Northern epilepsy syndrome

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Northern epilepsy syndrome
Other namesNeuronal ceroid lipofuscinosis, Northern epilepsy variant
Autosomal recessive - en.svg
This condition is inherited in an autosomal recessive manner.

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. [1] 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. [2] [3] [4]

Contents

Characteristics

Early childhood

Northern epilepsy syndrome causes recurrent seizures between the ages of five to ten. These seizures, that may last up to 15 minutes, can be classified mostly as tonic-clonic, but partial seizures could also occur. The seizures commonly involve muscle rigidity, convulsions and loss of consciousness. Generally, the recurrence is one to two times per month. In the years following the onset of seizures, a noticeable decrease in intellectual capacity is observed. [3]

Adolescence

During puberty, seizure frequency increases to one to two times per week. [4] Mental function has a rapid decline, as observed by a lack of coordination, failure to complete education and fine motor activities. [3] In rare cases, some suffered from loss of vision. [2]

Adulthood

Seizure frequency is reduced to four to six seizures per year. [3] By this time, they are mentally and physically incapable to live without assistance due to the total mental degradation. Life expectancy is at least 50 years of age, which is shorter than the average worldwide age of 70. [4]

Genetic causes

Northern epilepsy syndrome is caused by an inherited autosomal recessive mutation in the telomeric region of the short arm of chromosome 8. There are at least ten mutations within the chromosome that cause the disease, and the most common missense mutation occurs at codon 24, where a glycine takes the place of an arginine. This primary mutation can also be paired with a missense at codon 237, where an arginine takes the place of a glycine. When the two mutations interact, a lengthened progression of the disease is observed. [5] The primary mutation (Arg24Gly) creates the protein CLN8. A total of 1 in every 135 people of Finnish descent were reported to be a carrier of the mutation. [2] The difference between 1-CLN8 and 2-CLN8 is the number of mutations and the mutation's location in the chromosome. [2]

Pathophysiology

An accumulation of transmembrane protein is seen in the brain tissue of Northern epilepsy patients. This protein is a 286 amino acid transmembrane protein that has not been identified before, meaning that it is unique to Northern epilepsy syndrome. [4] CLN8 has been linked to the accumulation of subunit c of mitochondrial ATP synthase and a small amount of sphingolipid activator proteins in the neurons. β-amyloid, a peptide involved in Alzheimer's disease, is also seen in this protein accumulation. [4]

Diagnosis

A patient’s DNA is sequenced from a blood sample with the use of the ABI Big Dye Terminator v.3.0 kit. Since this is a genetic disease, the basis of diagnosis lies in identifying genetic mutations or chromosomal abnormalities. The DNA sequence can be run with CLN8 Sanger sequencing or CLN8 Targeted Familial Mutations whether its single, double, or triple exon sequencing. [2] Also, preliminary evidence of the disease can be detected by means of MRI and EEG. [4] These tests identify lipid content of the brain, and any anomaly from the norm may be linked to Northern epilepsy.[ citation needed ]

Treatment

Current available treatment is limited to treating the symptoms, not the cause. Seizure frequency can be regulated by the use of drugs such as clonazepam (or other benzodiazepines) and sodium valproate. Clonazepam functions by increasing GABA activity at the GABAA receptor. GABA is an inhibitory neurotransmitter, and therefore its increased activity hyperpolarizes cells. Clonazepam has been effective in minimising seizure activity, especially during puberty. [4] Sodium valproate prevents the depolarization of the cell by blocking sodium ion channels and inhibitory GABA enzymes. Both of these anticonvulsants lead to depression of the central nervous system.[ citation needed ]

Prognosis

Life expectancy is only moderately affected by NE because the rate of disease progression is slow. Patients usually survive past 40–50 years of age. [6]

History

Northern epilepsy originated in northern Finland, and it still appears to only affect individuals of Finnish ancestry. 1 in 10,000 individuals who live or are from the region of Kainuu in northern Finland have the condition.[ citation needed ]

Northern epilepsy was not initially recognized as a neuronal ceroid lipofuscinosis (NCL). In 1999, it was found to be the first disease identified caused by mutations in the CLN8 gene. The disease is now known as the mildest form of NCL. [7] There are two forms of this mutated gene: 1-CLN8 and 2-CLN8. 1-CLN8 is known as Northern epilepsy syndrome, while 2-CLN8 is primarily from Turkish descent. [2]

See also

Related Research Articles

Lysosomal storage disease Medical condition

Lysosomal storage diseases are a group of about 50 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).

Neuronal ceroid lipofuscinosis Medical condition

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. 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.

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 sufferers in total today – but relatively common in Finland due to the local founder effect.

Myoclonic epilepsy refers to a family of epilepsies that present with myoclonus. When myoclonic jerks are occasionally associated with abnormal brain wave activity, it can be categorized as myoclonic seizure. If the abnormal brain wave activity is persistent and results from ongoing seizures, then a diagnosis of myoclonic epilepsy may be considered.

CLN3

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.

Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where afflicted individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood. GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravet's syndrome, borderline SMEI (SMEB), and intractable epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative genes are the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and a GABAA receptor γ subunit gene, GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. Penetrance for this disorder is estimated at approximately 60%.

Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before 1 year of age, however it is usually around the sixth month of age that seizures begin, characterized by prolonged convulsions triggered by fever.

Palmitoyl(protein) hydrolase

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

Tripeptidyl peptidase I

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.

CLN6

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

CLN5

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

CLN8

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

PPT1

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.

Jansky–Bielschowsky disease 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 Sweden (Meänmaa) and 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.

MFSD8

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).

KCTD7

Potassium channel tetramerisation domain containing 7 is a protein in humans that is encoded by the KCTD7 gene. Alternative splicing results in multiple transcript variants.

Kufs disease is one of many diseases categorized under a disorder known as neuronal ceroid lipofuscinosis (NCLs). 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.

References

  1. ↑ Krystyna E. Wiśniewski; Nanbert Zhong; Jeffrey C. Hall (2001). Batten disease: diagnosis, treatment, and research. Academic Press. p. 243. ISBN   978-0-12-017645-8. page 125
  2. 1 2 3 4 5 6 "NEURONAL CEROID LIPOFUSCINOSIS 8 VIA THE CLN8 GENE". Prevention Genetics. Retrieved 23 March 2014.
  3. 1 2 3 4 "Northern epilepsy". U.S. National Library of Medicine. Retrieved 23 March 2014.
  4. 1 2 3 4 5 6 7 Ranta, S; Lehesjoki AE (2000). "Northern epilepsy, a new member of the NCL family". Neurological Sciences. 21 (1 Supplement): S43–S47. doi:10.1007/s100720070039. PMID   11073227. S2CID   11677694.
  5. ↑ Siintola, E; Lehesjoki AE; Mole SE (2006). "Molecular genetics of the NCLs -- status and perspectives". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1762 (10): 857–864. doi: 10.1016/j.bbadis.2006.05.006 . PMID   16828266.
  6. ↑ Herva, Riitta; Tyynelä, Jaana; Hirvasniemi, Aune; Syrjäkallio-Ylitalo, Marja; Haltia, Matti (2000-04-01). "Northern Epilepsy: A Novel Form of Neuronal Ceroid-Lipofuscinosis". Brain Pathology. 10 (2): 215–222. doi:10.1111/j.1750-3639.2000.tb00255.x. ISSN   1750-3639. PMID   10764041. S2CID   43726125.
  7. ↑ Warrier, V; Vieirab M; Mole SE (2013). "Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1832 (11): 1827–1830. doi: 10.1016/j.bbadis.2013.03.017 . PMID   23542453.
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