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OverviewEdit

Kufs disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). These disorders all affect the nervous system and impair movement and cognition. Unlike Kufs disease, most other NCLs also cause vision loss.[1] NCL consititues 8 different neurological disorders that result from built up amounts of lipopigments in the body's tissue. There are two types of Kufs disease: Type A and Type B. The two are similar in many instances but have some striking differences. Type A is characterized by uncontrollable siezures, myoclonic epilepsy, dementia, ataxia, extrapyramidal dysfunction (tremors),and dystharia. The main difference between Type A and B is that Type B does not have symptoms of epilepsy or dystharia. But like type A it does include dementia, ataxia, and extrapyramidal dysfunction. Also, Type B patients may also experience personality changes. 

Underlying BiologyEdit

The main gene involved with NCLs is Palmitoyl-protein thioesterase (PPT). This gene contains instructions for the synthesis of the palmitoyl-protein thioesterase protein. This protein is found in lysosomes that are responsible for breaking down cells and reusing different molecules. PPT also removes certain fats called long chain fatty acids from other proteins so the fats can be broken down and used for energy.[1] However, for the adult case of NCL--Type 4, Kufs disease--the main genes involved are CLN6 and DNAJC5, the mutation involved is with a cysteine string that's required for the membrane to be functional for targeting, and oligomerization for a cysteine-string protein alpha (CSPα).[2] The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene. [3]

Autorecessive

As you can see in the picture there is only a 25% chance that the child would contract the disease if each parent had one copy of the recessive mutation of the PPT gene

  

EpidemiologyEdit

Overall, there is a higher frequency of having NCLs if you are from the United States or Northern Europe; every 1 in 12,500 individuals develops a type of NCL whereas the the Adult variants of NCL, which is Kufs disease, has a prevelance of 1.3% to 10% of all NCLs. [4] The age of onset has a high range from 6 to 62 years old. The amount of cases seems to vary across different parts of the world. one study conducted in Germany states that there is an incidence of 1.28 per 100,000 [5], while a study in Italy reports there is an incidence of 0.56 per 100,000[6] and furthermore a study in Norway reports an 3.9 per 100,000 cases of NCL exist [7]. Kufs diesase is autosomal recessive, meaning that to acquire the disease you must have to recessive alleles to acquire the disease.

Differential DiagnosisEdit

Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis.[8]. Since Kufs disease has many overlapping symptoms as other NCLs, it can be mistaken for the 8 other types. Vision loss can be an indicator early on that the disease in question can be Batten disease and can be seen during an eye exam. During the exam the doctor can see the cell loss in the eyes and that can be indicatory of Batten's disease. However, Kufs disease is differentiated due to the fact that there is no vision loss in this type of NCL, thus one would not see the cell loss in the eyes. 

One study of a 45 year old woman was suspected of having Creutzfeldt-Jakob disease (CJD), the first of her symptoms began 18 months prior to admission. Progressive dementia and psychotic symptoms as well as auditory and visual hallucinations and delusions emerged, causing anxiety. Behavioural disturbances, including aggression, personal and social awareness, and lack of criticism were also observed. Additionally, speech disturbances developed gradually. The patient had also great problems with insomnia. Gait disturbances and urinary incontinence developed.[9] . Thus CJD can look quite similar to Kufs but the major difference here is,fingerprint deposits were found exclusively within vascular smooth muscle cells in all observed arterioles of the skeletal muscle biopsy which is a huge indicator of a lipoprotein disorder[9]. Additionally, an MRI of a patients with CJD would show a sponge like appearance whereas a patient with Kufs would not.

Infantile, Late Infantile, and Juvenile NCL are all similar types of NCLs and are very similar to Kufs disease. Infantile NCL is known to occur in only infants to 2 years of age and is autosomal recessive, it does however show similar symptoms to Kufs disease. But do to the age of onset it can easily be differentiated.[10] Late Infantile NCL is seen in 2 to 4 year olds and show ataxia and seizures and progressive mental deterioration as does Kufs disease. But again, age is the main differentiating factor.[11] Juvenile NCL (Batten Disease) is seen between 5 to 8 year olds and can progress for many years with patients living up to 30 years of age. Characteristically, is is almost identical to Kufs disease in that it has all the same symptoms except is can be distinguished by the fact that there is no vision loss in Kufs as there is in Batten disease and that Kufs is shown to appear later in life.[12] Additionally with genetic testing you would see differences in the genes that are affected in each of these diseases. Infantile show the characteristic PPT1 mutation, whereas Late Infantile shows a mutation in TPP1, Juvenile shows a mutation in CLN 3 and in Kufs the mutation is in the CLN 6 genes.[10][11][12]

Hallervorden-Spatz disease (HSD) is similar to Kufs in that its symptoms include extrapyramidal dysfunction, tremors, dysarthria, seizures and dementia. Presented with these symptoms it is hard to differentiate between Kufs and HSD but an MRI of the brain in patients with HSD shows iron deposit in the basal ganglia which is due to the mutation of the PANK2 gene that results in cell toxicity; we also see a high amount of Lewy bodies that aren't present in those with Kufs.[13]

Friedreich's ataxia (FA) is very similar to Kufs disease in that it those patients who have the disease show a loss of coordination due to cerebellar problems, dysarthia and truncal ataxia as well as a similar age of onset. However with FA, there is hearing impairment and vision impairment which is not seen in individuals with Kufs disease.[14]

Interestingly enough, Huntington's disease (HD) can be a common diagnosis for those who have Kufs disease. Huntington's patients can exhibit many of the same symptoms such as, dysarthia, cognitive problems leading to dementia, chorea like movement, memory problems, seizures, and personality changes. One important symptoms that can distinguish the two is eye problems, in that there is decreased eye movements and whereas in Kufs the eyes are uneffected.[15] Also, HD is caused by having two copies of the Huntington gene. [15]

Treatment and PrognosisEdit

There is no cure that can extinguish or slow down the progression of the disease. The symptoms however can be treated; seizures can be stopped by antiepileptic drugs. Other therapies such as physical, speech and occupational therapies can help those afflicted with Kufs maintain mobility. Only recently has the CLN5 mutation been discovered and scientists are now looking for ways to treat this through possible gene therapy but this is still in the construction phases and wont happen anytime soon. [16]

ReferencesEdit

[1] Kufs disease (http://ghr.nlm.nih.gov/condition/kufs-disease)

[2] Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026741)

[3] Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. (http://www.ncbi.nlm.nih.gov/pubmed/21820099)

[4] Accumulation of the adenosine triphosphate synthase subunit C in the mnd mutant mouse. A model for neuronal ceroid lipofuscinosis. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1887237/)

[5] Incidence of neuronal ceroid-lipofuscinoses in West Germany: variation of a method for studying autosomal recessive disorders. (http://www.ncbi.nlm.nih.gov/pubmed/1609834)

[6] Neuronal ceroid-lipofuscinoses in Italy: an epidemiological study.(http://www.ncbi.nlm.nih.gov/pubmed/7668318)

[7] Occurrence of and mortality from childhood neuronal ceroid lipofuscinoses in Norway. (http://www.ncbi.nlm.nih.gov/pubmed/17092455)

[8] Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6.(http://www.ncbi.nlm.nih.gov/pubmed/21549341)

[9] Kufs’ disease: diagnostic difficulties in the examination of extracerebral biopsies (http://www.termedia.pl/Kufs-8217-disease-diagnostic-difficulties-in-the-examination-of-extracerebral-biopsies,20,13182,1,1.html)

[10] CEROID LIPOFUSCINOSIS, NEURONAL, 1, VARIABLE AGE AT ONSET (http://omim.org/entry/256730)

[11] CEROID LIPOFUSCINOSIS, NEURONAL, 2, VARIABLE AGE AT ONSET JANSKY-BIELSCHOWSKY DISEASE (http://omim.org/entry/204500)

[12] CEROID LIPOFUSCINOSIS, NEURONAL, 3; CLN3 (http://omim.org/entry/204200)

[13] A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/11479594)

[14] Friedreich's ataxia: past, present and future. (http://www.ncbi.nlm.nih.gov/pubmed/21550666)

[15] Huntington's disease. (http://www.ncbi.nlm.nih.gov/pubmed/17240289)

[16] Discovery Of Gene Responsible For Kufs Disease Aided By New Technology (http://www.medicalnewstoday.com/releases/224472.php)


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