A, Atypical PKAN; C, classic PKAN; y, years; m, male; f, female.
LETTER TO THE EDITOR
Novel gene mutations and clinical features in patients with pantothenate kinase-associated neurodegeneration
Article first published online: 1 APR 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 87, Issue 1, pages 93–95, January 2015
How to Cite
Ma, L.-Y., Wang, L., Yang, Y.-M., Lu, Y., Cheng, F.-B. and Wan, X.-H. (2015), Novel gene mutations and clinical features in patients with pantothenate kinase-associated neurodegeneration. Clinical Genetics, 87: 93–95. doi: 10.1111/cge.12341
- Issue published online: 20 DEC 2014
- Article first published online: 1 APR 2014
- Manuscript Accepted: 6 JAN 2014
- Manuscript Revised: 3 JAN 2014
- Manuscript Received: 13 NOV 2013
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 . 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.
|Patients||Sex/age, y||Age at onset, y||Exon||Mutation||Result||Clinical type||Gait disturbance||Tremor||Dystonic opisthotonus||Dysarthria||Dysphagia||Dystonia||Cognitive decline (MMSE)|
|PKAN-01||M/27||18||1||464_465 ins Ca||E156fs180X||A||+||−||−||+||+||−(29)|
|Chan et al. ||M/12||10||4||C1391T||P464L||A||+||−||c||+||−||+||−b|
|Wu et al. -1||M/48||Childhood||3||A1133G||D378G||A||+||+||c||+||−||+||+|
|Wu et al. -2||M/59||51||3||A1133G||D378G||A||+||−||c||+||−||+||−|
|Pan et al. ||M/12||T1555C||F519L||A||+||−||c||−||−||+||−|
|Mak et al. ||M/28||27||1||G445T||E149X||A||−||+||c||−||−||−||−|
|Zhang et al. ||M/27||17||3||A803G||D268G||A||+||c||+||+||+||−|
|Shan et al. -1||F/41||14||3||T1130C||F377S||A||+||+||c||+||+||+||−(28)|
|IVS1-2 A > T|
|Shan et al. -2||M/32||8||3||T1130C||F377S||A||+||+||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 . 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.
We thank all the participants in this study.
aDepartment of Neurology,
Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences,
bDepartment of Neurology,
Beijing Tiantan Hospital,
Capital Medical University,
|cge12341-sup-0001-FigureS1.docx||Word document||380K||Fig S1. Sequence analysis of PANK2 in six families.|
|cge12341-sup-0002-FigureS2.docx||Word document||53K||Fig S2. Cloning sequencing results of PKAN-03's father.|
|cge12341-sup-0003-TableS1.doc||Word document||398K||Table S1. Polymerase chain reaction (PCR) primers.|
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