Neuronal Ceroid Lipofuscinoses


Background

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of neurodegenerative disorders. They are considered the most common of the neurogenetic storage diseases, with a prevalence of 1 in 12,500 in some populations. NCLs are associated with variable, yet progressive, symptoms, including seizures, dementia, visual loss, and/or cerebral atrophy. Prenatal diagnosis may be possible in a family with an affected child, depending upon the NCL subtype. (See Epidemiology and Presentation.)

NCL was later so named because of the accumulation of autofluorescent lipopigments resembling ceroid and lipofuscin seen in patients with the condition. Although NCLs are generally autosomal recessive disorders, in 1971 Boehme described autosomal dominant inheritance of the same disease in the Parry family of New Jersey. The enzymatic abnormalities were better defined in the 1980s, and the molecular genetics have now being described in some variants of NCL. A database of NCL mutations is maintained. (See Etiology.) [123]

Classification

The neuronal ceroid lipofuscinoses (NCLs) originally were defined by their age of onset and clinical symptoms. However, they have since been reclassified on the basis of newer molecular findings, which have provided evidence of far more overlap for the different genetic variants than had previously been suggested by the clinical phenotypes. [4(See Etiology and Presentation.)

Mortality

Patients with NCL have shortened life expectancy. The impact of NCL on life span clearly depends on the type of NCL that a patient has. [5]

Patient education

Genetic counseling is essential in the presence of NCL. Families may be referred to a number of support and research groups in the United States, including the following (see Treatment):

  • Batten Disease Support and Research Association: 1-800-448-4570 or www.bdsra.org.

  • Children's Brain Disease Foundation: 1-415-665-3003

  • Institute for Basic Research in Developmental Disabilities: 1-718-494-0600 or 1-718-494-5117

  • The National Institute of Neurologic Disorders and Stroke at the National Institutes of Health (NIH)

Etiology

The NCLs are almost all characterized by apoptosis and dysregulated sphingolipid metabolism. It is suspected that there are common pathways for many of the variants. Persaud-Sawin et al found that transfecting CLN1 (ceroid lipofuscinosis, neuronal 1)- or CLN2-deficient cells with CLN deoxyribonucleic acid (DNA) constructs for either CLN1 or CLN2 was somewhat protective against etoposide-induced apoptosis in both cell types. CLN6 and CLN8 constructions resulted in near total correction of growth defects in CLN3-deficient cells, and CLN2 DNA constructs were partially effective. CLN2, CLN3, and CLN8 constructs corrected growth for CLN6-deficient cells. CLN2, CLN3, and CLN6 constructs also corrected growth for CLN8-deficient cells. [6]

CLN1

In CLN1 NCL, a lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), is deficient. PPT1, which removes fatty acyl groups from cysteine residues on fatty-acid modified proteins, remains in the endoplasmic reticulum, where it is inactive, causing saposins A and D to accumulate in the lysosomes.

Mutations have been found in all 9 exons of the CLN1 gene. Although CLN1 usually has onset in infancy, later onset (including in adulthood) has been described. More than 49 mutations have been described in CLN1. [17]

Lyly et al found that glycosylation of N197 and N232, but not N212, is essential for PPT1’s activity and intracellular transport. They also found that PPT1 formed oligomers. They believe that mutations cause more glycosylation and complex formation. [8]

CLN2

Patients with CLN2 NCL are deficient in a pepstatin-insensitive lysosomal peptidase called tripeptidyl peptidase 1 (TTP1). TTP1 removes tripeptides from the N -terminal of polypeptides. Mutations have been reported in all 13 exons of the CLN2 gene. Some mutations result in a more protracted course. Although onset is usually in late infancy, later onset has been described. More than 58 mutations have been described in CLN2. [1]

CLN3

The CLN3 gene encodes a 438 ̶ amino acid protein that is thought to be a part of the lysosomal membrane. More than 42 mutations [1have been described in CLN3. The exact function of CLN3 is unknown, but its expression is highest in secretory/glandular tissues and in gastrointestinal cells. All patients with CLN3 NCL have visual failure by age 10 years. [9]

The most common CLN3 mutation is a 1.02-kb deletion that involves the loss of exons 7 and 8. Most patients with the classic phenotype of juvenile NCL (JNCL) are homozygous for the 1.02-kb deletion. Patients who are compound heterozygotes for this deletion may have atypical phenotypes.

Munroe reported 2 patients with visual failure who were compound heterozygotes for the 1.02-kb deletion. Only 1 of the patients had seizures, and both were able to hold full-time employment as adults. Wisniewski et al reported similar patients who initially presented with psychiatric or behavioral symptoms but otherwise had a typical course.

CLN4

The adult form of NCL (ANCL) is associated with mutations of the CLN4 gene. The CLN4 gene has not been mapped yet.

CLN5

Mutations in gene CLN5 are associated with Finnish variant late-infantile NCL (fLINCL). It occurs predominantly in the Finnish population. CLN5 encodes a 407 ̶ amino acid transmembrane protein. CLN5 only occurs in vertebrae. The expression of CLN5 increases during cortical neurogenesis. More than 17 mutations have been described in this gene. [1]

CLN6

The CLN6 gene is associated with variant LINCL (vLINCL). Disease caused by CLN6 mutations is also referred to as the Czech or Indian variant of NCL. The CLN6 gene has been mapped to band 15q21-q23 and encodes a 311 ̶ amino acid membrane protein. More than 36 mutations have been described in CLN6. [1Affected individuals with CLN6 mutations are primarily of Portuguese, Indian, Pakistani, or Czech ancestry.

CLN7

The CLN7 gene has been assigned to the Turkish LINCL (tLINCL) variant. Individuals with the tLINCL variant were thought to originate from Turkey. Siintola et al identified 6 mutations in 5 families, 4 Turkish families and 1 Indian family, in the MFSD8 gene. The authors mapped the locus to 4q28.1-q28.2. The gene encodes a 518 ̶ amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 localizes mainly to the lysosomal compartment and is ubiquitously expressed. [10Eight disease-causing mutations have been identified. [1]

CLN8

CLN8 encodes a 286 ̶ amino acid transmembrane protein that localizes to the endoplasmic reticulum and endoplasmic reticulum ̶ Golgi intermediate complex. The exact function of the CLN8 protein is unknown. More than 11 mutations have been described in CLN8. [1Some mutations cause vLINCL, but missense mutations (c.70C>G for p.Arg24Gly and c.709G>A for p.Gly237Arg in association with c.70C>G) can also result in progressive epilepsy with mental retardation (PEMR) or Northern epilepsy, which is a protracted disease.

CLN9

Schulz et al reported that CLN9 produces a protein that may be a regulator of dihydroceramide synthetase. Even though the CLN8 sequence was normal, transfection with CLN8 corrected growth and apoptosis in CLN9-deficient cells. [1112]

CLCN6

Two putative disease-causing mutations have also been identified for the CLCN6 (chloride channel 6) gene. [1]

Subunit C

Subunit C of the mitochondrial adenosine triphosphate (ATP) synthase complex accumulates in the lysosomes of patients with some variants of NCL, including the CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, and CLN8 variants. (Subunit C is part of a transmembrane proton channel located on the inner mitochondrial membrane; each ATP synthase complex has 10-12 copies of subunit C.) Subunit C also accumulates in some animal models of NCL, including the bovine and several canine variants. Subunit C, an extremely hydrophobic 75-amino-acid protein, is encoded by 2 separate genes, P1 and P2.P1 is on chromosome 17 and P2 is on chromosome 12. The messenger ribonucleic acid (mRNA) for P2 is the predominant form.

Epidemiology

Occurrence in the United States

Estimates suggest that approximately 25,000 families in the United States are affected with a form of NCL.

International occurrence

The prevalence of NCL is highest in the Scandinavian countries, especially Finland. Occurrence of different forms of NCL are as follows:

  • CLN1 NCL - In the Finnish population, the incidence is 1 in 20,000 persons, with a carrier frequency of 1 in 70 persons

  • CLN2 NCL - The worldwide prevalence is 0.6-0.7 per million inhabitants, with an incidence of 0.46 per 100,000 live births

  • CLN3 NCL - Worldwide, CLN3 NCL is the second most common form of NCL; the incidence is 7 cases per 100,000 live births in Iceland

Race- and age-related demographics

Although the age of onset depends in part upon the type of NCL, molecular genetic discoveries have revealed more clinical overlap than was previously appreciated.

Most cases of CLN1 NCL in the Finnish population have an infantile onset. Only 50% of CLN1 NCL cases have an infantile onset in the United States; the other cases have a late-infantile, a juvenile, or an adult onset.


History and Physical Examination

CLN1 NCL (also called Santavuori-Haltia type or infantile NCL)

The infantile phenotype includes the following characteristics:

  • Retarded head growth

  • Hypotonia

  • Hyperexcitability

  • Cognitive dysfunction

  • Visual failure

  • Ataxia

  • Extrapyramidal movements

  • Spasticity

  • Myoclonus

  • Increased risk of hypothermia and bradycardia with anesthesia. [13]

  • Loss of light perception at age 2 years

  • Loss of motor and social skills at age 3 years

  • Death between ages 6 and 13 years

The late-infantile phenotype includes the following characteristics:

  • Cognitive decline, epilepsy, visual loss at age 1.5-3.5 years

  • Resembles CLN2 NCL

  • Death between ages 10 and 13 years

The juvenile phenotype includes the following characteristics:

  • Visual loss or learning disabilities at age 5-7 years

  • Resembles CLN3 NCL, except that epilepsy occurs later and motor disability occurs earlier

The adult phenotype includes the following characteristics:

  • Starts in the third decade

  • Psychiatric symptoms with progressive cognitive decline

  • Ataxia

  • Parkinsonism

  • Optic nerve atrophy

  • Alive in mid-50s

CLN2 NCL (also called Jansky-Bielschowsky type or late-infantile NCL)

The late-infantile phenotype includes the following characteristics:

  • Onset between ages 2 and 4 years

  • Epilepsy

  • Cognitive decline

  • Ataxia

  • Myoclonus

  • Extrapyramidal symptoms

  • Pyramidal symptoms

  • Blindness at age 4-6 years

  • Death before or in the second decade of life

The juvenile phenotype includes the following characteristics:

  • Onset between ages 6 and 8 years

  • Progressive cognitive decline

  • Seizures

  • Ataxia

  • Motor dysfunction

  • Variable vision loss

  • Survival up to the fourth decade possible

CLN3 NCL (also called Spielmeyer-Sjögren type, Spielmeyer-Sjögren-Vogt type, juvenile NCL, or Batten disease)

The classic phenotype includes the following characteristics.

  • Progressive visual loss at age 4-7 years, with blindness within 2-10 years

  • Speech disturbance

  • Cognitive decline, including attention problems

  • Epilepsy

  • Psychiatric symptoms in 74% of patients, including aggression

  • Parkinsonism

  • Myoclonus

  • Sleep disturbance

  • Pyramidal symptoms

  • Cerebellar symptoms

  • Extrapyramidal symptoms

  • Progressive cardiac disease with conduction abnormalities and hypertrophy [14]

In the protracted form of CLN3 NCL, only visual loss occurs until age 40 years, after which other symptoms manifest.

Neuropsychological testing

Adams et al found that children with CLN3 NCL had significant impairment in auditory attention, memory, verbal intellectual function, and fluency. Neuropsychological impairment was progressive over time and correlated with disease duration and motor function. [1516]

CLN4 NCL (also called Kufs disease or adult NCL)

Symptoms usually at age 30 years but can present at age 11 years. The type A form includes the following characteristics:

  • Progressive myoclonic epilepsy

  • Dementia

  • Ataxia

  • Pyramidal symptoms

  • Extrapyramidal symptoms

The type B form of CLN4 NCL includes the following characteristics:

  • Behavioral abnormalities

  • Dementia

  • Motor dysfunction

  • Ataxia

  • Extrapyramidal symptoms

  • Suprabulbar symptoms

  • Onset possibly after age 50 years

CLN5 NCL (also called Finnish variant late-infantile NCL)

See the list below:

  • Onset at age 4.5-7 years

  • Motor clumsiness

  • Concentration problems

  • Similar to CLN2 NCL, but with a slower course

  • Death in the second or third decade

CLN6 NCL (also called variant late-infantile/early juvenile NCL or Lake Cavanagh disease)

See the list below:

  • Onset between ages 18 months and 8 years

  • Visual loss

  • Seizures

  • Resembles CLN2 NCL

  • Loss of motor skills between ages 4 and 10 years

  • Death in the second or third decade

CLN7 NCL

CL7 NCL includes the following characteristics [17:

  • Mean age of 5 years at disease onset

  • Seizures or motor impairment at onset

  • Mental regression

  • Myoclonus

  • Speech impairment

  • Loss of vision

  • Personality disorders

CLN8 NCL (also called Turkish variant late-infantile NCL or Northern epilepsy)

Turkish variant late infantile NCL includes the following characteristics:

  • Onset at age 3-7.5 years

  • Progressive visual loss

  • Speech delay

  • Seizures

  • Intellectual decline

  • Myoclonus

  • Ataxia

Northern epilepsy includes the following characteristics:

  • Epilepsy at age 5-10 years

  • Slight motor dysfunction

  • Slowly progressive mental retardation

  • May have reduced visual acuity

  • May survive to the sixth decade

CLN9 NCL

CLN9 NCL includes the following characteristics [18:

  • Onset at age 4 years, with declining vision and seizures

  • Progressive ataxia

  • Cognitive decline

  • Rigidity


Diagnostic Considerations

Conditions to consider in the differential diagnosis of neuronal ceroid lipofuscinoses (NCLs) are listed below.

Epileptic encephalopathies are as follows:

  • Ohtahara syndrome

  • West syndrome

  • Dravet syndrome

  • Doose syndrome

  • Lennox Gastaut syndrome

  • Landau Kleffner syndrome

  • Progressive myoclonic epilepsies - Lafora body disease, Unverricht-Lundborg disease

Infections are as follows:

  • HIV-1–associated central nervous system (CNS) complications

  • SSPE

  • Prion disease

Inherited metabolic disorders are as follows:

Chromosomopathies include Rett syndrome.

Other neurodegenerative conditions include Dentato-rubro-pallidal atrophy.

The NCLs are progressive and generally shorten life expectancy. No specific treatment or cure is available for any of the NCLs. Therefore, a delay in diagnosis is unlikely to affect the clinical course or prognosis of the patient.


Approach Considerations

Biochemical abnormalities in neuronal ceroid lipofuscinoses (NCLs) include the accumulation of subunit C of the ATP synthase complex (SCMAS) in the lysosomes of patients with mutations in CLN2CLN3CLN4CLN5CLN6CLN7, or CLN8. In CLN3 NCL, a large proportion of lymphocytes contain cytoplasmic vacuoles.

Enzyme levels

CLN1 NCL

Palmitoyl protein thioesterase (PPT) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Lymphoblast PPT is less than 0.2pmoles/min/mg (normal levels are 1-3). [19]

CLN2 NCL

Tripeptidyl peptidase 1 (TTP1) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Fibroblast TTP1 activity is approximately 17,000 micromoles of amino acids produced per hour per mg of protein. The TTP1 activity in CLN2 NCL is less than 4% of normal. [1920]

Electroencephalography

Electroencephalographic characteristics seen in CLN1 NCL (infantile form) include the following:

  • Lack of attenuation of posterior dominant rhythm to eye opening

  • Loss of sleep spindles

  • Progressive background abnormality and attenuation with the background flat by age 3 years

In CLN2 NCL, occipital spikes with photic stimulation at 1-2 Hz are seen on electroencephalograms (EEGs). In CLN3 NCL, the results are disorganized, and spike and slow wave complexes are seen.

Electroretinography

On electroretinography, characteristics include the following:

  • CLN1 NCL (infantile form) - Unrecordable at age 3 years

  • CLN1 NCL (juvenile form) - Unrecordable at diagnosis

  • CLN2 NCL (late-infantile form) - Abnormal at presentation and then extinguishes

  • CLN3 NCL - Abnormal early

Visual evoked potential

Visual evoked-potential studies are characterized as follows:

  • CLN1 NCL (infantile form) - Unrecordable at age 4 years

  • CLN2 NCL (late-infantile form) - Abnormally enhanced, but diminish in the final stages

  • CLN3 NCL - Abnormal early

Somatosensory evoked potential

Progressive attenuation in all NCLs is seen in somatosensory evoked-potential studies.

Staging

In CLN2 NCL, Worgall et al found that the Weill Cornell late-infantile NCL (LINCL) scale correlated better than the modified Hamburg LINCL scale did with age and time since the onset of initial clinical manifestations. In addition, they found that imaging measures also correlated better with the Weill Cornell scale. [21]

MRI and MR Spectroscopy

CLN1 NCL

Magnetic resonance imaging (MRI) findings in CLN1 NCL include the following:

  • Mild cerebral atrophy progresses after 4

  • Decreased T2-signal intensity in the thalami

  • Callosal thinning

  • Periventricular rims of hyperintensity that progress to diffuse white matter hyperintensity on T2

  • Cerebellar atrophy after age 3 years

In magnetic resonance (MR) spectroscopy, the following characteristics are seen in CLN1 NCL:

  • Almost complete loss of N- acetylaspartate (metabolite present only in neurons)

  • Reduction in creatine- and choline-containing compounds (ie, markers for glial membrane turnover)

  • Elevation of myoinositol (ie, a glial marker)

  • Elevation of lactate in gray and white matter

CLN2 NCL

In CLN2 NCL, progressive atrophy, especially infratentorial atrophy, is seen. In a study, Dyke et al found that a whole-brain apparent diffusion coefficient (ADC) correlated with the patient's age and disease duration. They determined that children in the study with CLN2 began to differ from controls at age 5 years. [22]

CLN3 NCL

MRI findings in CLN3 NCL include the following:

  • Cerebral atrophy

  • Cerebellar atrophy usually after age 15 years

  • In voxel-based morphometric study [23- Marked reduction in the gray matter volume of the dorsomedial thalami in particular and decreased white matter volume of the corona radiata are seen

CLN6 NCL

MRI findings in CLN6 NCL include severe cerebral and cerebellar atrophy.

PET Scanning

In positron emission tomography (PET) scanning, the following characteristics are seen:

  • CLN2 NCL - Severe, generalized hypometabolism

  • CLN3 NCL - Hypometabolism, earliest in the calcarine area

DNA Testing

DNA testing and electron microscopic ultrastructural findings in peripheral blood lymphocytes [24may be used, as well as other tissues. Resources such as genetests.org can be used to determine updated availability of genetic testing on a clinical or research basis. DNA testing considerations regarding CLN genes include the following:

  • Infantile NCL (INCL) -CLN1 gene localizes to chromosome 1p32 [Granular osmiophilic deposits = GROD]

  • Late-infantile NCL (LINCL) -CLN2 gene localizes to chromosome 11p15.5 [Curvilinear bodies = CV/Mixed]

  • Juvenile NCL (JNCL) -CLN3 gene localizes to chromosome 16p12.1 [Fingerprint profiles = FP/mixed]

  • Adult NCL (ANCL) -CLN4 gene not mapped yet [FP/granular]

  • Finnish variant late-infantile NCL (fLINCL) -CLN5 gene localizes to chromosome 13q21.1-q32 [FP, CV, rectilinear complex = RL]

  • Portuguese variant late-infantile NCL (pLINCL) -CLN6 gene localizes to chromosome 15q21-q23 [CV, FP, RL]

  • Turkish variant late-infantile NCL (tLINCL) -CLN7 gene mapped to 4q28.1-q28.2 [FP/mixed]

  • Progressive epilepsy with mental retardation (PEMR) -CLN8 gene localizes to chromosome 8p23 [CV or GROD-like inclusions]

  • CLN9 [GROD, CV, FP]

Histology

Histologic findings in CLN1 NCL include an almost complete loss of cortical neurons. In CLN3 NCL, findings include vacuolated lymphocytes, as well as selective necrosis of stellate cells in layers II and III and loss of pyramidal cells in layer V.

Findings in CLN5 NCL include the following:

  • Neuronal loss in the neocortex and cerebellum

  • Laminar pattern of neuronal loss, most severe in layers III and V

  • Meganeurites in layer III

  • Extensive gliosis

  • Almost complete loss of Purkinje and granule cells with gliosis

Findings in CLN6 NCL include the following:

  • Neuronal loss, especially layer V

  • Loss of granule cells, with relative preservation of Purkinje cells

  • SCMAS absent in liver, adrenals, and pancreas

Findings in CLN8 NCL include the following:

  • Slight loss in layer V and CA2 in hippocampus

  • SCMAS most prominent in layer III and hippocampus CA2-CA4

  • Meganeurites in layer III

  • Minimal SCMAS in Purkinje cells, substantia nigra, and locus ceruleus

  • Unlike other lysosomal storage diseases, usually no ectopic dendritic growth or axonal spheroids

  • Meganeurites caused by distention of the axon hillock and proximal axon (occasionally)


Approach Considerations

The only specific treatment available for neuronal ceroid lipofuscinoses (NCLs) is cerliponase alfa (Brineura) for neuronal ceroid lipofuscinosis type 2 (CLN2, also known as tripeptidyl peptidase 1 [TPP1] deficiency). Cerliponase alfa, a drug that requires intraventricular administration, was approved by the FDA in April 2017 to slow the loss of ambulation in symptomatic pediatric patients aged 3 years or older with late infantile neuronal CLN2. Approval was based on a nonrandomized, single-arm dose escalation study over 96 weeks. Results were compared with untreated patients from a natural history cohort. Twenty-four patients aged 3-8 years were enrolled in the clinical study. One patient withdrew after week 1 due to inability to continue with study procedures; 23 patients were treated with cerliponase alfa every other week for 48 weeks and continued treatment during the extension. Twenty-two patients were evaluated at week 96, 21 (95%) did not have a decline in the motor domain of the CLN2 clinical rating scale. Only the patient who terminated early was deemed to have a decline in the motor domain of the CLN2 clinical rating scale. [25]

Bone marrow transplantation has been tried in animal models as well as in a few infants, with disappointing results. Vitamin E and other antioxidants, as well as selenium, have been tried without significant efficacy. Seizures should be treated with standard anticonvulsants. [26]

Future treatments may involve stem cell transplantation, enzyme replacement, gene therapy, and/or immune therapy. [2728]

A study regarding the safety and preliminary efficacy of CNS stem cell transplantation in patients with palmitoyl protein thioesterase 1 (PPT1) or tripeptidyl peptidase 1 (TTP1) deficiency is currently ongoing. [29]

Replication-deficient adeno-associated virus gene transfer vector (AAV2-mediated CLN2 gene transfer) has been studied in mice, rats, and nonhuman primates. Studying this in children is of interest. [30313233]

Consultations

Consultation with a geneticist is helpful because prenatal diagnosis may be possible—using DNA analysis and electron microscopy of chorionic villus samples—for families with an affected child. [34Genetic counseling would include a discussion about the mode of inheritance and risks for recurrence so that couples can make rational family planning decisions.

An ophthalmologist consultation can be very helpful in the evaluation of children thought to have NCL, since abnormal findings may be noted on funduscopic examination, electroretinography, and/or fluorescein angiography.

Consultation by a physiatrist (physical medicine and rehabilitation physician) is very helpful to manage spasticity, therapy, and equipment needs.



Medication Summary

The only specific treatment available for neuronal ceroid lipofuscinoses (NCLs) is cerliponase alfa (Brineura) for neuronal ceroid lipofuscinosis type 2 (CLN2, also known as tripeptidyl peptidase 1 [TPP1] deficiency). [25]

Seizures in neuronal ceroid lipofuscinoses (NCLs) should be treated with standard anticonvulsants. Anticonvulsant agents used in NCL include the following:

  • Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)

  • Oxcarbazepine (Trileptal)

  • Phenytoin (Dilantin, Phenytek)

  • Valproic acid (Depakote, Depakene, Depacon, Stavzor)

  • Gabapentin (Neurontin)

  • Lamotrigine (Lamictal)

  • Topiramate (Topamax)

  • Tiagabine (Gabitril)

  • Felbamate (Felbatol)

  • Phenobarbital

  • Zonisamide (Zonegran)

  • Levetiracetam (Keppra)

Enzyme Replacement

Class Summary

The first enzyme replacement therapy for CLN2 disease (TPP1 deficiency) has been approved by the FDA.

Cerliponase alfa (Brineura, Recombinant human tripeptidyl peptidase 1 (rhtpp1))

Recombinant form of human tripeptidyl peptidase (TPP1) that provides enzyme replacement therapy. The enzyme results in a restored breakdown of the lysosomal storage materials that cause CLN2 disease.

Anticonvulsants

Class Summary

These agents are used to terminate clinical and electrical seizure activity as rapidly as possible and to prevent seizure recurrence.

Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)

Carbamazepine is effective for the treatment of complex partial seizures. It appears to act by reducing polysynaptic responses and blocking posttetanic potentiation. Carbamazepine's major mechanism of action is the reduction of sustained, high-frequency, repetitive neural firing.

Oxcarbazepine (Trileptal)

Oxcarbazepine's pharmacologic activity comes primarily from its 10-monohydroxy metabolite. Oxcarbazepine may block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. Its anticonvulsant effect may occur through the drug's affect on potassium conductance and high-voltage, activated calcium channels. Oxycarbazepine's pharmacokinetics are similar in older children (>8 y) and adults. Young children (< 8 y) have a 30-40% increased clearance, compared with older children and adults. Children younger than 2 years have not been studied in controlled clinical trials.

Phenytoin (Dilantin, Phenytek)

A phosphorylated formulation, fosphenytoin, is available for parenteral use and may be given intramuscularly or intravenously.

Valproic acid (Depakote, Depakene, Depacon, Stavzor)

Valproic acid is chemically unrelated to other drugs used to treat seizure disorders. Although its mechanism of action not established, the activity of valproic acid may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. Valproate may potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect.

Gabapentin (Neurontin)

Gabapentin has properties in common with other anticonvulsants. However, its exact mechanism of action is not known. Gabapentin is structurally related to GABA but does not interact with GABA receptors.

Lamotrigine (Lamictal)

Lamotrigine is a triazine derivative that is useful in the treatment of seizures and neuralgic pain. It inhibits the release of glutamate and also inhibits voltage-sensitive sodium channels, stabilizing the neuronal membrane.

Topiramate (Topamax)

Topiramate is a sulfamate-substituted monosaccharide. It has a broad spectrum of antiepileptic activity that may have state-dependent sodium channel–blocking action, potentiating the inhibitory activity of the neurotransmitter GABA. In addition, topiramate may block glutamate activity.

Tiagabine (Gabitril)

Tiagabine's mechanism of antiseizure effect is unknown. However, the effect is believed to be related to tiagabine's ability to enhance the activity of GABA, a major inhibitory neurotransmitter in the CNS. Tiagabine may block GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of postsynaptic cells. The drug also possibly prevents the propagation of neural impulses that contribute to seizures by GABAergic action. The modification of concomitant AEDs is not necessary unless clinically indicated.

Felbamate (Felbatol)

Felbamate is an oral antiepileptic agent with weak inhibitory effects on GABA-receptor binding and benzodiazepine-receptor binding. It interacts as an antagonist at the strychnine-insensitive glycine recognition site of the N-methyl-D-aspartate (NMDA) receptor ̶ ionophore complex.

Felbamate is not indicated as a first-line antiepileptic treatment. The drug is recommended for use only in patients whose epilepsy is so severe that felbamate's benefits outweigh the risks of aplastic anemia or liver failure.

Phenobarbital

Phenobarbital exhibits anticonvulsant activity in anesthetic doses and can be administered orally. If the intramuscular route is chosen, inject the drug into one of large muscles, such as the gluteus maximus or vastus lateralis, or into another area where there is little risk of encountering a nerve trunk or major artery. Injection into or near peripheral nerves may result in permanent neurologic deficit. Restrict intravenous use to conditions in which other routes of administration are not feasible, either because the patient is unconscious, as in cases of cerebral hemorrhage, eclampsia, or status epilepticus, or because prompt action is imperative.

Zonisamide (Zonegran)

One of newer antiepileptics recently introduced in the US market, zonisamide has been studied extensively in Japan and Korea and seems to have broad-spectrum properties. It blocks T-type calcium channels, prolongs sodium channel inactivation, and is a carbonic anhydrase inhibitor.

Levetiracetam (Keppra, Keppra XR, Spritam)

Levetiracetam is indicated for primary generalized tonic-clonic seizures in adults and children aged 6 years or older, as well as for use in juvenile myoclonic epilepsy and for partial seizures.



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