Clinical Diagnosis

Suspicion of pantothenate kinase-associated neurodegeneration (PKAN) often arises when characteristic 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

Figure 1. Panel A shows the 'eye of the tiger' change characteristic of PKAN, whereas Panel B shows only globus pallidus hypointensities, consistent with iron deposition and supporting a diagnosis of non-PKAN NBIA.

• 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 magnetic resonance imaging (≥1.5 Tesla). Observed in all affected individuals with one or two PANK2 mutations [Hayflick et al 2003, McNeill et al 2008] (Figure 1).

Brain magnetic resonance imaging (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:

• All individuals with PANK2 mutations have the 'eye of the tiger' sign.

• 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 are usually evident early in disease.

Note: While the authors expect to observe cases that challenge the correlation between MRI phenotype and PANK2 genotype, none of the "exceptions" that have been presented in the literature meet a reasonable standard [Authors, personal observations].

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 higher fraction 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 may be helpful if available. 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

• Abnormalities of plasma ceruloplasmin concentration or copper metabolism (see Wilson Disease)

• Evidence of neuronal ceroid lipofuscinosis by electron microscopy, enzymatic assay, or the presence of a DNA mutation in any of the genes associated with this condition

• β-hexosaminidase A deficiency or GM1-galactosidase deficiency

• Pathologic evidence of spheroid bodies in the peripheral nervous system, indicative of infantile neuroaxonal dystrophy

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.

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].

In PKAN, the accumulation of iron is specific to the globus pallidus and substantia nigra. These areas contain approximately three times the normal amount of iron. Systemic iron metabolism is normal [Dooling et al 1974] and a global increase in brain iron is not seen. 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 brain in which iron accumulates.

Molecular Genetic Testing

Gene. PANK2 is the only gene currently known to be associated with PKAN.

Clinical testing

• Sequence analysis. 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 the proposed molecular screening method [NBIA International Mutation Database].
  
  Approximately 23% of families with PKAN have known or suspected consanguinity and 33% of families with PKAN demonstrate homozygous PANK2 mutations.

• Deletion/duplication analysis. Exon and multiexon deletions in PANK2 may not be detected by sequence analysis; several such alleles have been reported (see Table A).

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1, 2	Test Availability
PANK2	Sequence analysis	Sequence variants 3	>99% of individuals with NBIA with 'eye of the tiger' sign on MRI 4 ~50% of individuals with clinical diagnosis of NBIA 2	Clinical
	Deletion / duplication analysis 5	Partial- and whole-gene deletions	~3%-5%

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Detection of at least one mutation

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. NBIA International Mutation Database

5. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

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].

For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• 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.

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 disease-causing mutations 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 disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in PANK2.

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].

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 [Pellecchia et al 2005].

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]. Mutations 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 mutations 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.

At this time, a discernable increased incidence has not been identified in any specific ethnic group.

A mutation founder effect has been described in The Netherlands [Rump et al 2005].

Neurodegeneration

Since Hallervorden and Spatz originally delineated a specific clinicopathologic entity, a heterogeneous group of individuals has 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 HSS, along with other recently delineated disorders of high brain iron, including four disorders with known genetic etiologies (see following: Later-onset, slowly progressive NBIA).

NBIA is generally classified as one of the following:

• Early-onset, rapidly progressive NBIA with onset during the first decade, which includes classic pantothenate kinase-associated neurodegeneration (PKAN) and infantile neuroaxonal dystrophy, a recently delineated disorder associated with mutations in PLA2G6 [Morgan et al 2006]

• Later-onset, slowly progressive NBIA with age at onset after the first decade, which includes the following:

  • Atypical PKAN

  • Neuroferritinopathy, a disorder associated with mutations in FTL, the gene encoding the ferritin light chain [Curtis et al 2001]

  • Aceruloplasminemia, which results from defects in the gene encoding ceruloplasmin [Gitlin 1998]

  • Atypical neuroaxonal dystrophy, a more protracted form than infantile neuroaxonal dystrophy that is also associated with PLA2G6 mutations [Morgan et al 2006]

  • Idiopathic NBIA

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 PANK2 mutations.

  • 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

A distinct subgroup of individuals with non-PKAN NBIA have early developmental delay with moderate-to-severe intellectual disability diagnosed in early childhood. These children may have spasticity and are often diagnosed with cerebral palsy. Their disease is static until late childhood or, more commonly, adolescence or early adulthood. With no clear inciting event, these individuals experience a sudden and rapid deterioration usually marked by prominent dystonia. At this later stage, brain MRI changes associated with NBIA may be seen.

Three 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.

• 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 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.

• 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:

• Neuronal ceroid lipfuscinosis

• Childhood-onset hereditary ataxias (especially SCA3 and SCA7)

• Dystonias such as DYT1 and Leigh syndrome (see also Mitochondrial Disorders Overview)

• Juvenile Huntington disease

• Chorea-acanthocytosis

• Lesch-Nyhan syndrome

• Wilson disease

• Recessive hereditary spastic paraplegia

• Tourette syndrome [Scarano et al 2002]

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.

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

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]

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 such as 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].

Professor Lars Timmerman, University Hospital, Cologne, Germany, is currently the principal investigator for an international clinical study of DBS outcomes in NBIA.

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. 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 patient populations. 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. A single case report suggests regression of symptoms in an adult with NBIA of unknown cause (i.e., non-PKAN NBIA) [Forni et al 2008]. One deferiprone trial is currently underway in Italy (clinicaltrials.gov) and a second trial has received FDA approval in the US. Clinical trials of deferiprone in PKAN and other NBIA are necessary to assess safety and efficacy.

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

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

NBIA Disorders Association Research Registry
The NBIA Disorders Association Web site has information about coordinating donations to brain banks to enable more detailed brain studies in the future. Use the Research link on the left of their homepage to learn more about the registry.
Phone: 619-588-2315
Fax: 619-588-4093
Email: pwood@nbiadisorders.org
Web: www.nbiadisorders.org

Registry for NBIA and Related Disorders
Oregon Health & Science University
Phone: 503-494-4344
Fax: 503-494-6886
Email: gregorya@ohsu.edu

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. 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 hypothetical treatment doubtful.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 obligate heterozygotes (carriers), and, therefore, carry one mutant allele.

• Heterozygotes have no symptoms.

• To date, no de novo mutations or examples of germline mosaicism have 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 disease-causing mutation.

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 disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

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 carriers or 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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.

Normal allelic variants. 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.

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

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 mutation, p.Gly521Arg, leads to a protein that is misfolded and devoid of activity [Zhang et al 2006]. However, nine other disease-associated mutations 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.

Literature Cited

1. Albright AL, Ferson SS. Intraventricular baclofen for dystonia: techniques and outcomes. Clinical article. J Neurosurg Pediatr. 2009;3:11–4. [PubMed: 19119897]
2. Benke T, Butterworth B. Palilalia and repetitive speech: two case studies. Brain Lang. 2001;78:62–81. [PubMed: 11412016]
3. Benke T, Hohenstein C, Poewe W, Butterworth B. Repetitive speech phenomena in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2000;69:319–24. [PMC free article: PMC1737094] [PubMed: 10945806]
4. Castelnau P, Cif L, Valente EM, Vayssiere N, Hemm S, Gannau A, Digiorgio A, Coubes P. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol. 2005;57:738–41. [PubMed: 15852393]
5. Ching KH, Westaway SK, Gitschier J, Higgins JJ, Hayflick SJ. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology. 2002;58:1673–4. [PubMed: 12058097]
6. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet. 2001;28:350–4. [PubMed: 11438811]
7. Danek A, Jung HH, Melone MA, Rampoldi L, Broccoli V, Walker RH. Neuroacanthocytosis: new developments in a neglected group of dementing disorders. J Neurol Sci. 2005;229-230:171–86. [PubMed: 15760637]
8. Danek A, Walker RH. Neuroacanthocytosis. Curr Opin Neurol. 2005;18:386–92. [PubMed: 16003113]
9. Dooling EC, Schoene WC, Richardson EP. Hallervorden-Spatz syndrome. Arch Neurol. 1974;30:70–83. [PubMed: 4808495]
10. Egan RA, Weleber RG, Hogarth P, Gregory A, Coryell J, Westaway SK, Gitschier J, Das S, Hayflick SJ. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). Am J Ophthalmol. 2005;140:267–74. [PMC free article: PMC2169522] [PubMed: 16023068]
11. Forni GL, Balocco M, Cremonesi L, Abbruzzese G, Parodi RC, Marchese R. Regression of symptoms after selective iron chelation therapy in a case of neurodegeneration with brain iron accumulation. Mov Disord. 2008;23:904–7. [PubMed: 18383118]
12. Freeman K, Gregory A, Turner A, Blasco P, Hogarth P, Hayflick S. Intellectual and adaptive behavior functioning in pantothenate kinase-associated neurodegeneration. Journal of Intellectual Disability Research. 2007;51:417–26. [PMC free article: PMC2099459] [PubMed: 17493025]
13. Gitlin JD. Aceruloplasminemia. Pediatr Res. 1998;44:271–6. [PubMed: 9727700]
14. Guimaraes J, Santos JV. Generalized freezing in Hallervorden-Spatz syndrome: case report. Eur J Neurol. 1999;6:509–13. [PubMed: 10362909]
15. Hallervorden J. Uber eine familiare Erkrankung im extrapyramidalen System. Dtsch Z Nervenheilkd. 1924;81:204–10.
16. Hartig MB, Hortnagel K, Garavaglia B, Zorzi G, Kmiec T, Klopstock T, Rostasy K, Svetel M, Kostic VS, Schuelke M, Botz E, Weindl A, Novakovic I, Nardocci N, Prokisch H, Meitinger T. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol. 2006;59:248–56. [PubMed: 16437574]
17. Hayflick SJ, Penzien JM, Michl W, Sharif UM, Rosman NP, Wheeler PG. Cranial MRI changes may precede symptoms in Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:166–9. [PubMed: 11551748]
18. Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, Gitschier J. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med. 2003;348:33–40. [PubMed: 12510040]
19. Houlden H, Lincoln S, Farrer M, Cleland PG, Hardy J, Orrell RW. Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic. Neurology. 2003;61:1423–6. [PubMed: 14638969]
20. Isaac C, Wright I, Bhattacharyya D, Baxter P, Rowe J. Pallidal stimulation for pantothenate kinase-associated neurodegeneration dystonia. Arch Dis Child. 2008;93:239–40. [PubMed: 18319387]
21. Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report. J Neurosurg. 1999;90:551–4. [PubMed: 10067928]
22. Koeppen AH, Dickson AC. Iron in the Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:148–55. [PubMed: 11551745]
23. Krause M, Fogel W, Tronnier V, Pohle S, Hörtnagel K, Thyen U, Volkmann J. Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration. Mov Disord. 2006;21:2255–7. [PubMed: 17078094]
24. Margolis RL, O'Hearn E, Rosenblatt A, Willour V, Holmes SE, Franz ML, Callahan C, Hwang HS, Troncoso JC, Ross CA. A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Ann Neurol. 2001;50:373–80.
25. McNeill A, Birchall D, Hayflick SJ, Gregory A, Schenk JF, Zimmerman EA, Shang H, Miyajima H, Chinnery PF. T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology. 2008;70:1614–19. [PMC free article: PMC2706154] [PubMed: 18443312]
26. Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S, Cangul H, Coryell J, Canham N, Nardocci N, Zorzi G, Pasha S, Rodriguez D, Desguerre I, Mubaidin A, Bertini E, Trembath RC, Simonati A, Schanen C, Johnson CA, Levinson B, Woods CG, Wilmot B, Kramer P, Gitschier J, Maher ER, Hayflick SJ. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006;38:752–4. [PMC free article: PMC2117328] [PubMed: 16783378]
27. Pellecchia MT, Valente EM, Cif L, Salvi S, Albanese A, Scarano V, Bonuccelli U, Bentivoglio AR, D'Amico A, Marelli C, Di Giorgio A, Coubes P, Barone P, Dallapiccola B. The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology. 2005;64:1810–2. [PubMed: 15911822]
28. Rump P, Lemmink HH, Verschuuren-Bemelmans CC, Grootscholten PM, Fock JM, Hayflick SJ, Westaway SK, Vos YJ, van Essen AJ. A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect. Neurogenetics. 2005;6:201–7. [PMC free article: PMC2105745] [PubMed: 16240131]
29. Scarano V, Pellecchia MT, Filla A, Barone P. Hallervorden-Spatz syndrome resembling a typical Tourette syndrome. Mov Disord. 2002;17:618–20. [PubMed: 12112223]
30. Shevell M. Hallervorden and history. N Engl J Med. 2003;348:3–4. [PubMed: 12510036]
31. Shields DC, Sharma N, Gale JT, Eskandar EN. Pallidal stimulation for dystonia in pantothenate kinase-associated neurodegeneration. Pediatr Neurol. 2007;37:442–5. [PubMed: 18021929]
32. Stevanin G, Camuzat A, Holmes SE, Julien C, Sahloul R, Dode C, Hahn-Barma V, Ross CA, Margolis RL, Durr A, Brice A. CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients. Neurology. 2002;58:965–7. [PubMed: 11914418]
33. Storch A, Schwarz J (2004) Diagnostic test for neuroacanthocytosis: quantitative measurement of red blood cell morphology. In: Danek A (ed) Neuroacanthocytosis Syndromes. Kluwer, Dordrecht, pp 71-7.
34. Swaiman KF. Hallervorden-Spatz syndrome and brain iron metabolism. Arch Neurol. 1991;48:1285–93. [PubMed: 1845035]
35. Swaiman KF. Hallervorden-Spatz syndrome. Pediatr Neurol. 2001;25:102–8. [PubMed: 11551740]
36. Terespolsky D, Clarke JT, Blaser SI. Evolution of the neuroimaging changes in fucosidosis type II. J Inherit Metab Dis. 1996;19:775–81. [PubMed: 8982951]
37. Walker RH, Rasmussen A, Rudnicki D, Holmes SE, Alonso E, Matsuura T, Ashizawa T, Davidoff-Feldman B, Margolis RL. Huntington's disease--like 2 can present as chorea-acanthocytosis. Neurology. 2003;61:1002–4. [PubMed: 14557581]
38. Yamashita S, Maeda Y, Ohmori H, Uchida Y, Hirano T, Yonemura K, Uyama E, Uchino M. Pantothenate kinase-associated neurodegeneration initially presenting as postural tremor alone in a Japanese family with homozygous N245S substitutions in the pantothenate kinase gene. J Neurol Sci. 2004;225:129–33. [PubMed: 15465096]
39. Yang EY, Campbell A, Bondy SC. Configuration of thiols dictates their ability to promote iron-induced reactive oxygen species generation. Redox Rep. 2000;5:371–5. [PubMed: 11140748]
40. Yoon SJ, Koh YH, Floyd RA, Park JW. Copper, zinc superoxide dismutase enhances DNA damage and mutagenicity induced by cysteine/iron. Mutat Res. 2000;448:97–104. [PubMed: 10751627]
41. Zhang YM, Rock CO, Jackowski S. Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration. J Biol Chem. 2006;281:107–14. [PubMed: 16272150]
42. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet. 2001;28:345–9. [PubMed: 11479594]

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]

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

• 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