Neuronal ceroid lipofuscinosis

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Neuronal ceroid lipofuscinosis
Other namesNCL
Lipofuscin neuro.jpg
Confocal image of a spinal motor neuron showing stained lipofuscin granules in blue and yellow.
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. [1] These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, 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.

Contents

Signs and symptoms

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, [2] [3] with the United States and Northern European populations having slightly higher frequency with an occurrence of one in 10,000. [4] Four classic diagnoses 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. [2]

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. [5] [6] [7] [8] Juvenile NCL (JNCL, Batten disease, or Spielmeyer-Vogt), with a prevalence of one in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinal dystrophy, with seizures, psychological degeneration, and eventual death in the mid- to late 20s or 30s ensuing. [9] 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 10 years later. [1]

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.[ citation needed ]

Genetics

Childhood NCLs are generally 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 gene, each of their children faces a 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. The most commonly identified mutations are in the CLN3 gene, which is located on the short arm of chromosome 16 (16p12.1). The normal function of the gene is not presently known, but results in a transmembrane protein.[ citation needed ]

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, no carriers of the gene are unaffected.[ citation needed ]

Many authorities refer to the NCLs collectively as Batten disease. [10]

Diagnosis

Because vision loss is often an early sign, 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 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 NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose NCL, the neurologist needs the patient's medical history and information from various laboratory tests.[ citation needed ]

Diagnostic tests used for NCLs include:

Types

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. [11] [12]

CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.

TypeDescription OMIM Gene
Type 1Infantile 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). 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. These patients are thought to have some partial enzyme production that leads to a protracted, less severe disease course. 256730 PPT1
Type 2Late infantile NCL (Jansky–Bielschowsky disease, LINCL) begins between ages 2 and 4. The typical early signs are loss of muscle coordination (ataxia) and seizures, along with progressive mental deterioration, though affected children may show mild to severe delays in speech development well before other symptoms appear. This form progresses rapidly and ends in death between ages 8 and 12. 204500 TPP1
Type 3Juvenile NCL (Batten disease, 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 have been known to live into their 30s. 204200 CLN3
Type 4Adult NCL (Kufs disease, 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. 204300 (AR), 162350 (AD) CLN6 [13] DNAJC5
Type 5Finnish late infantile (Finnish late infantile variant, vLINCL) – identified in Finland 256731 CLN5
Type 6Variant late infantile (late infantile variant, vLINCL) – identified in Costa Rica, South America, Portugal, the United Kingdom and other nations 601780 CLN6
Type 7CLN7 610951 MFSD8
Type 8CLN8 Northern epilepsy, progressive epilepsy with mental retardation (EPMR) 610003 CLN8
Type 8Turkish late infantile (Turkish late infantile variant, vLINCL) – identified in Turkey 600143 CLN8
Type 9Identified in Germany and Serbia 609055 Unknown, but possibly regulator of dihydroceramide synthase [14]
Type 10CLN10 (congenital, cathepsin D deficiency) 116840 CTSD

Mutations

Infantile form

Mannose-6-phosphate Mannose-6-phosphate.svg
Mannose-6-phosphate

Nonsense and frameshift mutations in the CLN1 gene (located at 1p32 [15] [16] [17] ) always induce classical INCL, while some missense 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). [18]

The wild-type PPT1 is a 306-amino acid polypeptide that is typically targeted for transport into lysosomes by the mannose 6-phosphate (M6P) receptor-mediated pathway. [5] [18] Here, the protein appears to function in removing palmitate residues by cleaving thioester linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. [5] [6] 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. 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. [5] 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 cleft and uncleft poly(ADP-ribose) polymerase and eventual apoptosis. [6]

Late infantile form

The CLN2 gene encodes a 46kDa protein called lysosomal tripeptidyl peptidase I (TPP1), which cleaves tripeptides from terminal amine groups of partially unfolded proteins. [7] [19] Mutations of this gene typically result in a LINCL phenotype. [20]

On April 27, 2017, the U.S. Food and Drug Administration approved cerliponase alfa (Brineura) as the first specific treatment for NCL. It is enzyme replacement therapy manufactured through recombinant DNA technology. The active ingredient in Brineura, cerliponase alfa, is intended to slow loss of walking ability in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as TPP1 deficiency. Brineura is administered into the cerebrospinal fluid by infusion via a surgically implanted reservoir and catheter in the head (intraventricular access device). [21]

Juvenile form

All mutations resulting in the juvenile variant of NCL have been shown to occur at the CLN3 gene on 16p12; [16] 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 mutations. [9] The wild-type CLN3 gene codes for a protein with no known function, [3] but 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. [22] Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D.[ citation needed ]

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 synthase.[ citation needed ]

Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation. [23] The mutations 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. [24]

Treatment

Currently, no widely accepted treatment can cure, slow down, or halt the symptoms in the great majority of patients with NCL, but seizures may be controlled or reduced with use of antiepileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible.[ citation needed ] Several experimental treatments are under investigation.[ citation needed ]

Cystagon

In 2001, a drug used to treat cystinosis, a rare genetic disease that can cause kidney failure if not treated, was reported to 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. Currently, two drug trials are underway for infantile NCL, both using Cystagon.[ citation needed ]

Gene therapy

A gene therapy trial using an adenoassociated virus vector called AAV2CUhCLN2 began in June 2004 in an attempt to treat the manifestations of late infantile NCL. [25] The trial was conducted by Weill Medical College of Cornell University [25] and sponsored by the Nathan's Battle Foundation. [26] In May 2008, the gene therapy given to the recipients reportedly was "safe, and that, on average, it significantly slowed the disease's progression during the 18-month follow-up period" [27] and "suggested that higher doses and a better delivery system may provide greater benefit". [28]

A second gene therapy trial for late infantile NCL using an adenoassociated virus derived from the rhesus macaque (a species of Old World monkey) called AAVrh.10 began in August 2010, and is once again being conducted by Weill Medical College of Cornell University. [28] Animal models of late infantile NCL showed that the AAVrh.10 delivery system "was much more effective, giving better spread of the gene product and improving survival greatly". [28]

A third gene therapy trial, using the same AAVrh.10 delivery system, began in 2011 and has been expanded to include late infantile NCL patients with moderate tosevere impairment or uncommon genotypes, and uses a novel administration method that reduces general anesthesia time by 50% to minimize potential adverse side effects. [29]

Flupirtine

Flupirtine Flupirtine.svg
Flupirtine

A painkiller available in several European countries, flupirtine, has been suggested to possibly slow down the progress of NCL, [30] 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, or the Hospital for Sick Children in Toronto.[ citation needed ]

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 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 was to be carried out in Oregon. [31]

Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone-marrow or 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.[ citation needed ]

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. [32]

Immunosuppressants

In late 2007, Dr. David Pearce et al. reported that Cellcept, an immunosuppressant medication commonly used in bone-marrow transplants, may be useful in slowing down the progress of juvenile NCL. [33]

Enzyme replacement therapy

On April 27, 2017, the U.S. FDA approved cerliponase alfa as the first specific treatment for NCL. [21]

Epidemiology

Incidence can vary greatly from type-to-type, and from country-to-country. [34]

In Germany, one study reported an incidence of 1.28 per 100,000. [35]

A study in Italy reported an incidence of 0.56 per 100,000. [36]

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. [37]

History

19th century

The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, [38] [39] [40] [41] 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.[ citation needed ]

1900 to 1950

More fundamental observations were reported by F. E. Batten in 1903, [42] and by Heinrich Vogt in 1905, [43] 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, [44] who have 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.[ citation needed ]

In 1913–14, Max Bielschowsky delineated the late infantile form of NCL. [45] 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, a Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease now called the Spielmeyer-Sjogren (juvenile) type is genetically separate from Tay–Sachs. [46]

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. [47] Simultaneously, Terry and Korey [48] and Svennerholm [49] 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 sphingolipidoses.[ citation needed ]

Subsequently, Santavuori and Haltia showed that an infantile form of NCL exists, [50] which Zeman and Dyken had included with the Jansky Bielschowsky type.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Tay–Sachs disease</span> Human medical condition

Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. Less commonly, the disease may occur in later childhood or adulthood. These forms tend to be less severe, but the juvenile form typically results in death by age 15.

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

Batten disease is a fatal disease of the nervous system that typically begins in childhood. Onset of symptoms is usually between 5 and 10 years of age. Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).

Infantile neuronal ceroid lipofuscinoses (INCL) or Santavuori disease or Hagberg-Santavuori disease or Santavuori-Haltia disease or Infantile Finnish type neuronal ceroid lipofuscinosis or Balkan disease is a form of NCL and inherited as a recessive autosomal genetic trait. The disorder is progressive, degenerative and fatal, extremely rare worldwide – with approximately 60 official cases reported by 1982, perhaps 100 with the condition in total today – but relatively common in Finland due to the local founder effect.

<span class="mw-page-title-main">Sandhoff disease</span> Medical condition

Sandhoff disease is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Accumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death. The rare autosomal recessive neurodegenerative disorder is clinically almost indistinguishable from Tay–Sachs disease, another genetic disorder that disrupts beta-hexosaminidases A and S. There are three subsets of Sandhoff disease based on when first symptoms appear: classic infantile, juvenile and adult late onset.

<span class="mw-page-title-main">Battenin</span> Protein-coding gene in the species Homo sapiens

Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16. Battenin is not clustered into any Pfam clan, but it is included in the TCDB suggesting that it is a transporter. In humans, it belongs to the atypical SLCs due to its structural and phylogenetic similarity to other SLC transporters.

<span class="mw-page-title-main">Palmitoyl(protein) hydrolase</span>

Palmitoyl protein hydrolase/thioesterases is an enzyme (EC 3.1.2.22) that removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. It catalyzes the reaction

<span class="mw-page-title-main">Tripeptidyl peptidase I</span> Protein-coding gene in the species Homo sapiens

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene. TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene. Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis.

<span class="mw-page-title-main">CLN6</span> Protein-coding gene in the species Homo sapiens

Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the CLN6 gene.

<span class="mw-page-title-main">CLN5</span> Protein-coding gene in the species Homo sapiens

Ceroid-lipofuscinosis neuronal protein 5 is a protein that in humans is encoded by the CLN5 gene.

<span class="mw-page-title-main">CLN8</span> Protein-coding gene in the species Homo sapiens

Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.

<span class="mw-page-title-main">PPT1</span> Protein-coding gene in the species Homo sapiens

Palmitoyl-protein thioesterase 1 (PPT-1), also known as palmitoyl-protein hydrolase 1, is an enzyme that in humans is encoded by the PPT1 gene.

<span class="mw-page-title-main">Jansky–Bielschowsky disease</span> Medical condition

Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body due to a deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. This late-infantile form of the disease progresses rapidly once symptoms are onset and ends in death between age 8 and teens. The prevalence of Jansky–Bielschowsky disease is unknown, however NCL collectively affects an estimated 1 in 100,000 individuals worldwide. Jansky–Bielschowsky disease is related to late-infantile Batten disease and LINCL, and is under the umbrella of neuronal ceroid lipofuscinosis.

A Finnish heritage disease is a genetic disease or disorder that is significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Northern Sweden (Meänmaa) and Northwest Russia. There are 36 rare diseases regarded as Finnish heritage diseases. The diseases are not restricted to Finns; they are genetic diseases with far wider distribution in the world, but due to founder effects and genetic isolation they are more common in Finns.

<span class="mw-page-title-main">Northern epilepsy syndrome</span> Medical condition

Northern epilepsy syndrome (NE), or progressive epilepsy with mental retardation (EPMR), is a subtype of neuronal ceroid lipofuscinosis and a rare disease that is regarded as a Finnish heritage disease. Unlike most Finnish heritage diseases, this syndrome has been reported only in Finland. The disease is characterized by seizures in early childhood that progressively get worse until after puberty. Once the onset of seizures occurs, mental degradation is seen. This continues into adulthood, even after seizure frequency has decreased. The cause of the disease is a missense mutation on chromosome 8. The creation of a new protein occurs, and the lipid content of the brain is altered because of it. The ratio of the mutation carriers is 1:135. There is nothing that has been found to stop the progression of the disease, but symptomatic approaches, such as the use of benzodiazepines, have helped control seizures.

<span class="mw-page-title-main">MFSD8</span> Protein-coding gene in the species Homo sapiens

Major facilitator superfamily domain containing 8 also called MFSD8 is a protein that in humans is encoded by the MFSD8 gene. MFSD8 is an atypical SLC, thus a predicted SLC transporter. It clusters phylogenetically to the Atypical MFS Transporter family 2 (AMTF2).

Kufs disease is one of many diseases categorized under a disorder known as neuronal ceroid lipofuscinosis (NCLs) or Batten disease. NCLs are broadly described to create problems with vision, movement and cognitive function. Among all NCLs diseases, Kufs is the only one that does not affect vision, and although this is a distinguishing factor of Kufs, NCLs are typically differentiated by the age at which they appear in a patient

Cerliponase alfa, marketed as Brineura, is an enzyme replacement treatment for Batten disease, a neurodegenerative lysosomal storage disease. Specifically, Cerliponase alfa is meant to slow loss of motor function in symptomatic children over three years old with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency, a soluble lysosomal enzyme deficiency. Approved by the United States Food and Drug Administration (FDA) on 27 April 2017, this is the first treatment for a neuronal ceroid lipofuscinosis of its kind, acting to slow disease progression rather than palliatively treat symptoms by giving patients the TPP1 enzyme they are lacking.

Sara Elizabeth Mole Crowley is a Professor of Molecular Cell Biology and Provost's Envoy for Gender Equality at University College London and the Great Ormond Street Hospital. She works on diseases caused by genetic changes, in particular neurodegenerative diseases that impact children.

Erika F. Augustine is an Associate Chief Science Officer and Director of the Clinical Trials Unit at Kennedy Krieger Institute. She was previously an Associate Professor of Neurology and Pediatrics at the University of Rochester Medical Center in Rochester, New York. Augustine co-directed the University of Rochester Batten Center, and was the associate director of both the Center for Health and Technology and the Udall Center of Excellence in Parkinson's Disease Research. Augustine's clinical research and medical practice specialize in pediatric movement disorders. She leads clinical trials for Batten diseases, a group of rare pediatric neurodegenerative disorders, and she has developed a novel telemedicine model to increase the efficacy of remote care for patients with rare diseases.

References

  1. 1 2 Mole, Sara E.; Williams, Ruth E. (1 January 1993). "Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY". Neuronal Ceroid-Lipofuscinoses. PMID   20301601 . Retrieved 11 December 2016.{{cite book}}: |journal= ignored (help)update 2013
  2. 1 2 Pardo, C.; et al. (1994). "Accumulation of the adenosine triphosphate synthase subunit c in the mnd mutant mouse". Am J Pathol. 144 (4): 829–835. PMC   1887237 . PMID   8160780. There are more than eight variants of NCL, found in 1 in 12,500 people worldwide.
  3. 1 2 Narayan SB, Pastor JV, Mitchison HM, Bennett MJ (Aug 2004). "CLN3L, a novel protein related to the Batten disease protein, is overexpressed in Cln3-/- mice and in Batten disease". Brain. 127 (Pt 8): 1748–54. doi: 10.1093/brain/awh195 . PMID   15240430.
  4. ↑ Vesa J, Chin MH, Oelgeschläger K, et al. (Jul 2002). "Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3". Mol Biol Cell. 13 (7): 2410–20. doi:10.1091/mbc.E02-01-0031. PMC   117323 . PMID   12134079.
  5. 1 2 3 4 Hellstein, E.; et al. (1996). "Human palmitoyl protein thioesterase". Eur Mol Bio Org J. 15 (19): 5240–5. doi:10.1002/j.1460-2075.1996.tb00909.x. PMC   452268 . PMID   8895569.
  6. 1 2 3 Kim, S.; et al. (2006). "PPT1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL". Hum Mol Genet. 15 (10): 1586–90. doi: 10.1093/hmg/ddl078 . PMID   16571600. Late Infantile NCL (LINCL or Jansky-Bielschowsky), on the other hand, initially presents as generalized tonic-clonic or myoclonic seizures beginning at around 2–3 years of age; following this is depressed cognitive development including slow learning, speech delays, and eventual dementia leading to death, usually between 14 and 36 years of age.
  7. 1 2 Ju, W.; et al. (2002). "Identification of CLN2 mutations shows Canadian specific NCL2 alleles". Journal of Medical Genetics. 39 (11): 822–825. doi:10.1136/jmg.39.11.822. PMC   1735024 . PMID   12414822.
  8. ↑ Isosomppi, J.; et al. (2002). "Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein". Hum Mol Genet. 11 (8): 885–91. doi:10.1093/hmg/11.8.885. PMID   11971870.
  9. 1 2 Persaud-Sawin, D.; et al. (2002). "Motifs within the CLN3 protein". Hum Mol Genet. 11 (18): 2129–2142. doi: 10.1093/hmg/11.18.2129 . PMID   12189165.
  10. ↑ "Batten Disease Fact Sheet | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 27 December 2019.
  11. ↑ Mole SE, Williams RE, Goebel HH (September 2005). "Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses". Neurogenetics. 6 (3): 107–26. doi:10.1007/s10048-005-0218-3. PMID   15965709. S2CID   9916771.
  12. ↑ Online Mendelian Inheritance in Man (OMIM): 256730
  13. ↑ Arsov, T; et al. (13 May 2011). "Kufs Disease, the Major Adult Form of Neuronal Ceroid Lipofuscinosis, Caused by Mutations in CLN6". American Journal of Human Genetics. 88 (5): 566–73. doi:10.1016/j.ajhg.2011.04.004. PMC   3146726 . PMID   21549341.
  14. ↑ Schulz A, Mousallem T, Venkataramani M, et al. (February 2006). "The CLN9 protein, a regulator of dihydroceramide synthase". J. Biol. Chem. 281 (5): 2784–94. doi: 10.1074/jbc.M509483200 . PMID   16303764.
  15. ↑ NCBI Entrez Gene: PPT1 [Homo Sapiens] https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5538&ordinalpos=28&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum
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  17. ↑ Online Mendelian Inheritance in Man (OMIM): NCL1, CLN1 - 256730
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  20. ↑ Gao, H.; et al. (2002). "Mutations in a novel CLN6-encoded transmembrane cause variant NCL in man and mouse". American Journal of Human Genetics. 70 (2): 324–35. doi:10.1086/338190. PMC   384912 . PMID   11791207.
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  29. ↑ "AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis With Uncommon Genotypes or Moderate/Severe Impairment" . Retrieved 16 December 2011.
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  33. ↑ "BDSRA – Batten Disease Support and Research Association". Archived from the original on 2008-07-24.
  34. ↑ "eMedicine – Neuronal Ceroid Lipofuscinoses : Article by Celia H Chang". 15 July 2021.
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  39. ↑ synd/7 at Who Named It?
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