Clinical spectrum of NBIA, newer insights and management

Dr. Raghu ram Dept of neurology NIMS, Hyderabad

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.

• 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

Holotransferrin = Transferrin + 2 ferric ions

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

Iron entry into CNS

FPN--

TFRC

Iron metabolism in the brain

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).

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

•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

•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

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)

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

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.

[Hugo Spatz 1888-1969]

• 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’

• 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

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

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

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.

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.

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

video

• 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

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.

HARP syndrome

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

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.

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.

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

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

•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.

D/d s of ‘Eye of theTiger’ Sign

• Organic Acidurias

• Leigh’s disease

• MSA, CBD

• Neurofibromatosis

• SCA 3

• Multiple sclerosisKumar N et al: The “eye-of-the-tiger” sign is not pathognomonic of the PANK2 mutation. Arch Neurol 63: 292-293, 2006

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

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

• 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

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

• 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.

• 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.

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

• 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

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

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)

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

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.

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

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

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.

• 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 .

Unlike PKAN, iron depositionin basal ganglia is not associated with central T2 hyperintensity

• 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

‘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

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

(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

Diagnostic approach for PLAN

• Treatment is limited to palliation.

•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 episodesof status dystonicus. Oculogyric crises resolved almost completely

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.

•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.

•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.

•The disorder is similar in many ways to PLAN, except that neither the

peripheral neuropathy nor the profound axial hypotonia observed in PLAN

is a feature.

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).

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.

•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.

•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

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

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.

•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.

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

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

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

•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

•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;

• 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

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-Synucleinspheroids

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”

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%).

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.

• 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

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

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

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%).

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.

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

The proteinaceous ferritin shell is porous in neuroferritinopathy

LC

HC

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.

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.

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

Cavitary lesion Markedly vacuolated nuclei

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

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 clearanceThe downregulation of ATP13A2 results in cell death and α- synuclein accumulation.

• Brain MRI in KRD reveals gen cortical/subcortical atrophy and

hypointensities of the caudate and putamen on T2 sequences

compatible with augmented iron deposition.

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).

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 .

•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

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

clinical practice .

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.

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.

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

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.

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

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 .

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.

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