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C20orf48; HARP; HSS; NBIA1; PKAN

Associated disorders

The PANK2 gene is associated with autosomal recessive pantothenate kinase-associated neurodegeneration (PKAN) (MedGen UID: 6708).

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The PANK2 gene encodes the mitochondrial enzyme pantothenate kinase, which plays an essential role in coenzyme A (CoA) biosynthesis and thus in fatty acid metabolism. Disruption of PANK2 and enzyme dysfunction causes progressive neurodegeneration disorders with brain iron accumulation.

Clinical condition

PANK2 (NBIA1; OMIM: 606157) is the most common gene associated with the most prevalent form of progressive neurodegeneration with brain iron accumulation (NBIA), pantothenate kinase-associated neurodegeneration I (PKAN), formerly known as Hallervorden-Spatz disease (OMIM: 234200; PMID: 14631201). NBIA is a set of inherited conditions characterized by iron accumulation in the globus pallidus and/or substantia nigra of the basal ganglia (PMID: 28821231). Characteristic signs and symptoms include ataxia, spasticity, progressive dystonia, dysarthria, parkinsonism, neuropsychiatric manifestations, and retinal degeneration (PMCID: 2675558). MRI abnormalities in the globus pallidus and substantia nigra, referred to as the “eye of the tiger” sign, are thought to be pathognomonic for PANK2-associated PKAN (PMID: 12519949, 18443312).

There are two forms of the disorder:

  • Classic PKAN/early-onset form has an onset before 10 years of age and is associated with rapid neurodegeneration. Some affected children are considered clumsy before they are diagnosed. Most of these individuals lose the ability to walk 10-15 years post-diagnosis, and retinal pigmentary changes are also common (PMCID: 2675558; PMID: 12510040). Disease progression in this group is remarkably similar between patients (PMID: 28034613).
  • Atypical/later-onset form has a mean age of onset at 13-14 years of age and is associated with slower progression (PMID: 28034613). Atypical PKAN often presents with gait abnormality, speech difficulties, dysarthria, and neuropsychiatric issues in older individuals (PMCID: 2675558, PMID: 12510040). There is great variability in onset, symptoms, and rate of disease progression. Age of onset is not always correlated with rate of progression. Some children have developmental delay, which is confined to motor milestones, and others have global developmental delay. Children and adolescents can be diagnosed with attention deficit hyperactivity disorder before a recognition of the underlying cause (PMID: 18981035). Action-induced jaw dystonia with eating and speech as the triggers is an unusual feature in this group of patients (PMID: 28034613).

Both groups can exhibit opisthotonus posturing, and this feature is highly suggestive of PKAN (PMID: 28034613).

Acanthocytes have been reported in 10% of PKAN patients (PMID:12510040) and specifically in a cohort of patients from the Dominican Republic who are homozygous for the c.680G>A mutation in the PANK2 gene (PMID: 25915509).

Families with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) with PANK2 pathogenic variants are thought to fall on the PKAN spectrum (OMIM: 607236; PMID: 12058097).

Differential diagnosis

PKAN can usually be distinguished from the other forms of NBIA by the “eye of the tiger” MRI findings and the absence of seizures that are common with other forms (PMID: 20301663). Over 99% of individuals with the specific MRI findings have pathogenic variants in PANK2 (NBIA International Mutation Database, Oregon Health and Science University, unpublished data).

There are many types of NBIA. Other genes that cause NBIA include: ATP13A2, C19orf12, CP, CoASY, DCAF17, FA2H, FTL, PLA2G6, WDR45, FUCA1, and SQSTM1 (PMID: 20301663).

Disorders with similar features to classic PKAN include (PMID: 20301663, 18981035):

  • X-linked Dandy Walker and alpha-L-fucosidosis due to MRI findings (not “eye of the tiger”); however, children with these disorders have visceromegaly and coarsened facial features
  • Leigh syndrome due to MRI findings that can resemble “eye of the tiger”
  • Infantile neuroaxonal dystrophy characterized by MRI findings in the same areas of the brain but not the “eye of the tiger” malformation
  • Other childhood-onset neurodegenerative disorders

Disorders with similar findings to later-onset, atypical PKAN include (PMID: 20301663, 18981035):

  • Early-onset Parkinson’s and PLA2G6-associated dystonia-parkinsonism due to onset, dystonia, and rigidity
  • Primary familial brain calcifications due to calcium deposits that can resemble typical MRI findings
  • Aceruloplasminemia caused by mutations in the CP gene due to similar retinal changes
  • Neuroferritinopathy caused by changes in the FTL gene due to the movement disorder; however, affected individuals do not have the characteristic speech difficulties that atypical PKAN patients exhibit
  • Other neurodegenerative disorders that affect the basal ganglia

Please note that a patient with a C19orf12 expansion has been reported with the “eye of the tiger” feature (PMID: 21981780).

Gene information

PANK2 encodes a mitochondrial enzyme that phosphorylates vitamin B5 (known as pantothenate) in one of the first steps in coenzyme A (CoA) biosynthesis (PMID: 25110004). CoA is critical for energy metabolism and fatty acid synthesis and degradation (PMID: 21286947). It is unknown whether iron accumulation is causal or a downstream phenomenon (PMID: 24847269). Along with a deficiency of pantothenate kinase 2, pathogenic variants in PANK2 also result in an accumulation of cysteine-containing cytotoxic substrates (PMID: 11140748). Pathogenic variants in PANK2 account for approximately 50% of NBIA cases in Caucasians (PMID: 18981035).

Inheritance/Genetic counseling

PANK2-associated NBIA is inherited in an autosomal recessive manner. In the case where only one pathogenic variant in PANK2 is identified and MRI findings are pathognomonic, expert opinion may be useful.


Clinical management interventions and recommendations include (PMID: 28034613):

  • Pediatric neurology assessment and followup
  • Neuropsychiatric testing to assess for developmental delay
  • Ophthalmologic assessment for retinopathy and optic atrophy
  • Assessment and follow-up by a neurologist specializing in movement disorders (for adults)
  • Rehabilitation medicine therapy to maintain function
  • Genetic counseling for the family, and in cases where only one PANK2 pathogenic variant is found and MRI findings support the diagnosis, discussion with a PKAN expert
  • Family support to address the psychosocial issues of dealing with a family member with a progressive neurodegenerative disorder
  • Multidisciplinary care provides the best approach to affected patients and families.

Symptom-based interventions
For dystonia and spasticity, the first-line drugs are trihexyphenidyl for dystonia, and clonazepam and baclofen for spasticity. The second-line drugs include clonidine, gabapentin, tetrabenazine, and pregabalin (PMID: 28034613). Botulinum toxin intramuscular injections can be effective for a period of time in treating rigidity in limbs and facial muscles (PMID: 18981035). Deep-brain stimulation has helped a subset of patients with atypical PKAN (PMID: 21286947). In older patients with parkinsonism, dopaminergic medications are unlikely to be effective (PMID: 28034613).

Treatment-based therapeutics have targeted the biochemical defects using supplementation with pantetheine, pantothenate (vitamin B5), and CoA. Recent consensus guidelines recommend a 3-month course of high-dose pantothenate (PMID: 28034613). Iron chelation studies with deferiprone, which crosses the blood-brain barrier, are ongoing (Clinicaltrials.gov; PMID: 28034613).

Patients with pathogenic PANK2 variants are thought to be deficient in phosphopantothenic acid (PPA), which leads to decreased CoA levels. Ongoing clinical trials are testing a small molecule precursor of PPA called fosmetpantotenate with hopes of bypassing the enzyme deficiency. Unlike 4’-phosphopantothenic acid, fosmetpantotenate can permeate cell membranes (PMID: 28567317).

With ongoing clinical trials, molecular confirmation for PKAN disorders is necessary. If the MRI findings are not pathognomonic for PANK2, NBIA panel testing is recommended.

Review date: October 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
PANK2 NM_153638.2