Neuronal Ceroid Lipofuscinosis
Encyclopedia
Neuronal Ceroid Lipofuscinoses (NCL) is the general name for a family
of at least eight genetically separate neurodegenerative disorders that result from excessive accumulation of lipopigments (lipofuscin
) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem lipo-, which is a variation on "lipid
" or "fat", and from the term pigment, used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver
, spleen
, myocardium, and kidneys.
In the Early Infantile variant of NCL (also called INCL or Santavuori-Haltia), probands appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age a vegetative state is reached and by 4 years isoelectric encephalograms confirm brain death. Late Infantile Variant usually manifests between 2 and 4 years of age with Seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years. Juvenile NCL (JNCL, Batten Disease, or Spielmeyer-Vogt), with a prevalence of 1 in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinitis pigmentosa, with seizures, psychological degeneration, and eventual death in the mid- to late-20s ensuing. Adult variant NCL (ANCL or Kuf’s Disease) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs ten years later.
All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism - most commonly with the reuse of vesicle proteins.
in 1903, and by Heinrich Vogt
in 1905, who performed extensive clinicopathological studies on several families. Retrospectively, these papers disclose that the authors grouped together different types of the syndrome. Furthermore Batten, at least for some time, insisted that the condition that he described was distinctly different from Tay-Sachs disease
, the prototype of a neuronal lysosomal disorder now identified as GM2 gangliosidosis type A. Around the same time, Walther Spielmeyer
reported detailed studies on three siblings, suffering from the Spielmeyer-Sjogren (juvenile) type, which led him to the very firm statement that this malady is not related to Tay-Sachs disease
. Subsequently, however, the pathomorphological studies of Károly Schaffer
made these authors change their minds to the extent that they reclassified their respective observations as variants of Tay-Sachs disease, which caused confusion lasting about 50 years.
In 1913-14, Max Bielschowsky
delineated the late infantile form of NCL. However, all forms were still thought to belong in the group of "familial amaurotic idiocies", of which Tay-Sachs was the prototype.
In 1931, Torsten Sjögren, the Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease which we now call the Spielmeyer-Sjogren (juvenile) type is genetically separate from Tay-Sachs.
.
Subsequently, it was shown by Santavuori and Haltia that an infantile form of NCL exists, which Zeman and Dyken had included with the Jansky Bielschowsky type.
CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.
and frameshift
mutations in the CLN1 gene (located at
1p32) always induce classical INCL, while some misssense mutations
have been associated with ANCL in addition to the Infantile and Juvenile forms. The mutation typically results in a deficient form of a lysosomal
enzyme
called palmitoyl protein thioesterase
1 (PPT1).
The wild type
PPT1 is a 306 amino acid
polypeptide that is typically targeted for transport into lysosome
s by the mannose 6-phosphate (M6P) receptor mediated pathway. Here the protein appears to function in removing palmitate residues
by cleaving thioester
linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. Defective polypeptides, however, are unable to exit the endoplasmic reticulum
(ER), most likely due to misfolding; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. It is important to note that the human PPT gene shows 91% similarity to bovine PPT and 85% similarity to rat PPT; these data indicate that the PPT gene is highly conserved and likely plays a vital role in cell metabolism. In addition buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This homeostasis
-altering event leads to increased mitochondrial membrane permeability and subsequent activation of caspase-9
, eventually leading to an accumulation of cleaved and uncleaved poly(ADP-ribose) polymerase (PARP) and eventual apoptosis
.
(TPPI) which cleaves tripeptides from terminal amine
groups of partially unfolded proteins. Mutations of this gene typically result in a LINCL phenotype.
s. The wild type CLN3 gene codes for a protein with no known function; however, studies of the yeast CLN3 ortholog, the product of which is called Battenin (after its apparent connections to Batten’s Disease, or JNCL), have suggested that the protein may play a role in lysosomal pH
homeostasis
. Furthermore, recent studies have also implied the protein’s role in cathepsin D deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D.
.
Two independent families have been shown to have mutations in the DNAJC5
gene - one with a transvertion and the other with a deletion mutation. The muations occur in a cysteine
-string domain, which is required for membrane targeting/binding, palmitoylation and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene.
In Germany, one study reported an incidence of 1.28 per 100,000.
A study in Italy reported an incidence of 0.56 per 100,000.
A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades.
, each of their children faces one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children.
Adult NCL may be inherited as an autosomal recessive (Kufs) or, less often, as an autosomal dominant (Parry's) disorder. In autosomal dominant inheritance
, all people who inherit a single copy of the disease gene develop the disease. As a result, there are no unaffected carriers of the gene
.
Diagnostic tests used for Batten disease/NCLs include:
Several experimental treatments are under investigation.
, a rare genetic disease that can cause kidney failure if not treated, may be useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL.
It is preliminarily shown that the addition of another drug seems to be more effective than Cystagon alone and all patients on the trials, including the first six, are being put on this drug.
Currently there are two drug trials underway for infantile Batten disease/NCL. Both trials are using the drug Cystagon. For additional information regarding this trial, contact the Batten Disease Support and Research Association.
trial, funded by several families gathered together under Nathan's Battle Foundation, started in June 2004. As a phase I trial trying to establish the safety of the gene therapy, the trial has been limited to eleven children and, so far, eight children have been treated. The trial was temporarily halted when the fourth child treated died after the having the procedure in November 2004. However, it is thought the actual gene therapy was not the cause of the child's death and the trial has since resumed, with subsequent patients reported to be doing well with surgical recovery. However the child's death has led to a reluctance of the doctors treating patients to operate on any more patients that are severely afflicted with late infantile NCL. This reluctance is now leading to possible legal action by a family whose child has been denied treatment after initially promised a spot in the trial and having his surgery dates pushed back several times.
Media coverage of the trial, as well as information to the scientific community in general, has been very limited. However, several newspaper articles suggest that MRI scans show the therapy has been successful in halting, though not reversing, the progress of this disease. Nathan and P.J. Milto, among the first of the treated children and the sons of the Nathan's Battle Foundation founder, are reported to have no further progression of their disease and stable neurological status, though both remain severely handicapped. With less severely afflicted children now being treated, however, there is reason to hope and see if the late infantile NCL Gene Therapy Transfer could be an effective way of slowing or halting the progress of this condition.
In October 2005 three-year-old Jasmine Harris of London, England became the healthiest child to be treated in the late infantile NCL Gene Therapy trial so far. Due to an older brother, Jordan, being previously diagnosed with late infantile NCL in early 2003 after almost two years of deteriorating cognitive and motor skills Jasmine, though presyptomatic, was also tested for the disease at the end of 2003 and found to be positive for the condition at the age of twenty months. Although Jasmine has suffered several seizures and experienced a deterioration in her speech in the past year, MRI scans of her brain are reported to still be normal, and there is hope the treatment will prevent her from experiencing any more neurological degeneration. It will be months, even years, before scientists will fully know of the treatment has been successful in sparing Jasmine Harris the ravages of LINCL.
, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina
, and the Hospital for Sick Children in Toronto, Ontario
.
Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone marrow/stem cell transplants for this condition. A bone marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998.
Trials testing the effectiveness of bone marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported.
medication commonly used in bone marrow transplant
s, may be useful in slowing down the progress of Juvenile NCL. Fundraising is currently underway to gather the funds needed to start a clinical trial to test the safety and efficiency of CellCept for Juvenile NCL.
Family
In human context, a family is a group of people affiliated by consanguinity, affinity, or co-residence. In most societies it is the principal institution for the socialization of children...
of at least eight genetically separate neurodegenerative disorders that result from excessive accumulation of lipopigments (lipofuscin
Lipofuscin
Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, adrenals, nerve cells, and ganglion cells...
) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem lipo-, which is a variation on "lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
" or "fat", and from the term pigment, used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, myocardium, and kidneys.
Introduction
The classic characterization of the group of neurodegenerative, lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs) is through the progressive, permanent loss of motor and psychological ability with a severe intracellular accumulation of lipofuscins., with the United States and northern European populations having slightly higher frequency with an occurrence of 1 in 10,000. There are four classic diagnoses that have received the most attention from researchers and the medical field, differentiated from one another by age of symptomatic onset, duration, early-onset manifestations such as blindness or seizures, and the forms which lipofuscin accumulation takes.In the Early Infantile variant of NCL (also called INCL or Santavuori-Haltia), probands appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age a vegetative state is reached and by 4 years isoelectric encephalograms confirm brain death. Late Infantile Variant usually manifests between 2 and 4 years of age with Seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years. Juvenile NCL (JNCL, Batten Disease, or Spielmeyer-Vogt), with a prevalence of 1 in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinitis pigmentosa, with seizures, psychological degeneration, and eventual death in the mid- to late-20s ensuing. Adult variant NCL (ANCL or Kuf’s Disease) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs ten years later.
All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism - most commonly with the reuse of vesicle proteins.
19th century
The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, who described 4 affected siblings in a small mining community in Norway. Although no pathological studies were performed on these children the clinical descriptions are so succinct that the diagnosis of the Spielmeyer-Sjogren (juvenile) type is fully justified.1900 to 1950
More fundamental observations were reported by F. E. BattenFrederick Batten
Frederick Eustace Batten was an English neurologist and pediatrician who has been referred to as the "father of pediatric neurology"....
in 1903, and by Heinrich Vogt
Heinrich Vogt
Heinrich Vogt was a German neurologist. He published papers on tuberous sclerosis and Batten disease. Later he became a professor of psychiatry and published a handbook on the treatment of nervous diseases...
in 1905, who performed extensive clinicopathological studies on several families. Retrospectively, these papers disclose that the authors grouped together different types of the syndrome. Furthermore Batten, at least for some time, insisted that the condition that he described was distinctly different from Tay-Sachs disease
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...
, the prototype of a neuronal lysosomal disorder now identified as GM2 gangliosidosis type A. Around the same time, Walther Spielmeyer
Walther Spielmeyer
Walther Spielmeyer was a German neuropathologist who was a native of Dessau. He studied medicine at the University of Halle under Eduard Hitzig , and in 1906 went to Freiburg, where he was an assistant to Alfred Hoche...
reported detailed studies on three siblings, suffering from the Spielmeyer-Sjogren (juvenile) type, which led him to the very firm statement that this malady is not related to Tay-Sachs disease
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...
. Subsequently, however, the pathomorphological studies of Károly Schaffer
Károly Schaffer
Károly Schaffer was a Hungarian anatomist and neurologist. He was born in Vienna. The axon projection from CA3 to CA1 neurons in hippocampus, Schaffer collateral, is named after him....
made these authors change their minds to the extent that they reclassified their respective observations as variants of Tay-Sachs disease, which caused confusion lasting about 50 years.
In 1913-14, Max Bielschowsky
Max Bielschowsky
Max Bielschowsky was a German neuropathologist born in Breslau.After receiving his medical doctorate from the University of Munich in 1893, he worked with Ludwig Edinger at the Senckenberg Pathology Institute in Frankfurt-am-Main. At Senckenberg he learned histological staining techniques from...
delineated the late infantile form of NCL. However, all forms were still thought to belong in the group of "familial amaurotic idiocies", of which Tay-Sachs was the prototype.
In 1931, Torsten Sjögren, the Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease which we now call the Spielmeyer-Sjogren (juvenile) type is genetically separate from Tay-Sachs.
1950 to today
Departing from the careful morphological observations of Spielmeyer, Hurst, and Sjovall and Ericsson, Zeman and Alpert made a determined effort to document the previously suggested pigmentary nature of the neuronal deposits in certain types of storage disorders. Simultaneously, Terry and Korey and Svennerholm demonstrated a specific ultrastructure and biochemistry for Tay-Sachs disease, and these developments led to the distinct identification and also separation of the NCLs from Tay-Sachs disease by Zeman and Donahue. At that time, it was proposed that the Late Infantile (Jansky-Bielschowsky), the juvenile (Spielmeyer-Vogt), and the adult form (Kufs) were quite different from Tay-Sachs disease with respect to chemical pathology and ultrastructure and also different from other forms of sphingolipidosesSphingolipidoses
-Accumulated products:* Gangliosides: Gangliosidosis** GM1 gangliosidoses** GM2 gangliosidoses*** Tay-Sachs disease*** Sandhoff disease* Glycolipids** Fabry's disease** Krabbe disease** Metachromatic leukodystrophy*Glucocerebrosides**Gaucher's disease...
.
Subsequently, it was shown by Santavuori and Haltia that an infantile form of NCL exists, which Zeman and Dyken had included with the Jansky Bielschowsky type.
Forms
The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene.CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.
| Type | Description | OMIM | Gene >- | Type 1 |
Infantile NCL (Santavuori-Haltia disease, INCL): begins between about 6 months and 2 years of age and progresses rapidly. Affected children fail to thrive and have abnormally small heads (microcephaly Microcephaly Microcephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life... ). Also typical are short, sharp muscle contractions called myoclonic jerks. Initial signs of this disorder include delayed psychomotor development with progressive deterioration, other motor disorders, or seizures. The infantile form has the most rapid progression and children live into their mid childhood years. The gene responsible for Infantile NCL has been identified in some cases of juvenile/adult onset. It is thought these patients have some partial enzyme production that leads to a protracted, less severe disease course. |
PPT1 PPT1 Palmitoyl-protein thioesterase 1 , also known as palmitoyl-protein hydrolase 1, is an enzyme that in humans is encoded by the PPT1 gene.- Function :... >- | Type 2 |
Late Infantile NCL (Jansky-Bielschowsky disease Jansky-Bielschowsky disease Jansky-Bielschowsky disease is a late-infantile form of neuronal ceroid lipofuscinosis associated with a deficiency in tripeptidyl peptidase I.... , LINCL) begins between ages 2 and 4. The typical early signs are loss of muscle coordination (ataxia Ataxia Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum... ) and seizures along with progressive mental deterioration, though afflicted children may show mild-severe delays in speech development well before other symptoms appear. This form progresses rapidly and ends in death between ages 8 and 12. |
>- | Juvenile NCL (Batten disease Batten disease Batten disease is a rare, fatal autosomal recessive neurodegenerative disorder that begins in childhood... , JNCL) begins between the ages of 5 and 8 years of age. The typical early signs are progressive vision loss, seizures, ataxia or clumsiness. This form progresses less rapidly and ends in death in the late teens or early 20s, although some may live into their 30s. |
CLN3 CLN3 Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16.- Function :Battenin is involved in lysosomal function. Many alternatively spliced transcript variants have been found for this gene.-Clinical significance:... >- | Type 4 |
Adult NCL (Kufs disease, Parry's disase, ANCL) generally begins before the age of 40, causes milder symptoms that progress slowly and does not cause blindness. Although age of death is variable among affected individuals, this form does shorten life expectancy. | (AR), (AD) | CLN6 CLN6 Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the CLN6 gene.-External links:* -Further reading:... DNAJC5 DNAJC5 DnaJ homolog subfamily C member 5, also known as cysteine string protein or CSP is a protein, that in humans encoded by the DNAJC5 gene. It was first described in 1990.- Gene :... >- | Type 5 |
Finnish Late Infantile (Finnish Late Infantile Variant, vLINCL) - identified in Finland. | CLN5 CLN5 Ceroid-lipofuscinosis neuronal protein 5 is a protein that in humans is encoded by the CLN5 gene.-External links:* -Further reading:... >- | Type 6 |
Variant Late Infantile (Late Infantile Variant, vLINCL) - identified in Costa Rica, South America, Portugal, the United Kingdom and other nations. | CLN6 CLN6 Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the CLN6 gene.-External links:* -Further reading:... >- | Type 7 |
CLN7 | MFSD8 MFSD8 Major facilitator superfamily domain containing 8 also known as MFSD8 is a protein that in humans is encoded by the MFSD8 gene.-Function:... >- | Type 8 |
Turkish Late Infantile (Turkish Late Infantile Variant,vLINCL) - identified in Turkey. | CLN8 CLN8 Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.-Molecular biology:-Clinical:Mutations in this gene are associated with progressive epilepsy with mental retardation , a subtype of neuronal ceroid lipofuscinosis... >- | Type 9 |
potentially identified in Germany and Serbia. | Unknown, but possibly regulator of dihydro-ceramide synthase |
Infantile form
NonsenseNonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
and frameshift
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
mutations in the CLN1 gene (located at
1p32) always induce classical INCL, while some misssense mutations
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...
have been associated with ANCL in addition to the Infantile and Juvenile forms. The mutation typically results in a deficient form of a lysosomal
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
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...
called palmitoyl protein thioesterase
Palmitoyl protein thioesterase
Palmitoyl protein thioesterases are enzymes that remove thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation....
1 (PPT1).
The wild type
Wild type
Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
PPT1 is a 306 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
polypeptide that is typically targeted for transport into lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s by the mannose 6-phosphate (M6P) receptor mediated pathway. Here the protein appears to function in removing palmitate residues
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
by cleaving thioester
Thioester
Thioesters are compounds with the functional group C-S-CO-C. They are the product of esterification between a carboxylic acid and a thiol. Thioesters are widespread in biochemistry, the best-known derivative being acetyl-CoA.-Synthesis:...
linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. Defective polypeptides, however, are unable to exit the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER), most likely due to misfolding; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. It is important to note that the human PPT gene shows 91% similarity to bovine PPT and 85% similarity to rat PPT; these data indicate that the PPT gene is highly conserved and likely plays a vital role in cell metabolism. In addition buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
-altering event leads to increased mitochondrial membrane permeability and subsequent activation of caspase-9
Caspase-9
Caspase-9 is an initiator caspase, encoded by the CASP9 gene.CASP9 orthologs have been identified in all mammals for which complete genome data are available. Unique orthologs are also present in lizards, lissamphibians, and teleosts....
, eventually leading to an accumulation of cleaved and uncleaved poly(ADP-ribose) polymerase (PARP) and eventual apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Late infantile form
The CLN2 gene encodes a 46kDa protein called lysosomal tripeptidyl peptidase ITripeptidyl peptidase I
Tripeptidyl-peptidase 1 is an enzyme that in humans is encoded by the TPP1 gene.-Molecular biology:-Clinical:Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the...
(TPPI) which cleaves tripeptides from terminal amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
groups of partially unfolded proteins. Mutations of this gene typically result in a LINCL phenotype.
Juvenile form
All mutations resulting in the Juvenile variant of NCL have been shown to occur at the CLN3 gene on 16p12; of the mutations known to cause JNCL, 85% result from a 1.02 kb deletion, with a loss of amino acids 154-438, while the remaining 15% appear to result from either point or frameshift mutationFrameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
s. The wild type CLN3 gene codes for a protein with no known function; however, studies of the yeast CLN3 ortholog, the product of which is called Battenin (after its apparent connections to Batten’s Disease, or JNCL), have suggested that the protein may play a role in lysosomal pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
. Furthermore, recent studies have also implied the protein’s role in cathepsin D deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D.
Adult dominant form
Between 1.3% and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other NCLs retinal degeneration is absent. Pathologically the ceroid-lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial ATP synthaseATP synthase
right|thumb|300px|Molecular model of ATP synthase by X-ray diffraction methodATP synthase is an important enzyme that provides energy for the cell to use through the synthesis of adenosine triphosphate . ATP is the most commonly used "energy currency" of cells from most organisms...
.
Two independent families have been shown to have mutations in the DNAJC5
DNAJC5
DnaJ homolog subfamily C member 5, also known as cysteine string protein or CSP is a protein, that in humans encoded by the DNAJC5 gene. It was first described in 1990.- Gene :...
gene - one with a transvertion and the other with a deletion mutation. The muations occur in a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
-string domain, which is required for membrane targeting/binding, palmitoylation and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene.
Incidence
Incidence can vary greatly from type-to-type, and from country-to-country.In Germany, one study reported an incidence of 1.28 per 100,000.
A study in Italy reported an incidence of 0.56 per 100,000.
A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades.
Inheritance
Childhood NCLs are autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective geneGene
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...
, each of their children faces one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children.
Adult NCL may be inherited as an autosomal recessive (Kufs) or, less often, as an autosomal dominant (Parry's) disorder. In autosomal dominant inheritance
Inheritance
Inheritance is the practice of passing on property, titles, debts, rights and obligations upon the death of an individual. It has long played an important role in human societies...
, all people who inherit a single copy of the disease gene develop the disease. As a result, there are no unaffected carriers of the 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...
.
Diagnosis
Because vision loss is often an early sign, Batten disease/NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of Batten disease/NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often an eye specialist or other physician who suspects Batten disease/NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. In order to diagnose Batten disease/NCL, the neurologist needs the patient's medical history and information from various laboratory tests.Diagnostic tests used for Batten disease/NCLs include:
- Skin or tissue sampling. The doctor can examine a small piece of tissue under an electron microscopeElectron microscopeAn electron microscope is a type of microscope that uses a beam of electrons to illuminate the specimen and produce a magnified image. Electron microscopes have a greater resolving power than a light-powered optical microscope, because electrons have wavelengths about 100,000 times shorter than...
. The powerful magnification of the microscope helps the doctor spot typical NCL deposits. These deposits are found in many different tissues, including skinSkin-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, muscleMuscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, conjunctivaConjunctivaThe conjunctiva covers the sclera and lines the inside of the eyelids. It is composed of rare stratified columnar epithelium.-Function:...
, rectal and others. Blood can also be used. These deposits take on characteristic shapes, depending on the variant under which they are said to occur: granular osmophilic deposits (GRODs) are generally characteristic of INCL, while curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively. - Electroencephalogram or EEG. An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brain's electrical activity that suggest a patient has seizures.
- Electrical studies of the eyes. These tests, which include visual-evoked responses (VER) and electroretinogramElectroretinographyElectroretinography measures the electrical responses of various cell types in the retina, including the photoreceptors , inner retinal cells , and the ganglion cells. Electrodes are usually placed on the cornea and the skin near the eye, although it is possible to record the ERG from skin electrodes...
s (ERG), can detect various eye problems common in childhood Batten disease/NCLs. - Brain scans. Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is computed tomographyComputed tomographyX-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(CT), which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. A second imaging technique that is increasingly common is magnetic resonance imagingMagnetic resonance imagingMagnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
, or MRI. MRI uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain. - Enzyme assay. A recent development in diagnosis of Batten disease/NCL is the use of enzyme assays that look for specific missing lysosomalLysosomethumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
enzymeEnzymeEnzymes 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...
s for infantile and late infantile only. This is a quick and easy diagnostic test.
Treatment
Currently there is no widely accepted treatment that can cure, slow down, or halt the symptoms of NCL. However, seizures may be controlled or reduced with use of anti-epileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible.Several experimental treatments are under investigation.
Cystagon
In 2001 it was reported a drug used to treat cystinosisCystinosis
Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of the amino acid cystine. It is a genetic disorder that typically follows an autosomal recessive inheritance pattern. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group...
, a rare genetic disease that can cause kidney failure if not treated, may be useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL.
It is preliminarily shown that the addition of another drug seems to be more effective than Cystagon alone and all patients on the trials, including the first six, are being put on this drug.
Currently there are two drug trials underway for infantile Batten disease/NCL. Both trials are using the drug Cystagon. For additional information regarding this trial, contact the Batten Disease Support and Research Association.
Gene therapy
In late infantile NCL research a controversial gene therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
trial, funded by several families gathered together under Nathan's Battle Foundation, started in June 2004. As a phase I trial trying to establish the safety of the gene therapy, the trial has been limited to eleven children and, so far, eight children have been treated. The trial was temporarily halted when the fourth child treated died after the having the procedure in November 2004. However, it is thought the actual gene therapy was not the cause of the child's death and the trial has since resumed, with subsequent patients reported to be doing well with surgical recovery. However the child's death has led to a reluctance of the doctors treating patients to operate on any more patients that are severely afflicted with late infantile NCL. This reluctance is now leading to possible legal action by a family whose child has been denied treatment after initially promised a spot in the trial and having his surgery dates pushed back several times.
Media coverage of the trial, as well as information to the scientific community in general, has been very limited. However, several newspaper articles suggest that MRI scans show the therapy has been successful in halting, though not reversing, the progress of this disease. Nathan and P.J. Milto, among the first of the treated children and the sons of the Nathan's Battle Foundation founder, are reported to have no further progression of their disease and stable neurological status, though both remain severely handicapped. With less severely afflicted children now being treated, however, there is reason to hope and see if the late infantile NCL Gene Therapy Transfer could be an effective way of slowing or halting the progress of this condition.
In October 2005 three-year-old Jasmine Harris of London, England became the healthiest child to be treated in the late infantile NCL Gene Therapy trial so far. Due to an older brother, Jordan, being previously diagnosed with late infantile NCL in early 2003 after almost two years of deteriorating cognitive and motor skills Jasmine, though presyptomatic, was also tested for the disease at the end of 2003 and found to be positive for the condition at the age of twenty months. Although Jasmine has suffered several seizures and experienced a deterioration in her speech in the past year, MRI scans of her brain are reported to still be normal, and there is hope the treatment will prevent her from experiencing any more neurological degeneration. It will be months, even years, before scientists will fully know of the treatment has been successful in sparing Jasmine Harris the ravages of LINCL.
Flupirtine
A painkiller available in several European countries, FlupirtineFlupirtine
Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. Flupirtine is available as "Pruf",Snepdol in India...
, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina
Durham, North Carolina
Durham is a city in the U.S. state of North Carolina. It is the county seat of Durham County and also extends into Wake County. It is the fifth-largest city in the state, and the 85th-largest in the United States by population, with 228,330 residents as of the 2010 United States census...
, and the Hospital for Sick Children in Toronto, Ontario
Toronto
Toronto is the provincial capital of Ontario and the largest city in Canada. It is located in Southern Ontario on the northwestern shore of Lake Ontario. A relatively modern city, Toronto's history dates back to the late-18th century, when its land was first purchased by the British monarchy from...
.
Stem cells
On October 20, 2005, the Food and Drug Administration approved a phase I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first ever transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment will be carried out in Oregon.Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone marrow/stem cell transplants for this condition. A bone marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998.
Trials testing the effectiveness of bone marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported.
Immunosuppressants
In late 2007, it was reported by Dr. David Pearce et al. that Cellcept, an immunosuppressantImmunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
medication commonly used in bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
s, may be useful in slowing down the progress of Juvenile NCL. Fundraising is currently underway to gather the funds needed to start a clinical trial to test the safety and efficiency of CellCept for Juvenile NCL.