Pantothenate Kinase-Associated Neurodegeneration (PKAN)

Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden-Spatz Disease (HSD), is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. The disease was first described in 1922 by two German physicians, Hallervorden and Spatz, as a form of familial brain degeneration characterized by cerebral iron deposition. The term neurodegeneration with brain iron accumulation type 1 (NBIA-1), eventually came to be used for this condition,[1, 2] although the most recent term for the disorder is pantothenate kinase-associated neurodegeneration (see the image below). (See Etiology.)[3]

Magnetic resonance imaging (MRI) has increased the likelihood of antemortem diagnosis of Pantothenate kinase-associated neurodegeneration (PKAN). The typical MRI findings include bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted images. These imaging features, which are fairly diagnostic of PKAN, have been termed the "eye-of-the-tiger sign." The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling. The surrounding hypointensity is due to loss of signal secondary to iron deposition.

The onset of symptoms most commonly occurs in late childhood or early adolescence. The classic presentation is in the late part of the first decade or the early part of the second decade, between ages 7 and 15 years. However, the disease has been reported in infancy, and cases with adult onset have also been described. (See Presentation and Workup.)[4, 5, 6]

PKAN is relentlessly progressive. The clinical course is characterized by progressive dementia, spasticity, rigidity, dystonia, and choreoathetosis. The progression of the disease usually occurs over 10-12 years, and affected individuals typically die in the second or third decade; however, case reports describe patients surviving 30 years. (See Presentation and Prognosis.)[7, 8]

The disease can be familial or sporadic. When familial, PKAN is inherited recessively; it has been linked to chromosome 20.[9] A mutation in the pantothenate kinase (PANK2) gene on band 20p13 has been described in patients with PKAN. (See Etiology.)[10]

PKAN is a subtype of Neurodegeneration with Brain Iron Accumulation (NBIA). NBIA comprises a group of inherited neurodegenerative disorders that are characterized symptomatically by extrapyramidal movement disorders and pathologically by abnormal iron accumulation in deep basal ganglia. Ten forms have been described so far, and each has a corresponding gene and specific mode of inheritance. PKAN, PLA2G6-Associated Neurodegeneration (PLAN), Fatty Acid Hydroxylase-associated Neurodegeneration (FAHN), Coenzyme A synthase Protein-Associated Neurodegeneration (CoPAN), Mitochondrial-membrane Protein-Associated Neurodegeneration (MPAN), Kufor-Rakeb syndrome, Woodhouse-Sakati syndrome, and Aceruloplasminemia  are all autosomal recessive; whereas Beta-propeller Protein-Associated Neurodegeneration (BPAN) is X-linked dominant and Neuroferritinopathy is autosomal dominant.

In the United States, PKAN is the most common form of NBIA, comprising 50% of all NBIA cases. PLAN is the second most common, comprising 20% of all cases.[11]

Patient education

The Web site of the NBIA Disorders Association is helpful.

The exact etiology of PKAN is not known. One proposed hypothesis is that abnormal peroxidation of lipofuscin to neuromelanin and deficient cysteine dioxygenase lead to abnormal iron accumulation in the brain. While portions of the globus pallidus and pars reticulata of substantia nigra (SN) have high iron content in healthy individuals, individuals with PKAN have excess amounts of iron deposited in these areas.[3]

However, the exact role of iron in the etiology of this disease remains unknown. Also, whether the deposition of iron in basal ganglia in PKAN is the cause or consequence of neuronal loss and gliosis is not clear. Decreased activity of the enzyme cysteine dioxygenase was demonstrated in one affected child.[12] This was postulated to lead to accumulation of cysteine in the basal ganglia, since cysteine can chelate iron and thus result in its deposition. However, these findings were not confirmed in adult patients.

A role for mutation in the PANK2 gene (band 20p13) in the etiology of PKAN has been proposed. Deficiency of pantothenate kinase may lead to accumulation of cysteine and cysteine-containing compounds in the basal ganglia. This causes chelation of iron in the globus pallidus and free radical generation as a result of rapid auto-oxidation of cysteine in the presence of iron.[13] Mutations in the PANK2 gene account for most inherited PKAN cases. Such mutations result in an autosomal recessive inborn error of coenzyme A metabolism, which has been termed pantothenate kinase–associated neurodegeneration.[14, 15, 16, 17, 18]

Pathologic examination reveals characteristic rust-brown discoloration of the globus pallidus and SN pars reticulata secondary to iron deposition.[19, 20] Generalized atrophy of the brain may be noted, with a reduction in size of the caudate nuclei, SN, and tegmentum. Microscopically, the characteristic changes include the following:

• Variable loss of neurons, myelinated fibers, and gliosis in globus pallidus and SN, which may appear spongiotic when severe

• Widely disseminated rounded or oval, nonnucleated structures called spheroids (also known as axon schollen or neuroaxonal dystrophy); these represent swollen axons with vacuolated cytoplasm and are found most abundantly in the pallidonigral system, although they are also present in the cerebral cortex

• Accumulation of pigment, mostly containing iron, in the globus pallidus and SN

• Ceroid lipofuscin and neuromelanin containing iron, in the areas mainly affected (mentioned above)

Iron deposition may be found intracellularly and extracellularly and frequently is centered on vessels. These changes are found to a lesser degree in other parts of the brain and in the spinal cord.[21] The presence of axonal spheroids suggests a link between PKAN and infantile neuroaxonal dystrophy; however, no clinical or genetic relationship has been reported between the 2 diseases. Tau-positive neurofibrillary tangles and alpha-synuclein–positive Lewy bodies may be found in cortical and subcortical regions in patients with a prolonged clinical course.[1]

The clinical course of PKAN is variable, depending on its form (classic or atypical). In patients with the classic form, the disease has a progressive course extending over several years, leading to death in early childhood. Some patients experience rapid deterioration of function secondary to dystonia, rigidity, dysphagia, and respiratory compromise and die within 1–2 years of disease onset. Other patients undergo a slower progression or even plateau for many years and may continue to function into the third decade of life.[8]

Symptoms in pantothenate kinase-associated neurodegeneration (PKAN) include the following:

• Dystonia - A prominent and early feature

• Significant speech disturbances - Can occur early

• Dysphagia - A common symptom; caused by rigidity and corticobulbar involvement

• Dementia - Present in most individuals with PKAN

• Visual impairment - Caused by optic atrophy or retinal degeneration; not uncommon and can be the presenting symptom of the disease, although this is rare

• Seizures - Have been described[18]

Clinical manifestations of PKAN vary from patient to patient. The symptoms usually begin in the first decade with a motor disorder of extrapyramidal type and gait difficulty. Extrapyramidal symptoms dominate the clinical picture and include rigidity, slowness of movement, dystonia, choreoathetosis, and tremor.

In patients with atypical PKAN, extrapyramidal dysfunction may be delayed for several years, and spasticity and dysarthria may be the presenting symptoms.

Physical examination reveals signs consistent with extrapyramidal and corticospinal dysfunction. In addition to rigidity, dystonia, and chorea, patients may exhibit spasticity, brisk reflexes, and extensor plantar responses.

Based on the common clinical features, the following diagnostic criteria for PKAN have been proposed.[18] For a definitive diagnosis, all of the obligate findings and at least 2 of the corroborative findings should be present. None of the exclusionary factors should be present.

Obligate features of PKAN include the following:

• Onset during the first 2 decades of life

• Progression of signs and symptoms

• Evidence of extrapyramidal dysfunction, including 1 or more of the following: dystonia, rigidity, choreoathetosis

Corroborative features include the following:

• Corticospinal tract involvement

• Progressive intellectual impairment

• Retinitis pigmentosa and/or optic atrophy

• Seizures

• Positive family history consistent with autosomal recessive inheritance

• Hypointense areas on magnetic resonance imaging (MRI) involving the basal ganglia

• Abnormal cytosomes in circulating lymphocytes and/or sea-blue histiocytes in bone marrow

Exclusionary features include the following:

• Abnormal ceruloplasmin levels and/or abnormalities in copper metabolism

• Presence of overt neuronal ceroid lipofuscinosis, as demonstrated by severe visual impairment and/or seizures that are difficult to control

• Predominant epileptic symptoms

• Severe retinal degeneration or visual impairment preceding other symptoms

• Presence of familial history of Huntington chorea and/or other autosomal, dominantly inherited neuromovement disorders

• Presence of caudate atrophy on imaging studies

• Deficiency of hexosaminidase A

• Deficiency of ganglioside monosialic acid-1 (GM1)–galactosidase

• Nonprogressive course

• Absence of extrapyramidal signs

Patients with atypical PKAN show more varied clinical features, with slower progression. Presenting symptoms usually involve speech defects, such as palilalia (repetition of words or phrases), tachylalia/tachylogia (rapid speech), and dysarthria (poor articulation, slurring). Motor involvement is usually a later feature. Onset is in the first three decades (mean age 13.6 years).[22]

No biochemical markers have been found in pantothenate kinase-associated neurodegeneration (PKAN). Levels of copper, ceruloplasmin, lipids, amino acids, and acanthocytes typically are measured in the blood to exclude other conditions. Radionuclide scan reveals increased iron uptake in the basal ganglia.[23]

Cultured skin fibroblasts have been reported to accumulate iron (59 Fe) transferrin, but the isotope is no longer available for human use.

Increased platelet monoamine oxidase ̶ B activity has been reported.[24] Bone marrow histiocytes and peripheral lymphocytes may demonstrate the presence of abnormal cytosomes, including fingerprint, granular, and multilaminated bodies.[25, 26] The characteristics of the material suggest the presence of ceroid lipofuscin.

CT scanning

Computed tomography (CT) imaging is not very helpful in the diagnosis of PKAN but may show hypodensity in the basal ganglia and some atrophy of the brain. Calcification in the basal ganglia in the absence of any atrophy also has been described.

SPECT scanning

Iodine-123 (123 I)-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) scanning and (123 I)-iodobenzamide (IBZM)-SPECT scanning also have been used in making the diagnosis of PKAN.[27, 28]

MRI

MRI has increased the likelihood of antemortem diagnosis of PKAN.[29, 30, 31] The image below depicts the typical MRI appearance in PKAN, revealing bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted scanning. These imaging features are fairly diagnostic of PKAN and have been termed the "eye-of-the-tiger sign."[30, 31, 32, 33, 34]

Magnetic resonance imaging (MRI) has increased the likelihood of antemortem diagnosis of Pantothenate kinase-associated neurodegeneration (PKAN). The typical MRI findings include bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted images. These imaging features, which are fairly diagnostic of PKAN, have been termed the "eye-of-the-tiger sign." The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling. The surrounding hypointensity is due to loss of signal secondary to iron deposition.

A study by McNeill et al concluded that in most cases of PKAN, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2 and T2, fast ̶ spin echo brain MRI.[31]

Using a 7T MRI to quantify the amount of iron deposition, patients with PKAN were found to have a more than 3-fold higher concentration of iron in the globus pallidus, subthalamic nucleus and internal capsule, compared to normal controls. Patients heterozygous for the PANK2 mutation did not have any findings of iron deposition.[35]

A recent study of 21 patients with PKAN compared to 21 age-matched controls, showed reductions of fractional anisotropy on diffusion tensor imaging mainly in the periventricular substance surrounding the third ventricle, the medial part of both putamina and in the frontal white matter including the anterior limbs of the internal capsules and the corpus callosum. In the infratentorial region, cerebellar white matter and dorsal parts of the pons and medulla were affected. This new finding indicates that cerebral tissue dysfunction is likely more widespread than previously thought.[36]

Molecular genetic testing used in PKAN and NBIA comprises testing for PANK2 through sequence or deletion/duplication analysis. When one pathogenic variant (sequence variant or partial- and whole-gene deletion) is identified in a person with an "eye of the tiger" sign on MRI, the diagnosis of PKAN is confirmed.[37]

Historically, the treatment of patients with pantothenate kinase-associated neurodegeneration (PKAN) was mostly symptomatic. However, novel therapies have been studied as potential disease-modifying agents. These include iron chelators as well as fosmetpantotenate.

In terms of symptomatic therapy, tremor responds best to dopaminergic agents. The anticholinergic agent benztropine may be used to help rigidity and tremor. Benzodiazepines have been tried for choreoathetotic movements.

Hypertonia is usually a combination of rigidity and spasticity and may be difficult to treat. Dopamine agonists and anticholinergics may help to reduce rigidity. Baclofen in moderate doses relieves the stiffness and spasms and can reduce dystonia. Intramuscular botulinum toxin has also been used, in adults as well as children.[22, 38]

Deep brain stimulation, in particular targeting the bilateral subthalamic nuclei, has been tried for patients with prominent appendicular symptoms.[39]  Symptoms such as drooling and dysarthria can be troublesome. Medications such as methscopolamine bromide can be tried for excessive drooling. Dysarthria may respond to medications used for rigidity and spasticity. Speech therapy also may be useful, and computer-assisted devices may be used in advanced cases. A gastrostomy feeding may be necessary as the dysphagia progresses.

A multidisciplinary team approach involving physical, occupational, and speech therapists may be needed in selected patients with a protracted course to improve functional skills and communication.

Systemic chelating agents, such as desferrioxamine, have been used in an attempt to remove excess iron from the brain, but these have not proved beneficial. Dementia is progressive, and no treatment has proved clearly effective.

In vitro, pluripotent stem cells derived from PKAN patients responded to the administration of coenzyme A by preventing neuronal death and reactive oxygen species formation.[40]

Inpatient care

Admission for supportive care is occasionally necessary.

Referrals

Referral to a neurologist, particularly a movement disorders specialist, is helpful. Rehabilitation physicians often are consulted to coordinate the different therapy regimens.

Dystonia is the most prominent and disabling symptom of PKAN and may respond modestly to dopaminergic agents such as levodopa and bromocriptine (a dopamine agonist). Other dopamine agonists, such as ropinirole or pramipexole, can also be considered, although no formal studies have been conducted on their efficacy in PKAN.

Anticholinergics, such as trihexyphenidyl, may be used when dopaminergic agents are not helpful. However, these medications bring only transient relief for dystonia, and physical therapy is often of limited benefit as well. Botulinum toxin can be injected into severely affected muscles to relieve dystonia.

Deferiprone, an iron chelator used to treat patients with thalassemia, has emerged as a potential therapy for PKAN. It crosses the blood-brain barrier and is thought to reverse brain iron deposition. A pilot study examined the effects of deferiprone 15 mg/kg on five patients with PKAN. The patients experienced clinical improvement, and MRI studies showed decreased iron accumulation in the globus pallidus.[41]

Another promising treatment in the form of fosmetpantotenate has been suggested. Fosmetpantotenate bypasses the enzymatic defect induced by the PANK2 mutation. An open-label, uncontrolled 12-month trial of fosmetpantotenate in one patient with late-onset PKAN induced symptomatic improvement. It was noted to be well tolerated with only transient liver enzyme elevation that normalized after dose reduction.[42]

Because dystonia is a prominent feature of PKAN, the globus pallidus has been a target for surgical treatment. Stereotactic pallidotomy and bilateral thalamotomy have occasionally been tried in patients with severe dystonia, resulting in partial relief of symptoms.[43] Deep brain stimulation of the globus pallidus as well as the subthalamic nucleus has been used in these patients with promising results.[39, 44, 45]

In 2005, six individuals with PKAN underwent DBS. At follow-up, 6 to 48 months later, they all showed improvements in writing, speech, walking, and global measures of motor skills. In addition, a multicenter retrospective study of 23 patients from 16 centers, the majority of whom had PKAN, were tracked for 15 months post DBS. Overall, patients reported improvement in dystonia and quality of life. Patients with the most severe dystonia seemed to be the ones who benefited most from DBS.[22]

Continuous intrathecal baclofen infusion has been tried for refractory, generalized dystonia without much success. An alternative is intraventricular baclofen, of interest because this site may deliver benefit in patients who have primarily upper-body and facial dystonia, such as blepharospasm.[46]

Diet may play a role in the treatment of PKAN. A case study performed on a set of brothers with PKAN indicated a positive response to a hypercaloric diet. The brothers were placed on a diet of 50 kcal/kg for 2 weeks, and both were noted to have improvement particularly with regards to dystonia of the neck and trunk, as well as with gait and strength of hand grip.[47]

As previously mentioned, dopaminergic agents, such as levodopa and bromocriptine, can produce modest improvements in dystonia. If dopaminergic agents are not effective against dystonia, anticholinergics can be used, but they offer only transient relief. Botulinum toxin injections also can improve dystonic muscles.

Agents used to relieve rigidity and spasticity may prove effective against dysarthria, while methscopolamine bromide can deter excessive drooling.

Class Summary

These agents reduce morbidity associated with dopamine deficiency.

Levodopa/carbidopa (Sinemet, Sinemet CR, Parcopa)

Carbidopa (a decarboxylase inhibitor) is administered with levodopa to prevent the breakdown of levodopa and increase levodopa's bioavailability. Thus, carbidopa decreases the need for large doses of levodopa to achieve adequate brain dopamine levels. The levodopa/carbidopa combination is often used when symptom control with selegiline alone is insufficient. The CR levodopa/carbidopa formulation can help to prevent the on/off phenomenon in some patients.

The Sinemet tablet is available in a 4:1 ratio (Sinemet 100/25) and a 10:1 ratio (Sinemet 100/10 and 250/25) of levodopa to carbidopa. The Sinemet CR tablet contains a 4:1 ratio of levodopa to carbidopa (100/25 or 200/50); the daily dosage of Sinemet CR must be determined by careful titration.

Bromocriptine (Parlodel, Cycloset)

Bromocriptine is a semisynthetic ergot alkaloid derivative. It is a strong dopamine D2-receptor agonist and a partial dopamine D1-receptor agonist. Bromocriptine may relieve akinesia, rigidity, and tremor associated with Parkinson disease. It stimulates dopamine receptors in the corpus striatum. It is, however, less effective than other dopamine agonists. It can be used as an adjunct to levodopa/carbidopa.

Approximately 28% of the drug is absorbed from the gastrointestinal (GI) tract and metabolized in the liver. The approximate elimination half-life is 50 hours, with 85% of bromocriptine excreted in feces and 3-6% eliminated in urine. The drug is initiated at a low dose with slow titration; increase in the dose every 2 weeks. If severe adverse reactions occur, the dose is reduced in 2.5-mg decrements.

Class Summary

These agents are thought to act centrally by suppressing the conduction in the vestibular cerebellar pathways. They may have an inhibitory effect on the parasympathetic nervous system.

Trihexyphenidyl

This is a centrally acting anticholinergic agent that tends to diminish the muscle spasms.

Benztropine (Cogentin)

By blocking the striatal cholinergic receptors, benztropine may help in balancing the cholinergic and the dopaminergic activity in the striatum.

Scopolamine (Transderm Scop Patch, Scopace)

Scopolamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the central nervous system (CNS). It antagonizes the action of histamine and serotonin.

Class Summary

By binding to the specific receptor sites, these agents appear to potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Clonazepam (Klonopin)

Clonazepam suppresses the muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.

Class Summary

These agents produce symptomatic improvement in muscle strength by relieving spasticity and autonomic symptoms, or both in some patients.

Botulinum toxin type A (BOTOX)

This agent binds to the receptor sites on motor nerve terminals and inhibits the release of acetylcholine, which, in turn, inhibits the transmission of impulses at the neuromuscular junction.