102 Neurology India March 2005 Vol 53 Issue 1 Case Report Chitra Sarkar Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029, India. E-mail: [email protected] Hallervorden Spatz disease: MR and pathological findings of a rare case M. C. Sharma, N. Aggarwal, M. Bihari*, V. Goyal*, S. Gaikwed**, S. Vaishya***, C. Sarkar Departments of Pathology, *Neurology, **Neuroradiology and ***Neurosurgery, All India Institute of Medical Sciences, New Delhi, India We describe a child with pathologically proven Hallervorden Spatz disease. He presented with extrapyramidal symptoms and characteristic “eye-of-the-tiger” sign on magnetic reso- nance imaging. He was given the possible benefit if any of deep brain stimulation with no much improvement. Patho- logical examination of the brain showed iron deposition in bilateral globus pallidi, spongiform change and neuron ax- onal degeneration (spheroids). Key Words: Hallervorden Spatz disease, movement disor- der, pantothenate kinase 2 deficiency Introduction Hallervorden Spatz disease (HSD) is a rare neurodegenerative disorder of basal ganglia and is character- ized by extrapyramidal symptoms, mental deterioration, de- mentia, and retinal degeneration. Both familial and sporadic cases have been reported. Only six cases have been reported from India, clinical diagnosis based on clinical and magnetic resonance imaging characteristics. [1-4] (Table 1). We report a pathologically proven case of HSD from India. Case Report A 8-year-old boy presented with a 2 year history of abnormal flexor posturing of the right hand and wrist with clenching of the fist. Over 6 months it became fixed and persistent and also involved the left hand. Subsequently, he developed extension of the neck and flexion of the trunk, with grimacing of the face, tight closure of the mouth and deterioration of speech and walking. He was the product of a non-consanguineous marriage and was born at full term. The labor was prolonged. His developmental milestones were delayed and speech was slurred with inability to speak difficult words. He was mentally retarded with poor scholastic performance and was sent to a school for mentally challenged children. No other family members had similar or other movement disorders. With levodopa with carbidopa he had a mild improvement. Later baclofen and trihexyphenadyl were added. He continued to worsen progressively. On examination, he was bedridden with generalized dystonia, fixed contractures of the lower limbs and was incontinent. There was no evidence of Kayser-Fleischer ring or retinitis pigmentosa. Serum ferritin, ceruloplasmin levels were normal and blood smear was nega- tive for acanthocytes. Brain commuter tomography and MRI (low field strength) done 2 years back were normal. Repeat MRI showed hypointensity with an area of central hyperintensity (“eye-of-the- tiger”-sign) in both globus pallidi on T 2 weighted imaging (Figure 1). Based on the clinical and MRI features a diagnosis of Hallervorden Table 1: Clinical features of Hallervorden Spatz disease cases reported from India Authors and Years Age/ Sex Clinical features Family History Radiology Others Follow up Kaushik et al 5 9 yr/M Involuntary movements, Elder brother Not Done RBC- Not mentioned 1995 Dystonia, Retinitis Pigmentosa died at 9 yrs acanthocytes Singhi and Mitra 6 7 yr/M Dystonia, GTC 2 siblings died T1 W hypointense 1 year 1997 at 13.87 yrs Shah et al 7 1999 7 yr/M Mental retardation Parental uncle Eye-of-the-tiger-sign Not mentioned died at 13 yrs 23 yr/M Tremors, gait impairment - Eye-of-the-tiger-sign 11 yr/F Mental retardation - Eye-of-the-tiger-sign Extrapyramidal symptoms Rao et al 8 2003 9 mths/F Dystonic movementsTorticollis N.L. T1 W hypointensity Not mentioned Present case 8/M Dystonic N.L. Eye-of-the-tiger-sign — Died M – Male; F – Female; T1W1 – T1 weighted imaging; GTC generalized tonic clonic seizures
Hallervorden Spatz disease: MR and pathological findings of a rare case
Jan 11, 2023
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
NI_Jan-Mar_05.pmdCase Report
Chitra Sarkar Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029, India. E-mail: [email protected]
Hallervorden Spatz disease: MR and pathological findings of a rare case
M. C. Sharma, N. Aggarwal, M. Bihari*, V. Goyal*, S. Gaikwed**, S. Vaishya***, C. Sarkar Departments of Pathology, *Neurology, **Neuroradiology and ***Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
We describe a child with pathologically proven Hallervorden Spatz disease. He presented with extrapyramidal symptoms and characteristic “eye-of-the-tiger” sign on magnetic reso- nance imaging. He was given the possible benefit if any of deep brain stimulation with no much improvement. Patho- logical examination of the brain showed iron deposition in bilateral globus pallidi, spongiform change and neuron ax- onal degeneration (spheroids).
Key Words: Hallervorden Spatz disease, movement disor- der, pantothenate kinase 2 deficiency
Introduction
neurodegenerative disorder of basal ganglia and is character-
ized by extrapyramidal symptoms, mental deterioration, de-
mentia, and retinal degeneration. Both familial and sporadic
cases have been reported. Only six cases have been reported
from India, clinical diagnosis based on clinical and magnetic
resonance imaging characteristics.[1-4] (Table 1). We report a
pathologically proven case of HSD from India.
Case Report
A 8-year-old boy presented with a 2 year history of abnormal flexor
posturing of the right hand and wrist with clenching of the fist. Over
6 months it became fixed and persistent and also involved the left
hand. Subsequently, he developed extension of the neck and flexion
of the trunk, with grimacing of the face, tight closure of the mouth
and deterioration of speech and walking. He was the product of a
non-consanguineous marriage and was born at full term. The labor
was prolonged. His developmental milestones were delayed and speech
was slurred with inability to speak difficult words. He was mentally
retarded with poor scholastic performance and was sent to a school
for mentally challenged children. No other family members had similar
or other movement disorders. With levodopa with carbidopa he had a
mild improvement. Later baclofen and trihexyphenadyl were added.
He continued to worsen progressively.
On examination, he was bedridden with generalized dystonia, fixed
contractures of the lower limbs and was incontinent. There was no
evidence of Kayser-Fleischer ring or retinitis pigmentosa. Serum
ferritin, ceruloplasmin levels were normal and blood smear was nega-
tive for acanthocytes. Brain commuter tomography and MRI (low
field strength) done 2 years back were normal. Repeat MRI showed
hypointensity with an area of central hyperintensity (“eye-of-the-
tiger”-sign) in both globus pallidi on T 2 weighted imaging (Figure
1). Based on the clinical and MRI features a diagnosis of Hallervorden
Table 1: Clinical features of Hallervorden Spatz disease cases reported from India
Authors and Years Age/ Sex Clinical features Family History Radiology Others Follow up Kaushik et al5 9 yr/M Involuntary movements, Elder brother Not Done RBC- Not mentioned 1995 Dystonia, Retinitis Pigmentosa died at 9 yrs acanthocytes Singhi and Mitra6 7 yr/M Dystonia, GTC 2 siblings died T1 W hypointense 1 year 1997 at 13.87 yrs Shah et al7 1999 7 yr/M Mental retardation Parental uncle Eye-of-the-tiger-sign Not mentioned
died at 13 yrs 23 yr/M Tremors, gait impairment - Eye-of-the-tiger-sign 11 yr/F Mental retardation - Eye-of-the-tiger-sign
Extrapyramidal symptoms Rao et al8 2003 9 mths/F Dystonic movementsTorticollis N.L. T1 W hypointensity Not mentioned Present case 8/M Dystonic N.L. Eye-of-the-tiger-sign — Died
M – Male; F – Female; T1W1 – T1 weighted imaging; GTC generalized tonic clonic seizures
103Neurology India March 2005 Vol 53 Issue 1
Sharma MC, et al: Hallervorden Spatz disease
Spatz Disease was made.
In view of poor response to pharmaco-therapy he was given the
possible benefit if any of deep brain stimulation (DBS). Electrodes
were implanted in bilateral globus pallidus interna. Postoperatively
he developed severe stridor and could not be extubated and needed a
tracheostomy. He developed pneumonia and died three months after
the procedure.
At autopsy the brain weighed 1100 grams before fixation with an
unremarkable external surface. Coronal slicing of the brain showed
brownish yellow discolouration of the bilateral globus pallidi. (Fig-
ure 2a). Microscopic examination of the cerebellum and different
lobes of the cerebral hemispheres revealed slight prominence of mela-
nin containing cells in the leptomeninges without any hypoxic changes.
Sections examined from the globus pallidi showed brownish black
color pigment deposition in the parenchyma both extracellularly and
intracellularly in the neurons and astrocytes, and as mulberry-like
encrustation of blood vessel wall (Figure 2b). This pigment on Pearl’s
reaction proved to be iron (Figure 2c) and did not stain with the
calcium stains. There was spongiosis, loss of neurons, gliosis and
eosinophillic spheroids (Figure 2d) (neuron axonal dystrophy, NAD).
These spheroids were immunoreactive to neurofilament. Iron depo-
sition and spheroids were also seen in the corticostriate tracts but
were not associated with demyelination or axonolysis of the tracts
and white matter. Sections from the electrode site implantation re-
vealed cyst formation and collection of foamy macrophages along
with reactive gliosis of the surrounding parenchyma. These features
were consistent with HSD.
cessive neurodegenerative disorder with aberrant iron metabo-
lism in the brain, first described by Hallervorden and Spatz
in 1922. It is characterized by childhood onset of extrapy-
ramidal motor symptoms. Some patients may present with
mental changes, dementia and vision disturbances. Average
survival after diagnosis onset is 11.8 years. Pathological find-
ings include iron deposition, axonal swellings or spheroids
(NAD) predominantly in the globus pallidus and pars
reticularis of the substantia nigra. Since the first description
of this disease, little progress has been made in the treatment.
Recently, the gene for the disease has been localized to chro-
mosome 20p12.3-13, coding for pantothenate kinase 2[5] which
is required for the phosphorylation of pantothenic acid in the
formation of coenzyme A. Due to defective phosphorylation of
pantothenic acid there is under utilization of cystine which,
when in excess causes chelation of iron leading to free toxic
radicals production. The preferential involvement of basal
ganglia is attributed to the excess of pantothenate kinase
receptors. Thus, the term pantothenate kinase 2-associated
neurodegeneration (PKAN) may be preferable instead of
HSD.[6]
The characteristic MR finding of “eye-of-the-tiger”-sign
corresponds to the pathological findings. The hypointensity
on T 2 weighted image is because of iron deposition and cen-
tral hyperintensity is secondary to gliosis and spongiosis.[7]
This is well corroborated pathologically in this case also. The
other conditions in which high signal intensity, like HSD can
be observed are metabolic disorders, like organic acidurias,
early onset levadopa responsive Parkinsonism and cortical-
basal ganglionic degeneration. The other disorder affecting
basal ganglia such as Leigh’s disease, mitochondrial encepha-
lopathies, infantile bilateral necrosis and Wilson’s disease more
frequently involve the putamen rather than the globus pal-
lidus.
basal ganglia and “eye-of-the-tiger”-sign include
aceruloplasminemia and neuroferritinopathy. These are dis-
tinct conditions of abnormal iron metabolism but unlike HSD
present in adult or late life. Neuroferritinopathy is character-
ized by onset at 40-55 years of age and defect is localized to
gene encoding ferritin light chain polypeptide at 19q13.3. A
Figure 1: T2W1 showing central area of hyperintensity surrounded by hypointense area in both basal ganglia in the globus pallidi region
Figure 2a-d: Coronal section of the brain showing yellowish brown discolouration of both globus pallidi (a) Microphotograph from this
region showing brown encrustation of the vessel wall as well as pigment deposition in the parenchyma (b) H/E x100. This pigment
stained bluish with iron stain (c) H/E x100. Photomicrograph showing spongiform change and eosinophilic spheroids (d) H/E x200)
104 Neurology India March 2005 Vol 53 Issue 1
ceruloplasminemia is associated with diabetes mellitus and
there is complete deficiency of ceruloplasmin protein. The gene
is localized to chromosome 3q13.3. Recently,
neurodegenerative diseases of brain with accumulation of iron
have been classified according to the age of onset and gene
defect into different groups (Table 2). Hayflick et al[8] studied
123 cases from 98 families and classified HSD clinically as
classic disease and atypical form. Classical HSD is character-
ized by early onset, rapid progression and presence of typical
“eye-of-the-tiger”-sign with PANK2 mutations. In contrast,
atypical disease is characterized by late onset with slow pro-
gression and only one-third of the cases showed PANK2 mu-
tations. “Eye-of-the-tiger”-sign may or may not be present.
They concluded that all patients with “eye-of-the-tiger”-sign,
whether classic or atypical, showed PANK2 mutations and
this favoured to the diagnosis of HSD.
Management is symptomatic and there is no definitive treat-
ment of this disease. Resistance, drugs adverse effects and
ineffectiveness of the medical treatment in stopping the dis-
ease progression in movement disorders has led to explora-
tion of surgical modalities in the treatment of these disorders.
The role of surgical treatment for dystonia is evolving. Stere-
otactic pallidotomy[9] and thalamotomy[10] have been tried with
good short-term results. However, these are permanent pro-
cedures with increased risk of side effects. In contrast, DBS
is a relatively newly described technique, which is reversible
and is seemingly free of side effects and complications apart
from the risk of infection. It is however expensive. The princi-
ple of this technique is based on the concept that high fre-
quency stimulation of neural cells lead to suppression or modu-
lation of their activity, without generating irreversible ana-
PKAN Others PKAN Neuroferritinopathy
Table 2: Showing classification of neurodegenerative disorder with iron accumulation in the brain
tomical lesions. Bilateral DBS was tried in this case but with-
out any benefit. Future therapeutic strategies may involve
direct delivery of phosphorylated pantothenate to the cells
bypassing pantothenate kinase. Neuroprotection by the brain
permeable iron chelator, VK-28 which inhibits both basal and
Fe/ascorbate induced mitochondrial membrane lipid
peroxidation, has shown promising results in rats.[11] Its po-
tency is comparable to proteolytic iron chelator, desferal, which
does not cross the blood-brain-barrier.
Thus, HSD is a rare neurodegenerative disorder character-
ized by iron deposition in the globus pallidus with character-
istic radiological “eye-of-the-tiger”-sign. Pre- and post-natal
molecular diagnosis is possible. The role of DBS needs to be
evaluated on large number of patients before it is discarded.
Acknowledgements
Authors are thankful to Dr. P. K. Ghosh, Associate Professor, Department of Pediatrics,
PostGraduate Institute of Medical Education and Research, Chandigarh, India who
discussed this case in Clinicopathological Conference held on 29th October 2003 at
All India Institute of Medical Sciences, New Delhi, India.
References
1. Kaushik A, Longia S, Jagadeesh R, Kishore V. Hallervorden-spatz disease.
Indian Pediatr 1995;32:483-5.
2. Singhi PD, Mitra S. Hallervorden spatz disease: Late infantile type. J Child
Neurol 1997;12:281-2.
3. Shah J, Patkar D, Patankar T, Krishnan A, Prasad S, Limdi J. Hallervorden
spatz disease: MR imaging. J Postgrad Med 1999;45:114-7.
4. Rao C, Murthy V, Hedge R, Asha, Vishwanath. Hallervorden spatz disease.
Indian J Pediatr 2003;70:513-4.
5. Zhou B, Westway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A
novel patothenate kinase gene (PANK2) is defective in Hallervorden spatz syn-
drome. Nature Genetics 2001;28:345-9.
Hallervorden-Spatz Syndrome). J Neurol Sci 2003;207:106-7.
7. Adams RJ, Nichols FT, McKie V, McKie K, Milner P, Gammal TE. Hallervorden
spatz syndrome: Clinical and magnetic resonance imaging correlations: Ann
Neurol 1988;24:692-4.
8. Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et
al. Genetic, clinical and radiographic delineation of Hallervorden-Spatz Syn-
drome. N Engl J Med 2003;348:33-40.
9. Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child
with Hallervorden- spatz disease. J Neurosurg 1999;90:551-4.
10. Tsukamoto H, Inui K, Taniike M, Nishimoto J, Midorikawa M, Yoshimine T, et
al. A case of Hallervorden-spatz disease: progressive and intractable dystonia
controlled by bilateral thalamotomy. Brain Dev 1992;14:269-72.
11. Shachar DB, Kahana N, Kampel V, Warshawsky A, Youdim MB.
Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-
hydrodopamine lesion in rats. Neuropharmacology 2004;46:254-63.
Accepted on 09.11.2004.
Chitra Sarkar Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029, India. E-mail: [email protected]
Hallervorden Spatz disease: MR and pathological findings of a rare case
M. C. Sharma, N. Aggarwal, M. Bihari*, V. Goyal*, S. Gaikwed**, S. Vaishya***, C. Sarkar Departments of Pathology, *Neurology, **Neuroradiology and ***Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
We describe a child with pathologically proven Hallervorden Spatz disease. He presented with extrapyramidal symptoms and characteristic “eye-of-the-tiger” sign on magnetic reso- nance imaging. He was given the possible benefit if any of deep brain stimulation with no much improvement. Patho- logical examination of the brain showed iron deposition in bilateral globus pallidi, spongiform change and neuron ax- onal degeneration (spheroids).
Key Words: Hallervorden Spatz disease, movement disor- der, pantothenate kinase 2 deficiency
Introduction
neurodegenerative disorder of basal ganglia and is character-
ized by extrapyramidal symptoms, mental deterioration, de-
mentia, and retinal degeneration. Both familial and sporadic
cases have been reported. Only six cases have been reported
from India, clinical diagnosis based on clinical and magnetic
resonance imaging characteristics.[1-4] (Table 1). We report a
pathologically proven case of HSD from India.
Case Report
A 8-year-old boy presented with a 2 year history of abnormal flexor
posturing of the right hand and wrist with clenching of the fist. Over
6 months it became fixed and persistent and also involved the left
hand. Subsequently, he developed extension of the neck and flexion
of the trunk, with grimacing of the face, tight closure of the mouth
and deterioration of speech and walking. He was the product of a
non-consanguineous marriage and was born at full term. The labor
was prolonged. His developmental milestones were delayed and speech
was slurred with inability to speak difficult words. He was mentally
retarded with poor scholastic performance and was sent to a school
for mentally challenged children. No other family members had similar
or other movement disorders. With levodopa with carbidopa he had a
mild improvement. Later baclofen and trihexyphenadyl were added.
He continued to worsen progressively.
On examination, he was bedridden with generalized dystonia, fixed
contractures of the lower limbs and was incontinent. There was no
evidence of Kayser-Fleischer ring or retinitis pigmentosa. Serum
ferritin, ceruloplasmin levels were normal and blood smear was nega-
tive for acanthocytes. Brain commuter tomography and MRI (low
field strength) done 2 years back were normal. Repeat MRI showed
hypointensity with an area of central hyperintensity (“eye-of-the-
tiger”-sign) in both globus pallidi on T 2 weighted imaging (Figure
1). Based on the clinical and MRI features a diagnosis of Hallervorden
Table 1: Clinical features of Hallervorden Spatz disease cases reported from India
Authors and Years Age/ Sex Clinical features Family History Radiology Others Follow up Kaushik et al5 9 yr/M Involuntary movements, Elder brother Not Done RBC- Not mentioned 1995 Dystonia, Retinitis Pigmentosa died at 9 yrs acanthocytes Singhi and Mitra6 7 yr/M Dystonia, GTC 2 siblings died T1 W hypointense 1 year 1997 at 13.87 yrs Shah et al7 1999 7 yr/M Mental retardation Parental uncle Eye-of-the-tiger-sign Not mentioned
died at 13 yrs 23 yr/M Tremors, gait impairment - Eye-of-the-tiger-sign 11 yr/F Mental retardation - Eye-of-the-tiger-sign
Extrapyramidal symptoms Rao et al8 2003 9 mths/F Dystonic movementsTorticollis N.L. T1 W hypointensity Not mentioned Present case 8/M Dystonic N.L. Eye-of-the-tiger-sign — Died
M – Male; F – Female; T1W1 – T1 weighted imaging; GTC generalized tonic clonic seizures
103Neurology India March 2005 Vol 53 Issue 1
Sharma MC, et al: Hallervorden Spatz disease
Spatz Disease was made.
In view of poor response to pharmaco-therapy he was given the
possible benefit if any of deep brain stimulation (DBS). Electrodes
were implanted in bilateral globus pallidus interna. Postoperatively
he developed severe stridor and could not be extubated and needed a
tracheostomy. He developed pneumonia and died three months after
the procedure.
At autopsy the brain weighed 1100 grams before fixation with an
unremarkable external surface. Coronal slicing of the brain showed
brownish yellow discolouration of the bilateral globus pallidi. (Fig-
ure 2a). Microscopic examination of the cerebellum and different
lobes of the cerebral hemispheres revealed slight prominence of mela-
nin containing cells in the leptomeninges without any hypoxic changes.
Sections examined from the globus pallidi showed brownish black
color pigment deposition in the parenchyma both extracellularly and
intracellularly in the neurons and astrocytes, and as mulberry-like
encrustation of blood vessel wall (Figure 2b). This pigment on Pearl’s
reaction proved to be iron (Figure 2c) and did not stain with the
calcium stains. There was spongiosis, loss of neurons, gliosis and
eosinophillic spheroids (Figure 2d) (neuron axonal dystrophy, NAD).
These spheroids were immunoreactive to neurofilament. Iron depo-
sition and spheroids were also seen in the corticostriate tracts but
were not associated with demyelination or axonolysis of the tracts
and white matter. Sections from the electrode site implantation re-
vealed cyst formation and collection of foamy macrophages along
with reactive gliosis of the surrounding parenchyma. These features
were consistent with HSD.
cessive neurodegenerative disorder with aberrant iron metabo-
lism in the brain, first described by Hallervorden and Spatz
in 1922. It is characterized by childhood onset of extrapy-
ramidal motor symptoms. Some patients may present with
mental changes, dementia and vision disturbances. Average
survival after diagnosis onset is 11.8 years. Pathological find-
ings include iron deposition, axonal swellings or spheroids
(NAD) predominantly in the globus pallidus and pars
reticularis of the substantia nigra. Since the first description
of this disease, little progress has been made in the treatment.
Recently, the gene for the disease has been localized to chro-
mosome 20p12.3-13, coding for pantothenate kinase 2[5] which
is required for the phosphorylation of pantothenic acid in the
formation of coenzyme A. Due to defective phosphorylation of
pantothenic acid there is under utilization of cystine which,
when in excess causes chelation of iron leading to free toxic
radicals production. The preferential involvement of basal
ganglia is attributed to the excess of pantothenate kinase
receptors. Thus, the term pantothenate kinase 2-associated
neurodegeneration (PKAN) may be preferable instead of
HSD.[6]
The characteristic MR finding of “eye-of-the-tiger”-sign
corresponds to the pathological findings. The hypointensity
on T 2 weighted image is because of iron deposition and cen-
tral hyperintensity is secondary to gliosis and spongiosis.[7]
This is well corroborated pathologically in this case also. The
other conditions in which high signal intensity, like HSD can
be observed are metabolic disorders, like organic acidurias,
early onset levadopa responsive Parkinsonism and cortical-
basal ganglionic degeneration. The other disorder affecting
basal ganglia such as Leigh’s disease, mitochondrial encepha-
lopathies, infantile bilateral necrosis and Wilson’s disease more
frequently involve the putamen rather than the globus pal-
lidus.
basal ganglia and “eye-of-the-tiger”-sign include
aceruloplasminemia and neuroferritinopathy. These are dis-
tinct conditions of abnormal iron metabolism but unlike HSD
present in adult or late life. Neuroferritinopathy is character-
ized by onset at 40-55 years of age and defect is localized to
gene encoding ferritin light chain polypeptide at 19q13.3. A
Figure 1: T2W1 showing central area of hyperintensity surrounded by hypointense area in both basal ganglia in the globus pallidi region
Figure 2a-d: Coronal section of the brain showing yellowish brown discolouration of both globus pallidi (a) Microphotograph from this
region showing brown encrustation of the vessel wall as well as pigment deposition in the parenchyma (b) H/E x100. This pigment
stained bluish with iron stain (c) H/E x100. Photomicrograph showing spongiform change and eosinophilic spheroids (d) H/E x200)
104 Neurology India March 2005 Vol 53 Issue 1
ceruloplasminemia is associated with diabetes mellitus and
there is complete deficiency of ceruloplasmin protein. The gene
is localized to chromosome 3q13.3. Recently,
neurodegenerative diseases of brain with accumulation of iron
have been classified according to the age of onset and gene
defect into different groups (Table 2). Hayflick et al[8] studied
123 cases from 98 families and classified HSD clinically as
classic disease and atypical form. Classical HSD is character-
ized by early onset, rapid progression and presence of typical
“eye-of-the-tiger”-sign with PANK2 mutations. In contrast,
atypical disease is characterized by late onset with slow pro-
gression and only one-third of the cases showed PANK2 mu-
tations. “Eye-of-the-tiger”-sign may or may not be present.
They concluded that all patients with “eye-of-the-tiger”-sign,
whether classic or atypical, showed PANK2 mutations and
this favoured to the diagnosis of HSD.
Management is symptomatic and there is no definitive treat-
ment of this disease. Resistance, drugs adverse effects and
ineffectiveness of the medical treatment in stopping the dis-
ease progression in movement disorders has led to explora-
tion of surgical modalities in the treatment of these disorders.
The role of surgical treatment for dystonia is evolving. Stere-
otactic pallidotomy[9] and thalamotomy[10] have been tried with
good short-term results. However, these are permanent pro-
cedures with increased risk of side effects. In contrast, DBS
is a relatively newly described technique, which is reversible
and is seemingly free of side effects and complications apart
from the risk of infection. It is however expensive. The princi-
ple of this technique is based on the concept that high fre-
quency stimulation of neural cells lead to suppression or modu-
lation of their activity, without generating irreversible ana-
PKAN Others PKAN Neuroferritinopathy
Table 2: Showing classification of neurodegenerative disorder with iron accumulation in the brain
tomical lesions. Bilateral DBS was tried in this case but with-
out any benefit. Future therapeutic strategies may involve
direct delivery of phosphorylated pantothenate to the cells
bypassing pantothenate kinase. Neuroprotection by the brain
permeable iron chelator, VK-28 which inhibits both basal and
Fe/ascorbate induced mitochondrial membrane lipid
peroxidation, has shown promising results in rats.[11] Its po-
tency is comparable to proteolytic iron chelator, desferal, which
does not cross the blood-brain-barrier.
Thus, HSD is a rare neurodegenerative disorder character-
ized by iron deposition in the globus pallidus with character-
istic radiological “eye-of-the-tiger”-sign. Pre- and post-natal
molecular diagnosis is possible. The role of DBS needs to be
evaluated on large number of patients before it is discarded.
Acknowledgements
Authors are thankful to Dr. P. K. Ghosh, Associate Professor, Department of Pediatrics,
PostGraduate Institute of Medical Education and Research, Chandigarh, India who
discussed this case in Clinicopathological Conference held on 29th October 2003 at
All India Institute of Medical Sciences, New Delhi, India.
References
1. Kaushik A, Longia S, Jagadeesh R, Kishore V. Hallervorden-spatz disease.
Indian Pediatr 1995;32:483-5.
2. Singhi PD, Mitra S. Hallervorden spatz disease: Late infantile type. J Child
Neurol 1997;12:281-2.
3. Shah J, Patkar D, Patankar T, Krishnan A, Prasad S, Limdi J. Hallervorden
spatz disease: MR imaging. J Postgrad Med 1999;45:114-7.
4. Rao C, Murthy V, Hedge R, Asha, Vishwanath. Hallervorden spatz disease.
Indian J Pediatr 2003;70:513-4.
5. Zhou B, Westway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A
novel patothenate kinase gene (PANK2) is defective in Hallervorden spatz syn-
drome. Nature Genetics 2001;28:345-9.
Hallervorden-Spatz Syndrome). J Neurol Sci 2003;207:106-7.
7. Adams RJ, Nichols FT, McKie V, McKie K, Milner P, Gammal TE. Hallervorden
spatz syndrome: Clinical and magnetic resonance imaging correlations: Ann
Neurol 1988;24:692-4.
8. Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et
al. Genetic, clinical and radiographic delineation of Hallervorden-Spatz Syn-
drome. N Engl J Med 2003;348:33-40.
9. Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child
with Hallervorden- spatz disease. J Neurosurg 1999;90:551-4.
10. Tsukamoto H, Inui K, Taniike M, Nishimoto J, Midorikawa M, Yoshimine T, et
al. A case of Hallervorden-spatz disease: progressive and intractable dystonia
controlled by bilateral thalamotomy. Brain Dev 1992;14:269-72.
11. Shachar DB, Kahana N, Kampel V, Warshawsky A, Youdim MB.
Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-
hydrodopamine lesion in rats. Neuropharmacology 2004;46:254-63.
Accepted on 09.11.2004.
Related Documents
