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Pantothenate Kinase-Associated Neurodegeneration

Synonym: PKAN. Includes: HARP Syndrome

, MS, CGC and , MD.

Author Information
, MS, CGC
Genetic Counselor and Research Instructor
Oregon Health & Science University
Portland, Oregon
, MD
Professor and Chair, Molecular and Medical Genetics
Professor, Pediatrics and Neurology
Oregon Health & Science University
Portland, Oregon

Initial Posting: ; Last Update: January 31, 2013.

Summary

Disease characteristics. Pantothenate kinase-associated neurodegeneration (PKAN) is a form of neurodegeneration with brain iron accumulation, or NBIA (formerly called Hallervorden-Spatz syndrome). PKAN is characterized by progressive dystonia and basal ganglia iron deposition with onset that usually occurs before age ten years. Commonly associated features include dysarthria, rigidity, and pigmentary retinopathy. Approximately 25% of affected individuals have an 'atypical' presentation with later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease.

Diagnosis/testing. PANK2 is the only gene in which mutation is known to cause PKAN. Brain magnetic resonance imaging (MRI) reveals the 'eye of the tiger' sign (a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus) in all individuals with either classic or atypical disease and at least one PANK2 mutation detected by sequence analysis. Large intragenic deletions may account for some of the mutations missed by PANK2 sequence analysis.

Management. Treatment of manifestations: Intramuscular botulinum toxin, intrathecal or oral baclofen, ablative pallidotomy or thalmotomy, oral trihexyphenidyl, deep brain stimulation for dystonia; services for the blind, educational programs; physical therapy and occupational therapy to maintain normal joint mobility; adaptive aids (walker, wheelchair) for gait abnormalities; speech therapy and/or assistive communication devices.

Prevention of secondary complications: Full-mouth dental extraction when severe orobuccolingual dystonia results in recurrent tongue-biting; adequate nutrition through swallowing evaluation, dietary assessment, gastrostomy tube feeding as needed.

Surveillance: Evaluation for treatable causes of pain during episodes of extreme distress; monitoring of height and weight; routine ophthalmologic assessment; regular assessments of ambulation and speech abilities.

Genetic counseling. PKAN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are possible if both pathogenic variants have been identified in an affected family member.

Diagnosis

Clinical Diagnosis

Suspicion of pantothenate kinase-associated neurodegeneration (PKAN) often arises when characteristic magnetic resonance imaging (MRI) changes are demonstrated in an individual with suggestive clinical features. Following the discovery of PANK2 [Zhou et al 2001], Hayflick et al [2003] delineated two clinical forms of PKAN, the classic form and an atypical form, based on age at onset and rate of disease progression.

The diagnostic criteria continue to evolve to reflect the distinctions between PKAN and other forms of neurodegeneration with brain iron accumulation (NBIA).

Hallmark features of classic and atypical PKAN (see Figure 1)

Figure 1

Figure

Figure 1. T2-weighted brain MRI of PKAN (A) and non-PKAN NBIA (B)

A. Arrow indicates the 'eye of the tiger' change characteristic of PKAN.
B. MRI shows globus pallidus hypointensities only, consistent with iron deposition and (more...)

  • Extrapyramidal dysfunction, including one or more of the following:
    • Dystonia
    • Rigidity
    • Choreoathetosis
  • Onset
    • Classic form. Usually in first decade of life
    • Atypical form. More commonly in the second or third decade of life
  • Loss of ambulation
    • Classic form. Often occurring within ten to 15 years of onset
    • Atypical form. Often occurring within 15 to 40 years of onset
  • ‘Eye of the tiger’ sign on T2-weighted MRI (≥1.5 Tesla). Observed in nearly all affected individuals with one or two PANK2 mutations [Hayflick et al 2003, McNeill et al 2008] (Figure 1).

Brain MRI is standard in the diagnostic evaluation of all forms of NBIA. The 'eye of the tiger' sign, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus, is highly correlated with the presence of a PANK2 mutation in both classic and atypical disease [Hayflick et al 2001]. In studies to date:

  • Most individuals with PANK2 mutations have the 'eye of the tiger' sign. In some cases the sign may be absent in the early stages of disease [Chiapparini et al 2011]. Some studies suggest that in later disease the hyperintense region is replaced by iron, becoming more uniformly hypointense [Baumeister et al 2005, Delgado et al 2012]. In an isolated population with PKAN in the Dominican Republic in which all affected individuals are homozygous for the same PANK2 mutation, six of 21 affected individuals lacked the ‘eye of the tiger sign’ despite their ages and levels of progression being similar to others with this finding [Delgado et al 2012].
  • All individuals with the 'eye of the tiger' sign have at least one PANK2 mutation [Hayflick et al 2003, McNeill et al 2008].
  • MRI has also accurately predicted PKAN in presymptomatic sibs of affected individuals [Hayflick et al 2001], as characteristic changes may be evident early in disease.

Note: Some cases with a purported ‘eye of the tiger’ sign will be found to have MPAN (mitochondrial membrane protein-associated neurodegeneration), a different form of NBIA with hyperintense streaking of the medial medullary lamina that can look similar to PKAN radiologically [Hogarth et al 2013].

Corroborative features

  • Corticospinal tract involvement
    • Spasticity
    • Extensor toe signs
  • Retinal degeneration or optic atrophy
    • In classic PKAN, two thirds of affected individuals demonstrate pigmentary retinopathy [Hayflick et al 2003], a much larger proportion than was previously reported. Funduscopic changes initially include a flecked retina and later progress to bone spicule formation, conspicuous choroidal vasculature, and 'bull's-eye' annular maculopathy. Although retinopathy occurs early in the disease, it is not often recognized until a full diagnostic evaluation including electroretinogram (ERG) and visual field testing is performed. As a corollary, individuals with a normal ophthalmologic examination at the time of diagnosis generally do not develop retinopathy later.
    • In atypical PKAN, ocular abnormalities are rare, although recent data suggest that subclinical retinal changes may be more common than previously thought.
  • Acanthocytosis. Acanthocytes have been reported in a subset of individuals with PKAN. The best procedure for the determination of RBC acanthocytosis requires dilution of whole blood samples 1:1 with heparinized saline and incubation for 60 minutes at room temperature; wet cell monolayers are then prepared for phase-contrast microscopy. When all RBC with spicules (corresponding to type AI/AII acanthocytes and echinocytes) are counted, normal controls show less than 6.3% acanthocytes/echinocytes [Storch & Schwarz 2004]. Confirmation of erythrocyte morphology by scanning electron microscopy (if available) may be helpful. Lipofuscin and acanthocytes both result from lipid peroxidation, a process stimulated by iron.
  • Low or absent plasma pre-beta lipoprotein fraction (see Clinical Description, HARP syndrome)
  • Family history consistent with autosomal recessive inheritance, including consanguinity

Exclusionary findings

Pathologic diagnosis. Before the availability of MRI, neurodegeneration with brain iron accumulation (NBIA; formerly called Hallervorden-Spatz syndrome [HSS]) was a post-mortem diagnosis. Interpretation of neuropathologic literature is limited by the heterogeneity of conditions grouped under this diagnosis. A recent study of genetically confirmed PKAN brain tissue from six affected individuals has shed more light on findings specific to this form of NBIA [Kruer et al 2011].

HSS was initially characterized by the appearance of rust-brown pigmentation in the globus pallidus and the reticular zone of the substantia nigra. Iron is the major component of this pigment [Hallervorden 1924].

Overall, the majority of pathology is found in the globus pallidus and variably in adjacent structures [Kruer et al 2011]. In the index case reported by Kruer et al, the ‘eye of the tiger’ sign identified on MRI images correlated to a region of rarefaction in the center of the globus pallidus interna, which was depleted of viable neurons. Iron, mainly as coarse granular hemosiderin deposits, was distributed in a perivascular pattern.

In regions of iron accumulation, spheroid bodies are also seen [Koeppen & Dickson 2001]. Spheroids are thought to represent swollen axons. In PKAN, axonal spheroids have been observed in the pallidonigral system as well as in the white and gray matter of the cerebrum [Swaiman 2001]. They are not limited to those portions of the brain in which iron accumulates.

It was recently reported that two separate processes in PKAN give rise to the spheroidal structures previously described [Malandrini et al 1995]. The larger, more abundant population of spheroid structures previously described comprises degenerating neurons, which consistently stain positive for ubiquitin. In contrast, smaller (and rarer) true axonal spheroids were best detected by immunoreactivity for amyloid precursor protein and demonstrated less staining with anti-ubiquitin immunohistochemistry [Kruer et al 2011].

Molecular Genetic Testing

Gene. PANK2 is the only gene in which mutation is known to cause PKAN.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in PKAN and NBIA

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3, 4
PANK2Sequence analysis Sequence variants 5>99% of individuals with NBIA with 'eye of the tiger' sign on MRI 6, 7
~50% of individuals with clinical diagnosis of NBIA 4
Deletion/duplication analysis 8Partial- and whole-gene deletions~3%-5% 9

1. See Table A. Genes and Databases for chromosome locus and protein name

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Detection of at least one mutation

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

6. NBIA International Mutation Database, Oregon Health & Science University, unpublished data

7. Sequence analysis of the coding region and splice sites of PANK2 identifies at least one mutation in all individuals with the 'eye of the tiger' sign on MRI. Preliminary data indicate that approximately 5% of individuals with clinical and radiographic evidence of PKAN demonstrate only one mutation by sequence analysis. Approximately 23% of families with PKAN have known or suspected consanguinity and 33% of families with PKAN demonstrate homozygous PANK2 mutations.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Exonic and multiexonic deletions in PANK2 may not be detected by sequence analysis; several such alleles have been reported (see Table A).

Interpretation of test results. When one mutation is identified in an individual with an 'eye of the tiger' sign, the diagnosis of PKAN is confirmed [Hartig et al 2006].

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Single gene testing
    • Sequence analysis of PANK2 is recommended after MR imaging demonstrates high brain iron in the globus pallidus.
    • If no mutations or only one heterozygous mutation is identified, deletion/duplication analysis should be considered.

      Note: In some laboratories this test may be done automatically by the laboratory without a separate order from the clinician.
  • Multi-gene panels. Another strategy for molecular diagnosis of a proband suspected of having PKAN is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Note: Even in the absence of a true 'eye of the tiger' sign, molecular genetic testing is recommended.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Description

Natural History

Classic PKAN. The neurologic signs and symptoms of early-onset, rapidly progressive (classic) pantothenate kinase-associated neurodegeneration (PKAN) are primarily extrapyramidal and include dystonia, dysarthria, and rigidity.

Dystonia is always present and usually an early manifestation. Cranial and limb dystonia are frequent and may lead, respectively, to recurrent trauma to the tongue, in some cases requiring full-mouth dental extraction, or to atraumatic long bone fracture from the combination of extreme bone stress and osteopenia.

Corticospinal tract involvement is common and includes spasticity, hyperreflexia, and extensor toe signs.

Seizures are rare.

Intellectual impairment may be a major feature of PKAN. A study of 16 children and adults with PKAN showed varied cognitive expression as measured by standardized evaluation tools, with skills ranging from high average to markedly below average. Age of onset had a strong inverse correlation with intellectual impairment (i.e., earlier onset was associated with greater impairment) [Freeman et al 2007]. However, a more recent study of cognitive function in a population of individuals with PKAN undergoing deep brain stimulation suggests that cognitive decline may be overestimated in those with PKAN. The authors proposed that this is due to difficulty accessing cognition in those with PKAN because of the severity of their motor impairments [Mahoney et al 2011].

Pigmentary retinal degeneration occurs in two thirds of affected individuals with classic PKAN. The retinal degeneration follows a typical clinical course, with nyctalopia (night blindness) followed by progressive loss of peripheral visual fields and sometimes eventual blindness. Evaluation by electroretinogram often detects retinal changes that are asymptomatic.

Optic atrophy is rarely seen in PKAN. Abnormal eye movements, including vertical saccades and saccadic pursuits, are common. In one study, eight of ten individuals with PKAN had sectoral iris paralysis and partial loss of the pupillary ruff consistent with bilateral Adie's pupil [Egan et al 2005].

The clinical features of classic PKAN are remarkably homogeneous. It presents in early childhood, usually before age six years (mean age: 3.4 years). The most common presenting symptom is impaired gait resulting from a combination of lower-extremity rigidity, dystonia, and spasticity, as well as restricted visual fields in those children with retinopathy. Some children have developmental delay, which is primarily motor but occasionally global. Visual symptoms may bring children with PKAN to medical attention. Toe-walking and upper-extremity dystonia are less common presenting signs.

PKAN is a progressive disorder. Lost skills are usually not regained. The rate of progression correlates with age at onset: those with early symptoms decline more rapidly. As the disease advances, dystonia and spasticity compromise the child's ability to ambulate; most of those with early-onset disease are wheelchair bound by the mid-teens, and some much earlier. PKAN progresses at a non-uniform rate. Affected individuals experience episodes of rapid deterioration, often lasting one to two months, interspersed with longer periods of stability. Common causes of stress and catabolism do not seem to correlate with periods of decline, a phenomenon for which no cause has been found.

Premature death does occur. However, life span is variable; with improvements in medical care, a greater number of affected individuals are living into adulthood. Orofacial dystonia can result in the secondary effects of swallowing difficulty and poor nutrition. Premature death is more likely related to these secondary effects (e.g., nutrition-related immunodeficiency, aspiration pneumonia) than to the primary neurodegenerative process.

Atypical PKAN. The clinical features of atypical PKAN are more varied than those of early-onset disease. Onset is in the first three decades (mean age: 13.6 years). Progression of the atypical form is slower than the classic form, and presenting features are distinct, usually involving speech as either the sole presenting feature or part of the constellation of problems. The speech defects include palilalia (repetition of words or phrases), tachylalia/tachylogia (rapid speech of words and/or phrases), and dysarthria (poor articulation, slurring) [Benke et al 2000, Benke & Butterworth 2001].

Psychiatric symptoms including personality changes with impulsivity and violent outbursts, depression, and emotional lability are common in late-onset disease. Affected individuals may also exhibit motor and verbal tics, obsessive-compulsive behavior, and, rarely, psychotic symptoms [Pellecchia et al 2005, del Valle-López et al 2011].

As with early-onset disease, cognitive impairment may be part of the late-onset PKAN phenotype, but additional investigations are needed. Freeman et al [2007] found that later age of onset is correlated with less intellectual and adaptive behavior impairment.

Motor involvement is usually a later feature, although individuals with motor involvement often have been described as clumsy in childhood and adolescence. Spasticity, hyperreflexia, and other signs of corticospinal tract involvement are common and eventually limit ambulation. Conspicuously reminiscent of Parkinson disease, "freezing" during ambulation (especially when turning corners or encountering surface variations) is observed [Guimaraes & Santos 1999].

An essential tremor-like syndrome has also been reported [Yamashita et al 2004].

Retinopathy is rare in atypical disease, and optic atrophy has not been associated with atypical disease.

HARP syndrome. HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) (OMIM 607236) is now considered part of the PKAN disease spectrum [Ching et al 2002, Houlden et al 2003]. Pathogenic variants in PANK2 have been identified in the only two families reported with HARP syndrome. In one family the affected individual was homozygous for a novel mutation that caused a truncated protein. In the other family the affected individual was a compound heterozygote and one of the pathogenic variants found, c.1413-1G>T (IVS4-1G>T), has also been reported in individuals diagnosed with PKAN. Further biochemical studies have been initiated to investigate the extent of lipoprotein abnormalities and acanthocytosis in other individuals with PKAN.

Genotype-Phenotype Correlations

A clear genotype-phenotype correlation for PKAN has not been observed.

However, individuals with two null mutations (which predict no protein production) consistently have classic PKAN. Other combinations of mutations (i.e., null/missense, homozygous missense, or compound heterozygous missense) yield either classic or atypical phenotypes in no predictable pattern.

Homozygosity for the missense mutation p.Gly521Arg consistently presents as a classic phenotype; however, the phenotype associated with homozygosity of other common alleles is unpredictable. Two thirds of individuals with PKAN are compound heterozygotes, with disease of unpredictable clinical course.

Within families, the phenotype is fairly consistent among affected individuals. Greater variance in age at onset, presenting features, and rate of progression is seen in families with atypical disease.

Nomenclature

The eponym Hallervorden-Spatz syndrome (HSS) is no longer favored in view of the unethical activities of these two German neuropathologists before and during World War II [Shevell 2003].

HARP syndrome is now considered to represent part of the PKAN disease spectrum.

Prevalence

No reliable prevalence data on this rare disorder have been collected. An estimate of one to three in 1,000,000 has been suggested based on observed cases in a population, assuming a small number of misdiagnoses and missed cases.

This figure would imply a general population carrier frequency of one in 275-500.

A mutation founder effect has been described in The Netherlands [Rump et al 2005]. A community in the southwest Dominican Republic also shares a common founder mutation: c.680A>G (p.Tyr227Cys). The carrier frequency in this small, isolated population is significantly increased [Delgado et al 2012].

Differential Diagnosis

Neurodegeneration with brain iron accumulation multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Neurodegeneration

Since Hallervorden and Spatz originally delineated a specific clinicopathologic entity, a heterogeneous group of individuals have been assigned this diagnosis. Based on new information about the etiologies of several extrapyramidal disorders with high brain iron, a new nosology and nomenclature for this group of disorders has emerged.

Neurodegeneration with brain iron accumulation (NBIA) is defined as the group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia [Hayflick et al 2003].

Diagnostic criteria for NBIA were first proposed by Dooling et al [1974] and later refined by Swaiman [1991]. The term NBIA, already in use in the medical literature, is sufficiently broad to include all disorders previously called Hallervorden-Spatz syndrome (HSS), along with other recently delineated disorders of high brain iron, including nine disorders with known genetic etiologies (see Later-onset, slowly progressive NBIA).

NBIA is generally classified as one of the following:

PKAN can be distinguished from other forms of NBIA by the following findings:

  • Brain MRI
    • In most individuals with non-PKAN NBIA, the globus pallidus is uniformly hypointense on T2-weighted images (see Figure 1), indicating high iron content. This change is distinct from the 'eye of the tiger' sign and is not seen in association with mutation of PANK2. It should be noted that in MPAN, hyperintense streaking of the medial medullary lamina between the globus pallidus interna and externa can resemble an ‘eye of the tiger’ sign [Hogarth et al 2013].
    • Iron deposition in the red nucleus and dentate nucleus in conjunction with cerebellar atrophy are common in the NBIA group.
  • Absence of seizures in PKAN; prominence of seizures in non-PKAN NBIA
  • Sea-blue histiocytes in bone marrow; historically a feature of HSS, not found in PKAN but sometimes observed in other forms of NBIA

Four disorders may show early clinical changes similar to those seen in classic PKAN:

  • X-linked intellectual disability with Dandy-Walker malformation. Unlike PKAN, affected children have severe intellectual disability. MRI of the brain, recommended for suspected PKAN, would rule out this diagnosis.
  • Alpha fucosidosis [Terespolsky et al 1996]. Affected children have coarse facial features and visceromegaly consistent with a lysosomal storage disease. Although a hyperintense signal in the globus pallidus has been documented by T2-weighted MRI in some cases, the 'eye of the tiger' sign has not been observed.
  • Leigh syndrome [Medina et al 1990]. Symmetric hyperintense signal in the globus pallidus on T2-weighted MRI can resemble an ‘eye-of-the-tiger’ sign but lacks the surrounding hypointensity caused by iron accumulation. Unlike PKAN, symmetric hyperintensities occur frequently in other regions of the basal ganglia.
  • Infantile neuroaxonal dystrophy (INAD). A portion of individuals show hypointense signal in the globus pallidus and substantia nigra, but the 'eye of the tiger' sign is absent and cerebellar atrophy is common. In INAD axonal spheroids are present in the peripheral nervous system and in PKAN they are only located in the central nervous system.

Differential diagnoses for adolescent- and adult-onset PKAN include the following:

  • Early-onset Parkinson disease including parkin type of juvenile Parkinson disease and PLA2G6-associated dystonia-parkinsonism may initially present similarly to atypical PKAN, with onset between age 20 and 40 years and lower-limb dystonia. Bradykinesia and rest tremor are also common features.
  • Primary familial brain calcification. Affected individuals have abnormal calcium deposits in the basal ganglia, including deposits in the globus pallidus that can resemble an ‘eye of the tiger’ sign. Features common to PKAN include Parkinsonism, dysarthria, dystonia, and spasticity. Calcium deposits accumulate over time in the basal ganglia and cerebral cortex, helping to distinguish it from PKAN.
  • Aceruloplasminemia. Affected individuals also have iron accumulation in the viscera and develop diabetes mellitus relatively early in the disease progression. They have retinal degeneration with characteristic yellow opacities in the retinal pigment epithelium.
  • Neuroferritinopathy typically presents with involuntary movements in the fourth to fifth decade of life and does not exhibit the marked dysarthria observed in PKAN.
  • Steele-Richardson-Olzewski syndrome (also known as progressive supranuclear palsy). Average age of onset is 66 years and other common features include vertical gaze palsy, diplopia, and photophobia, which are not features of PKAN.
  • Primary psychiatric illnesses. The presence of impulsivity and other behavioral changes without dysarthria could indicate a primary psychiatric illness. For all of the disorders in this category, T2-weighted MRI would distinguish PKAN based on the presence of the 'eye of the tiger' sign.

Other disorders to consider:

Neuroacanthocytosis syndromes. Neurologic disorders associated with RBC acanthocytosis are called neuroacanthocytosis syndromes [Danek et al 2005, Danek & Walker 2005].

One group of neuroacanthocytosis syndromes is associated with lipid malabsorption and primarily affects the spinal cord, cerebellum, and peripheral nervous system. The neurologic findings include the following:

  • A progressive spinocerebellar degeneration with ataxia of gait, dysmetria, and dysarthria
  • A demyelinating sensorimotor and axonal peripheral neuropathy with hyporeflexia and diminished vibration and position sense
  • Pyramidal tract signs (rare)
  • Cranial nerve involvement (rare)

These disorders include the following:

  • Hypobetalipoproteinemia type 1 (FHBL1)
  • Hypobetalipoproteinemia type 2 (FHBL2)
  • Abetalipoproteinemia (ABL, Bassen-Kornzweig disease)

FHBL1, FHBL2, and ABL share the findings of acanthocytosis, dysarthria, neuropathy, and areflexia, but differ in that ABL, FHBL1, and FHBL2 have pigmentary retinopathy and do not have basal ganglia involvement. ABL, FHBL1, and FHBL2 are caused by mutations affecting the microsomal triglyceride transfer protein causing vitamin E deficiency. ABL is inherited in an autosomal recessive manner. FHBL1 and FHBL2 have clinical manifestations in both the homozygous and heterozygous states.

A second group of neuroacanthocytosis syndromes predominantly affects the central nervous system, in particular the basal ganglia, resulting in a chorea syndrome resembling Huntington disease. These disorders include the following:

  • McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. Affected males have the McLeod blood group phenotype and RBC acanthocytosis. Neuromuscular manifestations of MLS comprise subclinical or mild sensorimotor axonopathy, myopathy, and cardiomyopathy. CNS manifestations of MLS resemble Huntington disease and consist of a choreatic movement disorder, "subcortical" cognitive deficits, psychiatric manifestations, and in some individuals, epileptic seizures. Inheritance is X-linked.
  • Chorea-acanthocytosis (ChAc) is characterized by chorea, myopathy, progressive cognitive and behavioral changes, and seizures. Mean age of onset is approximately 35 years, although ChAc can develop as early as the first decade or as late as the seventh decade.
  • Huntington disease-like 2 (HDL2) manifests in the third to fourth decade and has a progressive course over ten to 15 years [Margolis et al 2001]. Dystonia is a frequent finding; chorea or parkinsonism may change with evolution of the disease. Almost all affected individuals reported to date have been of African ancestry [Margolis et al 2001, Stevanin et al 2002, Walker et al 2003]. RBC acanthocytosis is variable.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with pantothenate kinase-associated neurodegeneration (PKAN), the following evaluations are recommended:

  • Neurologic examination for dystonia, rigidity, choreoathetosis, and spasticity, including evaluation of ambulation and speech
  • Ophthalmologic assessment for evidence of retinopathy and optic atrophy
  • Screening developmental assessment, with referral for more formal testing if delay is indicated
  • Assessment for physical therapy, occupational therapy, and/or speech therapy
  • Medical genetics consultation

Treatment of Manifestations

Pharmacologic and surgical interventions have focused on palliation of symptoms.

Symptomatic treatment is aimed primarily at the dystonia, which can be profoundly debilitating and distressing to the affected individual and caregivers. Therapies to manage dystonia in affected individuals that have been used with varying success include the following:

  • Intramuscular botulinum toxin
  • Ablative pallidotomy or thalmotomy. The dystonia does return, usually approximately one year following surgery [Justesen et al 1999].
  • Oral baclofen and trihexyphenidyl
  • Intrathecal baclofen
  • Deep brain stimulation, used clinically with increasing frequency and some evidence for benefit (see Therapies Under Investigation) [Castelnau et al 2005]
  • Physical and occupational therapy as indicated, particularly for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful. Speech therapy is often indicated for PKAN-related dysarthria.

It is important to help affected individuals to maintain independence. Regular review of communication needs and environmental adaptations is required.

Appropriate interventions to improve function for those with retinopathy are indicated.

Affected individuals should be referred to appropriate community resources for financial services, services for the blind (if retinopathy is present), and special education.

As needed, individuals should be referred for adaptive aids (e.g., a walker or wheelchair for gait abnormalities) and assistive communication devices.

Prevention of Secondary Complications

Affected individuals with recurrent tongue-biting from severe orobuccolingual dystonia often come to full-mouth dental extraction as the only effective intervention; bite-blocks and other more conservative measures often fail.

Swallowing evaluation and regular dietary assessments are indicated to assure adequate nutrition. Once the individual can no longer maintain an adequate diet orally, gastrostomy tube placement is indicated.

Surveillance

As the disease progresses, episodes of extreme distress may last for days or weeks. It is especially important during these episodes to evaluate for treatable causes of pain. These may include occult GI bleeding, urinary tract infections, and occult bone fractures. The combination of osteopenia in a nonambulatory individual with marked stress on long bones from dystonia places individuals with PKAN at especially high risk for fractures without apparent trauma.

The following should be performed on a regular basis:

  • Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status
  • Ophthalmologic assessment
  • Oral assessment for consequences of trauma
  • Assessment of ambulation and speech abilities

Agents/Circumstances to Avoid

Anecdotal reports of three sibs with atypical PKAN treated with alpha-tocopherol and idebenone indicated worsening of symptoms, with subsequent improvement once these compounds were stopped [JP Harpey, personal communication].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Deep brain stimulation (DBS). As DBS has become a common treatment for primary dystonia, it is also being used more frequently to attempt to treat the secondary dystonia seen in PKAN. There are significantly fewer data, however, on outcomes in this rare population, particularly since each individual is usually treated at a different DBS center.

The largest cohort studied at the same center is a group of six individuals with PKAN. Those treated with DBS showed overall improvements in writing, speech, walking, and global measures of motor skills [Castelnau et al 2005]. However, at publication the length of follow-up time varied from only six to 42 months. Even with this limitation, the study suggested that DBS may hold more promise than previously recognized.

Additional case reports with varying follow-up times and anecdotal reports from PKAN families also support that DBS can provide benefit in some cases [Krause et al 2006, Shields et al 2007, Isaac et al 2008, Mikata et al 2009, Lim et al 2012]. A multi-center retrospective study of 23 patients with NBIA from 16 centers tracked changes in dystonia and quality of life for up to 15 months post-procedure. The majority of the patients had PKAN, although some did have other NBIA. Improvement was found in both areas overall; patients with the most severe dystonia seemed to benefit most from DBS [Timmermann & Volkmann 2010].

Baclofen is one of the mainstay drugs, used both orally and intrathecally, to treat PKAN dystonia. In 2009 Albright and Ferson reported favorable outcomes from a new technique used to deliver intraventricular baclofen in a series of nine children and one adult with secondary dystonia, including one child with PKAN [Albright & Ferson 2009]. Additional studies are necessary to determine the optimal dose and efficacy in PKAN and other NBIA disorders. Intraventricular delivery of baclofen is of interest because delivery at this site may better treat upper-body and facial dystonia, such as blepharospasm, and may result in higher baclofen concentrations over the cortex.

Iron chelation. Interest in iron chelation has reemerged as data on deferiprone (Ferriprox®) have accumulated in several populations of affected individuals. Iron chelating agents have been tried in the past without clear benefit [Dooling et al 1974]. Until recently, trials were limited by the development of systemic iron deficiency before any clinical neurologic benefits were evident. Unlike earlier drugs, deferiprone crosses the blood-brain barrier and removes intracellular iron. One small phase II pilot trial has been performed to assess deferiprone in the PKAN population. Deferiprone was tolerated well in the nine affected individuals who completed the study, and there was a statistically significant reduction of iron in the pallida by MRI evaluation. However, there was no change in their clinical status. The authors suggested that a longer trial period may be necessary to produce clinical amelioration [Zorzi et al 2011]. An international clinical trial with longer duration is currently underway (www.ClinicalTrials.gov).

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Pantothenate. The existence of residual enzyme activity in some individuals with PKAN raises the possibility of treatment using high-dose pantothenate, the PANK2 enzyme substrate. Pantothenate has no known toxicity in humans; high oral doses of pantothenic acid or calcium pantothenate (≤10 g/day for several weeks) do not appear to be toxic to humans. The efficacy of pantothenate supplementation in ameliorating symptoms is currently unknown; some individuals with an atypical disease course have anecdotally reported improvement in their symptoms (dysarthria, gait imbalance, sense of well-being) when taking pantothenate.

Docosahexanoic acid (DHA). Based on the role of coenzyme A (CoA) in the synthesis and degradation of fatty acids, the importance of DHA as a major component of rod photoreceptor disc membranes, and the observation of retinal degeneration in a large portion of individuals with PKAN, DHA may have a role in preventing this complication, although no studies have yet been performed. The compound may be provided as an oral nutritional supplement in the form of omega-3 fats (fish oil) and is without known toxicity.

Other treatments. Therapies that may have a role in other forms of NBIA but generally do not help individuals with PKAN include levodopa/carbidopa and bromocriptine.

Treatment of PKAN with phosphopantothenate, the product of pantothenate kinase, is complicated by the lack of available compound as well as any information about its safety or toxicity in humans or animals. Furthermore, it is unlikely that phosphopantothenate would be readily transported across cell membranes, making the success of this hypothetic treatment doubtful.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pantothenate kinase-associated neurodegeneration (PKAN) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are expected to be obligate heterozygotes (carriers), and therefore carry one mutant allele. The mother of one affected individual did not carry a PANK2 mutant allele [Author, personal communication].
  • Heterozygotes have no symptoms.
  • To date, germline mosaicism has not been documented.

Sibs of a proband

  • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected (i.e., an at-risk sib who is asymptomatic beyond the typical age of onset), the risk of his/her being a carrier is 2/3.

Offspring of a proband

  • To date, reproduction among probands is rare.
  • The offspring of an individual with PKAN are obligate heterozygotes (carriers).
  • The offspring are at risk of being affected only if the proband's reproductive partner is a carrier for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Testing of asymptomatic at-risk sibs, especially those younger than the proband. Neurologic evaluation (including MRI) and genetic testing may be considered for the seemingly healthy sibs of probands, especially when they are younger than the proband. Although evaluation and testing of asymptomatic individuals younger than age 18 years has not been encouraged in the past, it may be more commonly considered in light of the availability of the current international deferiprone trial.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variants have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Pantothenate Kinase-Associated Neurodegeneration: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PANK220p13Pantothenate kinase 2, mitochondrialPANK2 homepage - Mendelian genesPANK2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Pantothenate Kinase-Associated Neurodegeneration (View All in OMIM)

234200NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1
606157PANTOTHENATE KINASE 2; PANK2
607236HYPOPREBETALIPOPROTEINEMIA, ACANTHOCYTOSIS, RETINITIS PIGMENTOSA, AND PALLIDAL DEGENERATION

Molecular Genetic Pathogenesis

Pantothenate kinase-associated neurodegeneration (PKAN) is attributed to a deficiency or complete absence of pantothenate kinase 2, which is encoded by PANK2, one of four human pantothenate kinase genes. Pantothenate kinase deficiency is thought to cause accumulation of N-pantothenoyl-cysteine and pantetheine, which may cause cell toxicity directly or via free radical damage as chelators of iron [Yang et al 2000, Yoon et al 2000]. Deficient pantothenate kinase 2 is also predicted to result in coenzyme A (CoA) depletion and defective membrane biosynthesis in those tissues in which this is the major pantothenate kinase or in tissues with the greatest CoA demand.

Rod photoreceptors continually generate membranous discs; therefore, the retinopathy frequently observed in classic PKAN may be secondary to this deficit. The biochemical perturbations leading to clinical sequelae are still not completely understood and require further investigation.

Gene structure. PANK2 encodes a 1.85-kb transcript that is derived from seven exons spanning just over 35 Mb of genomic DNA. Detailed sequence analysis reveals that PANK2 is a member of a family of eukaryotic genes consisting of a group of six exons that encode homologous core proteins, preceded by a series of alternative initiating exons, some of which encode unique amino-terminal peptides. Alternative splicing, involving the use of alternate first exons, results in multiple transcripts encoding different isoforms. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Aside from the three common PANK2 pathogenic variants described in Table 2, mutations are usually private to each family and vary in type.

Table 2. Selected PANK2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences 2
c.680A>Gp.Tyr227CysNM_153638​.2
NP_705902​.2
c.1351C>T 3
(1021C>T)
p.Arg451Ter 3
(p.Arg341Ter)
c.1561G>A
(1231G>A) 3, 4
p.Gly521Arg 3, 4
(p.Gly411Arg)
c.1583C>T 3
(1253C>T)
p.Thr528Met 3
(p.Thr418Met)
c.1413-1G>T
(IVS4-1G>T) 5
---

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Reference sequence is for the longest isoform, PANK2 isoform 1 preproprotein.

3. Common pathogenic variants (allele frequency): p.Gly521Arg (25%); p.Thr528Met (8%); p.Arg451Ter (3%)

4. Homozygosity for this allele results in classic disease.

5. Mutation results in PKAN disorder, but also seen in one person with HARP syndrome [Ching et al 2002].

Normal gene product. PANK2 encodes a predicted 50.5-kd protein that is a functional pantothenate kinase [Zhou et al 2001]. Pantothenate kinase is an essential regulatory enzyme in coenzyme A (CoA) biosynthesis, catalyzing the phosphorylation of pantothenate (vitamin B5), N-pantothenoyl-cysteine, and pantetheine. Pantothenate kinase is regulated by acyl-CoA levels in prokaryotes and by acetyl-CoA levels in eukaryotes.

Abnormal gene product. Mutations can generally be categorized into null or missense alleles. Individuals who are homozygous for null alleles usually have classic disease. It is currently unknown if individuals with atypical PKAN have partial enzyme function. Interallelic complementation has been postulated for those who are compound heterozygous for missense mutations. Interallelic complementation results when mutations in domains that interact between protein subunits are able to restore partial function. This is theorized to be mutation specific, with some mutations precluding complementation. Hence, some compound heterozygotes for missense mutations may present with classic disease while others have a more atypical course. A recent study of PANK2 mutations in affected individuals confirmed that the most frequent PANK2 pathogenic variant, p.Gly521Arg, leads to a protein that is misfolded and devoid of activity [Zhang et al 2006]. However, nine other pathogenic variants were found to result in proteins having normal catalytic activity and regulatory function. The authors suggested that PANK2 protein may have additional functions that are not yet appreciated.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Gregory A, Hayflick SJ. Neurodegeneration with brain iron accumulation. Folia Neuropathol. 2005;43:286–96. [PMC free article: PMC2117327] [PubMed: 16416393]
  2. Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet. 2009;46:73–80. [PMC free article: PMC2675558] [PubMed: 18981035]

Chapter Notes

Author History

Jason Coryell, MS; Oregon Health & Science University (2004-2007)
Allison Gregory, MS, CGC (2004-present)
Susan J Hayflick, MD (2002-present)

Revision History

  • 31 January 2013 (me) Comprehensive update posted live
  • 23 March 2010 (me) Comprehensive update posted live
  • 9 January 2008 (sh) Revision: deletion/duplication analysis no longer available clinically
  • 8 January 2007 (me) Comprehensive update posted to live Web site
  • 27 October 2004 (me) Comprehensive update posted to live Web site
  • 8 March 2003 (sh) Revision: Table 4; References
  • 25 February 2003 (sh) Revision: Resources
  • 13 August 2002 (me) Review posted to live Web site
  • 29 March 2002 (sh) Original submission
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