eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Hallervorden-Spatz Disease: Differential Diagnoses & Workup

Author: Philip A Hanna, MD, Associate Professor, Department of Neuroscience, Seton Hall University School of Graduate Medical Education; Residency Program Director, New Jersey Neuroscience Institute, JFK Medical Center; Neurology Director, Huntington's Disease Unit, JFK Hartwyck-Cedarbrook
Coauthor(s): Brian L Gerhardstein, MD, PhD, Staff Physician, Department of Neurology, New Jersey Neuroscience Institute, JFK Medical Center; Neeta Garg, MD, DM, Assistant Professor, Department of Neurology, State University of New York at Buffalo
Contributor Information and Disclosures

Updated: Dec 1, 2009

Differential Diagnoses

Huntington Disease
Neuroacanthocytosis
Neuronal Ceroid Lipofuscinoses
Wilson Disease

Other Problems to Be Considered

The differential diagnosis includes other diseases presenting with extrapyramidal-pyramidal-dementia complex.

Wilson disease usually presents with tremors, rigidity, dementia, and pseudobulbar features and has an autosomal recessive mode of inheritance. Slit-lamp examination of the eye may reveal a Kayser-Fleischer ring. MRI exhibits the characteristic changes consisting of high-intensity lesions in the basal ganglia, thalami, and mid brain. The normal low intensity of red nuclei and SN surrounded by abnormal high signal intensity in the tegmentum of mid brain gives rise to the typical "face-of-the-giant panda" sign. Serum ceruloplasmin and copper studies are usually abnormal and help confirm the diagnosis. Neurological symptoms are reversible if treated early with copper chelation therapy; hence, early diagnosis is important.

The juvenile form of Huntington disease may be confused with HSD. Patients with the juvenile form of Huntington disease can have a predominantly akinetic-rigid syndrome (ie, Westphal variant). The differentiating features include autosomal dominant mode of inheritance and presence of caudate atrophy on MRI.

Juvenile neuronal ceroid lipofuscinosis may be difficult to distinguish from HSD. It is an inherited disorder characterized by storage of ceroid and lipofuscin in neuronal and other tissues. The symptoms start in early childhood with vision loss, retinitis pigmentosa, dementia, rigidity, and dystonia. In contrast to the infantile and late-infantile forms of the disease, generalized tonic-clonic seizures and myoclonic seizures are not very common. The diagnosis can be made on the basis of clinical presentation, electrophysiologic studies, and skin biopsy findings. The electroretinogram reveals markedly reduced amplitude, and visual and somatosensory evoked responses are increased. The characteristic fingerprint inclusion bodies are identified easily in eccrine sweat glands and in circulating lymphocytes.

Machado-Joseph disease is inherited as an autosomal dominant trait, and the clinical disease usually has its onset when the individual is older than 20 years. Ataxia and other signs of spinocerebellar dysfunction are predominant. Some affected children may have extrapyramidal features, but prominent ataxia and the inheritance pattern should help differentiate Machado-Joseph disease from HSD.

Neuroacanthocytosis is characterized by onset of prominent orofacial dyskinesia, chorea, dystonia, and cognitive changes in the third or fourth decade. Other features include self-mutilation, peripheral neuropathy, and seizures. Recognition of acanthocytes (red blood cells with irregular spine on the cell surface) in the peripheral smear can lead to the diagnosis. HARP syndrome, which is characterized by hypoprebetalipoproteinemia, acanthocytes, retinitis pigmentosa, and pallidal degeneration, is another form of neuroacanthocytosis. Clinically it presents with dyskinesias, dystonia, and progressive dementia. The lipoprotein electrophoresis reveals absence of prebeta fraction, and MRI exhibits hypointense signal intensities in the globus pallidus.

Rare metabolic disorders such as GM1 and GM2 gangliosidoses in children sometimes can have features similar to HSD, but they have other clinical features and lab abnormalities and are differentiated readily.

Workup

Laboratory Studies

  • No biochemical markers have been found in HSD.
  • Levels of copper, ceruloplasmin, lipids, amino acids, and acanthocytes typically are measured in the blood to exclude other conditions.
  • Radionuclide scan reveals increased uptake of iron by the basal ganglia.15
  • Cultured skin fibroblasts have been reported to accumulate iron 59Fe transferrin, but the isotope is no longer available for human use.
  • Increased platelet monoamine oxidase B activity has been reported.16
  • Bone marrow histiocytes and peripheral lymphocytes may demonstrate the presence of abnormal cytosomes including fingerprint, granular, and multilaminated bodies.17,18 The characteristics of the material suggest the presence of ceroid lipofuscin.

Imaging Studies

  • CT imaging is not very helpful but may exhibit hypodensity in the basal ganglia and some atrophy of the brain. Calcification in the basal ganglia in the absence of any atrophy also has been described.
  • MRI has increased the likelihood of antemortem diagnosis of HSD.19,20,21
    • The image below depicts typical MRI appearance is of bilaterally symmetric hyperintense signal changes in anterior medial globus pallidus with surrounding hypointensity in the globus pallidus on T2-weighted images. These imaging features are fairly diagnostic of HSD and have been termed the eye-of-the-tiger sign.22

    • MRI has increased the likelihood of antemortem di...

      MRI has increased the likelihood of antemortem diagnosis of Hallervorden-Spatz (HSD) disease. The typical MRI appearance is of bilaterally symmetric hyperintense signal changes in anterior medial globus pallidus with surrounding hypointensity in the globus pallidus on T2-weighted images. These imaging features are fairly diagnostic of HSD and have been termed the "eye-of-the-tiger" sign. The hyperintensity represents pathologic changes including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is due to loss of signal secondary to iron deposition.

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      MRI has increased the likelihood of antemortem di...

      MRI has increased the likelihood of antemortem diagnosis of Hallervorden-Spatz (HSD) disease. The typical MRI appearance is of bilaterally symmetric hyperintense signal changes in anterior medial globus pallidus with surrounding hypointensity in the globus pallidus on T2-weighted images. These imaging features are fairly diagnostic of HSD and have been termed the "eye-of-the-tiger" sign. The hyperintensity represents pathologic changes including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is due to loss of signal secondary to iron deposition.

    • A study by McNeill et al concluded that in most cases, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2 and T2 fast spin echo brain MRI.21
    • The hyperintensity represents pathologic changes including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is due to loss of signal secondary to iron deposition.
  • Iodine 123 (123 I)-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) and (123 I)-iodobenzamide (IBZM)-SPECT also have been used in making the diagnosis of HSD.23

Histologic Findings

See the microscopic description in Pathophysiology.

More on Hallervorden-Spatz Disease

Overview: Hallervorden-Spatz Disease
Differential Diagnoses & Workup: Hallervorden-Spatz Disease
Treatment & Medication: Hallervorden-Spatz Disease
Follow-up: Hallervorden-Spatz Disease
Multimedia: Hallervorden-Spatz Disease
References
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References

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  2. Taylor TD, Litt M, Kramer P, et al. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat Genet. Dec 1996;14(4):479-81. [Medline].

  3. Zhou B, Westaway SK, Levinson B, et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden- Spatz syndrome. Nat Genet. Aug 2001;28(4):345-9. [Medline].

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  16. Zimmerman AW, Stover ML, Grasso JA, et al. Uptake of 59Fe by skin fibroblasts and MAO activity in platelets from patients with Hallervorden-Spatz syndrome. Neurology. 1981;51:48.

  17. Swaiman KF, Smith SA, Trock GL, et al. Sea-blue histiocytes, lymphocytic cytosomes, movement disorder and 59Fe- uptake in basal ganglia: Hallervorden-Spatz disease or ceroid storage disease with abnormal isotope scan?. Neurology. Mar 1983;33(3):301-5. [Medline].

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  33. Wakabayashi K, Fukushima T, Koide R, et al. Juvenile-onset generalized neuroaxonal dystrophy (Hallervorden-Spatz disease) with diffuse neurofibrillary and lewy body pathology. Acta Neuropathol (Berl). Mar 2000;99(3):331-6. [Medline].

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Further Reading

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Keywords

HSD, neurodegeneration with brain iron accumulation type 1, NBIA-1, Hallervorden-Spatz disease, progressive extrapyramidal dysfunction, dementia, PANK2 gene, pantothenate kinase-associated neurodegeneration, PKAN

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Contributor Information and Disclosures

Author

Philip A Hanna, MD, Associate Professor, Department of Neuroscience, Seton Hall University School of Graduate Medical Education; Residency Program Director, New Jersey Neuroscience Institute, JFK Medical Center; Neurology Director, Huntington's Disease Unit, JFK Hartwyck-Cedarbrook
Philip A Hanna, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and Movement Disorders Society
Disclosure: Nothing to disclose.

Coauthor(s)

Brian L Gerhardstein, MD, PhD, Staff Physician, Department of Neurology, New Jersey Neuroscience Institute, JFK Medical Center
Disclosure: Nothing to disclose.

Neeta Garg, MD, DM, Assistant Professor, Department of Neurology, State University of New York at Buffalo
Neeta Garg, MD, DM is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Medical Editor

Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Nestor Galvez-Jimenez, MD, MSc, MHA, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

 
 
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