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

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
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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    • "PKAN is inherited as an autosomal recessive genetic condition. Two distinct manifestations of the disease are observed: (i) classic PKAN patients have more rapid progression of symptoms within the first 10 years of life and typically do not survive past age 20, and (ii) atypical PKAN does not present symptoms until the second or third decade of life with disease progression occurring much slower than the classic PKAN [15]. Several PANK2 mutations result in a frame shift or premature "
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    ABSTRACT: Coenzyme A (CoA) is a ubiquitous cofactor involved in numerous essential biochemical transformations, and along with its thioesters is a key regulator of intermediary metabolism. Pantothenate (vitamin B5) phosphorylation by pantothenate kinase (PanK) is thought to control the rate of CoA production. Pantothenate kinase associated neurodegeneration is a hereditary disease that arises from mutations that inactivate the human PANK2 gene. Aryl phosphoramidate phosphopantothenate derivatives were prepared to test the feasibility of using phosphopantothenate replacement therapy to bypass the genetic deficiency in the Pank1(-/-) mouse model. The efficacies of candidate compounds were first compared by measuring the ability to increase CoA levels in Pank1(-/-) mouse embryo fibroblasts. Administration of selected candidate compounds to Pank1(-/-) mice corrected their deficiency in hepatic CoA. The PanK bypass was confirmed by the incorporation of intact phosphopantothenate into CoA using triple-isotopically labeled compound. These results provide strong support for PanK as a master regulator of intracellular CoA and illustrate the feasibility of employing PanK bypass therapy to restore CoA levels in genetically deficient mice.
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    • "Most cases were found to have a mutation of the PANK2 gene and can now be classified under the most recent designation of bpantothenate kinaseassociated neurodegenerationQ (PKAN, MIM 234200). A minority of cases, however, do not carry a mutation of this gene [30]. PANK2, the gene for pantothenate kinase 2, encodes a key regulatory enzyme in the biosynthesis of coenzyme A from pantothenate (vitamin B5). "

    Full-text · Dataset · Nov 2015
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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.
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