Users Online: 863
Home Print this page Email this page
Home About us Editorial board Search Browse articles Submit article Ahead of Print Instructions Subscribe Contacts Login 


 
Previous article Browse articles Next article 
CASE REPORT
Adv Biomed Res 2014,  3:191

Hallervorden-Spatz disease


Department of Neurology, Shahid Sadooghi Hospital, Isfahan, Iran

Date of Submission19-Jun-2012
Date of Acceptance01-May-2013
Date of Web Publication12-Sep-2014

Correspondence Address:
Maseumeh Dashti
Department of Neurology, Shahid Sadooghi Hospital, Isfahan
Iran
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2277-9175.140623

Rights and Permissions
  Abstract 

Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Hallervorden and Spatz first described the disease, in 1922 as a form of familial brain degeneration characterized by iron deposition in the brain. Here we present four HSD cases with different clinical pictures.

Keywords: Extra pyramdal sign, Hallervorden-Spatz Disease, dystonia, dementia


How to cite this article:
Dashti M, Chitsaz A. Hallervorden-Spatz disease . Adv Biomed Res 2014;3:191

How to cite this URL:
Dashti M, Chitsaz A. Hallervorden-Spatz disease . Adv Biomed Res [serial online] 2014 [cited 2019 Nov 17];3:191. Available from: http://www.advbiores.net/text.asp?2014/3/1/191/140623


  Introduction Top


Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Hallervorden and Spatz first described the disease, in 1922 as a form of familial brain degeneration characterized by iron deposition in the brain. The term neurodegeneration with brain iron accumulation type 1, instead of HSD, eventually came to be used for this condition; [1] although, the most recent term for the disorder is pantothenate kinase (PANK2)- associated neurodegeneration. [2]

Onset most commonly occurs in late childhood or early adolescence. The classic presentation is in the late part of the first decade or the early part of the second decade, when the individual is between ages 7 years and 15 years. However, the disease has been reported in infancy, and cases with adult onset have been described as well. [3],[4],[5]

HSD is relentlessly progressive. The course is characterized by progressive dementia, corticospinal signs (e.g., spasticity, hyper-reflexia), and extrapyramidal signs, including rigidity, dystonia, and choreoathetosis. The course of the disease usually proceeds over 10-12 years and affected individuals typically die in the second or third decade, but case reports describe patients surviving 30 years. [6],[7]

The disease can be familial or sporadic. When familial, HSD is inherited recessively; it has been linked to chromosome 20. [8] A mutation in the PANK2 gene on band 20p13 has been described in patients with typical HSD. [9]


  Case Reports Top


Case 1

A 19-year-old girl was relatively asymptomatic until the age of 15 years when she started developing dysphagia, dysarthria, and dysphonia. These abnormalities progressed over 4 years with anarthria, severe dysphagia and abnormal movement of tongue [Video 1].



There is no impairment of higher cortical functions. No visual abnormalities were detected. No significant family history was obtained. Neurological examination revealed sever slurred speech; sever tongue dystonia, mild bilateral rigidity on lower limbs, hyperreflexia, and auto babinski. Laboratory investigations including serum copper and ceruloplasmin levels were normal. Magnetic resonance imaging (MRI) scan revealed small hyper intensity in the inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [Figure 1].
Figure 1: Bilateral basal ganglia hypodensity

Click here to view


Drugs: Tetrabenazine 25 BID, Ammoral Bid

Case 2

A 20-year-old girl was relatively asymptomatic until age of 14 years when she started walking on toes and unsteady gait. Gradually, she developed motor difficulties in hands, dysphagia, and dysarthria.

She has positive family history for nearly similar symptoms in her cousin. Neurological examination revealed hyper-extension in neck muscles and because of that she was unable to look downward. No visual abnormalities were detected. She had slurred speech and difficulty in chewing. Dystonia was present on both upper and lower limbs. Axial rigidity was prominent finding. She had generalized rigidity. Deep tendon reflexes were exaggerated and babinski sign was positive [Video 2].



Lab data were negative for Wilson serology. MRI scans revealed small hyper intensity in the inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [Figure 2].
Figure 2: Magnetic resonance imaging revealed small hyper intensity in inner part of both GP, surrounded by hypointense rim peripherally on T2

Click here to view


Drugs: Pimozide 4 BID, Orlept 200 BID, Triphen 2 eight, Baclofen BID

Case 3

A 34-year-old woman who presented with limb tremor and mild slurring in speech. She was asymptomatic until age 17 when she developed dysarthria and right hand tremor. Gradually, the symptom worsened and it propagated to left foot and then left hand and right foot involved too [Video 3].



Her family history was positive.

Neurological examination revealed mild dysarthria, no rigidity or spasticity was detected. She had severe asymptomatic twisting tremor in hands. In lower limbs, tremor was more severe on the left side. Serology for Wilson disease was negative. MRI scan revealed small hyper intensity in inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [Figure 3].
Figure 3: Eye-of-the-tiger sign in T2 image

Click here to view


After 5 years of disease start she had a successful pregnancy, but after that her symptoms worsened.

Drugs: Isicome 250/25 ½ QID, Gabapentine 100 BID, Triphen 2 BID, Ammoral 100 BID

Case 4

A 22-year-old man presented with dysphagia, motor difficulties, and speech problems. His symptoms started 6 years ago with mild dysphagia and unsteady gait and abnormal posture of the right hand. In a short time, his dystonia propagated to other limbs and dysphagia worsened and he developed incomprehensive speech. When After start walking, a sudden severe pain pop out in both lower limbs and by standing and short resting it get resolved fast.

Neurological examination revealed marked diffuse rigidity (both pyramidal and extra pyramidal). Tone was increased. Deep tendon reflexes were brisk. Babinski sign was positive. After seating for a short time, he was unable to maintain upright posture and bending posture is produced.

Because of severe dystonia in limbs and tongue muscles, he was unable to eat easily as you can see in movie. Serum copper and ceruloplasmin levels were normal. MRI scan revealed small hyper-intensity in inner part of both GP, surrounded by the hypo-intense rim peripherally on T2 [Figure 4].
Figure 4: Eye of tiger sign in coronal view

Click here to view


Drugs: Isicom 250/25 1/2BID, Baclofen BID, Triphen BID, Tetrabenazine 25 BID, Na Valproate 200 BID

Etiology

The exact etiology of HSD is not known. One suggestion states that abnormal peroxidation of lipofuscin to neuromelanin and deficient cysteine dioxygenase lead to abnormal iron accumulation in the brain. While portions of the globus pallidus and pars reticulata of the substantia nigra (SN) have high iron content in healthy individuals, individuals with HSD have excess amounts of iron deposited in these areas.

However, the exact role of iron in the etiology of this disease remains unknown. However, whether the deposition of iron in basal ganglia in HSD is the cause or consequence of neuronal loss and gliosis is not clear. Decreased activity of the enzyme cysteine di-oxygenase was demonstrated in 1 affected child. [10] This was postulated to lead to accumulation of cysteine in the basal ganglia, since cysteine can chelate iron and thus result in its deposition. However, these findings were not confirmed in adult patients.

A role for mutation in the PANK2 gene (band 20p13) in the etiology of HSD has been proposed. Deficiency of PANK2 may lead to accumulation of cysteine and cysteine-containing compounds in the basal ganglia. This causes chelation of iron in the globus pallidus and free radical generation as a result of rapid auto-oxidation of cysteine in the presence of iron. [11] Mutations in the PANK2 gene account for most HSD cases. Such mutations result in an autosomal recessive inborn error of coenzyme A metabolism called PANK2- associated neurodegeneration. [12],[13],[14],[15]

Pathologic evaluation reveals characteristic rust-brown discoloration of the globus pallidus and SN pars reticulata secondary to iron deposition. [16],[17]

History

Symptoms in HSD include the following:

  • Dystonia - A prominent and early feature
  • Significant speech disturbances - Can occur early
  • Dysphagia - A common symptom; caused by rigidity and corticobulbar involvement
  • Dementia - Present in most individuals with HSD
  • Visual impairment - Caused by optic atrophy or retinal degeneration; not uncommon and can be the presenting symptom of the disease, although this is rare
  • Seizures - Have been described. [16]


Clinical manifestations of HSD vary from patient to patient. The symptoms usually begin in the first decade with a motor disorder of extrapyramidal type and gait difficulty. Symptoms dominating the clinical picture include rigidity of extremities, slowness of movement, dystonia, choreoathetosis, and tremor.

In some patients, extrapyramidal dysfunction may be delayed for several years as spasticity and dysarthria may be the presenting symptoms.

Physical examination

Physical examination reveals signs consistent with extrapyramidal and corticospinal dysfunction. In addition to rigidity, dystonia, and chorea, patients may experience spasticity, brisk reflexes, and extensor plantar responses.

Based on the common clinical features, the following diagnostic criteria for HSD have been proposed. [16] All of the obligate findings and at least 2 of the corroborative findings should be present. None of the exclusionary factors should be present.

Obligate features of HSD include the following:

  • Onset during the first 2 decades of life
  • Progression of signs and symptoms
  • Evidence of extrapyramidal dysfunction, including 1 or more of the following: Dystonia, rigidity, choreoathetosis.


Corroborative features include the following:

  • Corticospinal tract involvement
  • Progressive intellectual impairment
  • Retinitis pigmentosa and/or optic atrophy
  • Seizures
  • Positive family history consistent with autosomal recessive inheritance
  • Hypo-intense areas on MRI involving the basal ganglia
  • Abnormal cytosomes in circulating lymphocytes and/or sea-blue histiocytes in bone marrow.


Diagnostic considerations

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

  • Wilson disease
  • Wilson disease
  • Juvenile form of Huntington disease
  • Juvenile neuronal ceroid lipofuscinosis
  • Machado-Joseph disease
  • Neuroacanthocytosis
  • Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration HARP syndrome.
  • GM gangliosidoses.


Approach considerations

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. [18]

Cultured skin fibroblasts have been reported to accumulate iron ( 59 Fe) transferrin, but the isotope is no longer available for human use.

Increased platelet monoamine oxidase - B activity has been reported. [19] Bone marrow histiocytes and peripheral lymphocytes may demonstrate the presence of abnormal cytosomes, including fingerprint, granular, and multilaminated bodies. [20],[21] The characteristics of the material suggest the presence of ceroid lipofuscin.

Computed tomography (CT) scanning

CT imaging is not very helpful in the diagnosis of HSD but may exhibit hypo-density 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.

Single-photon emission computed tomography (SPECT) scanning

Iodine-123 ( 123 I)-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (CIT) SPECT scanning and ( 123 I)-iodobenzamide (IBZM)-SPECT scanning also have been used in making the diagnosis of HSD. [22]

MRI

MRI has increased the likelihood of antemortem diagnosis of HSD. [23],[24],[25] The image below depicts the typical MRI appearance in HSD, revealing bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypo-intensity in the globus pallidus, on T2-weighted scanning. These imaging features are fairly diagnostic of HSD and have been termed the eye-of-the-tiger sign. [26],[27],[28]

A study by McNeill et al. concluded that in most cases of HSD, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2 and T2, fast - spin echo brain MRI. [25]

The hyper-intensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is due to the loss of signal secondary to iron deposition.

Treatment

The treatment of patients with HSD remains directed toward symptomatic findings. Tremor in patients with HSD responds best to dopaminergic agents. The anticholinergic agent benztropine helps rigidity and tremor. Benzodiazepines have been tried for choreoathetotic movements.

Hypertonia is usually a combination of rigidity and spasticity and may be difficult to treat. Dopamine agonists and anticholinergics may help to reduce rigidity. Baclofen in moderate doses relieves the stiffness and spasms and can reduce dystonia.

Symptoms such as drooling and dysarthria can be troublesome. Treat excessive drooling with a medication such as methscopolamine bromide. Dysarthria may respond to medications used for rigidity and spasticity. Speech therapy also may be useful, and computer-assisted devices may be employed in the treatment of patients with advanced cases. Gastrostomy feeding may be necessary in advanced cases of dysphagia.

A multidisciplinary team approach involving physical, occupational and speech therapists may be needed in selected patients with a protracted course to improve functional skills and communication.

Systemic chelating agents, such as desferrioxamine have been used in an attempt to remove excess iron from the brain, but these have not proved beneficial. Dementia is progressive, and no treatment has proved clearly effective.

Medication

As previously mentioned dopaminergic agents, such as levodopa and bromocriptine can produce modest improvements in dystonia. If dopaminergic agents are not effective against dystonia, anticholinergics can be used, but they offer only transient relief. Botulinum toxin injections also can improve dystonic muscles.

Agents used to relieve rigidity and spasticity may prove effective against dysarthria while methscopolamine bromide can deter excessive drooling.

 
  References Top

1.Neumann M, Adler S, Schlüter O, Kremmer E, Benecke R, Kretzschmar HA. Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. Acta Neuropathol 2000;100:568-74.  Back to cited text no. 1
    
2.Schneider SA, Hardy J, Bhatia KP. Iron accumulation in syndromes of neurodegeneration with brain iron accumulation 1 and 2: Causative or consequential? J Neurol Neurosurg Psychiatry 2009;80:589-90.  Back to cited text no. 2
    
3.Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ, Bird ED. Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology 1985;35:227-34.  Back to cited text no. 3
    
4.Grimes DA, Lang AE, Bergeron C. Late adult onset chorea with typical pathology of Hallervorden-Spatz syndrome. J Neurol Neurosurg Psychiatry 2000;69:392-5.  Back to cited text no. 4
    
5.Cooper GE, Rizzo M, Jones RD. Adult-onset Hallervorden-Spatz syndrome presenting as cortical dementia. Alzheimer Dis Assoc Disord 2000;14:120-6.  Back to cited text no. 5
    
6.Saito Y, Kawai M, Inoue K, Sasaki R, Arai H, Nanba E, et al. Widespread expression of alpha-synuclein and tau immunoreactivity in Hallervorden-Spatz syndrome with protracted clinical course. J Neurol Sci 2000;177:48-59.  Back to cited text no. 6
    
7.Hickman SJ, Ward NS, Surtees RA, Stevens JM, Farmer SF. How broad is the phenotype of Hallervorden-Spatz disease? Acta Neurol Scand 2001;103:201-3.  Back to cited text no. 7
    
8.Taylor TD, Litt M, Kramer P, Pandolfo M, Angelini L, Nardocci N, et al. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat Genet 1996;14:479-81.  Back to cited text no. 8
    
9.Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001;28:345-9.  Back to cited text no. 9
    
10.Perry TL, Norman MG, Yong VW, Whiting S, Crichton JU, Hansen S, et al. Hallervorden-Spatz disease: Cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidus. Ann Neurol 1985;18:482-9.  Back to cited text no. 10
    
11.Hayflick SJ. First scientific workshop on Hallervorden-Spatz syndrome: Executive summary. Pediatr Neurol 2001;25:99-101.  Back to cited text no. 11
    
12.Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46:73-80.  Back to cited text no. 12
    
13.Johnson MA, Kuo YM, Westaway SK, Parker SM, Ching KH, Gitschier J, et al. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann N Y Acad Sci 2004;1012:282-98.  Back to cited text no. 13
    
14.Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM. Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci 2005;25:689-98.  Back to cited text no. 14
    
15.Leoni V, Strittmatter L, Zorzi G, Zibordi F, Dusi S, Garavaglia B, et al. Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Mol Genet Metab 2012;105:463-71.  Back to cited text no. 15
    
16.Swaiman KF. Hallervorden-Spatz syndrome and brain iron metabolism. Arch Neurol 1991;48:1285-93.  Back to cited text no. 16
    
17.Halliday W. The nosology of Hallervorden-spatz disease. J Neurol Sci 1995;134 Suppl:84-91.  Back to cited text no. 17
    
18.Vakili S, Drew AL, Von Schuching S, Becker D, Zeman W. Hallervorden-Spatz syndrome. Arch Neurol 1977;34:729-38.  Back to cited text no. 18
    
19.Zimmerman AW, Stover ML, Grasso JA. Uptake of 59Fe by skin fibroblasts and MAO activity in platelets from patients with Hallervorden-Spatz syndrome. Neurology 1981;51:48.  Back to cited text no. 19
    
20.Swaiman KF, Smith SA, Trock GL, Siddiqui AR. 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 1983;33:301-5.  Back to cited text no. 20
    
21.Alberca R, Rafel E, Chinchon I, Vadillo J, Navarro A. Late onset parkinsonian syndrome in Hallervorden-Spatz disease. J Neurol Neurosurg Psychiatry 1987;50:1665-8.  Back to cited text no. 21
    
22.Hermann W, Reuter M, Barthel H, Dietrich J, Georgi P, Wagner A. Diagnosis of Hallervorden-Spatz disease using MRI, (123)I-beta-CIT-SPECT and (123)I-IBZM-SPECT. Eur Neurol 2000;43:187-8.  Back to cited text no. 22
    
23.Feliciani M, Curatolo P. Early clinical and imaging (high-field MRI) diagnosis of Hallervorden-Spatz disease. Neuroradiology 1994;36:247-8.  Back to cited text no. 23
    
24.Shah J, Patkar D, Patankar T, Krishnan A, Prasad S, Limdi J. Hallervorden Spatz disease: MR imaging. J Postgrad Med 1999;45:114-7.  Back to cited text no. 24
[PUBMED]  Medknow Journal  
25.McNeill A, Birchall D, Hayflick SJ, Gregory A, Schenk JF, Zimmerman EA, et al. T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 2008;70:1614-9.  Back to cited text no. 25
    
26.Sethi KD, Adams RJ, Loring DW, el Gammal T. Hallervorden-Spatz syndrome: Clinical and magnetic resonance imaging correlations. Ann Neurol 1988;24:692-4.  Back to cited text no. 26
    
27.Delgado RF, Sanchez PR, Speckter H, Then EP, Jimenez R, Oviedo J, et al. Missense PANK2 mutation without "eye of the tiger" sign: MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN). J Magn Reson Imaging 2012;35:788-94.  Back to cited text no. 27
    
28.Chiapparini L, Savoiardo M, D'Arrigo S, Reale C, Zorzi G, Zibordi F, et al. The "eye-of-the-tiger" sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration. Neuropediatrics 2011;42:159-62.  Back to cited text no. 28
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


This article has been cited by
1 Pantothenate kinase-associated neurodegeneration (PKAN) a rare clinical entity
Appas Saha,Srushti Shabnam,Swapna N
Acta Oto-Laryngologica Case Reports. 2016; 1(1): 90
[Pubmed] | [DOI]



 

Top
Previous article  Next article
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Case Reports
References
Article Figures

 Article Access Statistics
    Viewed2038    
    Printed36    
    Emailed0    
    PDF Downloaded311    
    Comments [Add]    
    Cited by others 1    

Recommend this journal