Clinical ObservationsIdiopathic Basal Ganglia Calcifications: An Atypical Presentation of PKAN
Introduction
Pantothenate kinase–associated neurodegeneration (PKAN) (OMIM #234200), a rare autosomal recessive disorder resulting from mutations in the pantothenate kinase 2 gene (PANK2), is characterized by progressive extrapyramidal dysfunction and iron accumulation in the basal ganglia. The classic eye-of-the-tiger sign seen on T2-weighted magnetic resonance imaging (MRI) scan refers to symmetrical rings of hypointensity representing iron deposition in the globus pallidi, with a central spot of high signal that may be due to gliosis or edema. This characteristic neuroimaging finding has been considered pathognomonic for PKAN.1, 2
Patients with idiopathic basal ganglia calcification (IBGC), previously known as Fahr's disease, experience similar clinical symptoms as those with PKAN, but neuroimaging studies reveal basal ganglia calcifications as opposed to iron deposits. The underlying cause of IBGC remains unknown. We describe a teenage girl with clinical features of IBGC, but who was found to have a compound heterozygote for two disease-causing mutations in exon 6 of the PANK2 gene, confirming a diagnosis of PKAN.
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Patient and Methods
A 14-year-old black girl presented with involuntary hand movements and slowly progressive hand, neck, and oromandibular dystonia. She developed subtle behavioral changes including emotional lability and impulsivity. By age 18 she suffered severe dystonia of the jaw, tongue, neck, and arms; significant dysarthria and bradykinesia; and a mildly abnormal gait. Her cognition remained normal, and she was an excellent student. Family history was noncontributory, including two unaffected half maternal
Results
Exome analysis for the family trio did not uncover homozygous recessive or predicted pathogenic de novo changes in disease-associated genes. Examinations of exonic changes present in a compound heterozygote state uncovered two missense mutations in PANK2 (exon6: g.1561G>A + g.1583C>T, p.G521R + p.T528M, transcript uc002wkc.3) of maternal and paternal origin, respectively, leading to changes to highly conserved amino acids that are known to be disease associated with PKAN (Fig 2).4 We also found
Discussion
We report a patient with genetically confirmed PKAN presenting as IBGC, previously known as Fahr's disease. This case illustrates how whole exome sequencing can expand our understanding of rare neurodegenerative syndromes and establishes PANK2 mutations as a newly recognized cause of IBGC. This case also expands the phenotypic spectrum of PKAN to include patients who exhibit globus pallidi calcifications and no eye-of-the-tiger sign.
PKAN accounts for about half of all patients with NBIA.1 In
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Cited by (27)
Abnormal Brain Iron Accumulation is a Rare Finding in Down Syndrome Regression Disorder
2023, Pediatric NeurologyCitation Excerpt :Across the NBIA disorders, the temporal and anatomic patterns of iron accumulation are varied and do not correlate with clinical course, suggesting that iron accumulation is not a primary pathophysiology but rather a secondary effect. For example, with disease progression in pantothenate kinase-associated neurodegeneration, initial hyperintense signal later becomes dominated by hypointense iron signal on T2-weighted images, and calcium deposits may occasionally develop in the GP.11,12 Prior surveys by imaging and postmortem pathologic examinations suggest that BG calcification in DS occurs frequently, may be more common with age, and is not usually associated with any neurological symptoms.13
Basal ganglia calcification
2020, Revue de Medecine InterneNovel PANK2 mutation discovered among South East Asian children living in Thailand affected with pantothenate kinase associated neurodegeneration
2019, Journal of Clinical NeuroscienceCitation Excerpt :PANK2 mutations were identified in all five cases (100%). Only one case in our series (C.O.) revealed an allele carrying the known pathogenic mutation p.Thr528Arg that has been described elsewhere; all other mutations detected in our study were novel [4,19]. Four of five cases carried a novel splicing mutation at c.982-1 or IVS2-1 G>C that met criteria as a likely pathogenic variant according to the standard guideline provided by American College of Medical Genetics and Genomics (ACMG) [20].
Intracranial Calcifications in Young Children
2018, Seminars in Pediatric NeurologyAtypical pantothenate kinase-associated neurodegeneration: Clinical description of two brothers and a review of the literature
2017, Revue NeurologiqueCitation Excerpt :A molecular study was again not performed due to the lack of its availability in Algeria. To determine the various clinical presentations and ages of onset for atypical PKAN, a review of the literature was carried out to identify all published cases with positive PANK2 mutations (Table 1) [4–22]. It is worth noting that optic atrophy, dysmorphia syndrome and a weak atrophic tongue are uncommon presentations of atypical PKAN; the most common one is dystonia and, often, craniocervical dystonia, leading to dysarthria and swallowing difficulties.
Basal ganglia calcification in a case of PKAN
2017, Parkinsonism and Related Disorders