Consensus clinical management guideline for pantothenate kinase-associated neurodegeneration (PKAN)

https://doi.org/10.1016/j.ymgme.2016.11.004Get rights and content

Highlights

  • Clinical experts have developed consensus opinions about the management of PKAN that can serve as a guideline for care.

  • Guidance is provided for diagnosis and management, treatment and surveillance, including for status dystonicus and other emergency care, and education and psychosocial support.

  • This guideline is a living document that will require ongoing review and revision.

Introduction

Pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden–Spatz syndrome, OMIM #234200) is the most common neurodegeneration with brain iron accumulation (NBIA) disorder, with an estimated incidence of 1–3 per million [1] and accounting for about half of NBIA cases [2]. As is the case for most rare disorders, evidence-based guidance for the clinical management of PKAN is limited, often relying instead on anecdotal evidence, case reports and small series studies. Despite the small number of geographically dispersed people with PKAN, clinicians with concentrated experience have developed opinions and expertise about their optimal care. Moreover, family members and affected individuals themselves develop substantial personal experience in meeting their needs. In this document we have amalgamated such professional expertise, lay experiences and published data into a consensus guideline. This guideline summarizes what we believe are current best practices and therapeutic approaches for the care of people with PKAN and their families.

Section snippets

Methods

This guideline largely reflects the consensus opinion of clinical experts in PKAN. In addition, peer-reviewed publications were systematically searched for, evaluated, and their conclusions incorporated into this document when applicable. PubMed (http://www.ncbi.nlm.nih.gov/pubmed) was searched January–February 2016 using the following search terms: ‘PKAN’, ‘pantothenate kinase-associated neurodegeneration’, ‘HSS’, ‘Hallervorden-Spatz syndrome’, ‘NBIA’, and ‘neurodegeneration with brain iron

Diagnosis and initial care

The diagnosis of PKAN is usually considered on the basis of clinical suspicion and radiological data. Often, the clinical features are suggestive, and the diagnosis becomes strongly suspected after the characteristic brain MRI pattern is revealed. Since the PANK2 gene discovery [3], the phenotypic spectrum of PKAN has broadened, and with it, the range of presenting features. Greater access to early neuroimaging using MRI sequences that are sensitive to iron and to clinical whole exome

Rational therapeutics

Although there currently is no disease-modifying therapy for PKAN, rational therapeutics that target the primary biochemical defect are in development [3], [10]. For now, medication management is primarily symptomatic, and ongoing care follows general recommendations developed for people with a chronic progressive disease.

Compounds that bypass the defective PANK2 enzyme, including pantetheine, phosphopanthetheine, and coenzyme A and their derivatives, have shown promise in ameliorating various

Concluding remarks

As we learn more about the natural history of PKAN and enter the era of disease-modifying therapeutics, our recommendations will change to reflect these advances. This guideline is intended to be a living document that will benefit from continual review and revision. We look forward to a time when our interventions fundamentally change the course of this devastating disease.

Author contributions

Penelope Hogarth, Allison Gregory, Susan J. Hayflick: literature search, figures, study design, data collection, data analysis, data interpretation, writing, and editing of manuscript.

Manju A. Kurian: study design, writing, and editing of manuscript.

Barbara Csányi, Tamara Zagustin, Tomasz Kmiec, Patricia Wood, Angelika Klucken, Natale Scalise, Francesca Sofia, Thomas Klopstock, Giovanna Zorzi, Nardo Nardocci: writing and editing of manuscript.

Funding

This work was funded by the NBIA Disorders Association, Hoffnungsbaum e.V., and the Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro (AISNAF).

Acknowledgements

We are grateful to the people with PKAN and their families, who over the past three decades have taught us how best to care for them, and to our clinical partners worldwide whose day-to-day care improves lives. Thanks to Mark Karakourtis MD, DDS for guidance on management of oral health complications. This work was supported in kind by the European Commission 7th Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement No. 277984, TIRCON).

Key resources

NBIAcure.org Information for

First page preview

First page preview
Click to open first page preview

References (58)

  • M.B. Hartig et al.

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

    Ann. Neurol.

    (2006)
  • K.D. Sethi et al.

    Hallervorden-Spatz syndrome: clinical and magnetic resonance imaging correlations

    Ann. Neurol.

    (1988)
  • F.A. Baumeister et al.

    The eye-of-the-tiger sign is not a reliable disease marker for Hallervorden-Spatz syndrome

    Neuropediatrics

    (2005)
  • L. Chiapparini et al.

    The "eye-of-the-tiger" sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration

    Neuropediatrics

    (2011)
  • R.F. Delgado et al.

    Missense PANK2 mutation without “eye of the tiger” sign: MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN)

    Journal of magnetic resonance imaging: JMRI

    (2012)
  • A. Rana et al.

    Pantethine rescues a drosophila model for pantothenate kinase-associated neurodegeneration

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • D. Brunetti et al.

    Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

    Brain J. Neurol.

    (2014)
  • B. Srinivasan et al.

    Extracellular 4'-phosphopantetheine is a source for intracellular coenzyme a synthesis

    Nat. Chem. Biol.

    (2015)
  • E.C. Dooling et al.

    Hallervorden-Spatz syndrome

    Arch. Neurol.

    (1974)
  • G. Zorzi et al.

    Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial

    Mov. Disord.

    (2011)
  • Gregory A, Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration. 2002 Aug 13 [Updated 2013 Jan 31]. In: Pagon...
  • B.M. Schramm et al.

    Dystonic reaction to propofol attenuated by benztropine (cogentin)

    Anesth. Analg.

    (2002)
  • I. Balas et al.

    Staged bilateral stereotactic pallidothalamotomy for life-threatening dystonia in a child with Hallervorden-Spatz disease

    Mov. Disord.

    (2006)
  • J. Hinkelbein et al.

    Anesthesia for patients with pantothenate-kinase-associated neurodegeneration (Hallervorden-Spatz disease) - a literature review

    Acta Neuropathol.

    (2006)
  • R. Sinha et al.

    Anaesthetic management of a child with panthothenate kinase-associated neurodegeneration

    Indian J Anaesth

    (2015)
  • A.L. Albright et al.

    Intraventricular baclofen for dystonia: techniques and outcomes. Clinical article

    J. Neurosurg. Pediatr.

    (2009)
  • B.G. Rocque et al.

    Intraventricular vs intrathecal baclofen for secondary dystonia: a comparison of complications

    Neurosurgery

    (2012)
  • M. Turner et al.

    Intraventricular baclofen as an alternative to intrathecal baclofen for intractable spasticity or dystonia: outcomes and technical considerations

    J. Neurosurg. Pediatr.

    (2012)
  • L. Timmermann et al.

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

    Brain J. Neurol.

    (2010)
  • Cited by (63)

    • Experimental pharmacology: Targeting metabolic pathways

      2023, International Review of Neurobiology
    • Deep Brain Stimulation (DBS) with Subthalamic Nucleus (STN) as Target for Pediatric Patients with PKAN

      2022, World Neurosurgery
      Citation Excerpt :

      Although there have been reports showing that pantethine feeding may rescue brain degeneration in Drosophila and rodent models,22,23 no ascertained benefit was observed in human models.2 The consensual management of patients with PKAN included early involvement of multidisciplinary teams, symptom-based therapeutics with focus on dystonia, periodic systematic and critical review of selection of medication regimen, and avoidance of insulting agents.2 Surgical intervention has demonstrated to be effective in symptom relief in some cases of PKAN, but optimal procedure selection and timing for patients with PKAN remain undefined.

    • Characterization of sleep in six patients with pantothenate kinase-associated neurodegeneration

      2021, Sleep Medicine
      Citation Excerpt :

      Patients with classic PKAN have a younger age at onset (mostly during early childhood) and a more rapid progression with tendency to severe generalized dystonia and postural instability leading to lose of ambulation by the age of 10 years. In atypical PKAN the onset of symptoms is in later childhood, adolescence or adulthood, rate of progression is slower, and the range of symptoms and disability is broader, and usually milder than in classic PKAN [3,4]. Although the discovery of the gene causing the disease has made possible to outline the clinical picture of these patients with greater precision, aspects such as sleep have rarely been evaluated.

    View all citing articles on Scopus
    View full text