Pantothenate Kinase-Associated Neurodegeneration

[PKAN]

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 the PANK2 gene [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

• 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

• 

  Figure 1. Left image shows the 'eye of the (more...)

  

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

  Eye of the tiger' sign on T2-weighted magnetic resonance imaging (1.5 Tesla or greater). Observed in all affected individuals with one or two PANK2 mutations [Hayflick et al 2003; Authors, personal observations] (see 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 and all individuals with the 'eye of the tiger' sign have at least one PANK2 mutation [Authors, personal observations]. 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. 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 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 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

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.—ED.

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

Clinical uses

• Confirmatory diagnostic testing

• Carrier testing

• Prenatal diagnosis

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.

Research testing

• Deletion/duplication testing. Large intragenic deletions may account for some of the mutations missed by sequence analysis; however, these alleles have not yet been fully characterized.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in PKAN and NBIA

Test Method	Mutations Detected	Mutation Detection Rate 1	Test Availability
Sequence analysis	PANK2 sequence variants	>99% of individuals with NBIA with the 'eye of the tiger' sign on MRI 2 ~50% of individuals with clinical diagnosis of NBIA 2	Clinical
Duplication/ deletion testing	PANK2 deletions	3%-5%	Research only

1. Detection of at least one mutation
2. NBIA International Mutation Database

Interpretation of test results. A single identified PANK2 mutation in the presence of the 'eye of the tiger' sign should be considered confirmatory of PKAN.

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

Testing Strategy

Sequence analysis of PANK2 is recommended after MR imaging demonstrates high brain iron in the globus pallidus. Even in the absence of a true 'eye of the tiger' sign, molecular genetic testing is recommended.

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].

Genetically Related (Allelic) Disorders

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

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.

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 midteens, 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.

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, these individuals demonstrate "freezing" during ambulation, especially when turning corners or encountering surface variations [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 to represent part of the PKAN disease spectrum [Ching et al 2002, Houlden et al 2003]. Mutations in the PANK2 gene 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, 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 does not yet exist.

However, individuals who have two null mutations, and are thus predicted to have no protein, 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 1231G>A 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 have been collected on this rare disorder. 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 (formerly Hallervorden-Spatz syndrome) 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 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 the PLA2G6 gene [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]

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

  • NBIA of unknown cause

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 hypodense 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 mental retardation diagnosed in early childhood. They 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 mental retardation with Dandy-Walker malformation. Unlike PKAN, affected children have severe mental retardation. MRI of the brain, recommended for suspected PKAN, would rule out this diagnosis.

• Alpha fucosidosis [Terepolsky 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. 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. This disorder 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, Jung 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 (1) a progressive spinocerebellar degeneration with ataxia of gait, dysmetria, and dysarthria; (2) a demyelinating sensorimotor and axonal peripheral neuropathy with hyporeflexia and diminished vibration and position sense; (3) rarely, pyramidal tract signs; (4) rarely, cranial nerve involvement. 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 about 35 years, although it 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 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 and intrathecal baclofen [Albright et al 1996]

• Ablative pallidotomy or thalmotomy. The dystonia does return, usually about one year following surgery [Justesen et al 1999].

• Oral baclofen and trihexyphenidyl

• Deep brain stimulation, used clinically on a very limited basis with possible 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].

Testing 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) has recently been investigated in 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.

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

Other

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 panthothenic acid or calcium pantothenate (up to 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 atypical individuals have anecdotally reported improvement in their symptoms (dysarthria, gait imbalance, sense of well-being) when taking pantothenate.

Based on the role of coenzyme A (CoA) in the synthesis and degradation of fatty acids, the importance of docosahexanoic acid (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.

Iron chelating agents have been tried without clear benefit [Dooling et al 1974, Albright et al 1996]. Trials have been limited by the development of systemic iron deficiency before any clinical neurologic benefits were evident. The development of iron chelating agents that are better able to reach the central nervous system may hold promise for this mode of treatment [Arthur et al 1997, Miyajima et al 1997].

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 are a source of 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.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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 available on a clinical basis once the mutations have been identified in the proband.

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.

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. 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 about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 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 in an affected family member. For laboratories offering PGD, see .

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: The PANK2 gene 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. 5' RACE and EST data provide evidence for at least five initiating exons for PANK2, but only one of these has an open reading frame with potential initiation codons that splice in-frame to exon 2 [Zhou et al 2001].

Pathologic allelic variants: Over 86 mutations and eight polymorphisms have been identified [NBIA International Mutation Database]. See Genomic Databases Table.

The three common mutations are shown in Table 2.

Normal gene product: The PANK2 gene 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 human PANK2 mutations confirmed that the most frequent PANK2 mutation, 1231G>A, 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

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

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

• 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