Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans

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Abstract

Objective

Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea.

Methods

We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN).

Results

Four subtypes of NBIA including PKAN ( n = 30), PLA2G6-related neurodegeneration ( n = 2), beta-propeller protein-associated neurodegeneration ( n = 1), and aceruloplasminemia ( n = 1) have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG). Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN.

Conclusions

We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

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Most cited references 26

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Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.

Evelyn Botz, Thomas Meitinger, Ivana Novaković … (2006)

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by magnetic resonance imaging (MRI) changes in basal ganglia. Both missense and nonsense mutations have been found in such patients in a gene encoding the mitochondrial pantothenate kinase (PANK2). We completed a mutation screen in 72 patients with the diagnosis NBIA based on clinical findings and radiological imaging. The entire coding region of the PANK2 gene (20p12.3) was investigated for point mutations and deletions. We uncovered both mutant alleles in 48 patients. Deletions accounted for 4% of mutated alleles. Patients with two loss-of-function alleles (n = 11) displayed symptoms always at an early stage of life. In the presence of missense mutations (n = 37), the age of onset correlated with residual activity of the pantothenate kinase. Progression of disease measured by loss of ambulation was variable in both groups. We did not observe a strict correlation between the eye-of-the-tiger sign and PANK2 mutations. In 24 patients, no PANK2 mutation was identified. Deletion screening of PANK2 should be part of the diagnostic spectrum. Factors other than enzymatic residual activity are determining the course of disease. There are strong arguments in favor of locus heterogeneity.

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Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation

L. Timmermann, K A M Pauls, K. Wieland … (2010)

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale—Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

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Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration.

Volker Tronnier, Ute Thyen, Konstanze Hörtnagel … (2006)

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with onset in childhood and rapid progression. There is no causative and insufficient symptomatic drug therapy. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been reported to improve motor function. Most case reports, however, are limited to short observational periods. The impact of DBS on the progression and life expectancy in PKAN is unknown. We present a 5-year outcome and video documentation of bilateral GPi-DBS of an adolescent patient suffering from genetically defined PKAN. Copyright 2006 Movement Disorder Society.

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Author and article information

Journal

Journal ID (nlm-ta): J Mov Disord

Journal ID (iso-abbrev): J Mov Disord

Journal ID (publisher-id): JMD

Title: Journal of Movement Disorders

Publisher: The Korean Movement Disorders Society

ISSN (Print): 2005-940X

ISSN (Electronic): 2093-4939

Publication date (Print): January 2016

Publication date (Electronic): 25 January 2016

Volume: 9

Issue: 1

Pages: 20-27

Affiliations

[1 ]Department of Neurology, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea

[2 ]Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

[3 ]Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

[4 ]Department of Neurology, Seoul National University Hospital, Seoul, Korea

[5 ]Department of Neurology, Hallym University Sacred Heart Hospital, Anyang, Korea

[6 ]Department of Neurology, Yonsei University Wonju College of Medicine, Wonju, Korea

[7 ]Department of Pediatrics, Pusan National University Yangsan Hospital, Yangsan, Korea

[8 ]Department of Neurology, Gachon University Gil Hospital, Incheon, Korea

[9 ]Department of Neurology, Kangwon National University School of Medicine, Chuncheon, Korea

[10 ]Department of Neurology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea

[11 ]Department of Neurology, Pusan National University Hospital, Busan, Korea

[12 ]Department of Neurology, Dong-Eui Hospital, Busan, Korea

[13 ]Department of Neurology, Gangnam Severance Hospital, Seoul, Korea

[14 ]Department of Neurology, Korea University College of Medicine, Korea University Guro Hospital, Seoul, Korea

[15 ]Department of Neurology, Yonsei University College of Medicine, Seoul, Korea

[16 ]Department of Neurology, Yeungnam University Medical Center, Daegu, Korea

Author notes

Corresponding author: Jae-Hyeok Lee, MD, PhD, Department of Neurology, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea / Tel: +82-55-360-2453 / Fax: +82-55-360-2152 / E-mail: jhlee.neuro@ 123456pusan.ac.kr

Article

Publisher ID: jmd-15058

DOI: 10.14802/jmd.15058

PMC ID: 4734989

PubMed ID: 26828213

SO-VID: 5469188d-15ff-4ed0-926b-37fdba903a46

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 18 November 2015

Date revision received : 7 December 2015

Date accepted : 7 December 2015

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Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans

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Abstract

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Most cited references 26

Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.

Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation

Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration.

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Cited by 12

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