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Disease Profile

Pantothenate kinase-associated neurodegeneration

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

All ages

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ICD-10

G23.0

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

PKAN; Neurodegeneration with brain iron accumulation; NBIA;

Categories

Nervous System Diseases

Summary

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease characterized by a progressive degeneration of the nervous system (neurodegenerative disorder) and buildup of iron in the brain. PKAN is usually classified into two forms: classic and atypical. Classic PKAN causes symptoms in the first ten years of life. The atypical form of PKAN usually occurs after the age of ten and progresses more slowly. All individuals with PKAN have an abnormal buildup of iron in certain areas of the brain. A particular change, called the eye-of-the-tiger sign, which indicates a buildup of iron, is typically seen on magnetic resonance imaging (MRI) scans of the brain in people with this disorder. PKAN is inherited in an autosomal recessive manner and is caused by mutations in the PANK2 gene.[1][2] Treatment depends on the symptoms, and may include medication (such as botulinum toxin), surgery, deep brain stimulation and physical therapy.[2][3] Research for a more effective treatment is ongoing.[2][3][4] 

Symptoms

There are two forms of PKAN, classical and atypical.

Classic PKAN: Symptoms of classic PKAN develop during early childhood, usually before age 10, and usually include:[5][6] 

  • Dystonia (sustained muscle contractions causing repetitive movements) and poor balance: The first symptom is often difficulty with movement and walking. Children are often first considered clumsy as their legs can be rigid, dystonic (an abnormality of muscle tone) and have involuntary muscle spasms (spasticity); these symptoms worsen over time and affect the arms. As affected individuals age, they may eventually lose control of voluntary movements. Muscle spasms combined with decreased bone mass can result in bone fractures. The disease may be stable for long periods of time and then undergo intervals of rapid deterioration, often lasting one to two months. Children usually lose the ability to walk by 10-15 years after the beginning of symptoms.
  • Speech, chewing and swallowing problems: Many people may have speech problems and may also have enough trouble with chewing and swallowing that a feeding tube becomes necessary, due to dystonia affecting the muscles in the mouth and throat.
  • Vision problems: Two-thirds of children with classical PKAN develop peripheral (side) vision loss and night blindness due to a degeneration of parts of the retina. 
  • Intellectual disability: Cognitive functioning varies from person to person and can range from high average to below average.

Atypical form: Features of the atypical form usually progress more slowly and appear within the first three decades of life. Signs and symptoms may include:[2][6]

  • Speech difficulty: Are usually the first symptoms, characterized by speech difficulty such repetition of words or phrases (palilalia), rapid speech (tachylalia), and poor articulation/slurring (dysarthria). 
  • Psychiatric symptoms such as behavioral problems, personality changes, violent outburst, and depression are more commonly observed. 
  • Movement problems: While movement problems are a common feature, it usually develops later than the classic form. Loss of independent walking often occurs 15-40 years after the initial development of symptoms. 
  • Vision problems: Retinal degeneration is rare in the atypical form.

All individuals with PKAN have an abnormal buildup of iron in certain areas of the brain. A particular change, called the eye-of-the-tiger sign, which indicates an accumulation of iron, is typically seen on magnetic resonance imaging (MRI) scans of the brain in people with this disorder.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Iris hypopigmentation
Light eye color
0007730
30%-79% of people have these symptoms
Abnormal cranial nerve morphology
0001291
Abnormal foot morphology
Abnormal feet structure
Abnormality of the feet
Abnormality of the foot
Foot deformities
Foot deformity

[ more ]

0001760
Choreoathetosis
0001266
Constipation
0002019
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty

[ more ]

0002015
Gastroesophageal reflux
Acid reflux
Acid reflux disease
Heartburn

[ more ]

0002020
Hyperreflexia
Increased reflexes
0001347
Recurrent respiratory infections
Frequent respiratory infections
Multiple respiratory infections
respiratory infections, recurrent
Susceptibility to respiratory infections

[ more ]

0002205
Rigidity
Muscle rigidity
0002063
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Tremor
0001337
5%-29% of people have these symptoms
Abnormality of skin pigmentation
Abnormal pigmentation
Abnormal skin color
Abnormal skin pigmentation
Abnormality of pigmentation
Pigmentary changes
Pigmentary skin changes
Pigmentation anomaly

[ more ]

0001000
Akinesia
0002304
Bradykinesia
Slow movements
Slowness of movements

[ more ]

0002067
Cachexia
Wasting syndrome
0004326
Dementia
Dementia, progressive
Progressive dementia

[ more ]

0000726
Depressivity
Depression
0000716
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood

[ more ]

0002376
Dysarthria
Difficulty articulating speech
0001260
Dysphonia
Inability to produce voice sounds
0001618
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Joint dislocation
Joint dislocations
Recurrent joint dislocations

[ more ]

0001373
Obsessive-compulsive trait
Obsessive-compulsive traits
0008770
Seizure
0001250
Visual impairment
Impaired vision
Loss of eyesight
Poor vision

[ more ]

0000505
Percent of people who have these symptoms is not available through HPO
Abnormal pyramidal sign
0007256
Acanthocytosis
0001927
Ataxia
0001251
Autosomal recessive inheritance
0000007
Blepharospasm
Eyelid spasm
Eyelid twitching
Involuntary closure of eyelid
Spontaneous closure of eyelid

[ more ]

0000643
Cerebral degeneration
0007313
Decreased muscle mass
0003199
Eye of the tiger anomaly of globus pallidus
0002454
Eyelid apraxia
Difficulty opening the eyelids
0000658
Facial grimacing
0000273
Feeding difficulties in infancy
0008872
Global brain atrophy
Generalized brain degeneration
0002283
Global developmental delay
0001263
Hyperactivity
More active than typical
0000752
Hyperpigmentation of the skin
Patchy darkened skin
0000953
Motor tics
0100034
Myopathy
Muscle tissue disease
0003198
Neurodegeneration
Ongoing loss of nerve cells
0002180
Optic atrophy
0000648
Orofacial dyskinesia
0002310
Palilalia
0031814
Parkinsonism
0001300
Pigmentary retinopathy
0000580
Rapidly progressive
Worsening quickly
0003678
Retinal degeneration
Retina degeneration
0000546
Urinary incontinence
Loss of bladder control
0000020
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Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • Orphanet lists international laboratories offering diagnostic testing for this condition.

    Treatment

    The treatment of patients with PKAN is mostly symptomatic, and may include:[2][5][3][4][6]

    • Medication: The tremors best respond to dopaminergic agents. Benzodiazepines are used to improve muscular contraction and twisting and writhing movements. Dystonia is treated with oral trihexyphenidyl, oral baclofen or a baclofen pump, and oral clonazepam. Intramuscular botulinum toxin is used for muscle spasms, especially in treating a limited body region (injections in the facial muscles can greatly improve speech and eating abilities). Methscopolamine bromide can be used for excessive drooling.
    • Surgical procedures: Procedures to destroy specific parts of the brain, the pallidus (ablative pallidotomy) or the thalamus (thalmotomy) may provide temporary relief for dystonia.
    • Deep brain stimulation: A procedure where a medical device called a brain pacemaker is implanted to send electric impulses to specific parts of the brain for the treatment of movement and mood disorders.
    • Services for the blind and educational programs.
    • Physical therapy and occupational therapy to maintain normal joint mobility
    • Adaptive aids (walker, wheelchair) for gait abnormalities.
    • Speech therapy and/or communication devices.

    Drugs that reduce the levels of iron in the body (iron chelation) may be effective in some cases but more studies are needed. Supplements of vitamin B5 (pantothenate) may be helpful in people with the atypical PKAN but there are not enough studies confirming that it is effective.[6] 

    A recent study with one patient using a medication known as fosmetpantotenate, which restores the CoA levels (a helper molecule, needed for the activation of several enzymes) decreased in this disease, showed good results.[4]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
      • Genetics Home Reference (GHR) contains information on Pantothenate kinase-associated neurodegeneration. This website is maintained by the National Library of Medicine.
      • The National Institute of Neurological Disorders and Stroke (NINDS) collects and disseminates research information related to neurological disorders. Click on the link to view information on this topic.

        In-Depth Information

        • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Pantothenate kinase-associated neurodegeneration. Click on the link to view a sample search on this topic.

          Selected Full-Text Journal Articles

            References

            1. Pantothenate kinase-associated neurodegeneration. Genetics Home Reference. 2015; https://www.ghr.nlm.nih.gov/condition/pantothenate-kinase-associated-neurodegeneration.
            2. Gregory A & Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration. GeneReviews. 2013; https://www.ncbi.nlm.nih.gov/books/NBK1490/.
            3. Bokhari M, Bokhari SR. Hallervorden Spatz Disease (Pantothenate Kinase-Associated Neurodegeneration, PKAN). StatPearls. June, 2017; https://www.ncbi.nlm.nih.gov/books/NBK430689/.
            4. Christou Y-P, Tanteles GA, Kkolou E, et al. Open-Label Fosmetpantotenate, a Phosphopantothenate Replacement Therapy in a Single Patient with Atypical PKAN doi:10.1155/2017/3247034.. Case Reports in Neurological Medicine. 2017; 2017:3247034. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439260/.
            5. Gregory, A. Polster, B J, and Hayflick, S J. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. Journal of Medical Genetics. February 2009;
            6. Pantothenate Kinase-Associated Neurodegeneration. NORD. 2016; https://rarediseases.org/rare-diseases/pantothenate-kinase-associated-neurodegeneration/.

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