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|LETTERS TO EDITOR
|Year : 2019 | Volume
| Issue : 3 | Page : 883-886
Two siblings with atypical pantothenate-kinase-associated neurodegeneration
Gunasekaran K, Sivakumar S, Thiruvarutchelvan K
Department of Neurology, Government Mohan Kumaramangalam Medical College Hospital, Salem, Tamil Nadu, India
|Date of Web Publication||23-Jul-2019|
Dr. Gunasekaran K
No. 230, Kumalankuttai, Collectorate Post, Erode - 638 011, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gunasekaran, Sivakumar, Thiruvarutchelvan. Two siblings with atypical pantothenate-kinase-associated neurodegeneration. Neurol India 2019;67:883-6
Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders that present with a progressive extrapyramidal syndrome associated with abnormal iron accumulation in the brain. About 10 types have been recognized in NBIA. Pantothenate-kinase-associated neurodegeneration (PKAN) is the commonest form of NBIA (35%-50%). Although the portions of globus pallidus and pars reticularis of substantia nigra have relatively higher iron content even in healthy individuals, patients with PKAN have excessive amounts of iron accumulated in these nuclei. PKAN is characterized by motor abnormalities [both corticospinal (spasticity, hyperreflexia, Babinski sign) and extrapyramidal (rigidity, dystonia, and choreoathetosis) features] and intellectual impairment. Among the two types, classic PKAN is characterized by early childhood onset and rapid progression of symptoms, whereas atypical PKAN is characterized by later age of onset and progression slowly for years. We report two siblings in a family with atypical PKAN.
The first patient (proband) was a 19-year-old boy who presented with insidious onset and slowly progressive difficulty in using the right hand of 2 years duration, and slurred and rapid speech with frequent swallowing difficulty of 1 year duration. His scholastic performances were poor and he had stopped his studies for the past 1.5 years. Also, recently he had often shown an aggressive behavior and impulsivity. His birth and developmental history were normal.
On examination, the patient was inattentive. Dysarthria was present. Right-hand dystonia was present which worsened while doing tasks such as buttoning shirt [Video 1] and writing [Video 2 and [Figure 1]. There were no pyramidal signs. Psychiatric evaluation was suggestive of borderline intellectual functioning. Ophthalmological evaluation did not reveal Kayser–Fleischer (KF) ring and there was no evidence of retinitis pigmentosa.
The proband's eldest sister, who was about 35 years old, presented with involuntary turning of head to the right side with slurring of speech of 2-3 years duration. Examination showed cervical dystonia [Figure 2] with head turning to the right side [Video 3] with intermittent blepharospasm and chorea in the right upper limb [Video 4]. Dysarthria was present. There were no pyramidal signs. Psychiatric evaluation showed mild intellectual disability. Like her brother, she also did not have KF ring or retinitis pigmentosa.
Both patient's basic blood and urine investigations and nerve conduction study were normal. Their magnetic resonance imaging (MRI) brain scan showed “eye of the tiger” sign [Figure 3] and [Figure 4].
|Figure 3: MRI Brain T2-wieghted image showing bilateral symmetrical hypointensity in globus pallidus with central hyperintensity (eye of the tiger sign)|
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|Figure 4: MRI brain T2-wieghted image showing bilateral symmetrical hypointensity in the globus pallidus with central hyperintensity (eye of the tiger sign)|
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The first patient (proband) was the fifth child and his sister (second case) was the eldest, both born out of third-degree consanguinity [Figure 5]. Three other siblings (two female and one male) did not have similar features and were apparently normal. Other members of their family are normal. Both patients were treated with baclofen, trihexyphenedyl, physiotherapy, and advised regular follow-up.
PKAN is a rare autosomal recessive disorder caused by mutation in the pantothenate kinase 2 (PANK2) gene located in chromosome 20. All cases of classic PKAN and one-third cases of atypical PKAN have mutation in the PANK2 gene. Its prevalence is estimated to be 1-3 in 1,000,000 population. PANK2 stifles the accumulation of N-pantothenoyl-cysteine and pantetheine. When this accumulation is not suppressed, the result is direct cell toxicity or toxicity due to free radical formation. The phenotype 'classic PKAN' is characterized by the onset in the first decade (usually early childhood, before 6 years) and fairly rapid, progressive course leading to loss of independence 10-15 years after the onset. The other phenotype 'atypical PKAN' is characterized by onset in the second or third decade (mean age 13.6 years) and slower disease course that may last 40 years. In both forms, focal dystonias are a common presenting and prominent feature. As the disease progresses, corticospinal tract signs such as spasticity and hyperreflexia may develop. Progressive cognitive impairment occurs in both forms. Pigmentory retinopathy is common (two-thirds of cases) in classic PKAN, whereas orolingual dystonia leading to dysarthria and dysphagia is common in atypical PKAN. Likewise, psychiatric symptoms (depression, anxiety, impulsivity, emotional lability, obsessive compulsive disorder, and psychosis) are common in atypical PKAN.
The majority of cases of PKAN have a characteristic MRI finding known as the “eye of the tiger” sign. Abnormal iron accumulation is seen as diffuse and bilateral low T2-weighted signal intensity lesions in the globus pallidus (internal and external segments) surrounding a central area of high T2-weighted signal intensity in the anteromedial globus pallidus corresponding to neuronal loss and gliosis and producing the image of an “eye of the tiger”. Diagnosis of PKAN is confirmed by identification of biallelic PANK-2 pathogenic variants on molecular genetic testing. Currently, therapy is directed at specific manifestations of the disease, like dystonia is treated with intramuscular botulinum toxin, baclofen (oral or intrathecal), trihexyphenedyl, and clonazepam. Recently, ablative pallidotomy and thalamotomy have been replaced by deep brain stimulation of the globus pallidus.
In our study, the onset of symptoms was late in these two patients (second decade in the boy and third decade in his sister). Apart from focal dystonia (hand dystonia in the male, cervical dystonia in the female), both of them had orolingual dystonia manifesting as dysarthria and dysphagia. Also, they had psychiatric symptoms and intellectual impairment. Their MRI brain showed “eye of the tiger” sign.
Similar case reports of atypical PKAN are found in the literature and some of them have been tabulated in [Table 1]. But all the above reports are single cases in their family (except the one by Mahoui S et al., which has not been mentioned in the table, in which two brothers of a family were affected).
In our study, although we could not do a molecular genetic analysis, the clinical features, family history, and neuroimaging were consistent with atypical PKAN.
As atypical PKAN in two siblings of a family is rarely reported in literature, we are presenting this study here.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We would like to thank Dr. Sundareswaran, Associate Professor, Department of Radiology of our institute for his academic help and valuable discussion regarding the radiodiagnosis of this case.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]