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To the Editor:

Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz syndrome, is a rare autosomal recessive degenerative brain disease because of mutations in the pantothenate kinase 2 (PANK2) gene [1]. Until now, no specific genotype–phenotype correlations have been identified.

We identified six Chinese patients with sporadic PKAN, all of whom revealed the typical ‘eye of the tiger’ sign upon brain magnetic resonance imaging (MRI). PANK2 mutational analyses were conducted in all patients and their available family members. Informed consents were obtained and blood samples were collected. The genotypes and clinical correlates of patients are presented in Fig. 1 and Table 1.

image

Figure 1. (a) Patients with compound heterozygous PANK2 gene mutations and their family members. The blackened squares denote the number of patients. (b) ‘Eye of the tiger sign’ of patients PKAN-02, 03 and 04 in T2-magnetic resonance imaging (MRI) image.

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Table 1. Genetic and clinical findings in 14 patients with pantothenate kinase-associated neurodegeneration (PKAN)
PatientsSex/age, yAge at onset, yExonMutationResultClinical typeGait disturbanceTremorDystonic opisthotonusDysarthriaDysphagiaDystoniaCognitive decline (MMSE)
  1. A, Atypical PKAN; C, classic PKAN; y, years; m, male; f, female.

  2. a

    Novel genes.

  3. b

    MMSE is normal but showed poor academic performance.

  4. c

    Dystonic opisthotonus symptom were not recorded.

PKAN-01M/27181464_465 ins CaE156fs180XA++ +−(29)
   3C1193TaA397V        
PKAN-02M/16131T398AaM111KA++ +−(28)b
   2G970TaD324Y        
PKAN-03M/15102C745TaR249WA+++ +−(28)
   2G970TaD324Y        
   3A1133GD378G        
PKAN-04M/46244A1411GaR471GA+++ +−(29)
   5A1510GaI504V        
PKAN-05M/40302G970TaD324YA++ −(29)
   3A1133GD378G        
PKAN-06M/26223A1133GD378GA++ +−(27)b
   5A1499TaN500I        
Chan et al. [2]M/12104C1391TP464LA+c++b
Wu et al. [3]-1M/48Childhood3A1133GD378GA++c+++
   4A1355GD452G        
Wu et al. [3]-2M/59513A1133GD378GA+c++
   4A1355GD452G        
Pan et al. [4]M/12  T1555CF519LA+c+
    A1607GY536C        
Mak et al. [5]M/28271G445TE149XA+c
   3A1133GD378G        
Zhang et al. [6]M/27173A803GD268GA +c+++
   5T1172AI391N        
Shan et al. [7]-1F/41143T1130CF377SA++c+++−(28)
    IVS1-2 A > T         
Shan et al. [7]-2M/3283T1130CF377SA++c++++(18)
    IVS1-2 A > T         

Nine missense mutations (D378G, E156fs180X, A397V, M111K, D324Y, R249W, R471G, I504V and N500I) were identified, all of which were not detected in 100 normal controls (see Supporting Information). All but D378G were novel. All cases have compound heterozygotes of maternal and paternal origin except for PKAN-03. Interestingly, we detected three PANK2 mutations in PKAN-03. His father, who was healthy and asymptomatic, had two mutations in PANK2, R249W and D378G. R249W, though not reported before, was predicted to be deleterious by sift (http://sift.jcvi.org/) and polyphen software (http://genetics.bwh.harvard.edu/pph2/).

To date, >100 mutations have been documented worldwide. In our study, D378G and D324Y were the most common alleles, found in 3/6 cases separately (50%). Extending the data to include six previously reported unrelated patients of Chinese origin in the analysis [2-7] (Table 1), the most prevalent mutation was D378G (5/12, 41.7%) followed by D324Y (3/12, 25%), which are quite different from European and Korean subjects.

A rare phenomenon was found in PKAN-03 who had three mutations in the PANK2 gene. This is quite rare, though it has been reported in a patient with atypical PKAN [8]. His father, who has no neurological symptoms, had two mutations. Clone sequencing revealed that the two mutations were on the same chromosome so that the activity of pantothenate kinase-2 was relatively normal (see Supporting Information). This is the first individual who has compound heterozygous mutations in the PANK2 gene but without PKAN.

The three most common symptoms of PKAN are gait disturbance (12/14), dysarthria (12/14) and dystonia (11/14) (Table 1). Dystonic opisthotonus was seen in two of our cases and the prevalence was 33.3% (2/6). We reviewed the clinical features of all cases of Chinese origin with D378G and D324Y mutations, but found no specific genotype–phenotype correlations.

In conclusions, we identified eight novel compound heterozygous mutations in the PANK2 gene and expanded the gene-mutation pool for PKAN. D378G and D324Y are commonly affected alleles and are probably ‘hotspots’ in PKAN patients of Chinese origin.

Acknowledgements

We thank all the participants in this study.

  • L.-Y. Maa,b

  • L. Wanga

  • Y.-M. Yanga

  • Y. Lua

  • F.-B. Chenga

  • X.-H. Wana

  • aDepartment of Neurology,

  • Peking Union Medical College Hospital,

  • Chinese Academy of Medical Sciences,

  • Beijing

  • China

  • bDepartment of Neurology,

  • Beijing Tiantan Hospital,

  • Capital Medical University,

  • Beijing

  • China

References

  1. Top of page
  2. References
  3. Supporting Information
  • 1
    Zhou B, Westaway SK, Levinson B et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001: 28 (4): 345349.
  • 2
    Chan KY, Lam CW, Lee LP, Tong SF, Yuen YP. Pantothenate kinase-associated neurodegeneration in two Chinese children: identification of a novel PANK2 gene mutation. Hong Kong Med J 2008: 14 (1): 7073.
  • 3
    Wu YR, Chen CM, Chao CY, Lyu RK, Lee-Chen GJ. Pantothenate kinase-associated neurodegeneration in two Taiwanese siblings: identification of a novel PANK2 gene mutation. Mov Disord 2009: 24 (6): 940941.
  • 4
    Pan LS, Yu LH, Yin YY, Xu YM. A novel PANK2 mutation in a 12-year-old Chinese boy with pantothenate kinase-associated neurodegeneration. Neurol India 2013: 61 (2): 175176.
  • 5
    Mak CM, Sheng B, Lee HH et al. Young-onset parkinsonism in a Hong Kong Chinese man with adult-onset Hallervorden-Spatz syndrome. Int J Neurosci 2011: 121 (4): 224227.
  • 6
    Zhang YH, Tang BS, Zhao AL et al. Novel compound heterozygous mutations in the PANK2 gene in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration. Mov Disord 2005: 20 (7): 819821.
  • 7
    Shan J, Wen B, Zhu J, Lin P, Zheng J, Yan C. Novel PANK2 gene mutations in two Chinese siblings with atypical pantothenate kinase-associated neurodegeneration. Neurol Sci 2013: 34 (4): 561563.
  • 8
    Seo JH, Song SK, Lee PH. A novel PANK2 mutation in a patient with atypical pantothenate-kinase-associated neurodegeneration presenting with adult-onset parkinsonism. J Clin Neurol 2009: 5 (4): 192194.

Supporting Information

  1. Top of page
  2. References
  3. Supporting Information
FilenameFormatSizeDescription
cge12341-sup-0001-FigureS1.docxWord document380KFig S1. Sequence analysis of PANK2 in six families.
cge12341-sup-0002-FigureS2.docxWord document53KFig S2. Cloning sequencing results of PKAN-03's father.
cge12341-sup-0003-TableS1.docWord document398KTable S1. Polymerase chain reaction (PCR) primers.

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