Pantothenate kinase-associated neurodegeneration
Encyclopedia
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. Julius Hallervorden
and Hugo Spatz
's affiliation with the Nazi regime and the ethically unacceptable manner in which they obtained some autopsy specimens), 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.
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.
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, however there have been reported cases of compound heterozygosity
in which heterozygous individuals do develop the classic form of the disease.
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-kDaprotein
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 mutation
s most notably a 7bp deletion in the PANK2 gene
coding sequence.
This disorder has been reported in specific communities based on intra-community marriages where both parents of the child are carrying the same mutation. One of the communities reported is Agrawal (Agarwal) Community mainly based in Northern Part of India.
. Development of diagnostic criteria continues in the hope of further separating PKAN from other forms of neurodegenerative diseases featuring NBIA.
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.
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.
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) and Jankovic et al. (1985).
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), Tanfani et al. (1987), Sethi et al. (1988),Angelini et al. (1992), Casteels et al. (1994), and Malandrini et al. (1995). The gene was localized to chromosome 20p by Taylor et al. (1996) who suggested that this disorder should be referred to as neurodegeneration with brain iron accumulation (NBIA1) to avoid the objectionable eponym of Hallervorden-Spatz. The disease was named 'pantothenate kinase-associated neurodegeneration' or PKAN by Zhou et al. (2001) 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.
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.
Julius Hallervorden
Julius Hallervorden was a German physician and neuroscientist. In 1938, he became the head of the Neuropathology Department of the Kaiser Wilhelm Institute for Brain Research. He was a member of the Nazi Party, and admitted to knowingly performing much of his controversial research on the brains...
and Hugo Spatz
Hugo Spatz
Hugo Spatz was a German neuropathologist. In 1937, he was appointed director of the Kaiser Wilhelm Institute for Brain Research. He was a member of the Nazi Party, and admitted to knowingly performing much of his controversial research on the brains of executed prisoners...
's affiliation with the Nazi regime and the ethically unacceptable manner in which they obtained some autopsy specimens), is a degenerative disease
Degenerative disease
A degenerative disease, also called neurodegenerative disease, is a disease in which the function or structure of the affected tissues or organs will progressively deteriorate over time, whether due to normal bodily wear or lifestyle choices such as exercise or eating habits...
of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
that can lead to parkinsonism
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
that progressively builds up in the brain.
Signs and 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:- dystoniaDystoniaDystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
(repetitive uncontrollable muscle contractions that may cause jerking or twisting of certain muscle groups) - dysphagiaDysphagiaDysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
& dysarthriaDysarthriaDysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
due to muscle groups involved in speech being involved - rigidity/stiffness of limbs
- tremorTremorA tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
- writhing movements
- dementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
- spasticitySpasticitySpasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
- weaknessWeaknessWeakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a...
- seizureSeizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s - retinitis pigmentosaRetinitis pigmentosaRetinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
, another degenerative disease that affects the individual’s retinaRetinaThe vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, 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.
Genetics
GeneticallyGenetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
speaking, PKAN is an autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
disorder. The parents of an afflicted child must both be heterozygous carriers for the disease and therefore must carry one mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
. As it is an autosomal disorder, those heterozygous for the disorder may not display any atypical characteristics that are considered suggestive of the disorder, however there have been reported cases of compound heterozygosity
Compound heterozygosity
Compound heterozygosity in medical genetics is the condition of having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state...
in which heterozygous individuals do develop the classic form of the disease.
The disorder is caused by a mutant PANK2 gene located at the chromosomal
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
: 20p13-p12.3. PANK2 is responsible in coding for the protein Pantothenate kinase
Pantothenate kinase
Pantothenate kinase is the first enzyme in the Coenzyme A biosynthetic pathway. It phophorylates pantothenate to form 4'-phosphopantothenate.-Types:...
2, which in turn is responsible for stifling the accumulation of N-pantothenoyl-cysteine and pantetheine
Pantetheine
Pantetheine is the cysteamine amide analogue of pantothenic acid . The dimer of this compound, pantethine is more commonly known, and is considered to be a more potent form of vitamin B5 than pantothenic acid. Pantetheine is an intermediate in the production of coenzyme A by the body....
. It is believed that when this accumulation is not suppressed, the result is direct cell toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
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-kDaprotein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that is a functional pantothenate kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
, an essential regulatory enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
in coenzyme A
Coenzyme A
Coenzyme A is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...
(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 mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
s most notably a 7bp deletion in the PANK2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
coding sequence.
This disorder has been reported in specific communities based on intra-community marriages where both parents of the child are carrying the same mutation. One of the communities reported is Agrawal (Agarwal) Community mainly based in Northern Part of India.
Diagnosis
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 gangliaBasal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
. Development of diagnostic criteria continues in the hope of further separating PKAN from other forms of neurodegenerative diseases featuring NBIA.
Neuropathology
Microscopic features of PKAN include:- Iron granules
- Spheroid bodies
- Lewy bodies within neurons
Treatment
As of yet there are no major breakthroughs in the treatment of PKAN, with most pharmacologicPharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
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
Coenzyme Q
Coenzyme Q10, also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10 , CoQ, Q10, or Q, is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the number of isoprenyl chemical subunits in its tail.This oil-soluble, vitamin-like substance...
, and other anti-oxidants.
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.
History & epidemiology
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. AutopsiesAutopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
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
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
, backing up his hypothesis with clinical and genetic analysis. Further investigation and insights were provided by Malmstrom-Groth and Kristensson (1982) and Jankovic et al. (1985).
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), Tanfani et al. (1987), Sethi et al. (1988),Angelini et al. (1992), Casteels et al. (1994), and Malandrini et al. (1995). The gene was localized to chromosome 20p by Taylor et al. (1996) who suggested that this disorder should be referred to as neurodegeneration with brain iron accumulation (NBIA1) to avoid the objectionable eponym of Hallervorden-Spatz. The disease was named 'pantothenate kinase-associated neurodegeneration' or PKAN by Zhou et al. (2001) 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.
Survival rates for those diagnosed with typical PKAN is 11.18 years with a standard deviation of 7.8 years. Prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
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.