PKAN

PKAN or Pantothenate Kinase-Associated Neurodegeneration, is the most common form of NBIA. Between 35 and 50 percent of the NBIA population has PKAN.

PKAN is an inherited autosomal recessive disorder caused by mutations in the PANK2 gene. This gene provides the instructions for making an enzyme called pantothenate kinase.

There are two forms of PKAN: classic and atypical, although some people have symptoms that place them in between the two categories.

Classic PKAN

  • Individuals with classic PKAN experience a more rapid progression of symptoms; developing in the first 10 years of life (starting around age 3 1/2, on average) and usually require a wheelchair by their mid-teens.

  • Most indivuals with classic PKAN will lose the ability to move or walk independently 10 - 15 years after symptoms begin.  Also, by this time, a feeding tube becomes necessary due to trouble with chewing and swallowing.

  • Dystonia (a movement disorder that causes the muscles to contract and spasm involuntarily) is always present and usually an early manifestation. Head and limb dystonia are frequent and in some extreme cases can lead to damage to the tongue and possibly bone fractures from the combination of extreme bone stress and osteopenia.

  • Individuals with classic PKAN are at risk of premature death. The dystonia can result in swallowing difficulty and poor nutrition. Such secondary effects are more likely to cause premature death than the primary neurodegenerative process.

  • Approximately two out of three individuals with classic PKAN develop retinal degeneration (it is more common in classic PKAN).

  • Life span varies among individuals with classic PKAN. With improvements in medical care, a greater number of affected individuals are living into adulthood.

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Atypical PKAN

  • The atypical form of PKAN usually occurs after age 10 and within the first three decades of life. The average age for developing symptoms is 13.

  • The disease progresses more slowly than classic PKAN and generally is less severe.

  • The symptoms vary from case to case and are more different than those of early-onset disease. The inability to walk typically occurs 15 to 40 years after symptoms develop.

  • Speech is affected early on and can manifest as repeating words or phrases, rapid speech, and slurring words.

  • Psychiatric symptoms are more commonly observed in atypical PKAN and can include impulsive behavior, violent outbursts, depression and rapid mood swings.

  • Movement problems are common, although they develop later. 

  • Individuals with Atypical PKAN often are described as having been clumsy in childhood and adolescence.

  • Similar to Parkinson’s disease, “freezing” while walking may occur, especially when turning a corner or encountering surface variations. Shaking or tremors also have been reported.

  • Degeneration of the retina may also occur, though much less often than classic PKAN.

Clinical Diagnosis of PKAN

  • All individuals with PKAN have high levels of brain iron, mainly in the globus pallidus.

  • PKAN has a unique characteristic seen on an MRI, known as the ‘eye of the tiger' sign.  Iron accumulation generally makes the brain look dark on certain (T2-weighted) MRI views. In PKAN, this dark area has a very bright spot in the center, called the "eye of the tiger". It is rarely seen in other forms of NBIA.  The sign sometimes is absent in the early stages of disease. 

  • Some cases with a purported ‘eye of the tiger’ sign will be found to have Mitochondrial-membrane Protein-Associated Neurodegeneration or MPAN, a different form of NBIA that can look similar to PKAN when comparing scans.

  • Another hallmark feature is the presence of a movement disorder, including one or more of the following: dystonia, rigidity or choreoanthetosis (twisting and writhing).

  • Other common features include corticospinal tract involvement which is responsible for conducting impulses from the brain to the spinal cord, extensor toe signs that indicate damage to the central nervous system and spasticity, along with retinal degeneration or optic atrophy.

  • Seizures are rare.

To establish the extent of disease in an individual diagnosed with PKAN, the following evaluations are recommended:

  • Neurologic examination for dystonia, rigidity, choreoathetosis and spasticity, including evaluation of walking and speech

  • An eye exam for evidence of retinopathy and optic atrophy

  • Screening to access if there are delays in development.

  • Assessment for physical therapy, occupational therapy, and/or speech therapy

  • Medical genetics consultation

Treatment of Dystonia

This is the most debilitating and distressing symptom of the disease. Therapies that are used with varying success include botox injected into the muscles; oral baclofen and trihexyphenidyl; intrathecal baclofen; deep brain stimulation; and physical and occupational therapy as indicated, particularly for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful.

What to Expect

 

  • Those individuals with PKAN who develop retinal degeneration may experience a loss of peripheral vision.  This can contribute to falling and gait problems in the early stages of 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.

  • Individuals with a normal eye examination at the time of diagnosis generally do not develop retinopathy later.

  • Optic atrophy is only found in 3 percent of individuals with classic PKAN and has not been observed in atypical PKAN.

  • PKAN is a progressive disorder and affected individuals experience episodes of rapid deterioration, often lasting one to two months, interspersed with longer periods of stability. Reasons for this are not clearly understood.

  • As the disease progresses, episodes of extreme distress may last for days or weeks. It is especially important during these episodes to evaluate for causes of pain, so it can be treated. These may include occult GI bleeding, urinary tract infections and bone fractures. Individuals with PKAN are at an especially high risk for fractures without apparent trauma because of osteopenia and stress on long bones from dystonia.

  • Swallowing evaluation and regular dietary assessments are needed to assure adequate nutrition. Once the individual can no longer maintain an adequate diet orally, a gastrostomy tube becomes necessary.

  • 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; eye assessment; oral assessment for consequences of trauma; assessment of walking and speech abilities.

Please see the link on this page for more detailed clinical information on PKAN at Gene Reviews, which was used as a source for some of the above information. Gene Reviews is primarily for the use of genetics professionals so the terminology and information may be difficult to understand for the general public.

Gene Review authors: Allison Gregory, MS, CGC and Susan J. Hayflick, MD.

Please visit the NBIA Disorders Association website, which was used as a primary source for the above information.