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HALLERVORDEN SPATZ DISEASE.

PRESENTATION OF CASE

A 22-year-old male came with complaints of difficulty in walking and writing with right hand. He was the product of a non-consanguineous marriage and had been born at full term. There was history of normal development till the age of 20 years. A history of perinatal hypoxic insult or birth trauma was absent. There was no other relevant family history. There was history of fall two and half year back on right shoulder.

Neurological examination revealed a generalized increase in the tone in right extremities, with mute plantar responses; with speech deterioration. Ophthalmic evaluation was normal. No evidence of a Kayser-Fleischer ring was seen on slit-lamp examination.

CLINICAL DIAGNOSIS

Pantothenate Kinase Associated Neurodegeneration (PKAN)

DIFFERENTIAL DIAGNOSIS

In cases of iron deposition in the basal ganglia and the "eye-of-the-tiger" sign, differential diagnosis includes aceruloplasminemia and neuroferritinopathy. These conditions present in adults. Association of diabetes mellitus has been reported in aceruloplasminemia, along with deficiency of the ceruloplasmin protein. The locus for ceruloplasmin protein is chromosome 3q13.3. The age of onset in neuroferritinopathy is approximately the 5th to 6th decade. A few other metabolic disorders, such as organic aciduria, cortical basal ganglionic degeneration, and early-onset levodopa-responsive parkinsonism, also show hyperintense signals within the basal ganglia. Wilson disease, Leigh disease, infantile bilateral necrosis, and mitochondrial encephalopathies also show involvement of the lentiform nucleus, but in these disorders the putamen is predominantly involved rather than the globus pallidus. [9]

At present, there is no specific treatment for PKAN and the management is symptomatic. [4,5] Recently, iron chelators such as VK-28 have been used for decreasing basal as well as iron/ascorbate-induced mitochondrial lipid peroxidation in rats [10] Serial MRS can be used for the follow-up of PKAN patients on iron chelators to quantitatively assess the axonal damage and gliosis. The medical treatment of PKAN is ineffective, prolonged, and has many side effects and so surgical modalities like stereo-pallidotomy and thalamotomy, [11] have also been used to reduce dystonia. The benefits however are short lasting with many side effects and complications. Future management strategies may involve direct delivery of phosphorylated pantothenate to the cells, bypassing pantothenate kinase. [12]

PATHOLOGICAL DISCUSSION

Serum electrolytes, iron, copper, and ceruloplasmin levels were within normal limits. Amino acid chromatographic analysis was normal. Severe eosinophilia was seen in the blood smear.

MRI examination was performed on a 1.5T scanner (Radiology Department SKNMC, Pune). MRI showed marked hypointensity within both globus pallidi, with a small area of central hyperintensity (Eye-of-the-Tiger Sign) on T2W images [Figure 1]. Similar hypointense signals were also seen on the FLAIR images [Figure 2]. The marked hypointensity in the globus pallidi was better appreciated on susceptibility weighted images, suggesting iron deposition [Figure 3]. Based on the clinical assessment and the typical MRI findings, we arrived at the diagnosis of PKAN.

Hallervorden-Spatz disease, commonly known as Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disorder associated with iron accumulation in brain nuclei. It is characterized by progressive extrapyramidal dysfunction and dementia.

According to some studies prevalence of PKAN is 1-9/1000000. The classic presentation is in late part of the first decade or early part of second decade, between ages 7 and 15 years. However, the disease onset has been reported in all age groups including infancy and adulthood.

Hallervorden-Spatz disease was first described in 1922 by two German physicians, Hallervorden and Spatz, as a form of familial brain degeneration characterized by cerebral iron deposition and hence the name so. It is a subset of Neurodegeneration with brain iron accumulation (NBIA), in the basal ganglia, with subsequent variable neurological dysfunction.

The exact aetiology of PKAN is not well understood. Aberrant oxidation of lipofuscin to neuromelanin and insufficient cysteine dioxygenase leading to abnormal iron accumulation in the brain is the proposed hypothesis. While portions of globus pallidus and pars reticularis of substantia nigra have relatively higher iron content in healthy individuals, patients of PKAN have excessive amounts of iron accumulated in these nuclei.

Mutation in the PANK2 gene (band 20p13) accounts for most inherited PKAN cases. Mutations result in an autosomal recessive inborn error of coenzyme A metabolism and results in deficiency of pantothenate kinase enzyme. This leads to accumulation of cysteine and cysteine-containing compounds in basal ganglia and causes chelation of iron in the globus pallidus and other basal ganglia and rapid auto-oxidation of cysteine in the presence of iron with subsequent free radical production. Pathologic examination reveals characteristic rust-brown discoloration of the globus pallidus and substantia nigra pars reticularis due to underlying iron deposition and a reduction in the size of these nuclei. Generalized atrophy of the brain parenchyma may be seen in severely advanced cases.

Pathologic examination reveals characteristic rust-brown discoloration of the globus pallidus and substantia nigra pars reticularis due to iron deposition and a reduction in the size of the caudate nuclei, substantia nigra, and tegmentum as well as generalized atrophy of the brain.

Microscopically Marked Neuroaxonal and Myelin Degeneration is a Distinctive Pathologic Feature of PKAN.

* Ubiquitinated spheroids, which represent swollen axons with vacuolated cytoplasm inactivated by attachment of ubiquitin, are found most abundantly in the pallidonigral system and in the cerebral cortex.

* Accumulation of iron-containing pigment mostly neuromelanin and ceroid lipofuscin in the palladonigral system.

PKAN is a rare neurodegenerative disorder that was first described by Hallervorden and Spatz in 1922. [1] The inheritance pattern is autosomal recessive. On an average, the diagnosis is usually made in the 1st decade of life or in early adolescence. [2] After diagnosis, average survival is for about 12 years. [3]

The globus pallidus, subthalamic nuclei, and pars reticulata of the substantia nigra are normally rich in iron. Aberrant storage of iron is an essential factor in the causation of PKAN. [4-6] Excess deposition of iron causes neuronal degeneration, gliosis, and spheroid formation (Vacuolization). [7] The characteristic MRI findings of bilateral symmetrical hyperintense signals surrounded by hypointensity on T2W images lead to the "Eye-of-the-Tiger" sign. [4,5,7] The surrounding hypointensity is caused by signal loss (Susceptibility) from the iron deposition, while the central hyperintensity is due to axonal swelling, formation of spheroids, gliosis, and neuronal loss and degeneration. [8] Although this finding is considered specific for PKAN, it can be found in other parkinsonian syndromes as well. The MRI findings correspond well with the histopathological changes. [8] Gliosis and spongiosis appear hyperintense on T2W images, while iron deposition appears hypointense due to susceptibility-related signal loss and is better appreciated on GRE images.

The locus of the causative gene is 20p12.3-13 and it codes for pantothenate kinase-2 (PANK2). [4,5] PANK2 is required for the phosphorylation of pantothenic acid in the formation of coenzyme A. Defective phosphorylation causes underutilization of cystine which, when present in excess, chelates iron, resulting in free radical formation. Excessive presence of pantothenate kinase receptors is responsible for the preferential involvement of the globus pallidi, subthalamic nuclei, and pars reticularis of the substantia nigra.

Recently, Hayflick et al. [4] on the basis of the age of onset and the gene defect present have classified neurodegenerative disorders of the brain with iron accumulation into different groups. The classical form, with the PANK2 mutation, is characterized by early onset, rapid progression, and the presence of the typical eye-of-the-tiger sign. Atypical disease is characterized by late onset and slow progression. In patients with atypical disease, PANK2 mutation is present in only 33% of cases. [7] The eye-of-the-tiger sign may or may not be present in these patients.

Our patient was classified as classical PKAN disease on the basis of the age of onset, clinical evaluation, and the specific pattern demonstrated on MRI.

DISCUSSION OF MANAGEMENT

There is no treatment for this disease; the only option that remains is symptomatic treatment of psychiatric and neurological symptoms. The overall prognosis of this disorder is very poor with the affected individual dying by 2nd to 3rd decade or within one to ten years of onset of severe symptoms. Unfortunately, we lost follow-up of our patient within a month of discharge from our center.

FINAL DIAGNOSIS

Hallervorden Spatz Disease (Pantothenate Kinase Associated Neurodegeneration, PKAN)

REFERENCES

[1] Hallervorden J, Spatz H. Eigenartige Erkrankung im extrapyramidalen System mot besonderer Beteiligung des Globus pallidus und der Substantia nigra: Ein Beitrag zu den Beziehungen zwischen diesen beiden Zentren. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr 1922;79(1):254-302.

[2] Jankovic J, Kirkpatrick JB, Blomquist KA, et al. Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology 1985;35(2):227-34.

[3] Saito Y, Kawai M, Inoue K, et al. Widespread expression of alpha-synuclein and tau immunoreactivity in Hallervorden-Spatz syndrome with protracted clinical course. J Neurol Sci 2000;177(1):48-59.

[4] Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003;348(1):33-40.

[5] Gordon N. Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome). Eur J Child Neurol 2002;6(5):243-7.

[6] Muller T, Amoiridis G, Kuhn W, et al. Iron deposits in the subthalamic nuclei in Hallervorden-Spatz Disease. Eur Neurol 1999;42(4):240-1.

[7] Koeppen AH, Dickson AC. Iron in the HallervordenSpatz syndrome. Pediatr Neurol 2001;25(2):148-55.

[8] Sethi KD, Adams RJ, Loring DW, et al. Hallervorden spatz syndrome: clinical and magnetic resonance imaging correlations. Ann Neurol 1988;24(5):692-4.

[9] Yock DH. MRI of CNS disease: a teaching file. 2nd edn. St. Louis: Mosby 1995: p. 319.

[10] Shachar DB, Kahana N, Kampel V, et al. Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology 2004;46(2):254-63.

[11] Tsukamoto H, Inui K, Taniike M, et al. A case of Hallervorden-spatz disease: progressive and intractable dystonia controlled by bilateral thalamotomy. Brain Dev 1992;14(4):269-72.

[12] Sharma MC, Aggarwal N, Bihari M, et al. Hallervorden spatz disease: MR and pathological findings of a rare case. Neurol India 2005;53(1):102-4.

Dhairyasheel D. Patii (1), Samruddhi Pujalwar (2), Y. D. Singh (3)

(1) Resident, Department of Medicine, Smt. Kashibai Navale Medical College and General Hospital, Pune, Maharashtra, India.

(2) Resident, Department of Radiology, Smt. Kashibai Navale Medical College and General Hospital, Pune, Maharashtra, India.

(3) Professor, Department of Medicine, Facuity of Medicine, AIMST University, Maiaysia.

'Financial or Other Competing Interest': None.

Submission 16-11-2018, Peer Review 10-12-2018, Acceptance 17-12-2018, Published 24-12-2018.

Corresponding Author: Dr. Dhairyasheel D. Patil, Resident Hostel No. 1, Room No. 322, Smt. Kashibai Navale Medical College and General Hospital, Pune-411041, Maharashtra, India.

E-mail: dhairyasheel94@gmail.com

DOI: 10.14260/jemds/2018/1232

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Title Annotation:Case Report
Author:Patil, Dhairyasheel D.; Pujalwar, Samruddhi; Singh, Y.D.
Publication:Journal of Evolution of Medical and Dental Sciences
Article Type:Case study
Date:Dec 24, 2018
Words:1751
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