neurodegeneration due to braiin iron accumulation

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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

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

5. 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

6. --- 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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.

14. 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

15. Treatment Similar to PLAN

16. 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

17. 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

18. 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

19. 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.

20. 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

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

22. 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

23. 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”

24. 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

25. PKAN vs NFT

26. 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

27. 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

28. 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 c erebral, 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 .

29. 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.

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