Pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration
Classification and external resources
Pantetheine
ICD-10	G23.0
ICD-9	333.0
OMIM	234200
DiseasesDB	29462
MedlinePlus	001225
eMedicine	neuro/151
MeSH	D006211

Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and formerly called Hallervorden-Spatz syndrome (use of this eponym is discouraged due to Drs. Hallervorden and Spatz's affiliation with the Nazi regime and the ethically unacceptable manner in which they obtained some autopsy specimens^{[1] [2]}), is a degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron that progressively builds up in the brain.

Symptoms

Symptoms typically begin in childhood and are progressive, often resulting in death by early adulthood. Symptoms of PKAN begin before middle childhood, and most often are noticed before ten years of age. Symptoms include:

• dystonia (repetitive uncontrollable muscle contractions that may cause jerking or twisting of certain muscle groups)
• dysphagia & dysarthria due to muscle groups involved in speech being involved
• rigidity/stiffness of limbs
• tremor
• writhing movements
• dementia
• spasticity
• weakness
• seizures
• retinitis pigmentosa, another degenerative disease that affects the individual’s retina, often causing alteration of retinal color and progressive deterioration of the retina at first causing night blindness and later resulting in a complete loss of vision

25% of individuals experience an uncharacteristic form of PKAN that develops post-10 years of age and follows a slower, more gradual pace of deterioration than those pre-10 years of age. These individuals face significant speech deficits as well as psychiatric and behavioral disturbances.

Being a progressive, degenerative nerve illness, PKAN leads to early immobility and often death by early adulthood.

Signs and tests

A neurological examination would show evidence of muscle rigidity; weakness; and abnormal postures, movements, and tremors. If other family members are also affected, this may help determine the diagnosis. Genetic tests can confirm an abnormal gene causing the disease. However, this test is not yet widely available. Other movement disorders and diseases must be ruled out. Individuals exhibiting any of the above listed symptoms are often tested using MRI (Magnetic Resonance Imaging) for a number of neuro-related disorders. As PKAN is a disease prominently evident in the brain, MRIs are very useful in making a sound diagnosis. An MRI usually shows iron deposits in the basal ganglia. Development of diagnostic criteria continues in the hope of further separating PKAN from other forms of neurodegenerative diseases featuring NBIA.

History & Statistics

PKAN was first described by Hallervorden and Spatz (1922). Their discovery was brought about by a diagnosis of a family of 12 in which five sisters exhibited progressively increasing dementia and dysarthria. Autopsies revealed brown discolorations in different areas of the brain (particularly of interest were the globus pallidus and substantia nigra regions). Further investigation and description was brought about by Meyer (1958) who diagnosed 30 separate cases of PKAN. Meyer(1958) was followed by Elejalde et al. (1978) who described 5 affected family members and hypothesized that the disorder originated in central Europe, backing up his hypothesis with clinical and genetic analysis. Further investigation and insights were provided by Malmstrom-Groth and Kristensson (1982)^[3] and Jankovic et al. (1985).^[4]

Diagnosis of PKAN hit a milestone with the availability of MRIs, as well as the in-depth descriptions of those MRIs provided by Littrup and Gebarski (1985),^[5] Tanfani et al. (1987),^[6] Sethi et al. (1988),^[7] Angelini et al. (1992),^[8] Casteels et al. (1994),^[9] and Malandrini et al. (1995).^[10] The disease was named 'pantothenate kinase-associated neurodegeneration' or PKAN by Zhou et al. (2001)^[11] who suggested the name to avoid misinterpretation and to better reflect the true nature of the disorder. Most recently Pellecchia et al. (2005) published a report of 16 patients afflicted with PKAN, confirmed by genetic analysis.^[12]

Survival rates for those diagnosed with typical PKAN is 11.18 years with a standard deviation of 7.8 years. Prevalence data regarding this disorder remains incomplete, however it is estimated that anywhere between 1 in 1,000,000 to 3 in 1,000,000 individuals will be afflicted with this disorder (based upon observed cases in a population), but once again this is only an estimate as the disease is so rare it is difficult to statistically and accurately ascertain.

Treatment

As of yet there are no major breakthroughs in the treatment of PKAN, with most pharmacologic treatments focusing on the easing or temporary relieving of PKAN’s symptoms. Iron chelating agents have been used somewhat successfully in retarding the disorder, however they have not been anywhere near what one would consider a significant success

Many believe taking certain vitamins may be beneficial, including pantothenate, Coenzyme Q, and other anti-oxidants.^{[citation needed]}

Current research focuses on the future use of high dose pantothenate, the PANK2 enzyme substrate, in possibly alleviating symptoms as well as the further development of iron chelating agents that may be better aimed at reaching the central nervous system and working to better remove excess iron from the individual’s system.

Complications may result from the medication used to treat symptoms. Immobility from the disease can also lead to skin breakdown, respiratory infections, and blood clots, among others.

Genetics

Genetically speaking, PKAN is an autosomal recessive disorder. The parents of an afflicted child must both be heterozygous carriers for the disease and therefore must carry one mutant allele. As it is an autosomal disorder, those heterozygous for the disorder may not display any atypical characteristics that are considered suggestive of the disorder.

The disorder is caused by a mutant PANK2 gene located at the chromosomal locus: 20p13-p12.3. PANK2 is responsible in coding for the protein Pantothenate kinase 2, which in turn is responsible for stifling the accumulation of N-pantothenoyl-cysteine and pantetheine. It is believed that when this accumulation is not suppressed, the result is direct cell toxicity or cell toxicity as a result of free radical damage due to the lack of suppression.

PANK2 encodes a 1.85Kb transcript which is derived from seven exons covering a total distance of approximately 3.5Mb of genomic DNA. The PANK2 gene also encodes a 50.5-kDa protein that is a functional pantothenate kinase, an essential regulatory enzyme in coenzyme A (CoA) biosynthesis, and catalyzing the phosphorylation of pantothenate (Vitamin B5), N-pantothenoyl-cysteine, and pantetheine (OMIM).

Mutant PANK2 gene coded proteins are often caused by null or missense mutations most notably a 7bp deletion in the PANK2 gene coding sequence.

References

External links

• pkan at NIH/UW GeneTests
• 02041 at CHORUS
• synd/1082 at Who Named It?
• nbia at NINDS
• http://nbiadisorders.org/ NBIA Disorders Association