Atypical Pantothenate Kinase-Associated Neurodegeneration with Variable Phenotypes in an Egyptian Family

Atypical Pantothenate Kinase-Associated Neurodegeneration with Variable Phenotypes in an Egyptian Family | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Atypical Pantothenate Kinase-Associated Neurodegeneration with Variable Phenotypes in an Egyptian Family Ali Shalash, Thomas Rösler, Ibrahim Abdelrahman, Hatem Abulmakarem, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-324151/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pantothenate kinase-associated neurodegeneration (PKAN) is a rare hereditary neurodegenerative disease characterized by an accumulation of iron within the brain. In the present report, we describe a family with 4 affected siblings presenting with variable clinical manifestations, e.g., parkinsonian features, dystonia and slow disease progression over 5 years. Exome sequencing revealed a causative variant in the pantothenate kinase 2 gene ( PANK2 ). Variant NM_024960.6:c.710C > T was homozygous in all affected subjects. Our report describes the first genetically confirmed cases of PKAN in the Egyptian population. Studying genetics of neurodegenerative diseases in different ethnicities is very important for determining clinical phenotypes and understanding pathomechanisms of these diseases. Neurology Pantothenate kinase-associated neurodegeneration PANK2 neurodegeneration iron accumulation genetics Figures Figure 1 Figure 2 Introduction Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative disease characterized by abnormal accumulation of iron in distinct brain areas. It has an estimated worldwide incidence of 2 affected individuals in 1 million which is even lower among the African population (Brezavar and Bonnen 2019 ). However, in the heterogenous group of neurodegenerative disorders with brain iron accumulation (NBIA), it is considered to be the most common (Hayflick et al. 2003 ;Hartig et al. 2006 ). PKAN is a genetically inheritable disease following an autosomal recessive pattern with causative mutations in the pantothenate kinase 2 ( PANK2 ) gene. Pantothenate kinases control the biosynthesis of the coenzyme A (Zhou et al. 2001 ). Clinically, PKAN shows a wide range of signs and symptoms including motor manifestations, e.g., dystonia, parkinsonism, dysarthria, dysphagia and spasticity, psychiatric and cognitive impairment as well as oculomotor disturbances (Lee et al. 2016 ). According to age of onset and disease progression, PKAN is classified into typical and atypical types. Atypical PKAN is characterized by later onset and slower progression (Hartig et al. 2006 ). Genetic determinants of PKAN, however, are not well characterized. Additionally, the current knowledge about PKAN is mainly built on individual case reports and case series (Marshall et al. 2019 ). The disease progression, severity of symptoms and even correlation between specific mutations and the disease phenotype is highly variable (Tomic et al., 2015 ). Neurogenetic studies about PKAN are scarce in North Africa. So far, only one case report described a female patient with PKAN in a consanguineous Moroccan family, identifying a causative homozygous deletion in PANK2 (Efthymiou et al., 2020 ). In the present study, we describe an Egyptian family with 4 affected members revealing slow progression of atypical PKAN. The patients had different ages of onset and showed variable clinical presentations (parkinsonism, dystonia), normal serum ferritin levels, absence of acanthocytes, the brain MRI characteristic eye-of-the-tiger sign, all caused by the same homozygous mutation in PANK2 . Materials And Methods Ethics Statement The family presented to the Movement Disorders Clinic, Department of Neurology at Ain Shams University Cairo, where six members (affected and healthy) were examined by three movement disorders experts (A.S.S., F.H. and G.U.H.). Blood samples were collected from healthy and affected members. Standard brain MRI at 1.5 Tesla with T1-, T2-, and FLAIR-sequences of patients II.3 and II.10 was performed. Ethical approval was obtained from Mansoura University, Egypt (RP/42) and Technical University of Munich, Germany (203/15s). All participants provided an informed consent. Cases The examined family consisted of fourth-degree consanguineous parents and 10 children (see Fig. 1 ). The father had a history of psychiatric illness (psychosis). In total, four children were affected. Patient II.3 presented at age 38 mainly parkinsonian features (i.e., bradykinesia, rigidity and kinetic tremor), which had started at age 30, and were followed by open jaw dystonia and depression. Patients II.4 and II.10 were presented at ages 32 and 17 respectively with generalized dystonia including open jaw dystonia, upper limb dystonia, associated with dysarthria, agitation, and behavioral changes. Age at symptom onset of patients II.4 and II.10 was 15 and 7 years, respectively. Patient II.9 died at age 23. He had a history of forced eyelid closure and open jaw dystonia which started at age 18. The patients were re-assessed 5 years after the initial clinical examination and showed mild progression of their symptoms with normal or minimally impaired gait (see Table 1 ). Table 1 Clinical characteristics of PKAN patients. Features Patient II.3 Patient II.4 Patient II.10 Sex Female Female Male Age at presentation (y) 38 32 17 Age of onset (y) 30 15 7 Disease duration (y) 8 17 10 Symptoms at onset Dysarthria, UL bradykinesia Tongue protrusion, open jaw dystonia Behavioral changes, open jaw dystonia Open jaw dystonia Mild, sensory tricks Present Severe Tongue protrusion - Repeated Occasional Limb dystonia - Present; more in UL (generalized dystonia) Present; more in UL (generalized dystonia) Dysarthria Present Present Severe (anarthria) Dysphagia - Present Present Stuttering Present - - Choking - Present Present Sialorrhea - - Present Parkinsonism Present; symmetrical bradykinesia, rigidity, kinetic tremor, mainly UL, no response to levodopa Present; mild rigidity of UL - Pyramidal weakness Present Present - Spasticity Present Present - Plantar reflex Extensor Extensor Flexor Deep tendon reflexes Exaggerated Exaggerated Exaggerated Depression Present Present - Anxiety Present Present - Agitation Occasional Occasional Present Behavioral changes - - Present Cognition Average (MMSE 26/30) Impaired (MMSE 14/27) No reported impairment Fundus Normal Normal Normal Serum ferritin Normal (188 ng/mL) Normal (210 ng/mL) Normal (199.5 ng/mL) Blood acanthocytosis Absent Absent Absent Brain MRI scan Eye-of-the-tiger-sign Not available Eye-of-the-tiger-sign Course of disease Slowly progressing, mild worsening of OJD Slowly progressing Slowly progressing, mild worsening of LL dystonia OJD, Open jaw dystonia; UL, upper limbs; LL, lower limbs All patients had normal serum ferritin levels and did not show blood acanthocytosis. Brain magnetic resonance imaging (MRI) was done for patients II.3 and II.10 revealing the characteristic eye-of-the-tiger sign (see Fig. 2 a, b). Genetic Analyses Exome sequencing was performed in the two affected individuals II:4 and II:10. Genomic DNA libraries were captured using the Nextera Rapid Capture Expanded Exome Kit (Illumina, San Diego, CA), and DNA fragments were sequenced on an Illumina HiSeq2000 system with an average coverage of 80x. Variants were identified by a standard analysis pipeline and annotated using ANNOVAR (Wang et al. 2010 ). We discarded variants with a minor allele frequency (MAF) > 0.01 in gnomAD (Genome Aggregation Database, https://gnomad.broadinstitute.org ) “all” exome as well as genome data. We discarded variants without an annotated exonic or splicing function and variants with a CADD (Combined Annotation Dependent Depletion) score below 15 (Kircher et al. 2014 ). Since the parents are related, we assumed autosomal recessive inheritance and homozygosity of the causative variant. However, to guarantee of not missing any variants of importance, we filtered for variants present in both II:4 and II:10 but not for homozygosity. We filtered for specific genes with the symbols ATP13A2 , C19orf12 , COASY , CP , DCAF17 , FAH2 , FTL , PANK2 , PLA2G6 , WDR45 known to harbor variants causing NBIA and related phenotypes. The filtering resulted in only one homozygous variant in the PANK2 gene, NM_024960.6:c.710C > T causing the amino acid change NP_079236.3:p.Thr237Met in the PANK2 protein in both exome sequenced affected family members (see Table 2 and Fig. 1 ). Segregation of this variant was ascertained by Sanger sequencing of all family members of whom DNA was available. We confirmed the presence of the variant and showed that patient II:3 also carries this variant in the homozygous state. The mother I:1 is a heterozygous carrier of the variant and her healthy son II:2 did not show this variant (see Fig. 1 ). DNA samples of the father I:2, the deceased affected brother II:9 and other siblings were not available for analysis. Table 2 Identified variant in the PANK2 gene (GRCh38/hg38) Genetic finding Variant Chromosome level chr20.hg38:g.3918717C > T Genomic level NC_000020.11:g.3918717C > T Coding sequence level NM_024960.6:c.710C > T Protein level NP_079236.3:p.Thr237Met CADD (Phred-scaled) 22 MutationTaster (score/ class) 0.926/deleterious PolyPhen-2 HVAR (score/ class) 0.242/benign gnomAD exomes (MAF, nr. of alleles analyzed) 0.000012 dbSNP (153 all) rs137852967 HGMD (public 01.08.21) Not listed ClinVar Pathogenic, multiple submitters, no conflict CADD, Combined Annotation Dependent Depletion; dbSNP, database of single nucleotide polymorphism; gnomAD, Genome Aggregation Database; HGMD, Human Gene Mutation Database; MAF, minor allele frequency The effects of amino acid substitutions on protein function were predicted using MutationTaster (Schwarz et al. 2014 ), PolyPhen-2 (Adzhubei et al. 2010 ), and CADD (Rentzsch et al. 2019 ). Furthermore, we searched the public version of the Human Gene Mutation Database (Stenson et al. 2020 ) and ClinVar (Landrum et al. 2018 ) for the variant (see Table 2 ). Discussion In the last two decades, genetic research in neurodegenerative diseases has tremendously progressed, especially through focused analyses of families with Mendelian mode of inheritance in different populations. However, such progress is not globally oriented. Including more genetic findings from understudied populations such as Africans, will help to identify variable phenotypes, enhance discoveries and offer better understanding of the diseases’ pathophysiology and genotype-phenotype correlation. Our report confirms the pathogenicity of the PANK2 variant NM_024960.6:c.710C > T which causes PKAN. Although this variant has been described before, this is the first report of a pathogenic PANK2 variant in the Egyptian population. Homozygous and compound heterozygous variants in PANK2 have been identified as the most common cause of NBIA (Zhou et al. 2001 ;Hayflick et al. 2003 ). The here identified variant has been reported by multiple submitters to the ClinVar database (Landrum et al. 2018 ) as pathogenic and can be found in other published genetic studies of NBIA (Hartig et al. 2006 ) but is not listed in the public version of the HGMD (Human Gene Mutation Database). Because the homozygous state of this variant segregates in the examined Egyptian family with the disease and has already been shown to be pathogenic, it is clearly the cause of NBIA in this Egyptian family. Several variants in PANK2 have been identified in PKAN cases. The most common is the PANK2 variant G521R which accounts for approximately 30% of cases (Zhou et al. 2001 ). This variant leads to a catalytically inactive Pank2 protein due to improper folding (Zhang et al. 2006 ). As Pank2 is localized to the mitochondria where it is a key enzyme in the biosynthesis of coenzyme A (Leonardi et al. 2007 ), influencing important metabolic processes, nonfunctional Pank2 proteins have a tremendous influence on cell energy processes. However, the PANK2 variant (T528M) which we have identified in the Egyptian family is less common for PKAN and does not induce catalytic or regulatory deficits (Zhang et al. 2006 ). This implies that other presently unknown effects and functions of this variant might contribute to its pathogenicity. Remarkably, the identified PANK2 mutation led to variable phenotypes and ages of onset within the same family. Previous studies reported the mutation to cause predominant open jaw dystonia, limb dystonia, and dysarthria (Hartig et al. 2006 ;Tomic et al. 2015 ;Yapici et al. 2016 ). Predominant parkinsonism was less commonly reported (Chang et al. 2020 ). However, in the present family we could observe combinations of these symptoms. The affected members showed early cranial symptoms and a slow course of disease progression compared to previous reports (Tomic et al. 2015 ). This milder course of late onset PKAN revealed no contractures and preserved ambulation, however, further follow-up is required. Our finding of a clinical variability within the reported family confirms the relevance of atypical PKAN as a differential diagnosis for familial movement disorders with variable phenotypes such as Wilson’s disease (Schneider et al. 2006 ;Shalash et al. 2014 ). Conclusion The current report describes variable clinical phenotypes and disease progression of atypical PKAN in affected members of an Egyptian family. To the best of our knowledge, it is the second report of a family with PKAN in Africa. These findings add to our knowledge about the genetics of this disease in North Africa. Declarations AUTHOR CONTRIBUTIONS All authors contributed to the study concept and design. ASS, MS, GK, TWR, FH, GUH and SHM collected and analyzed data. ASS, GUH, HSA, FH and GK carried out medical examinations. MS, ASS, TWR and GK drafted the manuscript. All authors corrected and approved the final manuscript. FUNDING This work was supported by the German Academic Exchange Service (DAAD) through the funding programme “Higher Education Dialogue with the Muslim World”, project “GeneFINDER”. ACKNOWLEDGEMENTS We would like to thank Lena Jaschkowitz for technical assistance. CONFLICT OF INTEREST The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. DATA AVAILABILITY The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-324151","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":17288844,"identity":"a87cc061-e7b1-4406-88cf-98d403c7f774","order_by":0,"name":"Ali Shalash","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"Shalash","suffix":""},{"id":17288845,"identity":"9f542ab4-fc1d-4f42-aae8-52a0eeb6a9bd","order_by":1,"name":"Thomas Rösler","email":"","orcid":"","institution":"Technical University of Munich: Technische Universitat Munchen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Rösler","suffix":""},{"id":17288846,"identity":"822d74a0-4117-4c38-8e46-d21bfffd4930","order_by":2,"name":"Ibrahim Abdelrahman","email":"","orcid":"","institution":"Egyptian Atomic Energy Authority","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ibrahim","middleName":"","lastName":"Abdelrahman","suffix":""},{"id":17288847,"identity":"a744b678-bba3-4e52-b0fc-2a58f3bc4ff0","order_by":3,"name":"Hatem Abulmakarem","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hatem","middleName":"","lastName":"Abulmakarem","suffix":""},{"id":17288848,"identity":"4fbfc104-67dd-4638-bc24-b2d8d11653e2","order_by":4,"name":"Stefanie Müller","email":"","orcid":"","institution":"UCL: University College London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stefanie","middleName":"","lastName":"Müller","suffix":""},{"id":17288849,"identity":"16a24dd3-e256-487d-a7f3-71ab0f00cf51","order_by":5,"name":"Franziska Hopfner","email":"","orcid":"","institution":"Hannover Medical School: Medizinische Hochschule Hannover","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Franziska","middleName":"","lastName":"Hopfner","suffix":""},{"id":17288850,"identity":"b90ff330-1895-440a-9530-15c6a2af5b6f","order_by":6,"name":"Gregor Kuhlenbäumer","email":"","orcid":"","institution":"Kiel University: Christian-Albrechts-Universitat zu Kiel","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gregor","middleName":"","lastName":"Kuhlenbäumer","suffix":""},{"id":17288851,"identity":"dcffcc2e-4270-41b4-ade7-206a0a89aea1","order_by":7,"name":"Günter Höglinger","email":"","orcid":"","institution":"Hannover Medical School: Medizinische Hochschule Hannover","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Günter","middleName":"","lastName":"Höglinger","suffix":""},{"id":17288852,"identity":"22a5c415-9180-4df0-9428-e0c2cf40262a","order_by":8,"name":"Mohamed Salama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYJCCA0AsA8SMj8FcZuYGvMp5oFpANLMxA4MBkGIkrAVGs0mDtTAQ0GLP3mN44McfOx7+aYefVRdU/Inmbwdq+VGxDbctPMcSDva2JfNI3E4zuz3jjEHujMOMDYw9Z27j1iKRfACohpmH4XaC2W3eNoPcBhCXsQ2flsSGwwx/6nnkb6d/KwZpmU9YC9AWBrbDPAa3c8yYQVo2ENRyBuyX4zyGt3OKpXnOGOduBGo5iM8v7O09xh9+/KmWk7udvvEzT4Vc7rzzhw8++FGBWwt2cIBE9aNgFIyCUTAK0AAAIDhW4svFjoUAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-1644-0273","institution":"The American University in Cairo","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Salama","suffix":""}],"badges":[],"createdAt":"2021-03-13 08:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-324151/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-324151/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":7172247,"identity":"1df3d4d2-9e3d-4735-8579-6f95ee4903de","added_by":"auto","created_at":"2021-03-19 22:55:07","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":235385,"visible":true,"origin":"","legend":"Pedigree of the examined family. The unaffected consanguineous parents (double line) had 10 children. Four children developed PKAN (black filling), two female (circle) and two male (square), of whom one already had deceased (diagonal slash). The genotypes of PANK2 variant NM_024960.6:c.710C\u003eT are shown for all family members who provided DNA.","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-324151/v1/926acfdfe87297f1ea5a049f.jpeg"},{"id":7172597,"identity":"c02cb23b-0f03-4ce4-8b32-de5cab805f09","added_by":"auto","created_at":"2021-03-19 22:58:07","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":767818,"visible":true,"origin":"","legend":"Brain MRI scans of PKAN-affected family members. Images show axial brain MRI scans of patient II.3 (A, FLAIR) and II.10 (B, T2WI) with hyperintensity surrounded by hypointensity of globus pallidus with the characteristic eye-of-the-tiger sign.","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-324151/v1/628c1b2c1210b338ea808d8b.jpeg"},{"id":13682227,"identity":"18bbe305-b4a0-4143-ae37-69f4fefe4782","added_by":"auto","created_at":"2021-09-17 11:56:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":332522,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-324151/v1/dd6f6373-3df7-4792-87da-6b2020f421f2.pdf"}],"financialInterests":"","formattedTitle":"Atypical Pantothenate Kinase-Associated Neurodegeneration with Variable Phenotypes in an Egyptian Family","fulltext":[{"header":"Introduction","content":" \u003cp\u003ePantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative disease characterized by abnormal accumulation of iron in distinct brain areas. It has an estimated worldwide incidence of 2 affected individuals in 1\u0026nbsp;million which is even lower among the African population (Brezavar and Bonnen \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). However, in the heterogenous group of neurodegenerative disorders with brain iron accumulation (NBIA), it is considered to be the most common (Hayflick et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2003\u003c/span\u003e;Hartig et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). PKAN is a genetically inheritable disease following an autosomal recessive pattern with causative mutations in the pantothenate kinase 2 (\u003cem\u003ePANK2\u003c/em\u003e) gene. Pantothenate kinases control the biosynthesis of the coenzyme A (Zhou et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2001\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinically, PKAN shows a wide range of signs and symptoms including motor manifestations, e.g., dystonia, parkinsonism, dysarthria, dysphagia and spasticity, psychiatric and cognitive impairment as well as oculomotor disturbances (Lee et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). According to age of onset and disease progression, PKAN is classified into typical and atypical types. Atypical PKAN is characterized by later onset and slower progression (Hartig et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Genetic determinants of PKAN, however, are not well characterized. Additionally, the current knowledge about PKAN is mainly built on individual case reports and case series (Marshall et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The disease progression, severity of symptoms and even correlation between specific mutations and the disease phenotype is highly variable (Tomic et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNeurogenetic studies about PKAN are scarce in North Africa. So far, only one case report described a female patient with PKAN in a consanguineous Moroccan family, identifying a causative homozygous deletion in \u003cem\u003ePANK2\u003c/em\u003e (Efthymiou et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In the present study, we describe an Egyptian family with 4 affected members revealing slow progression of atypical PKAN. The patients had different ages of onset and showed variable clinical presentations (parkinsonism, dystonia), normal serum ferritin levels, absence of acanthocytes, the brain MRI characteristic eye-of-the-tiger sign, all caused by the same homozygous mutation in \u003cem\u003ePANK2\u003c/em\u003e.\u003c/p\u003e "},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eEthics Statement\u003c/h2\u003e\u003cp\u003eThe family presented to the Movement Disorders Clinic, Department of Neurology at Ain Shams University Cairo, where six members (affected and healthy) were examined by three movement disorders experts (A.S.S., F.H. and G.U.H.). Blood samples were collected from healthy and affected members. Standard brain MRI at 1.5 Tesla with T1-, T2-, and FLAIR-sequences of patients II.3 and II.10 was performed. \u003cdiv class=\"Ethics-ToolTip\"\u003eEthical approval was obtained from Mansoura University, Egypt (RP/42) and Technical University of Munich, Germany (203/15s).\u003c/div\u003e\u003cdiv class=\"Ethics-ToolTip\"\u003eAll participants provided an informed consent.\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eCases\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"Ethics-ToolTip\"\u003eThe examined family consisted of fourth-degree consanguineous parents and 10 children (see Fig.\u003c/div\u003e\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The father had a history of psychiatric illness (psychosis). In total, four children were affected. Patient II.3 presented at age 38 mainly parkinsonian features (i.e., bradykinesia, rigidity and kinetic tremor), which had started at age 30, and were followed by open jaw dystonia and depression. Patients II.4 and II.10 were presented at ages 32 and 17 respectively with generalized dystonia including open jaw dystonia, upper limb dystonia, associated with dysarthria, agitation, and behavioral changes. Age at symptom onset of patients II.4 and II.10 was 15 and 7 years, respectively. Patient II.9 died at age 23. He had a history of forced eyelid closure and open jaw dystonia which started at age 18. The patients were re-assessed 5 years after the initial clinical examination and showed mild progression of their symptoms with normal or minimally impaired gait (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of PKAN patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFeatures\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatient II.3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatient II.4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePatient II.10\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at presentation (y)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge of onset (y)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease duration (y)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSymptoms at onset\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDysarthria, UL bradykinesia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTongue protrusion, open jaw dystonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBehavioral changes, open jaw dystonia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOpen jaw dystonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMild, sensory tricks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSevere\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTongue protrusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRepeated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOccasional\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLimb dystonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent; more in UL (generalized dystonia)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePresent; more in UL (generalized dystonia)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDysarthria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSevere (anarthria)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDysphagia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStuttering\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChoking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSialorrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParkinsonism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent; symmetrical bradykinesia, rigidity, kinetic tremor, mainly UL, no response to levodopa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent; mild rigidity of UL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePyramidal weakness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpasticity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlantar reflex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExtensor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExtensor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFlexor\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeep tendon reflexes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExaggerated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExaggerated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExaggerated\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDepression\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnxiety\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAgitation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOccasional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOccasional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBehavioral changes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCognition\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAverage (MMSE 26/30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eImpaired (MMSE 14/27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo reported impairment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFundus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum ferritin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNormal (188 ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal (210 ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal (199.5 ng/mL)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood acanthocytosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBrain MRI scan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEye-of-the-tiger-sign\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNot available\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEye-of-the-tiger-sign\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCourse of disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSlowly progressing, mild worsening of OJD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSlowly progressing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSlowly progressing, mild worsening of LL dystonia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eOJD, Open jaw dystonia; UL, upper limbs; LL, lower limbs\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAll patients had normal serum ferritin levels and did not show blood acanthocytosis. Brain magnetic resonance imaging (MRI) was done for patients II.3 and II.10 revealing the characteristic eye-of-the-tiger sign (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, b).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eGenetic Analyses\u003c/h2\u003e\u003cp\u003eExome sequencing was performed in the two affected individuals II:4 and II:10. Genomic DNA libraries were captured using the Nextera Rapid Capture Expanded Exome Kit (Illumina, San Diego, CA), and DNA fragments were sequenced on an Illumina HiSeq2000 system with an average coverage of 80x. Variants were identified by a standard analysis pipeline and annotated using ANNOVAR (Wang et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). We discarded variants with a minor allele frequency (MAF)\u0026thinsp;\u0026gt;\u0026thinsp;0.01 in gnomAD (Genome Aggregation Database, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gnomad.broadinstitute.org\u003c/span\u003e\u003c/span\u003e) \u0026ldquo;all\u0026rdquo; exome as well as genome data. We discarded variants without an annotated exonic or splicing function and variants with a CADD (Combined Annotation Dependent Depletion) score below 15 (Kircher et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Since the parents are related, we assumed autosomal recessive inheritance and homozygosity of the causative variant. However, to guarantee of not missing any variants of importance, we filtered for variants present in both II:4 and II:10 but not for homozygosity. We filtered for specific genes with the symbols \u003cem\u003eATP13A2\u003c/em\u003e, \u003cem\u003eC19orf12\u003c/em\u003e, \u003cem\u003eCOASY\u003c/em\u003e, \u003cem\u003eCP\u003c/em\u003e, \u003cem\u003eDCAF17\u003c/em\u003e, \u003cem\u003eFAH2\u003c/em\u003e, \u003cem\u003eFTL\u003c/em\u003e, \u003cem\u003ePANK2\u003c/em\u003e, \u003cem\u003ePLA2G6\u003c/em\u003e, \u003cem\u003eWDR45\u003c/em\u003e known to harbor variants causing NBIA and related phenotypes. The filtering resulted in only one homozygous variant in the \u003cem\u003ePANK2\u003c/em\u003e gene, NM_024960.6:c.710C\u0026thinsp;\u0026gt;\u0026thinsp;T causing the amino acid change NP_079236.3:p.Thr237Met in the \u003cem\u003ePANK2\u003c/em\u003e protein in both exome sequenced affected family members (see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Segregation of this variant was ascertained by Sanger sequencing of all family members of whom DNA was available. We confirmed the presence of the variant and showed that patient II:3 also carries this variant in the homozygous state. The mother I:1 is a heterozygous carrier of the variant and her healthy son II:2 did not show this variant (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). DNA samples of the father I:2, the deceased affected brother II:9 and other siblings were not available for analysis.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eIdentified variant in the PANK2 gene (GRCh38/hg38)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGenetic finding\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVariant\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChromosome level\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr20.hg38:g.3918717C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGenomic level\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNC_000020.11:g.3918717C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoding sequence level\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNM_024960.6:c.710C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProtein level\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNP_079236.3:p.Thr237Met\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCADD (Phred-scaled)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMutationTaster (score/ class)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.926/deleterious\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePolyPhen-2 HVAR (score/ class)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.242/benign\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003egnomAD exomes (MAF, nr. of alleles analyzed)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.000012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003edbSNP (153 all)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers137852967\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHGMD (public 01.08.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot listed\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinVar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePathogenic, multiple submitters, no conflict\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCADD, Combined Annotation Dependent Depletion; dbSNP, database of single nucleotide polymorphism; gnomAD, Genome Aggregation Database; HGMD, Human Gene Mutation Database; MAF, minor allele frequency\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe effects of amino acid substitutions on protein function were predicted using MutationTaster (Schwarz et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2014\u003c/span\u003e), PolyPhen-2 (Adzhubei et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2010\u003c/span\u003e), and CADD (Rentzsch et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Furthermore, we searched the public version of the Human Gene Mutation Database (Stenson et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) and ClinVar (Landrum et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) for the variant (see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eIn the last two decades, genetic research in neurodegenerative diseases has tremendously progressed, especially through focused analyses of families with Mendelian mode of inheritance in different populations. However, such progress is not globally oriented. Including more genetic findings from understudied populations such as Africans, will help to identify variable phenotypes, enhance discoveries and offer better understanding of the diseases\u0026rsquo; pathophysiology and genotype-phenotype correlation.\u003c/p\u003e \u003cp\u003eOur report confirms the pathogenicity of the \u003cem\u003ePANK2\u003c/em\u003e variant NM_024960.6:c.710C\u0026thinsp;\u0026gt;\u0026thinsp;T which causes PKAN. Although this variant has been described before, this is the first report of a pathogenic \u003cem\u003ePANK2\u003c/em\u003e variant in the Egyptian population. Homozygous and compound heterozygous variants in \u003cem\u003ePANK2\u003c/em\u003e have been identified as the most common cause of NBIA (Zhou et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2001\u003c/span\u003e;Hayflick et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). The here identified variant has been reported by multiple submitters to the ClinVar database (Landrum et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) as pathogenic and can be found in other published genetic studies of NBIA (Hartig et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2006\u003c/span\u003e) but is not listed in the public version of the HGMD (Human Gene Mutation Database). Because the homozygous state of this variant segregates in the examined Egyptian family with the disease and has already been shown to be pathogenic, it is clearly the cause of NBIA in this Egyptian family.\u003c/p\u003e \u003cp\u003eSeveral variants in \u003cem\u003ePANK2\u003c/em\u003e have been identified in PKAN cases. The most common is the \u003cem\u003ePANK2\u003c/em\u003e variant G521R which accounts for approximately 30% of cases (Zhou et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). This variant leads to a catalytically inactive Pank2 protein due to improper folding (Zhang et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). As Pank2 is localized to the mitochondria where it is a key enzyme in the biosynthesis of coenzyme A (Leonardi et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), influencing important metabolic processes, nonfunctional Pank2 proteins have a tremendous influence on cell energy processes. However, the \u003cem\u003ePANK2\u003c/em\u003e variant (T528M) which we have identified in the Egyptian family is less common for PKAN and does not induce catalytic or regulatory deficits (Zhang et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). This implies that other presently unknown effects and functions of this variant might contribute to its pathogenicity.\u003c/p\u003e \u003cp\u003eRemarkably, the identified \u003cem\u003ePANK2\u003c/em\u003e mutation led to variable phenotypes and ages of onset within the same family. Previous studies reported the mutation to cause predominant open jaw dystonia, limb dystonia, and dysarthria (Hartig et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2006\u003c/span\u003e;Tomic et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2015\u003c/span\u003e;Yapici et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Predominant parkinsonism was less commonly reported (Chang et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). However, in the present family we could observe combinations of these symptoms. The affected members showed early cranial symptoms and a slow course of disease progression compared to previous reports (Tomic et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). This milder course of late onset PKAN revealed no contractures and preserved ambulation, however, further follow-up is required. Our finding of a clinical variability within the reported family confirms the relevance of atypical PKAN as a differential diagnosis for familial movement disorders with variable phenotypes such as Wilson\u0026rsquo;s disease (Schneider et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2006\u003c/span\u003e;Shalash et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eThe current report describes variable clinical phenotypes and disease progression of atypical PKAN in affected members of an Egyptian family. To the best of our knowledge, it is the second report of a family with PKAN in Africa. These findings add to our knowledge about the genetics of this disease in North Africa.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study concept and design. ASS, MS, GK, TWR, FH, GUH and SHM collected and analyzed data. ASS, GUH, HSA, FH and GK carried out medical examinations. MS, ASS, TWR and GK drafted the manuscript. All authors corrected and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the German Academic Exchange Service (DAAD) through the funding programme \u0026ldquo;Higher Education Dialogue with the Muslim World\u0026rdquo;, project \u0026ldquo;GeneFINDER\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Lena Jaschkowitz for technical assistance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. 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Nat Genet 28:345\u0026ndash;349\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pantothenate kinase-associated neurodegeneration, PANK2, neurodegeneration iron accumulation, genetics","lastPublishedDoi":"10.21203/rs.3.rs-324151/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-324151/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePantothenate kinase-associated neurodegeneration (PKAN) is a rare hereditary neurodegenerative disease characterized by an accumulation of iron within the brain. In the present report, we describe a family with 4 affected siblings presenting with variable clinical manifestations, e.g., parkinsonian features, dystonia and slow disease progression over 5 years. Exome sequencing revealed a causative variant in the pantothenate kinase 2 gene (\u003cem\u003ePANK2\u003c/em\u003e). Variant NM_024960.6:c.710C\u0026thinsp;\u0026gt;\u0026thinsp;T was homozygous in all affected subjects. Our report describes the first genetically confirmed cases of PKAN in the Egyptian population. Studying genetics of neurodegenerative diseases in different ethnicities is very important for determining clinical phenotypes and understanding pathomechanisms of these diseases.\u003c/p\u003e","manuscriptTitle":"Atypical Pantothenate Kinase-Associated Neurodegeneration with Variable Phenotypes in an Egyptian Family","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-19 22:55:05","doi":"10.21203/rs.3.rs-324151/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c7650c5a-88df-445b-8d98-15e9fef83492","owner":[],"postedDate":"March 19th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":3098877,"name":"Neurology"}],"tags":[],"updatedAt":"2021-03-30T05:43:07+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-19 22:55:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-324151","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-324151","identity":"rs-324151","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}