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Neurodegeneration with Brain Iron Accumulation

PKAN

Pantothenate Kinase-Associated Neurodegeneration, is one of the most common forms of NBIA caused by mutations in the PANK2 gene.

PKAN represents actually 35% of the NBIA population. The PANK2 gene provides the instruction for the manufacture of an enzyme called pantothenate kinase. Current research is investigating how this missing enzyme can damage nerve cells and contribute to the characteristic accumulation of iron in the brain.

PKAN is generally separated into classical and atypical forms, depending on the age of onset of the disease and the rate of progression. The characteristics of the disease in some people place them between these two categories. Symptoms vary according to these two forms, so there is a wide range of symptoms.

Classic PKAN

A more rapid progression of symptoms that appear in the early childhood, before the age of 6 years, on average around the age of 3 years. Gait problems around the age of 3 years and later progressive dystonia, dysarthria, rigidity, spasticity, hyperreflexia and extensor toe signs.

These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Eventually, falling becomes more common. Because they have trouble protecting themselves during falls, affected children may have repeated injury to the face and chin.

Pigmentary retinal degeneration occurs in two thirds of affected individuals with classic PKAN. Loss of peripheral vision may 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 patients and has not been observed in atypical PKAN.

Atypical PKAN

In most cases, a slow progression of symptoms that appear over several years, even decades, later and less sever than those of classic 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 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.

Movement problems are common, although they develop later. Patients 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.

Retinopathy is rare in atypical PKAN.

The symptoms of Classical PKAN

Progressive 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 may lead to recurrent trauma to the tongue, in some extreme cases requiring full-mouth dental extraction, or bone fractures from the combination of extreme bone stress and osteopenia. 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.

Spasticity

Dysarthria speech difficulties

Rigidity

Choreoathetosis, involuntary movements in a combination of chorea (irregular migrating contractions) and athetosis (twisting and writhing)

Pigmentary retinal degeneration is common

The symptoms of Atypical PKAN or Late PKAN

more variable symptoms appear after age 10. There are prominent speech disorders and more frequently psychiatric symptoms, and more gradual progression of disease.

Psychiatric symptoms impulsive behavior, violent outbursts, depression and rapid mood swings.

Movement disorders

Retina degeneration less common

Diagnosis and tests for classical PKAN and Atypical PKAN

Movement disorders onset in the first to third decade of life

Pigmentary retinopathy or optic atrophy

Intellectual and developmental disabilities mainly in children with very young onset

Seizure are rare

MRI (magnetic resonance imaging)”Eye of the tiger” sign on T2-weighted brain. Dark area has a very bright spot in the center, rarely seen in other forms of MBIA indicates the high levels of brain iron. A central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus.

The sign sometimes is absent in the early stages of disease. In the Dominican Republic, where 21 affected individuals have been diagnosed with PKAN and have the same PANK2 mutation, it has been reported that six individuals lacked the ‘eye of the tiger sign’ despite their similarities to others in this group.

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.

Genetic testing Identification of biallelic PANK2 pathogenic variants on molecular genetic testing confirms the diagnosis.

Family history consistent with autosomal recessive inheritance, including consanguinity.

Evaluations of disease progression

The extent of disease can be established by

TREATMENT

Dystonia

The most debilitating and distressing symptom of the disease can be treated by

physical therapy and occupational therapy for those who are only mildly symptomatic to maintain joint mobility, referral for adaptive aids (walker, wheelchair) for gait abnormalities,

Speech therapy and/or assistive communication devices,

ophthalmological tests

Prevention of secondary complications Full-mouth dental extraction when severe orobuccolingual dystonia results in recurrent tongue biting; gastrostomy tube feeding as needed.

Surveillance Evaluation for treatable causes of pain during episodes of extreme distress; monitoring of height and weight; routine ophthalmologic assessment; oral assessment for trauma, assessment of ambulation and speech abilities, feeding and nutrition assessment.

Treatments Under Investigation

Iron Chelation

Deferiprone (Ferriprox®) crosses the blood-brain barrier and removes iron from the brain cells.

An international clinical trial over 2 1/2 year has now been completed and the results are published. All in all Deferiprone was well tolerated, lowered the Brain iron accumulation and slow down the progression of the disease in a significant number of the patients recruited in this clinical trial. Therefore Deferiprone is proposed to treat Neurodegeneration associated with Brain iron accumulation showing some benefits to these patients at the moment.

Pantothenate and pantothenate derivatives

The possibility of the existence of 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 pantothenic acid or calcium pantothenate (≤10 g/day for several weeks) do not appear to be toxic to humans. We don’t yet know how effective pantothenate supplementation is in ameliorating symptoms. Some individuals with an atypical disease course have anecdotally reported improvements in dysarthria, gait imbalance and a sense of well-being when taking pantothenate.

Clinical studies are underway to investigate the potential of a form of pantothenate, which is pantethine and pantethine derivatives, to treat PKAN. Studies with fruitflys show that when pantethine is provided in their food, they live longer and have a lower rate of nervous system decline.

In a grant provided by the NBIA Disorders Association, Dr. Ody Sibon from the University Medical Center Groningen, in Groningen, Netherlands, studied pantethine derivatives to see if they are more stable in the human digestive system and blood. Also, as part of the 2011- 2015 European Union grant called Treat Iron-Related Childhood-Onset Neurodegeneration, or TIRCON, pantethine derivatives were identified as a possible treatment for PKAN. Please see more information on TIRCON and the clinical trials for PKAN.

Brain Imaging: Researchers at the Oregon Health & Science University are doing a brain imaging study to explore brain blood flow, called perfusion, in PKAN. They hope to gain new insights into how the disease progresses.

Progression

PKAN is a progressive disorder. 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.

Many individuals with the classic form of PKAN require a wheelchair by their mid-teens. Most lose the ability to move or walk independently between 10 and 15 years after the beginning of symptoms, and also by this time may have enough trouble with chewing and swallowing that a feeding tube becomes necessary. 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.

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.

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.

Patients are at risk of premature death. However, life span varies among patients. With improvements in medical care, a greater number of affected individuals are living into adulthood.

Genetics

PKAN is inherited and is called an autosomal recessive disorder. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and pass their changed genes on to their child.

There are

25% chance that two carriers would have an affected child,

50% that the couple will have a child who also is a carrier

25% chance the child won’t have the gene mutation.

Carrier testing for at-risk relatives and prenatal testing can be obtained if both disease-causing mutations have been identified in an affected family member.

Molecular genetic testing approaches are

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies can be done by analyzing DNA extracted from fetal cells in amniocentesis (usually performed at 15 to 18 weeks of gestation) or chorionic villus sampling (usually performed at 10 to 12 weeks of gestation).

Preimplantation genetic diagnosis may be an option when the disease-causing mutations have been identified.

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