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Year : 2022  |  Volume : 70  |  Issue : 2  |  Page : 737--739

Novel Compound Heterozygous Mutation in PANK2 in a Patient with an Atypical Form of Pantothenate Kinase Associated Neurodegeneration and His Family

Jing Yuan1, Canling Zhanga2, Shan Qiao1, Aihua Wang1, Shanchao Zhang1,  
1 Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
2 Nursing Department, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China

Correspondence Address:
Dr. Shanchao Zhang
Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan


Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive disease characterized by iron accumulation in the brain due to PANK2 gene mutation. The typical “eye-of-the-tiger” sign is the characteristic manifestation of brain magnetic resonance imaging (MRI). We report a Chinese patient with atypical PKAN whose brain MRI scans displayed the typical “eye-of-the-tiger” sign in bilateral pallidum. Genetic analysis identified a compound heterozygous mutation (c. 629-2A > T, c. 1130T > C) for the PANK2 gene. These two mutations were further demonstrated in his parents and other relatives.

How to cite this article:
Yuan J, Zhanga C, Qiao S, Wang A, Zhang S. Novel Compound Heterozygous Mutation in PANK2 in a Patient with an Atypical Form of Pantothenate Kinase Associated Neurodegeneration and His Family.Neurol India 2022;70:737-739

How to cite this URL:
Yuan J, Zhanga C, Qiao S, Wang A, Zhang S. Novel Compound Heterozygous Mutation in PANK2 in a Patient with an Atypical Form of Pantothenate Kinase Associated Neurodegeneration and His Family. Neurol India [serial online] 2022 [cited 2022 Aug 15 ];70:737-739
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Full Text

PKAN is an autosomal recessive disorder due to PANK2 gene mutations.[1] Approximately half of the patients with neurodegeneration with brain iron accumulation (NBIA) are carriers of PANK2 mutations.[2] The clinical manifestations of PKAN are heterogeneous, including progressive dystonia, dysarthria, and corticospinal signs, in which parkinsonism, freezing of gait, and generalized dystonia are the characteristic motor manifestations.[3] Classical PKAN is characterized by an early onset in the first decade and a rapid progression, while the atypical phenotype manifests within the second and third decades of life, showing slower disease progression.[2] The “eye-of-the tiger” sign can be observed in both forms.[4] Here, we present the identification of novel compound PANK2 gene mutations (c.1130T>C, NM_153638; c. 629-2A>T, NM_153638) from a Chinese patient with atypical PKAN and his family.


The patient was the youngest child of a Chinese nonconsanguineous couple with unremarkable pregnancy and delivery history [Figure 1]a. His older brother and two other older sisters were healthy.

The 40-year-old man had delayed language acquisition and postural unsteadiness concomitant with frequent fall at the age of 9. He progressively developed slurred speech, rigidity, limb dystonia, and gait impairment as well as intellectual decline after disorder onset. Neurological examination showed impairment of intellectual development, strength, tendon reflexes, rigidity involving all limbs, and tremor on the left upper limb. Peripheral blood smear was negative for acanthocyte. Blood count test, biochemical evaluation, liver and renal function tests, serum ferritin, ceruloplasmin, albumin, and lipoproteins were within reference values. No K-F ring was observed using slit-lamp examination. Brain MRI represented the “eye-of-the-tiger” typical sign [Figure 1]b.{Figure 1}

Genomic DNA of the proband and other pedigree members was extracted from peripheral blood by using Genomic DNA Mini Kit (ThermoFisher). Whole-exome sequencing (WES) was performed using IDT xGenExome Research Panel v1 (Integrated DNA Technologies) for all subjects. DNA sequence analyses revealed compound heterozygous mutations in the PANK2 gene of the patient. The first one is located in intron 1 (c. 629-2A > T, NM_153638), which was predicted to cause ectopic PANK2 mRNA splice using dbscSNV ( and Mutation Taster ( The second one is located in exon 3 (c.1130T>C, NM_153638), leading to phenylalanine to serine substitution at position 377 (p.Phe377Ser) of the enzyme. This mutation was predicted to be damaging by SIFT ( and possibly damaging by Polyphen2 ( 2/). The father was the carrier of the first mutation c.629-2A>T, and the mother was the carrier of the second mutation c. 1130T>C [Figure 2]a. Multiple sequence alignment of the sequence region containing c.1130T>C indicated that amino acid residues were highly conserved across species through the analysis of UniProt ( [Figure 2]b. Genetic analysis in DNA from other relatives is listed in [Figure 2]c, indicating that the patient's older brother was the carrier of c. 1130T > C mutation from his mother, and his two older sisters were the carriers of c.629-2A>T mutation from their father. Furthermore, the patient's son as well as two children of the patient's elder sisters was the healthy carrier of c.629-2A>T mutation. The novel c.1130T>C and c.629-2A>T mutations were not present in DNA from 100 ethnically matched unrelated healthy controls (200 alleles). In addition, these two mutations are not annotated at the Exome Aggregation Consortium (ExAc; and the 1000 Genomes Project databases (www.{Figure 2}

Written informed consent was obtained from all of the participants prior to blood sample collection. This study was approved by the ethics committee of the First Hospital Affiliated with Shandong First Medical University.


In this report, we described an atypical PKAN patient with PANK2 mutation (c.629-2A>T, NM_153638, c.1130T>C, NM_153638). Based on the age of onset, symptoms, and progression in clinical manifestation, the patient was diagnosed as atypical form. Based on previous literature,[5],[6],[7] our report also suggested that great heterogeneity in the clinical manifestations of PKAN was partly due to variable mutation sites in the PANK2 gene, and the differences may be more evident among different races.

Variable types of mutations in the PANK2 gene could appear in classic and atypical forms, including splicing, missense, and nonsense mutations.[8] A recent study summarized 14 PANK2 gene mutations in Chinese PKAN patients, the most common being missense variants.[9] Herein, we found c.629-2A>T in intron 1 and c.1130T>C in exon 3 in the PKAN2 gene. Previous studies reported that almost all null mutations resulting in truncated proteins occurred in patients with the classic form, whereas missense mutations could maintain a residual PANK2 activity, which thus contributed to late-onset phenotypes and milder symptoms observed in atypical symptoms.[2] In our case, the disturbance of pre-mRNA splicing via c.629-2A>T was evaluated as pathogenic mutation (PVS1) according to ACMG/AMP sequence variant interpretation guidelines. Analogously, the mutation of c.1130T>C was considered as likely pathogenic for phylogenetic conservation across distinct species according to ACMG/AMP sequence variant interpretation guidelines. These PANK2 gene mutations may result in the impairment of PANK2 protein structure and function to some extent, causing the loss of coenzyme A and accumulation of cysteine-containing substrates.[10] Aberrant cysteine accumulation further leads to high production of free radicals in the presence of iron, exerting a toxic effect on cell energy metabolism.[11]


PKAN is a main subtype of NBIA commonly seen in childhood and adolescence. Characteristic MRI findings with genetic examination could shed light on the diagnosis of PKAN. Further research is required to elucidate treatment and management options.


We thank the patient and his family members for participation.

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.

Financial support and sponsorship

This study was supported by grants from the Natural Science Foundation of Shandong Province, China (No. ZR2016HP04 and No. ZR2019MH062) and the National Natural Science Foundation of China (No. 81601020).

Conflicts of interest

There are no conflicts of interest.


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