User:Gor4kd/sandbox

Possible sources:

Gene reviews: https://www.ncbi.nlm.nih.gov/books/NBK1428/

2015 review of genetics of Batten: https://www.ncbi.nlm.nih.gov/books/NBK1428/

CLN3 protein function: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334816/pdf/nihms364841.pdf

Info for citing the book: "The Neuronal Ceroid Lipofuscinoses (Batten Disease), second edition, Edited by Sara E. Mole, Ruth E. Williams, Hans H. Goebel, Oxford University Press 2011

Major edit proposed - The term 'Batten Disease' is used to describe both the NCLs as a whole the CLN3 juvenile subtype (source-Mole, Williams & Goebel). The article mentions this, but it's unclear what the focus of the article is. Most of the time it seems to focus on CLN3, but sometimes switches to talking about all of the NCLS, and it's really confusing. Since this article links to a separate article on the NCLs as a whole and seems to focus mostly on CLN3, I think that it should be edited to focus on that, and that the list of all of the disease genes under causes isn't appropriate on this page.

Intro

Batten Disease is used to refer to both the Neuronal Ceroid Lipofuscinoses (NCLs) as a whole as well as specifically to the CLN3 disease, juvenile subtype. This article describes CLN3 disease, one of the most prevalent NCLs worldwide. Rarely, mutations in other genes cause variant juvenile NCL, but most cases are due to a mutation in the CLN3 gene. 85-95% of patients have a common 1 kb deletion in this gene. The initial symptom of Batten's disease is vision failure first occurring between ages 4-7. The individual is usually completely blind 2-4 years after onset. Epilepsy generally develops around the age of 10 and the progression of motor symptoms usually leads to the loss of independent mobility as well as speech difficulty. Eventually, this disease leads to early death at the average age of 24 in individuals homozygous for the 1 kb deletion. Life expectancy varies in individuals that are compound heterozygotes for the 1 kb deletion.

Cause

CLN3 disease, juvenile is caused by mutations in CLN3, a gene with 15 exons and 14 introns located on human chromosome 16. CLN3 is well conserved in species from humans to yeast . It is expressed at low levels in most tissues, indicative of a housekeeping function. More than 40 mutations in CLN3 have been found to cause CLN3 disease, but 85-95% of patients have a 1kb deletion that removes exons 7 and 8, resulting in a premature stop codon and a reduction in CLN3 mRNA levels . Alternative splice variants, notably a deletion of exons 5 that correct the reading frame, have been detected in Cln3^Δex7/8 mice. Other mutations in CLN3 are mostly private mutations including splice site, missense and nonsense mutations, insertions and deletions.

CLN3 encodes the 438 amino acid protein CLN3 or battenin, the function of which is unknown. Study of CLN3 structure and function is complicated by a lack of good antibodies and the hydrophobicity and low expression level of the protein. CLN3 is predicted to have 6 transmembrane domains and cytosolic N- and C-termini. It is thought to localize to endosomes and lysosomes, though it has also been reported in the plasma membrane, lipid rafts and synaptosomes. Disease-causing mutations often lead to retention of the protein in the ER and degradation. CLN3 does not share homology with any known proteins or domains, though its 6 transmembrane domains are indicative of a transporter, and its predicted structure shares some similarities with the Major Facilitator Superfamily of transporters. CLN3 is thought to be involved in lysosome and endosome function, trafficking between the Golgi and endosomes and microtubule system function. Defects in lysosomal pH regulation and osmoregulation, lysosomal arginine transport, autophagosome maturation and endocytosis have been observed in disease models.

Characteristic lipopigment inclusions, both vacuolar and non-vacuolar, are found in many cell types. A mix of fingerprint, rectilinear complex and curvilinear inclusions is seen, with different distributions in various tissues. Most CLN3 storage bodies contain subunit C of mitochondrial ATP synthase, in addition to saposins and other compounds. The storage material does not appear to disrupt cellular function. It is not clear what causes neuronal death in CLN3 disease, though excitotoxicity and defects in intracellular trafficking are thought to play a role.

Treatment

There is currently no cure for CLN3 disease, juvenile, and life expectancy is quite short (late teens to early 20s). However, there are a variety of palliative treatments, psychological and physical, available. Once a child has been diagnosed with CLN3 disease, juvenile, the parents can prepare for the symptoms that they should expect their child to develop. Parents frequently enroll CLN3 disease, juvenile patients in specialized educational programs, where teachers are well prepared to better deal with these patients.

All types of seizures can occur in these patients. At first, when epilepsy is mild and infrequent, preventative medications are held off. However, once the severity and frequency increases, a combination of sodium valproate and lamotrigine is usually administered to patients. These help control the number and severity of epilepsy. Other medications have been found to alleviate epilepsy, but they are not commonly used. Levetiracetam has been found to diminish Parkinson tremors as well as treating epilepsy. Because these treatments have possible detrimental side effects, a balance is usually struck between epilepsy and its side effects to ensure a better quality of life for the patient. Benzodiazepines can be used to control clusters of seizures; clobazam/diazepam can be used to treat frequent seizures. A study also found that Flupirtine can block apoptosis in CLN3 and CLN2 deficient neurons.

Psychological symptoms such as restlessness, panic attacks, anxiety, and aggressiveness are controlled by promoting self-esteem by allowing patients to develop as independently as possible. In other words, allowing patients to perform things by themselves helps build self-esteem. Drugs such as risperidone are used to deter some of these symptoms. SSRIs to deal with depression are sometimes necessary, though rarely. Benzodiazepines can be helpful for sleep disturbances.

Motor problems arise later on in the disorder. Performing physical activities from childhood help slow down the progression of these motor problems, and improve self-esteem. Physical therapy is done later on when activities become difficult.

There are very few alternatives when it comes to problems in communication, but speech therapy is helpful to promote speech early on. Speech therapists can also help in teaching patients to eat in certain positions that avoid complications. A gastrostomy tube may be necessary later on when chewing and swallowing becomes difficult/impossible.

Diagnosis

CLN3 disease, juvenile experiences visual failure often around the ages of 4-7, which later leads to blindness. Shortly after the onset of visual impairment, individuals begin to experience learning difficulties. Epilepsy often develops around the age of 10. Once the individual hits puberty, they might experience difficulties involving motor function which continues until mobility becomes difficult without some form of aid. Alongside these motor symptoms they also express difficulty in speech. Outside of these clinical features, here are some possible tests that could be performed in order to give a proper diagnosis:

Electroretinography: This allows the doctor to better look at the state of the retinopathy, damage caused to the retina. Individuals with CLN3 disease often experience vision loss gradually, therefore electroretinography provides a means for looking into damage in the retina.

Blood Smear: A type of blood test that can be examined using light microscopy. The test is able to determine if the proportion of lymphocytes exhibiting large clear vacuoles in the cytoplasm exceeds 10%, which often is caused by CLN3 disease.

Molecular Genetic analysis: This test is able to locate the common 1kb deletion in CLN3, however if the deletion is not found, then the whole gene should be sequenced. The test can also be performed prenatally, and is often done so if it is a clear at-risk pregnancy.

Magnetic Resonance image: Individuals with Batten's disease express enlarged cerebral sulci and third ventricle on an MRI. The severity of this enlargement depends on whether or not the individual is homozygous or heterozygous for the 1.02-kb deletion.

Upon receiving a diagnosis, families are educated and informed about potential scenarios to prepare for. Therefore proper explanation of Batten's disease will ensure that proper care is given. For example, discussing with the family or caregivers about epilepsy and providing instructions on how to handle seizures prior to the first seizure occurring. Another topic of discussion would include the education process, which entails properly informing the school, faculty, and nurse aids and planning. Families should also be provided with info on support groups.  

Research

Researchers believe the neurological deficits common in JNCL could be due to overactive AMPA receptors in the cerebellum. To test this hypothesis, researchers administered AMPA antagonist drugs into affected mice. The motor skills of the affected mice showed significant improvement after the antagonist treatment, which supported the hypothesis that the neurological deficits in JNCL are due to overactivity of the receptors. This research could eventually help to alleviate neurological deficits of JNCL in humans by suppressing AMPA receptor activity.

Not only does inhibition of AMPA receptors appear to alleviate symptoms of JNCL, but inhibition of NMDA receptors appears to help as well. In a 2012 study using mouse models, researchers demonstrated the potential therapeutic effect on motor skills inhibition of NMDA receptors could have on JNCL patients. However, the therapeutic effect appears to be age-dependent. In the study, memantine, an NMDA receptor antagonist, was first given to the mice at 1 month old. At this time, no improvement was seen in the motor skills of the mice. However, when the memantine was given to mice at a later time, 6 or 7 months of age, extended improvement of their motor skills was observed. This reflects the changes seen in Batten's disease throughout its progression. As a treatment option, it appears acute inhibition of NMDA receptors through a drug such as memantine may alleviate some of the motor skill deficits seen in JNCL patients.

In 2011, researchers determined use of immunosuppression resulted in significant motor improvements for CLN3 -/- mice. Also, the researchers determined immune suppression led to reduced neuroinflammation in the animals. The immunosuppressor MMF was used for the experiment and given to the mice on a daily basis. The motor skills of the mice were evaluated using a simple rotarod test. This led to the conclusion that immunosuppression, using MMF, resulted in improved motor performance. The reduction in neuroinflammation corresponded with a decrease in autoantibodies circulating within the mouse brain. Results of this study are promising in regard to human application as MMF has been deemed safe for use on humans. However, uncertainty still exists as to whether the immunosuppression helps treat the cause of JNCL, or rather, simply treats symptoms associated with the disease.