out
so that the material can be utilized’

19. • 1952: Seitelberger described the early-onset form of PLAN,
subsequently labeled as ‘‘infantile neuroaxonal dystrophy’’ (INAD)
by Cowen and Olmstead
• Zhou B et al in 2001. A novel pantothenate kinase gene (PANK2) is
defective in Hallervorden–Spatz syndrome.
• Morgan et al in 2006 described mutations in phospholipase A2
(PLA2G6) as a recessive cause of INAD associated with high brain
iron levels
Cowen D, Olmstead EV. Infantile neuroaxonal dystrophy. J Neuropathol Exp Neurol 1963

22. Penelope Hogarth , J Mov Disord 2015;8(1):1-13

23. NBIA are considered to be “ultra-rare” with less than 1/1000000 affected

25. Epidemiology
• Estimated prevalence of 1-3/ million population has been suggested
based on observed cases in a population.
• PKAN: highest prevalence & founder mutation in Central Europe
• Neuroferritinopathy is classically seen in patients from the Cumbrian
region of England, though cases from France, NA, & Japan have been
reported.
• Aceruloplasminemia is almost exclusively seen
in patients of Japanese origin.

26. PKAN/NBIA 1
• PKAN is the most frequent NBIA, accounting for more than 50% of cases
(Gregory et al., 2009)
• Hallmark feature of PKAN is extrapyramidal dysfunction, one or more of
either- dystonia, rigidity or choreoathetosis
• Pyramidal features, prominent oromandibular involvement
• No definite diagnostic criteria
• 2 clinical forms based on age of onset and rate of progression.

27. Classical Vs Atypical type
• Classical PKAN: rapid progression
- 1st decade, 90 % < 6 yrs
- Gait/postural difficulty presenting
symptom
- RP very common, but no optic
atrophy
- Loss of ambulation within 10–15
years after onset
- Dystonia severe, generalized:
status dystonicus may be seen
• Atypical PKAN: slow progression
- 2nd or 3rd decade(14 yrs mean age)
- Speech- palilalia(40%), tachylalia,
dysarthria, psychatirc disturbances
common
- RP rare
- Loss of ambulation within 15–40
years after onset
Dystonia less severe

30. video

31. • Other authors have identified rare presentations of PKAN:
- pure akinesia (Molinuevo et al., 2003)
- MND like phenotype (Vasconcelos et al., 2003)
- early-onset parkinsonism (Zhou et al., 2001)
- intermittent severe dystonia
• PKAN exclusionary features:
- e/o NCL by electron microscopy, f/h/o HD or other dominantly
inherited movement disorder, Caudate atrophy, β hexos A def
or
GM1 galactosidase def, e/o Wilson disease

35. Posterior pole (top) and nasal retina (bottom) of a patient with PKAN at age 33 yrs. The
retinal vessels are markedly attenuated and the nasal retina shows scattered bone spicule
formations. The macula shows a soft-bordered atrophic lesion with a small area of focal
hyperpigmentation.

36. HARP syndrome
• First described by Higgins et al (Neurology 1992) in a 11 yr old girl
with prominent orofacial dyskinesia and abnormal serum
lipoproteins.

37. Genetics and Pathophysiology
• AR disorder of CoA synthesis c/b mutations in gene
encoding PANK2 enzyme at Ch 20p13
• CoA is critical to energy metabolism, fatty acid
metabolism, & glutathione metabolism
• High conc of Co A in cells with highest energy , myelin
maintenance demand- retinal rods & GP neurons
• Insufficient energy production generation of
ROS lipid peroxidation apoptosis
• Null mutations-classical form
• Missense mutations- Atypical form
The metabolic pathway illustrates how PANK def results in impaired synthesis of coenzyme A
and in increased levels of iron-chelating cysteine, leading to NBIA.

39. Cysteine hypothesis in PKAN
• Cysteine has been reported to accumulate in the GP of pts with PKAN
• Excessive tissue cysteine, an amino acid with iron chelating properties,
may mediate the regional accumulation of iron in these patients.
• In the presence of iron, cysteine undergoes rapid autoxidation yielding
reactive oxygen and sulfur species which promote oxidative neuronal
injury in basal ganglia.

40. The characteristic MR imaging feature, the eye-of-the-tiger sign,
• Axial or coronal T2 or SWI
sequences through the globus pallidi demonstrate
symmetric lesions that mimic a pair of eyes.
• The central zone of T2 hyperintensity
is caused by neuronal loss, gliosis, and
cavitation of the neurons
•The T2 hypointensity develops
gradually with disease
progression,and ultimately
becomes the dominant imaging
finding

41. Duration
•White matter abnormality is typically absent in PKAN.
• Significant brain atrophy is not a feature of PKAN.
•DAT SPECT, measure of striatal dopamine function is normal in PKAN

42. •Transcranial sonography demonstrated bilateral hyperechogenicity in the SN
and lenticular nucleus.
•Transcranial sonography may be used as an inexpensive and simple screening
method for the diagnosis of NBIA.

43. D/d s of ‘Eye of theTiger’ Sign
• Organic Acidurias
• Leigh’s disease
• MSA, CBD
• Neurofibromatosis
• SCA 3
• Multiple sclerosis
Kumar N et al: The “eye-of-the-tiger” sign is not pathognomonic of
the PANK2 mutation. Arch Neurol 63: 292-293, 2006

44. Neuropathology of PKAN
• Distinctive pattern consisting of
• (1)partially destructive lesions of the GP, and the SNpr with loss of
myelinated fibers and neurons with gliosis;
• (2) widely disseminated, rounded/oval nonnucleated structures
("spheroids") identifiable as swollen axons, especially numerous in the
GP, and the SN, but not confined to these areas.
• (3) accumulation of iron, as well as some in the form of ceroid-
lipofuscin and neuromelanin, in the regions chiefly affected.
• Little if any inflammatory response

45. Kruer et al. Novel HP findings in molecularly-confirmed PKAN. Brain 2011
rarefied area that corresponds to the ‘eye of
the tiger’ observed radiographically
Both large degenerating neurons and
smaller neuroaxonal spheroids were
present in the globus pallidus

46. • Numerous papers on NBIA reported the presence of Lewy bodies and
NFT with accumulations of tau and α-synuclein.
• However,in gene proven cases , LBs were absent( incontrast to NBIA2)
Kruer et al. Novel HP findings in molecularly-confirmed PKAN. Brain 2011
On Perl’s stain Iron-positive astrocytes are more conspicuous and greatly outnumber
those present in normal globus pallidus

47. Differentials of ‘Spheroids’ in Brain
• Spheroids are found in the brain in a few other conditions :
1. PLA2G6 associated Neurodegeneration ( NBIA 2 )
2. Infantile GM2 gangliosidosis
3. Niemann-Pick disease type C
4. Menkes disease

48. • Treatment considerations in PKAN
• Currently, treatment is symptomatic.
• Dystonia and spasticity are usually managed with anticholinergics, benzodiazepines
and other anti-spasticity agents such as baclofen, which may be delivered
intrathecally.
• Botulinum toxin injections can also provide targeted relief of dystonia and
spasticity.
• Deep brain stimulation has shown promise, but studies are limited to individual
case reports, small case series and a retrospective study, which included non-PKAN
cases, challenging the generalizability of the results.

49. • One of the most challenging problems for the patient, family and clinician in
PKAN is dystonic crisis or “dystonic storm .
• It can occur without an obvious precipitant, but the child should be screened
for infection, and occult fractures to be certain there is not a treatable cause.
• The torsional stress created by the severe dystonia of classic PKAN can result in
occult fractures of long bones, especially in children who are no longer weight-
bearing and may be osteopenic.

50. NBIA2: Phospholipase (PLA2G6) associated
neurodegeneration (PLAN)
• PLAN comprises a continuum of 3 phenotypes with overlapping
clinical/radiologic features:
1. Classic infantile neuroaxonal dystrophy (INAD)
2. Atypical neuroaxonal dystrophy (atypical NAD)
3. PLA2G6-related dystonia-parkinsonism( PARK14)
• Age dependent phenotype (similar to PKAN)
• INAD used to be called as Seitelberger‘s disease

51. •INAD/atypical NAD are AR disorders c/b mutations in PLA2G6 gene
which encodes PL-A2, phospholipase which catalyses the hydrolysis of
glycerophospholipids, generating a FFA (usually arachidonic acid) and a
lysophospholipid

52. •PLA2G6 may interfere with synthesis and remodelling of the mitochondrial inner membrane
lipid cardiolipin.

53. INAD
• Classical INAD is a devastating synrome of neuroregression c/b
hypotonia, hyperreflexia, and tetraparesis.
• Predominant features:
• Median age of onset: 1yr (5 m to 2.5 yrs)
• Psychomotor regression (most common presenting feature)
• Optic atrophy, Nystagmus, Strabismus
• Characteristic pattern of early truncal hypotonia followed by development of
spastic tetraparesis (usually with hyperreflexia in the early disease stages with
progression to areflexia later in the disease course)

54. INAD
• Other common features:
• Ataxia, gait instability
• Bulbar dysfunction
• NCV: distal axonal-type sensorimotor neuropathy in 40 %
• EEG : fast rhythms
• Seizures in 1/3rd cases
• Avg age of death 10 yrs

55. Patient 8 at the age of 4 years. Very freq diff high-amplitude (50–150 μV) fast activity (18–22 Hz)
. Sensitivity 7 μ/mm; TC 0.1 s; HF 30 Hz.

56. Atypical NAD
• Onset before age 20 years
• Psychomotor regression
• Prominent expressive language difficulties and autistic-like
behavior,diminished social interaction
• Gait instability/ataxia (prominent )
• Progressive dystonia and dysarthria
• Optic atrophy, nystagmus similar to classical type
• Truncal hypotonia, strabismus and fast rhythms not described

57. PLA2G6-Related Dystonia-Parkinsonism
• Predominant features:
• Onset varies from childhood to young adulthood
• Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired
postural responses)
• Dystonia
• Cognitive decline
• Neuropsychiatric changes
• Initial dramatic response to dopaminergic treatment followed by the early
development of dyskinesias
Paisan Ruiz et al Ann Neurol 2008

59. Genotype-Phenotype Correlation in PLAN
• Genotype correlates with phenotype to a limited extent:
• All individuals with two null alleles of PLA2G6 have INAD.
• The less severe atypical NAD phenotype is caused exclusively by missense
mutations.

60. • Both vermian and cerebellar hemisphere atrophy is the dominant imaging finding and
is seen in up to 95% of patients with PLA2G26 mutation and typically precedes iron
deposition
• As cerebellar atrophy in this age group is not associated with other NBIA subtypes,
presence of cerebellar atrophy with or without brain iron accumulation in the proper
clinical setting is strongly suggestive of PLAG2A6 mutation .

61. Unlike PKAN, iron deposition
in basal ganglia is not associated with central T2 hyperintensity

62. •Optic atrophy associated with reduced volume of optic chiasm is seen in more than3/4
of the patients
Abnormal posterior corpus callosum is a universal finding in PLAN with a thin, simple
appearing splenium

63. ‘Apparent claval hypertrophy’ has been
proposed as an early radiological marker of
typical PLAN.
Hypertrophy of the clava, a new MRI sign in patients with
PLA2G6 mutations.
Maawali A., Yoon G., Halliday W

64. Tissue Pathology
• The pathologic hallmarks are axonal swellings & spheroid bodies in
pre-synaptic terminals in both CNS & PNS, which can be detected on
skin, conjunctiva, skin, muscle, sural nerve, or rectum biopsy.
• CNS changes more widespread as compared to PKAN
• Majority of brains also exhibit tau pathology with NFT along with
diffuse α-synuclein accumulation and numerous Lewy bodies, similar
to end-stage PD

65. (A) Note brownish discoloration of GP (arrow) contrasting to the more gray putamen
(B) H-E stain showing neuronal loss, iron accumulation and large eosinophilic spheroids (arrows).
(D) Lewy bodies (arrows) were observed in substantia nigra with H-E staining and by immunostaining
E, Synuclein +ve LBs

66. Diagnostic approach for
PLAN
• Treatment is limited to
palliation.

67. •Bilateral implantation of internal globus pallidus (GPi) and ventral intermediate
thalamic (Vim) nuclei was performed 16 days after the onset of dystonic storm
•Suspension of sedation and extubation were possible 10 days after DBS debut.
•At 9-month follow-up, she had experienced no further episodes
of status dystonicus. Oculogyric crises resolved almost completely

68. Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
•This recently described subtype of NBIA develops in response to mutations in the
fatty acid 2 hydroxylase (FA2H) gene.
•The FA2H gene product is responsible for hydroxylating fatty acids and plays a key
role in myelin production in the central nervous system and in cell cycle regulation.
•FA2H-genemutations have also been associated with leukodystrophies and
hereditary spastic paraplegia, thus leading to an overlapping clinical picture.

69. •FA2H deficiency is responsible for abnormal myelin production, resulting in profound
axonal loss and overlapping symptomatology with leukodystrophies.
•The structure and function of peripheral nerves are largely unaffected.

70. •FAHN typically begins with focal dystonia and gait impairment.
• Ataxia follows, and dysarthria and progressive spastic quadriparesis with
pyramidal tract signs develop.
•Strabismus and nystagmus may ensue, along with optic atrophy leading to
progressive loss of visual acuity.
• Intellectual performance is variable, and the intellect may be relatively
spared in some cases.
• Seizures may be observed later in the disease course and are typically
responsive to anticonvulsants.

71. MRI in FAHN
MRI:
- b/l T2 hypointensities of the GP
s/o ↑ iron,
-Severe pontocerebellar atrophy, -
mild diffuse cortical atrophy,
-Corpus Callosal thinning
- Confluent PV WM T2 HI( which
represents overlap with FA2H
associated leukodystrophy).

72. Beta-Propeller Protein-Associated Neurodegeneration (BPAN)
•Beta-propeller protein-associated neurodegeneration is unique among the NBIAs
in its mode of inheritance, its presumed pathophysiology.
•The only X-linked form of NBIA to date and a rare example of X-linked dominant
inheritance.
•Prior to the discovery of the causative gene, BPAN was described as “static
encephalopathy with neurodegeneration in childhood” (SENDA), but it has now
been named according to the established naming convention.

73. •Beta-propeller-associated neurodegeneration (BPAN) is characterized by a
stepwise regression.
•At disease onset, neuropsychiatric symptoms (autistic and affective Disorders
and developmental delay resembling atypical Rett or atypical Angelman
syndrome are core symptoms .
•In adulthood, there is sudden progression with fast deterioration with
development parkinsonism, dystonia, myoclonus, spasticity, dementia,
autonomic dysfunction, and epileptic seizures.

74. •WDR45 (also known as WIPI4) is a β -propeller scaffold protein that has been
predicted to have a role in autophagy.
•WDR45 provide a basis for protein–protein interactions and perform cellular
functions such as autophagy, cell cycle progression and transcriptional control.
Genetics & pathophysiology of BPAN

75. Perturbations throughout the pathway, from initiation of autophagosome formation to
degradation in the autolysosomes, have been suggested to be involved in neurodegenerative
diseases

76. MRI in BPAN
•Similar to the distinctive clinical presentations, BPAN also has typical radiologic
manifestations.
•Unlike PKAN and other subtypes of NBIA, earliest and maximum iron deposition
occurs in the SN compared to the globus pallidi.

77. •A unique and possibly pathognomonic
imaging appearance is bilateral,
symmetrical, linear, high-T1 signal
involving SN with a band of central T1
hypointensity .
•Iron binding to released neuromelanin
from the dying pigmented cells of the SN
pars compacta has been proposed as
explanation of the characteristic T1
hyperintensity.
•This sign has not been described in any
other CNS pathology. Similar to the PLAN,
brain atrophy is another common finding.

78. Department of Neurological Sciences, Christian Medical College,Vellore,Tamil Nadu, India
Neuropediatrics 2016;47:123–127.
This is the first genetically proven case from India

79. Treatment considerations in BPAN
•In childhood, the most challenging problem is refractory seizures, although only present
in a minority of patients.
•In adulthood, the parkinsonism can be treated successfully with dopaminergic
medications, although as mentioned, motor fluctuations and dyskinesias pose problems
and the drug benefit is not durable.
• Dopamine agonists might be predicted to have adverse neuropsychiatric effects in BPAN
where cognitive impairment is a prominent part of the phenotype

80. Mitochondrial Membrane Protein-Associated
Neurodegeneration (MPAN)
•This is relatively newly described subtype of NBIA that is caused by mutations
in the C19orf12 gene.
•This is transmitted in an autosomal recessive pattern and accounts for
approximately 5% of all NBIA.
•Mutations of C19orf12, which codes for mitochondrial protein, cause
mis-localization of the protein, inability to respond to oxidative stress
and increased mitochondrial Ca

81. •Age of onset : first decade of life varialble ( 10-30 )
•In childhood, development of a spastic gait is typically the earliest sign,
commonly accompanied by optic atrophy, learning difficulties, dysarthria, and
sometimes behavioral and psychiatric features. Dystonia, when present, tends
to be limited to the feet and hands
•In adulthood, typically manifests with cognitive and behavioral changes,
parkinsonism and mixed gait disorders.
•Generally, the disease progresses slowly, and most individuals with childhood
onset survive into their 20s or beyond

82. •As the disease progresses, lower motor neuron signs may emerge, particularly
in childhood-onset patients.
• Cognitive decline appears to be universal in MPAN
•Bowel and bladder incontinence are common;

83. • Distinctive imaging abnormality of MPAN is linear T2 hyperintensity involving the medial
medullary lamina between globus pallidus interna and externa.
•Although this imaging finding is present in about one-fifth of patients, this may discriminate
MPAN from other NBIA subtypes .
•Rarefaction of the central globus pallidus (that gives rise to eye-of-the-tiger sign) is typically
absent.
•Cortical and cerebellar atrophy are other less common manifestations

84. Pathology of MPAN
•Pathologically, MPAN is a synucleinopathy, exhibiting a remarkable burden of Lewy bodies
and Lewy neurites not only in the basal ganglia but also in the neocortex.
• Cortical Lewy body pathology in MPAN exceeds that seen in sporadic Parkinson disease by
40-fold.
• Axonal spheroids, thought to represent dying neurons, are seen both peripherally and
centrally.
a-Synuclein
spheroids

85. COASY and CoPAN
•COASY protein-associated neurodegeneration (CoPAN) joins PKAN as the second
inborn error of coenzyme A metabolism.
•CoPAN manifests in the first decade of life with gait difficulties and mild cognitive
impairment.
• Oromandibular dystonia, dysarthria, and progressive spasticity follow, along with
the appearance of an axonal neuropathy.
•The emergence of parkinsonism further adds to the disability.
• MRI demonstrates non-homogenous T2 pallidal hypointensity with a region of
medial hyperintensity that is reminiscent of the “eye of the tiger”

86. Aceruloplasminemia
• Only form of NBIA that features prominent signs of peripheral organ
involvement.
• Typical clinical triad of ACP includes diabetes mellitus, retinal
degeneration, and neurological symptoms
• Iron accumulates in retina, liver, pancreas, myocardium and brain and
leads to retinal degeneration, DM, microcytic anemia.
• The usual onset of neurologic symptoms is in 5th decade
• The most common presenting feature is cognitive decline(42%),
accompanied by craniofacial dyskinesia (28%), cerebellar ataxia (46%),
and retinal degeneration (75%).

88. Genetics & pathophysiology
• ACP results from mutation in the ceruloplasmin gene on Chr 3q.
• AR inheritance, rarely reported outside Japan
• To date, the only clearly defined physiological function of ceruloplasmin is
its ferroxidase activity thus playing an important role in mobilizing iron
from tissues
• Loss of ceruloplasmin’s ferroxidase function leads to iron accumulation
within tissues and subsequent oxidative stress.

90. • Aceruloplasminaemia, iron entering the CNS as ferrous iron might not undergo
oxidation, and cells exposed to the resulting excess ferrous iron could readily
become iron-loaded through an unregulated pathway of non-transferrin-bound iron
uptake.
• The unregulated uptake of ferrous iron coupled with an inability to export iron
could produce the marked astrocytic iron overload.
• It is possible that iron does not reach neurons, causing them to die as a result of
both iron deficiency and exposure to toxins released from nearby astrocytes that are
dying from iron overload.
• Marked astrocytic iron overload in conjunction with neuronal loss is not only in the
basal ganglia but also in the cerebrum

92. MRI & Lab findings
•Brain MRI invariably shows profound iron accumulation in
striatum, GP, SN, thalamus, dentate nuclei and cortex along with
concurrent WM hyperintensity
Lab Abnormalities: Low Sr Iron, undetectable Cp, Cu levels,
High Sr Ferritin levels
•ACP may be suspected even before the onset of neurologic
symptoms in patients with DM and microcytic anemia along with
high serum ferritin and not responding to iron supplmentation

94. Rx of ACP
• Early diagnosis is imp since iron supplements should be avoided in the Rx of
hypochromic anemia because it may worsen neurological symptoms
• Most initial attempts to purge brain & body iron with deferoxamine have
proved unsuccessful, possibly because the iron burden in these individuals
favors the Fe2+ state in the absence of normal ferroxidase activity.
• FFP , Deferoxamine: improvement in ataxia, choreoathetosis
• Neurological improvements have also been reported after administration of
oral zinc sulfate and the iron chelator, deferasirox

95. Neuroferritinopathy
• Adult onset disorder, mean age of onset-39 yrs
• Phenotype varies with type of mutation and individuals with
identical mutations may differ substantially.
• The predominant clinical phenotype is an extrapyramidal disorder
in absence of major cognitive/psychiatric abnormalities early in the
disease, thus distinguishing it from HD.
• The most common movement disorder on presentation is chorea
(50%), f/b focal dystonia (43 %) and parkinsonism (7.5%).

96. Neuroferritinopathy
• Oromandibular dystonia & dysarthrophonia fairly common.
• Characteristic facial appearance, with an action-specific focal dystonia
leading to contraction of frontalis and platysma during speech
• Cerebellar ataxia, action tremor, and dementia described in Japanese,
French/Canadian kindreds
• The lack of associated ophthalmologic features can be helpful in
distinguishing neuroferritinopathy from other forms of NBIA.

97. Genetics of Neuroferritinopathy
• Mutations in the FTL gene on Chr 19q
• Differs from other disorders discussed here, as its inheritance is
autosomal dominant.
• Ferritin: hollow shell composed of a polymer of FTL & FTH, its
main function being sequestration & storage of metabolically
inert iron
• Sr Ferritin levels are usually low
• Mutations extend the C-terminus of FTL, disrupting the
dodecahedron structure of ferritin interfering with its ability to
transport iron

98. The proteinaceous ferritin shell is porous in neuroferritinopathy
LC
HC

99. Pathophysiology
• The primary cause of neuropathological changes is ↓ iron storage capacity of the
structurally changed ferritin and subsequent free iron release
• Chronic deposition of iron → oxidative stress, causing membrane & mitochondrial
damage → apoptotic cell death.
• Contrary to the original report from northern England, ferritin inclusions were found
also in the skin,muscle, kidney and liver.
• This implies that hereditary ferritinopathy rather than neuroferritinopathy may be a
more appropriate designation.

101. MRI Picture in Neuroferritinopathy
• Early disease: patchy T2 hypointensity of the
caudate nucleus, GP, putamen, thalamus, and
dentate nuclei occurs.
• Over time, T2 hyperintense lesions may evolve
and lead to a cavitary appearance.
• This probably represents tissue edema and
correlates with fluid-filled cysts found in the
globus pallidus at autopsy.

102. Affected neurons show pathognomonic distorted, enlarged, and vacuolated nuclei, most
prominently in the putamen.
Cavitary lesion Markedly vacuolated nuclei

104. Kufor-Rakeb syndrome
• KRD is a rare, autosomal recessive neurodegenerative disease originally
described in a Jordanian family from the village of Kufor-Rakeb.
• The typical clinical phenotype of KRD includes levodopa-responsive
Parkinsonism associated with pyramidal signs in adolescent patients.
• Oculogyric crisis, facial-faucial-finger minimyoclonus, autonomic
dysfunctions, and episodes of psychosis with frank visual hallucinations
may be present
104

105. GENETICS & PATHOPHYSIOLOGY
•Chromosome 1 , AR inheritance
•Homo/heterozygous mutations in ATP13A2 gene
•ATP13A2 is a transmembrane type protein present in lysosomal membrane
•degradation of substrates, processing of lysosomal enzymes and autophagosomes
clearance
The downregulation of ATP13A2 results in cell death and α- synuclein accumulation.

107. • Brain MRI in KRD reveals gen cortical/subcortical atrophy and
hypointensities of the caudate and putamen on T2 sequences
compatible with augmented iron deposition.

108. Woodhouse-Sakati Syndrome (WSS)
• WSS is a rare, autosomal recessive disorder c2orf37 gene mutation characterized by
• progressive dystonia with or without choreoathetosis.
• Pyramidal symptoms are not typical.
• Cognitive decline is a typical feature and can be progressive.
• In addition to the neurological manifestations, characteristic phenotypic abnormalities
including
• Dysmorphic facial appearance,
• Alopecia, polyendocrinopathies (diabetes mellitus, hypogonadism), sensorineural
hearing loss, and
• specific electrocardiogram abnormality (flat T wave).

112. Management of NBIA
•Currently there are no disease-modifying treatments for any form of
neurodegeneration with brain iron accumulation .
•Treatment options remain supportive and palliative.
•Multidisciplinary approach with close collaboration between health care
professionals is needed.
This includes:
•Neurologic management of extrapyramidal and pyramidal disorders, seizures, and
sleep disturbance; neuropsychiatric symptoms;
•Pain management & management of
•GIT issues such as constipation, , swallowing difficulties; nutritional status;
Appropriate orthopedic management of secondary complications .

113. •Baclofen may be suitable for patients predominantly with spasticity.
• For dystonia, first-line medications include trihexyphenidyl, as well as baclofen and
benzodiazepines.
•For more resistant dystonia, adjunct therapy with gabapentin, L-dopa, clonidine,
and some antiepileptic drugs (sodium valproate, carbamazepine) may be considered.
• If conservative approaches fail, focal botulinum toxin
Injections,Intrathecal/intraventricular baclofen,
Deepbrain stimulation (DBS), or other surgical options (e.g., surgical release of
contractures, thalamotomy) may be possible management options

114. New Advances in the Diagnosis and Treatment of NBIA
Advances in Diagnostic Techniques
Magnetic Resonance Imaging Techniques for Better Detection of Iron
•MRI scan of the brain is a first-line diagnostic investigation for NBIA,
•Advances in MR techniques improve early recognition and diagnosis
The increasing availability of 3T MRI, as well as refined T2-weighted
imaging/gradient echo sequences and SWI have all improved MR sensitivity for
iron detection.
• Newer Quantitative MRI techniques which measure an
Iron by an indirect way have been used more in the research arena, than in

115. Improved Genetic Diagnosis
• Sanger sequencing remains the “gold standard” investigation for genetic
confirmation of NBIA, it has limitations, that it cannot routinely, deeply intronic
mutations, or heterozygous deletions and duplications.
•Multiplex ligation-dependent probe amplification ( multiplex PCR ) has enhanced
routine diagnosis, increasing mutation pickup rates through detection of pathogenic
copy number variants.
•Newer technologies such as exome and genome sequencing will increase diagnosis
in NBIA as more clinical overlap between the different NBIA disorders observed
•There may be a role for next-generation platform multiple gene panels,
simultaneously testing several NBIA genes in a single individual.

116. Novel Therapeutic Strategies
Small Molecule-Based Therapies
Iron Chelation
•Desferrioxamine, Deferiprone is an has been used to reduce systemic iron overload
• The use of iron chelation in NBIA remains controversial for several reasons as iron
accumulation observed in most NBIAs is the cause or effect
•Treatment with iron chelation does not, therefore, address the underlying root cause of
disease.
•To date, there are limited data on the use of deferiprone in NBIA.
• Deferiprone (alone or in combination with other treatments such as intrathecal baclofen) has
been shown to improve dystonia and gait disturbance in individual Cases.

118. To specifically address this important question, there is currently an ongoing
randomized, double-blinded, placebo control trial named
Treat Iron-Related Childhood-Onset Neurodegeneration
that aims to study the tolerability and efficacy of deferiprone in patients with
PKAN

119. Vitamin B5 (Pantothenate) and B5 Derivatives for Pantothenate
Kinase–Associated Neurodegeneration (PKAN )
•In animal models of PKAN
, there have been some promising results with molecules
such as pantetheine that
bypass the pantothenate kinase 2 gene enzyme in the CoA
Pathway.
•To date, there have been no trials in
humans, but it is postulated that in patients with milder
Disease with residual enzyme function could be benefitted.
• Currently, there is ongoing research and
pharmaceutical interest in investigating the therapeutic efficacy
of different B5 metabolites in PKAN.

120. Polyunsaturated Fatty Acids ( PUFA s) and Docosahexaenoic Acid
•Omega-3 and omega-6 PUFAs are thought to be important for several physiological
processes, including myelin formation, neurotransmission, and anti-inflammatory
cascades.
• The most abundant omega-3 PUFA in the brain is docosahexaenoic acid (DHA).
• In the PLA2G6 murine model, brain DHA is thought to be reduced, and it is
postulated that this may contribute to the neurologic phenotype seen in this mouse
model
•It has therefore been postulated that dietary n-3 PUFA supplementation (cod liver
oil) should be considered in neurologic disorders including PLAN

121. Gene Therapy
•Gene therapy would is an attractive option for medically intractable life-limiting
NBIA disorders, but,
•To date, the lack of robust murine models, which accurately recapitulate the human
phenotype, has limited preclinical proof-of-concept animal studies.
•Gene therapy strategies for infantile neuroaxonal dystrophy are currently being
explored
Update in Neurodegeneration with Brain Iron Accumulation: Advances in
Molecular Diagnosis and Treatment Strategies, J Pediatr Neurol 2015;13:155–167.
Stem Cells
• It is currently unclear whether stem cells may have a therapeutic role in NBIA .

122. Deep Brain Stimulation
•Deep brain stimulation (DBS) has been undertaken in some patients with NBIA, and
mainly in PKAN with intractable dystonia.
• Initial motor improvements post-DBS insertion are described in some PKAN patients, but
these tend to be early, during first few months after surgery, with few patients reporting
sustained clinical improvement in the long-term.
• Lumsden et al recommend insertion of DBS during initial stages of the disease (within
the first 5 year) as both in primary and secondary dystonias, positive outcome was
correlated with early DBS intervention.
•Overall it appears that DBS is generally a safe and well-tolerated procedure it may be a
reasonable option for the palliation of severe pharmacoresistant dystonia.

124. THANK YOU