Hallervorden Spatz Disease

Pantothenate Kinase-Associated Neurodegeneration (PKAN)

1. Hallervorden Spatz Disease Ade Wijaya, MD – January 2019

2. Introduction F irst described in 1922 by two German physicians, Hallervorden and Spatz Pantothenate kinase-associated neurodegeneration ( PKAN ) A rare autosomal recessive neurodegenerative disorder A ssociated with iron accumulation in the brain nuclei   ( globus pallidus and pars reticularis of substantia nigra) C haracterized by progressive extrapyramidal dysfunction and dementia

3. Etiopathogenesis The exact etiology of PKAN is not well understood One of the proposed hypothesis is that aberrant oxidation of lipofuscin to neuromelanin and insufficient cysteine dioxygenase leading to abnormal iron accumulation in the brain A role for mutation in the  PANK2  gene (band 20p13) accounts for most inherited  PKAN cases Mutations result in an autosomal recessive inborn error of coenzyme A metabolism with resultant deficiency of pantothenate kinase enzyme which may lead to accumulation of cysteine and cysteine-containing compounds in the basal ganglia This causes chelation of iron in the globus pallidus and other basal ganglia and rapid auto-oxidation of cysteine in the presence of iron with subsequent free radical production

4. Pathology R ust-brown discoloration of the globus pallidus and substantia nigra pars reticularis due to underlying iron deposition and a reduction in the size of these nuclei . Generalized atrophy of the brain parenchyma Microscopically: - Ubiquitinated spheroids, which represent swollen axons with vacuolated cytoplasm inactivated by attachment of ubiquitin, are found most abundantly in the pallidonigral system and in the cerebral cortex. - Accumulation of  iron-containing pigment mostly neuromelanin and ceroid lipofuscin in the palladonigral system

5. Epidemiology Prevalence of PKAN is 1-9/1000000  The classic presentation is in the late part of the first decade or the early part of the second decade, between ages 7 and 15 years   The disease onset has been reported in all age groups including infancy and adulthood

6. Clinical features Extrapyramidal symptoms: Dystonia , dysarthria, muscular rigidity, spasms, Parkinson-like symptoms. Dystonia  (continuous spasms and muscle contractions)- A prominent and early feature Tremors, rarely bradykinesia (slowness of movement) and Choreoathetosis(involuntary movements in along with chorea(irregular migrating contractions) and athetosis (twisting and writhing) Significant speech disturbances - Can occur early Dysphagia - A common symptom; caused by rigidity of muscles and  associated corticobulbar abnormality Dementia - Present in most patients  with PKAN Visual impairment - Consequence of optic atrophy or retinal degeneration; can be the presenting symptom of the disease, although this is rare Seizures - Have been reported frequently Akathesis- (feeling of internal motor restlessness that can present as tension, nervousness, or anxiety) Neuropsychiatric dysfunction Optic atrophy Retinal degeneration

7. Obligate features Onset in the first two decades of life Progression of signs and symptoms; classic form: loss of ambulation occurring within 10-15 years of onset, atypical form: ambulatory loss occurs within 15-40 years of disease onset. Evidence of extrapyramidal dysfunction, including one or more of these neurological impairments: dystonia, rigidity, choreoathetosis.

8. Corroborative features Corticospinal tract involvement: spasticity, hyperreflexia, and extensor toe signs Progressive intellectual deterioration Retinitis pigmentosa and/or optic atrophy (seen with electroretinogram or visual field testing) Seizures Family history consistent with autosomal recessive inheritance( may include consanguinity) Hypointense areas on magnetic resonance imaging (MRI) in  the involved  basal ganglia Abnormal cytosomes in circulating lymphocytes Red blood cell acanthocytosis

9. Evaluation CT -   Hypodensity/calcification in the basal ganglia and some atrophy of the brain   MRI - T2 hypointensity reflecting areas of iron deposition, mainly in globi pallidi,  pars reticulata of the substantia nigra, and red nuclei . In PANK2 mutation: "eye of the tiger" on brain MRI, which is evident as bilateral symmetrical, central foci of hyperintense signals  in the anteromedial globus pallidus, with surrounding zone of  hypointensity in the globus pallidus on T2W MR scanning due to gliosis or vacuolization SWI/T2* Show susceptibility artifact (blooming low signal) in corresponding areas due to iron accretion . MR spectroscopy shows decreased NAA peak due to neuronal loss and may depict increased myoinositol.  SPECT Scanning Antenatal diagnosis

10. management M ostly symptomatic The tremors best respond to dopaminergic agents For rigidity and spasticity, dopamine agonists and anticholinergic agent alone or in combination Intrathecal or oral Baclofen in moderate doses relieves the stiffness and spasms and can reduce dystonia Intramuscular botulinum toxin has also been used for the alleviation of hypertonicity   Benzodiazepines have been used for choreoathetotic movements Medications such as methscopolamine bromide can be attempted for excessive drooling Multidisciplinary approach

11. Summary A rare autosomal recessive neurodegenerative disorder Associated with iron accumulation in the brain nuclei   Characterized by progressive extrapyramidal dysfunction and dementia . Mutation in the  PANK2   gene  MRI: eye of the tiger