Continuing Education Activity

Pantothenate kinase-associated neurodegeneration (PKAN), the most prevalent form of neurodegeneration with brain iron accumulation (NBIA), is an autosomal recessive disorder caused by mutations in the PANK2 gene. This inborn error of CoA metabolism results in excessive iron deposition in the basal ganglia, leading to progressive extrapyramidal symptoms, including dystonia, rigidity, and choreoathetosis. Clinicians may recognize PKAN by its hallmark “eye-of-the-tiger” sign on T2-weighted brain magnetic resonance imaging.

This course explores the complexities surrounding PKAN, including the current diagnostic criteria and various clinical presentations. PKAN presents in classic and atypical forms. Classic PKAN emerges in children, typically with the age of onset ≤10 years, followed by rapid progression and early disability or death. Atypical PKAN emerges in adolescence or early adulthood, followed by slower progression, milder symptomatology, and more diverse symptom manifestations. This activity for healthcare professionals is designed to enhance the learner's competence in identifying the PKAN, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this complex neurodegenerative condition.

Objectives:

• Compare key features that distinguish between the classic and the atypical presentations of pantothenate kinase-associated neurodegeneration.

• Evaluate individuals with pantothenate kinase-associated neurodegeneration using evidence-based and guideline-adherent approaches to genetic, laboratory, and imaging procedures.

• Implement symptom-specific clinical management for patients and caregivers to improve the quality of life in patients with pantothenate kinase-associated neurodegeneration.

• Collaborate with the interprofessional team to manage patients with pantothenate kinase-associated neurodegeneration to improve diagnostic precision and enhance patient outcomes.

Introduction

Pantothenate kinase-associated neurodegeneration (PKAN), an inborn error of coenzyme A (CoA) metabolism, represents the most common form of neurodegeneration with brain iron accumulation (NBIA). This rare neurodegenerative disorder involves progressive extrapyramidal dysfunction (eg, dystonia, rigidity, choreoathetosis), iron accumulation in the basal ganglia, and axonal spheroids within the central nervous system.[1] Among more than 20 alternative names for PKAN, Hallervorden-Spatz disease remains the most familiar to nonspecialist practitioners. Mutations in PANK2, which encodes the mitochondrially targeted pantothenate kinase 2, cause this autosomal recessive disorder.[2] Presenting symptoms often prompt clinical suspicion, which strengthens upon identification of the characteristic “eye-of-the-tiger” pattern—hypointense and hyperintense signals in the globus pallidus—on T2-weighted brain magnetic resonance imaging (MRI) sequences.[3] Systemic and cerebrospinal fluid iron levels, along with plasma ferritin, transferrin, and ceruloplasmin, remain within normal ranges.

Researchers have distinguished classic and atypical forms of PKAN. The classic form typically emerges in early childhood, usually by age 6, and leads to severe, rapidly worsening motor dysfunction. Most children who present early lose independent mobility and become wheelchair-bound by their mid-teens. The atypical form presents later, during childhood or adolescence, and progresses more slowly. Although symptom patterns vary, the atypical form more frequently involves speech disturbances and psychiatric manifestations than the classic type.[4] Current treatment approaches—such as deep brain stimulation (DBS) and symptomatic medications (eg, baclofen, trihexyphenidyl)—focus on alleviating symptoms without modifying disease progression. Disease-modifying therapies remain in early development. Promising therapies targeting underlying metabolic dysfunction and iron accumulation hold potential for advances in PKAN management, although further clinical trials are needed to confirm their efficacy and safety.[5][6]

Etiology

PKAN was first described in 1922 by the German physicians Hallervorden and Spatz as a familial form of brain degeneration marked by cerebral iron deposition.[7] This condition represents a subset of NBIA that affects the basal ganglia, leading to variable neurological dysfunction. Mutations in at least 10 different genes have been linked to distinct NBIA disorders, each producing a specific clinical entity.

Although the precise etiology of PKAN remains unclear, case reports have suggested an inborn error of metabolism involving neuromelanin and the dopaminergic system.[8] One proposed hypothesis suggests that the aberrant oxidation of lipofuscin to neuromelanin and reduced activity of cysteine dioxygenase may contribute to abnormal iron accumulation in the brain. While the globus pallidus and pars reticulata of the substantia nigra naturally contain relatively high iron levels, individuals with PKAN exhibit excessive iron accumulation in these regions.

The mutation in the PANK2 gene (located on band 20p13) accounts for most inherited PKAN cases in various studies. Mutations result in an autosomal recessive inborn error of CoA metabolism with a resultant deficiency of pantothenate kinase enzyme, which may lead to the accumulation of cysteine and cysteine-containing compounds in the basal ganglia. This causes iron chelation in the globus pallidus and basal ganglia, and rapid auto-oxidation of cysteine in the presence of iron with subsequent free radical production. Pathologic examination reveals characteristic rust-brown discoloration of the globus pallidus and substantia nigra pars reticulata due to underlying iron deposition and a reduction in the size of these nuclei. Generalized atrophy of the brain parenchyma may be seen in severely advanced cases.[9][10][11]

Case reports have documented a positive family history of PKAN and acanthocytosis, including an early onset of PKAN in 2 sisters, in which the diagnosis was based on clinical features, laboratory parameters, and MRI imaging findings.[12][13]

Epidemiology

According to bioinformatic and population-based analyses of large cohorts (eg, the Genome Aggregation Database, known as gnomAD, containing approximately 140,000 unrelated adults from global populations), the incidence of PKAN is estimated to be 2 individuals in every 1 million live births globally outside of Africa, with a much lower incidence of 1 in 1.5 million live births in the African population.[4]

Estimates of the prevalence of PKAN remain imprecise, but the condition may affect 1 to 3 per million people worldwide. PKAN’s rarity contributes to early diagnosis and management challenges because awareness among healthcare practitioners is limited.

Pathophysiology

The mechanism by which basal ganglia iron uptake is increased in PKAN is unknown since systemic and cerebrospinal fluid iron levels and plasma ferritin, transferrin, and ceruloplasmin are all normal. One of the proposed mechanisms is that the aberrant oxidation of lipofuscin to neuromelanin, combined with insufficient cysteine dioxygenase, leads to abnormal iron accumulation in the brain.

A mutation in the PANK2 gene accounts for the majority of inherited PKAN cases, serving as the etiology of PKAN in various studies. Previous studies mentioned that PANK2 mutations are associated with all cases of classic Hallervorden-Spatz syndrome and one-third of cases of atypical disease. At the same time, predicted levels of pantothenate kinase 2 protein were correlated with the severity of the disease.[14]

Mutations result in an autosomal recessive inborn error of CoA metabolism with a resultant deficiency of pantothenate kinase, which may lead to the accretion of cysteine and cysteine-containing compounds in the basal ganglia. This causes iron chelation in the globus pallidus and rapid auto-oxidation of cysteine in the presence of iron, with subsequent free radical generation. Pathologic examination shows characteristic rust-brown discoloration of the globus pallidus and pars reticularis of the substantia nigra because of the large amounts of iron deposition and a reduction in the size of the caudate nuclei, substantia nigra, and tegmentum, as well as generalized atrophy of the brain.[15][12]

Routine iron stains demonstrate that the iron is primarily located in the microglia and macrophages, but scattered neurons are also reactive. Moreover, axonal spheroids are characteristic of the disease.[16] Microscopically marked neuroaxonal and myelin degeneration is a distinctive pathologic feature of PKAN. The following findings can also be noted:

• Ubiquitinated spheroids, which represent swollen axons with vacuolated cytoplasm inactivated by attachment of ubiquitin, are found most abundantly in the pallidonigral system and the cerebral cortex.
• Accumulation of iron-containing pigment, mostly neuromelanin, and ceroid lipofuscin, in the palladonigral system

Previous literature reviews have reported widespread expression of alpha-synuclein and tau immunoreactivity in Hallervorden-Spatz syndrome, characterized by a protracted clinical course, including:

• Grossly, the brains showed severe frontotemporal lobar atrophy with abundant spheroids and mild iron deposits in the globus pallidus, associated with features of motor neuron disease. Diffuse sponginess in the atrophic cortex, along with widespread neurofibrillary tangles (NFTs) and Lewy bodies in the cortical and subcortical regions, including the spinal cord, was also present.
• Ultrastructurally, NFTs contained paired helical filaments and Lewy bodies with central dense cores and radiating fibrils. Discrete immunostaining was seen in NFTs and neuropil threads with different antibodies against phosphorylated tau, and in Lewy bodies with antibody versus alpha-synuclein.
• Diffuse, overlapping immunoreactivity of alpha-synuclein and phosphorylated tau was found within the cytoplasm of numerous neurons.[17]

On the other hand, recent studies have found that the decreased global structural connectivity within the white matter, as well as the negative correlation of motor system-related tracts, primarily those between the basal ganglia, cortical areas, and the cerebellum, coincides with the concept of a general functional disturbance of the motor system in PKAN.[18]

History and Physical

Pantothenate Kinase-Associated Neurodegeneration Clinical Features

PKAN affects muscular tone and voluntary movements, progressively causing difficulty with voluntary, coordinated movements, chewing, and swallowing. In the later stages of development, PKAN can lead to mental deterioration, emaciation, severe feeding difficulties, and visual impairment.[8]

Clinical manifestations of PKAN vary widely among patients. Classical and atypical presentations have been well documented, with progressive dystonia—beginning in the limbs or cranial region—representing the most typical clinical feature.[13] Recent systematic reviews have identified pigmentary retinal degeneration as a common finding in classic PKAN. Distinguishing features of classic PKAN include stiffness, dystonia, dysarthria, and choreoathetosis. Atypical PKAN typically presents after age 10 and involves prominent speech abnormalities, psychological disturbances, and a more gradual disease progression.[19][20]

Patients with this disease suffer from a variety of other neurological symptoms and signs, including:

• Extrapyramidal symptoms
• Dystonia is described as continuous spasms and muscle contractions. This is a prominent, progressive condition, and in classic form, the onset usually occurs in the first decade, which is more frequent for truncal and axial dystonia, including retrocollis, oromandibular-facial dystonia, and chorea.
• Dysarthria
• Muscular rigidity and spasms
• Gait disturbance
• Essential, dystonic, or parkinsonian tremors, rarely bradykinesia (slowness of movement), and choreoathetosis (involuntary movements, including chorea (irregular migrating contractions) and athetosis (twisting and writhing).[21] 
• Cognitive impairment and delay in milestones
• Visual impairment 
• Optic atrophy (may be bilateral) accompanied by visual loss [22] 
• Retinal degeneration or retinitis pigmentosa
• Oculomotor abnormalities, including blepharospasm [23] 
• Significant speech disturbances (may occur at an early age)
• Dysphagia (a common symptom, caused by rigidity of muscles and associated corticobulbar abnormality)
• Dementia (present in most patients with PKAN)
• Seizures (reported frequently)
• Akathesis (feeling of internal motor restlessness that can present as tension, nervousness, or anxiety)
• Neuropsychiatric dysfunction

Approximately 25% of individuals exhibit an "atypical" presentation, with symptom onset typically occurring in the second or third decade of life. These cases involve a delayed onset of extrapyramidal dysfunction and a more gradual disease progression. Recent reports have identified cerebellar ataxia, behavioral abnormalities, Parkinsonism, and apraxia of eyelid opening exclusively in late-onset patients.[13] The atypical form frequently features prominent speech defects, spasticity, and psychiatric disturbances. Reported symptoms include depression, nervousness, catatonia, and, less commonly, psychotic manifestations such as complex motor tics, stereotypic behavior, anxiety, auditory hallucinations, persecutory delusions, and social withdrawal.[24][25][26] One study described a 28-year-old male patient with difficulties in social interaction, impaired ability to perform daily activities, and muscle rigidity. The patient's history included head trauma 3 years prior. Neurological examination revealed bradykinesia, hypophonic speech, resting and postural tremor, rigidity, spasticity, hyperreflexia, and psychosis.[27]

Pantothenate Kinase-Associated Neurodegeneration Diagnostic Criteria

Based on the common clinical features, the following diagnostic criteria have been proposed. For a definitive diagnosis, all obligate findings and 2 or more corroborative findings should be present.

Obligate features of PKAN are the following:

• Onset in the first 2 decades of life
• Progression of signs and symptoms
  • Classic form: loss of ambulation occurring within 10 to 15 years of onset
  • Atypical form: ambulatory loss occurs within 15 to 40 years of disease onset
• Evidence of extrapyramidal dysfunction, including 1 or more of these neurological impairments:
  • Dystonia
  • Rigidity
  • Choreoathetosis

Corroborative features are listed as follows:

• Corticospinal tract involvement
  • Spasticity
  • Hyperreflexia
  • Extensor toe signs
• Progressive intellectual impairment
• Retinitis pigmentosa and optic atrophy (usually associated with visual field testing, visual evoked response, and electroretinogram abnormalities)
• Seizures
• Family history consistent with autosomal recessive inheritance (may include consanguinity)
• Hypointense areas on MRI in the involved basal ganglia (particularly in the substant
• ia nigra)
• Abnormal cytosomes in circulating lymphocytes
• Red blood cell acanthocytosis of sea-blue histiocytes in bone marrow [15] 

Evaluation

Computed Tomography Imaging

CT is not particularly helpful in the diagnosis of PKAN; however, this modality can occasionally reveal hypodensity in the basal ganglia and some brain atrophy. Calcification in the basal ganglia in the absence of any atrophy has also been described. 

For instance, a case study presented an 8-year-old boy with progressive muscle dystonia, neuroregression, frequent falls, multiple injury marks of different stages, and seizures that started at the age of 4 years. However, the child had been seizure-free due to valproate and levetiracetam treatment. The CT scan of this patient demonstrated bilateral basal ganglia calcification. Genetic testing identified mutations in the PANK2 gene.[11]

Brain Magnetic Resonance Imaging

Brain MRI is the standard diagnostic evaluation of all forms of NBIA. MRI has significantly increased the likelihood of a diagnosis of PKAN. Imaging findings are most conspicuous on T2W sequences which demonstrate hypointensity reflecting areas of iron deposition, mainly in globus pallidus, pars reticulata of the substantia nigra, and red nuclei (see Image. MRI of PKAN). Studies report that all patients with PANK2 mutations, whether classic or atypical, have the characteristic radiologic sign known as the "eye of the tiger" on brain MRI, which is evident as bilateral symmetrical, central foci of hyperintense signals in the anteromedial globus pallidus, with a surrounding zone of hypointensity in the globus pallidus on T2W MR scanning. In particular, a study described a child who presented with extrapyramidal symptoms and a pathognomonic eye-of-the-tiger sign on MRI, with pathological examination of the brain revealing iron deposition in the bilateral globus pallidus, spongiform change, and axonal neuron degeneration (characterized by spheroids).[28][20][29]

The central T2 relatively hyperintense spot or line within the globus pallidus is due to gliosis and vacuolization. This sign was not reported in patients without PANK2 mutations. The cortex is usually spared, but atrophy can be seen in advanced cases.

Susceptibility-Weighted and T2* Imaging

Susceptibility-weighted (SWI) and T2* imaging show susceptibility artifact (blooming low signal) in corresponding areas due to iron accretion. MR spectroscopy shows a decreased N-acetylaspartate peak due to neuronal loss and may depict increased myoinositol. Studies have also documented marked overall low signal from the globus pallidus on each side, with central zones of high signal on T2-weighted spin echo sequences together with unusually low signal in the zona reticularis of the substantia nigra.[30][31]

Furthermore, previous studies have compared MR findings with pathological studies and found that the low signal intensity in T2-weighted images at 1.5 T corresponds to iron deposits in dense tissue, and that the high signal intensity of the eye-of-the-tiger sign corresponds to an area of loose tissue with vacuolization. However, no correlation was observed in the 2 pathologic cases for the central spot of low signal intensity.[32]

Single-Photon Emission Computed Tomography Scanning

Iodine-123 ( I)-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane as single-photon emission computed tomography (SPECT) scanning and ( I)-iodobenzamide (IBZM)-SPECT scanning have been used in making the diagnosis of Hellervorden-Spatz disease, but are not commonly used in the clinical setup. Case reports mentioned a 123I-ioflupane SPECT scan demonstrating the absence of radiotracer uptake in the caudate nuclei and putamina.[33] 

Antenatal Diagnosis

Prenatal testing for pregnancies at risk is through DNA testing. Cells are usually obtained by amniocentesis at 15 to 20 weeks of gestation or by chorionic villus sampling at 10 to 13 weeks. At least 1 mutation in the proband of extracted DNA should be present for a prenatal diagnosis of NBIA. If both pathogenic variants have been found in an affected family member, carrier testing for at-risk relatives is possible by the same technique.

Treatment / Management

The treatment of patients with Hallervorden-Spatz disease or PKAN is primarily guided by the clinical symptoms present.[34][35][36] Various therapies for PKAN include:

• Intramuscular botulinum toxin: This treatment has also been used to alleviate hypertonicity.[37]
• Intrathecal or oral baclofen: Baclofen, administered in moderate doses, relieves stiffness and spasms and can help reduce dystonia.[37]
• Dopamine agonists and anticholinergic agents: Tremors best respond to dopaminergic agents. For rigidity and spasticity, dopamine agonists and anticholinergic agents (eg, oral trihexyphenidyl) alone or in combination may be used. Additionally, dysarthria could respond to medications employed for rigidity and spasticity.
• Benzodiazepines: This medication has been used for choreoathetotic movements. 
• Methscopolamine bromide: Medications such as methscopolamine bromide can be attempted for excessive drooling.
• Ophthalmology medications: These treatments may be used for patients with retinopathy.
• Iron chelation drugs: Agents for iron chelation include deferiprone and desferrioxamine.[34][37]
• Surgical procedures: Surgical approaches (eg, ablative pallidotomy or thalamotomy) may be considered.[34] 
• Stimulation surgical procedures: Deep brain stimulation targeting the globus pallidus interna and subthalamic nucleus stimulation can also serve as a candidate DBS target, especially among patients with prominent appendicular symptoms.[38]
• Ancillary supportive therapies: An interprofessional team approach including physical therapy and occupational therapy to maintain joint mobility, referral for adaptive aids (eg, walker and wheelchair) for gait abnormalities, speech therapy and assistive communication devices, swallowing evaluation, dietary assessment, and gastrostomy tube feeding
• Social services: Referral to community resources, eg, financial services, services for the blind, and educational programs.

Aside from L-dopa and Botulinum toxin injections, previous studies have used antioxidants in the management of PKAN cases.[39] Recent studies revealed that commercial supplements, pantothenate, pantethine, vitamin E, omega-3, carnitine, and thiamine were able to remove iron accumulation, increase PANK2, mtACP, and NFS1 expression levels, and improve pathological alterations in mutant cells with residual PANK2 expression levels. These findings suggest that commercial compounds can significantly correct the mutant phenotype in cellular models of PKAN. These compounds, either alone or in combination, are commonly used in clinical practice and may be beneficial for treating patients with PKAN who have residual enzyme expression levels.[40]

Likewise, psychiatric symptoms also improved after atypical antipsychotic treatment.[25] However, dementia is gradual and progressive and usually does not respond to treatments. Strategies for prevention of secondary complications include:

• Bite blocks
• Full-mouth dental extraction for recurrent tongue biting, severe orobuccolingual dystonia
• Gastrostomy tube feeding [20]

Moreover, a recent study revealed that fosmetpantotenate treatment was safe but did not improve function, as assessed by the PKAN-Activities of Daily Living (PKAN-ADL) scale, among patients with PKAN.[41]

Research and trials for the administration of CoA and high doses of pantothenate are ongoing. Advances in the etiological understanding and treatment of PKAN may provide new insights into the physiological significance of CoA, a cofactor crucial for the operation of various cellular metabolic processes.[42] However, no conclusive data are available.

Surveillance includes evaluation for treatable causes of pain during episodes of extreme distress; height and weight monitoring; routine assessment related to ophthalmology; oral trauma, ambulation, speech abilities, feeding, and nutrition.[20] Studies have revealed that the presence of low but considerable PANK2 expression, which can be increased in certain mutations, provides necessary information that justifies the use of a high dose of pantothenate as a treatment. A more effective therapeutic strategy can be achieved by comparing and monitoring the effects of different currently available pharmacological alternatives on the pathophysiological alterations in fibroblasts and neuronal cells obtained from patients with PKAN.

Furthermore, recent studies on the treatment of mutant cell cultures using various supplements, eg, pantothenate, pantethine, vitamin E, omega-3 fatty acids, α-lipoic acid, L-carnitine, or thiamine, have improved all pathophysiological alterations in PKAN fibroblasts, with residual expression of the PANK2 enzyme. These findings, obtained through pharmacological screenings in patient-derived cellular models, can help optimize therapeutic approaches for patients with PKAN.[19][43][44]

Differential Diagnosis

The differential diagnosis for patients with PKAN includes disorders with manifestations of atypical progressive extrapyramidal disorder and cognitive impairment.[12]

GM Gangliosidoses

GM gangliosidoses is an inherited deficiency of human beta-galactosidase due to the accumulation of glycosphingolipids within the liposomes. Clinical manifestations of lysosomal storage disorders are remarkably heterogeneous; they can appear at any age, and each of them can vary from mild to severe conditions. Case reports describe coarse facial features, eg, hypertelorism, a wide nose, a depressed nasal bridge with lingual protrusion, along with severe generalized hypotonicity, delayed development, and hepatosplenomegaly during the first month of life.[45]

Huntington's Disease

Huntington's disease (HD) is an autosomal-dominant hereditary neurodegenerative disorder with a hallmark feature of chorea. Although HD has classically been described as a triad of motor, cognitive, and psychiatric symptoms, a recent study mentioned HD as a systemic illness affecting the entire body.[46][47][48]

Juvenile Neuronal Ceroid Lipofuscinosis

Juvenile neuronal ceroid lipofuscinosis belongs to a group of neuronal ceroid lipofuscinoses described as autosomal recessive, inherited, lysosomal, and neurodegenerative disorders manifested as progressive dementia and psychomotor deterioration, movement disorders, ataxia, seizure and epilepsy, visual impairment, language delay/regression, and early death.[49][50]

Machado-Joseph Disease 

Machado-Joseph disease is an inherited neurodegenerative disease with progressive cerebellar ataxia, described as a lack of coordination and balance, along with significant vestibulo-ocular reflex. A recent study found that patients with Machado-Joseph disease exhibit vestibular signs and symptoms that meet the diagnostic criteria of Bilateral Vestibulopathy established by the International Society for Neuro-Otology. These findings are significant not only for the diagnosis and evaluation of progressive cerebellar diseases but also for the potential beneficial effect of vestibular rehabilitation techniques on dizziness, balance, and the emotional, physiological, and functional aspects of Machado-Joseph disease.[51]

Neuroacanthocytosis Syndromes

Neuroacanthocytosis syndromes are a group of rare genetic disorders characterized by abnormalities of red blood cell membranes, which result in acanthocytes and the progressive degeneration of the basal ganglia, leading to involuntary abnormal movements, as well as neuropsychiatric and cognitive alterations. The "rubber-man" gait is observed in advanced chorea-acanthocytosis and described as distinctive flexions of the neck, manifesting as head drops and the trunk.[52][53] 

Wilson Disease

Wilson disease or hepatolenticular degeneration is a rare autosomal recessive disease that primarily affects the liver and basal ganglia of the brain due to excess accumulation of copper resulting in disturbed cellular homeostasis of copper within the liver and cell injury to other organs like the kidneys, eyes, heart, muscles, and bones which explains the multifaceted clinical features, including liver-related symptoms (eg, vomiting, weakness, ascites, swelling of the legs, yellowish skin, and itchiness), neurological symptoms (eg, tremors, muscle stiffness, ataxia, writing problems, dysphagia, and trouble speaking) and behavioral symptoms (eg, personality changes, depression, psychosis, anxiety, and auditory or visual hallucinations) and renal tubular dysfunction.

Most patients with Wilson disease were observed to have liver dysfunction within the first decade of life, while the neuropsychiatric features appeared in the third/fourth decade of life. Other symptoms include Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. The modified Leipzig Scoring System aids in the diagnosis of Wilson's disease. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin.[54][55]

Prognosis

The long-term outcomes for patients with PKAN are generally poor, with significant variability depending on the age of onset and the form of the disease.

Classic PKAN typically presents in early childhood, with a median age of onset around 3 years, and follows a rapidly progressive course marked by severe neurological impairment. Early symptoms include dystonia, rigidity, and gait disturbances. According to a study by Chang et al, the median interval from disease onset to loss of independent ambulation is approximately 5 years, and about 20% of patients with early-onset PKAN die at a median age of 12.5 years. The majority of patients with classic PKAN experience significant functional decline, including oromandibular dystonia, generalized dystonia, and swallowing difficulties, becoming a wheelchair user by their mid-teens.

Atypical PKAN typically begins later, with a median age of onset around 18 years, and progresses more slowly, accompanied by comparatively milder symptoms. Patients may undergo an initial period of rapid symptom progression, followed by prolonged stability. Common symptoms include oromandibular dystonia, generalized dystonia, and gait disturbances. Long-term outcomes in atypical PKAN vary, with some individuals maintaining functional abilities for extended periods.

PKAN progresses relentlessly and lacks a curative treatment. Disease severity and progression rate depend on the specific PANK2 mutations involved. Patients with 2 null alleles typically exhibit an earlier onset and a more rapid decline. Premature death often results from secondary complications (eg, aspiration pneumonia and nutrition-related immunodeficiency) rather than from the primary neurodegenerative process.

Complications

As a progressive neurodegenerative disorder, PKAN presents with a wide spectrum of complications that evolve over time and significantly impair quality of life. In classic PKAN, early childhood onset leads to rapid deterioration marked by severe motor symptoms such as dystonia, rigidity, and gait disturbances. These symptoms often result in the loss of independent ambulation within five years of disease onset. Oromandibular dystonia and dysphagia frequently develop, increasing the risk of aspiration pneumonia, a leading cause of premature death. Visual impairment due to pigmentary retinal degeneration and communication difficulties from dysarthria further complicate daily functioning. Nutritional deficits and related immunodeficiency can also emerge, requiring complex interprofessional care.

In contrast, atypical PKAN, which generally begins during adolescence or early adulthood, progresses more slowly but still presents substantial challenges. While patients may retain functional independence for a longer period, the disease eventually impairs mobility through dystonia and gait abnormalities. Prominent psychiatric and behavioral symptoms—including depression, anxiety, catatonia, and psychosis—often dominate the clinical picture and contribute to social withdrawal and reduced autonomy. Cerebellar ataxia, Parkinsonism, and apraxia of eyelid opening have been reported in late-onset cases, highlighting the clinical variability. These complications demand continuous neurologic, psychiatric, and rehabilitative support, and significantly burden both patients and caregivers.

Effective management of PKAN requires a comprehensive, interprofessional approach involving neurologists, psychiatrists, physical, occupational, and speech therapists, and psychosocial support services. The severity and range of complications—whether rapid and profound in classic PKAN or progressive and multifaceted in atypical PKAN—highlight the critical importance of early diagnosis, regular monitoring, and tailored interventions to preserve function, minimize complications, and support patient and caregiver well-being.

Deterrence and Patient Education

Preventing or deterring the progression of PKAN remains a significant challenge due to the disorder's genetic origins and lack of curative treatments. While primary prevention through genetic counseling is crucial, especially for families with a known history of PKAN, most efforts focus on early detection, symptom management, and comprehensive caregiver education to mitigate complications and enhance quality of life. Prompt recognition of early motor symptoms and neuropsychiatric signs, followed by timely genetic testing and neuroimaging, can facilitate earlier interventions that may slow disease progression and support adaptive functioning.

Education and support for caregivers play a crucial role in effectively managing PKAN. Interprofessional teams, including neurologists, geneticists, therapists, and social workers, offer coordinated care and targeted education tailored to the specific needs of both patients and their families. Standardized, accessible educational materials that respect caregivers' cultural backgrounds and literacy levels can improve understanding of disease management strategies. Telehealth platforms and mobile applications extend access to specialist guidance, particularly in underserved areas. Practical, hands-on training in using mobility aids, administering therapies, and managing daily challenges empowers caregivers and reduces preventable complications. Emotional support through counseling, peer networks, and respite care helps sustain caregivers over the long term. These combined strategies not only improve patient outcomes but also ease the emotional and physical toll on families navigating this complex disorder.

Pearls and Other Issues

Genetic counseling is recommended since PKAN has an autosomal mode of inheritance. During conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Therefore, carrier testing for at-risk relatives, prenatal testing for a pregnancy at risk, and preimplantation genetic testing are possible if both pathogenic variants have been determined among family members.[20]

Enhancing Healthcare Team Outcomes

Effective management of PKAN demands a highly coordinated interprofessional approach to address the disorder’s complex and progressive nature. Physicians, particularly neurologists and geneticists, play a central role in diagnosing PKAN through clinical evaluation and confirmatory genetic testing, while also guiding therapeutic strategies that may include pharmacologic treatment for seizures and dystonia, as well as consideration of surgical interventions such as pallidal deep brain stimulation. Advanced practitioners and nurses provide ongoing clinical monitoring and patient education, helping to manage symptoms and coordinate follow-up care. Pharmacists contribute essential expertise in medication management, especially as patients often require multiple drugs to address movement disorders and psychiatric symptoms. Genetic counselors are crucial in supporting families through genetic testing processes, offering clear explanations of inheritance patterns, risks for future offspring, and psychosocial support during emotionally difficult periods.

Interprofessional communication and care coordination are critical to ensure a patient-centered approach that aligns with the unique needs of individuals with PKAN and their caregivers. Speech-language pathologists may assist with communication strategies or devices when dysarthria limits verbal interaction, and occupational and physical therapists develop plans to maximize mobility and function. Nurses and case managers often serve as the linchpin in care coordination, bridging communication among specialists, caregivers, and community resources. Shared responsibility among all healthcare team members improves safety, enhances quality of life, and supports caregivers in managing the physical and emotional challenges of long-term care. As PKAN remains incurable and eventually life-limiting, the team must also be prepared to incorporate palliative care principles, focusing on comfort, dignity, and emotional support. Continued collaboration and investment in emerging treatments—such as antioxidative therapy and gene-based approaches—offer hope for the future, even as teams strive to optimize care and outcomes in the present.