Teaching Case

A 12-year-old male patient presented with developmental regression detected at the age of 6. The examination revealed dysarthria, choreoathetosis predominantly in the upper limbs, postural tremor, rigid gait with dystonic movements of both legs, brisk tendon reflexes and right clonus. EEG, EMG, and metabolic tests were unremarkable.

In T2-weighted FSE and FLAIR sequences, two bilateral, symmetric, hyperintense lesions can be observed in the antero-medial region of both globus pallidus, with surrounding hypointese, band-like areas that extend posteriorly. These areas are also observed in T2* and DWI (b=1500 s/mm2) sequences, due to susceptibility effects produced by iron deposits. T1-weighted images show fine, comma-shaped hypointense lesions in the antero-medial region of both globus pallidus. No other remarkable signal alterations were observed in the substantia nigra or in other regions of the basal ganglia. The findings described above are consistent with the eye-of-the-tiger sign, which is characteristic – although not pathognomonic - of pantothenate kinase-associated neurodegeneration.

PKAN, formerly known as Hallervorden-Spatz syndrome, is a rare disease (1-3 per million individuals [1]) with autosomal recessive inheritance caused by mutations in the PKAN2-gene. This gene codifies a protein kinase that phosphorylates pantothenate, which combines with cysteine and, in association with iron, produces free radicals and cell damage, accumulating in the globus pallidus in patients with PKAN [2].
Two different clinical presentations of PKAN can be distinguished, i.e. classic (75%) and atypical (25%) [1-3]. Classic PKAN is characterised by an early onset (mean age: 3 years) and fast progression. Clinically, the presenting features include dementia, Parkinsonism, spasticity, dystonia and clumsiness, with associated retinopathy in up to two-thirds of patients [1-3]. Atypical PKAN normally prompts later in life (13-14 years) and has a slower progression rate [1-3]. In contrast to classic PKAN, neuropsychiatric, e.g. attention deficit hyperactivity disorder, obsessive-compulsive disorder, depression or schizophrenia, and speech disorders predominate the clinical presentation [4], and are later followed by extrapyramidal symptoms [3].
When PKAN is suspected, MRI is a first-line exam, and should include iron-sensitive sequences, i.e. SWI, GRE, T2*, to best demonstrate the characteristic iron-deposits in the globus pallidus. The so-called eye-of-the-tiger sign is a hallmark for PKAN. This sign consists of hypointense areas of iron deposits that surround a region of hyperintense signal due to gliosis in both globus pallidus on T2-weighted images [1-4]. In rare cases, the eye-of-the-tiger sign is not found in patients with PKAN, although pre-symptomatic diagnosis of the disease by means of MRI findings has been described [1]. In a similar vein, this sign has been described in patients with other conditions (e.g. multiple system atrophy, neuroferritinopathy, mitochondrial membrane protein associated neurodegeneration, progressive supranuclear palsy) [1, 2]. Hypointense signal in the substantia nigra can also be found [1, 4].
In the appropriate clinical setting, a presumptive diagnosis can be made if the eye-of-the-tiger-sign is demonstrated on MRI, but genetic tests demonstrating PKAN2-gene mutations are required for its confirmation [2]. In this patient, the syndrome was confirmed by genetic tests that revealed a PKAN2-gene mutation. With regard to prognosis, there is no current curative treatment for PKAN, thus the management is primarily symptomatic and supportive [2-4]. With regard to disease course, PKAN is a neuroregressive disorder and skills lost are not regained [1]. Death normally occurs in the third decade –although atypical PKAN seems to be less aggressive than classic forms- due to respiratory infections, cardiorespiratory complications or malnutrition [1, 4].

Written informed patient consent for publication has been obtained.