Genetic, Clinical, and Radiographic Delineation of Hallervorden-Spatz Syndrome

Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, OR 97201-3098, USA.
New England Journal of Medicine (Impact Factor: 55.87). 02/2003; 348(1):33-40. DOI: 10.1056/NEJMoa020817
Source: PubMed


Hallervorden-Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding pantothenate kinase 2 (PANK2); these patients are said to have pantothenate kinase-associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden-Spatz syndrome with and without mutations in PANK2.
One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations.
All patients with classic Hallervorden-Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease led to amino acid changes, those in patients with classic disease more often resulted in predicted protein truncation. Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with atypical disease. In all patients with pantothenate kinase-associated neurodegeneration, whether classic or atypical, T2-weighted magnetic resonance imaging (MRI) of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus. This pattern was not seen in any patients without mutations.
PANK2 mutations are associated with all cases of classic Hallervorden-Spatz syndrome and one third of cases of atypical disease. A specific MRI pattern distinguishes patients with PANK2 mutations. Predicted levels of pantothenate kinase 2 protein correlate with the severity of disease.

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Available from: Bing Zhou, Jun 12, 2014
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    • "The most common form of NBIA seems to be pantothenate-kinase-associated neurodegeneration (PKAN), accounting for 35–50% of NBIA cases [2]. The worldwide prevalence of PKAN has been estimated at a ratio of 1 : 1.000.000 "
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    ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) is a collective term to indicate a group of neurodegenerative diseases presenting accumulation of iron in the basal ganglia. These disorders can result in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Onset age ranges from infancy to late adulthood and the rate of progression is very variable. So far, the genetic bases of nine types of NBIA have been identified, pantothenate-kinase-associated neurodegeneration (PKAN) being the most frequent type. The brain MRI “eye-of-the-tiger” sign, T2-weighted hypointense signal in the globus pallidus with a central region of hyperintensity, has been considered virtually pathognomonic for PKAN but recently several reports have denied this. A significant percentage of individuals with clinical and radiographic evidence of NBIA do not have an alternate diagnosis or mutation of one of the nine known NBIA-associated genes (idiopathic NBIA). Here we present an adult-onset case of “undiagnosed” NBIA with the brain MRI “eye-of-the-tiger” sign, and with psychotic symptoms which were successfully treated with antipsychotic and mood stabilizer medications. Here, the term “undiagnosed” is used because the patient has not been screened for all known NBIA genes, but only for two of them.
    05/2014; 2014(Article ID 742042):3 pages. DOI:10.1155/2014/742042
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    • "The MRI analysis is a fundamental step in the diagnostic process given that the vast majority of the patients show a specific pattern defined as " eye of the tiger " at T2-weighted MR images. It corresponds to bilateral areas of hypointensity in the medial GP with central spots of hyperintensity (Hayflick et al., 2003). The area of reduced signal is due to iron accumulation in the tissue, as confirmed by the histology (Kruer et al., 2011), whereas the central hyperintense signal may be linked to the dramatic rarefaction of the tissue and the microglial activation (Sethi et al., 1988; Kruer et al., 2011). "
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    ABSTRACT: Perturbation of iron distribution is observed in many neurodegenerative disorders, including Alzheimer's and Parkinson's disease, but the comprehension of the metal role in the development and progression of such disorders is still very limited. The combination of more powerful brain imaging techniques and faster genomic DNA sequencing procedures has allowed the description of a set of genetic disorders characterized by a constant and often early accumulation of iron in specific brain regions and the identification of the associated genes; these disorders are now collectively included in the category of neurodegeneration with brain iron accumulation (NBIA). So far 10 different genetic forms have been described but this number is likely to increase in short time. Two forms are linked to mutations in genes directly involved in iron metabolism: neuroferritinopathy, associated to mutations in the FTL gene and aceruloplasminemia, where the ceruloplasmin gene product is defective. In the other forms the connection with iron metabolism is not evident at all and the genetic data let infer the involvement of other pathways: Pank2, Pla2G6, C19orf12, COASY, and FA2H genes seem to be related to lipid metabolism and to mitochondria functioning, WDR45 and ATP13A2 genes are implicated in lysosomal and autophagosome activity, while the C2orf37 gene encodes a nucleolar protein of unknown function. There is much hope in the scientific community that the study of the NBIA forms may provide important insight as to the link between brain iron metabolism and neurodegenerative mechanisms and eventually pave the way for new therapeutic avenues also for the more common neurodegenerative disorders. In this work, we will review the most recent findings in the molecular mechanisms underlining the most common forms of NBIA and analyze their possible link with brain iron metabolism.
    Frontiers in Pharmacology 05/2014; 5:99. DOI:10.3389/fphar.2014.00099 · 3.80 Impact Factor
    • "More recent work on PKAN has been elegant and impressive, particularly studies from the laboratory of Susan Hayflick, where the gene was located to chromosome 20p (Taylor et al., 1996) and the term 'neurodegeneration with brain iron accumulation type 1' (NBIA1) was proposed. When mutations were identified in PANK2 the term PKAN was suggested instead (Zhou et al., 2001) and this was quickly followed by comprehensive paper delineating the clinical, radiological and imaging findings in a series of genetically characterized patients (Hayflick et al., 2003). PKAN turns out to be one of a family of NBIAs and has led to an emergence of studies aimed at elucidating the molecular pathogenesis of brain iron accumulation (Rouault, 2013). "
    Brain 01/2014; 137(Pt 1):8-11. DOI:10.1093/brain/awt351 · 9.20 Impact Factor
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