An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies. 5th edition. New York: Oxford University Press; 2024. doi: 10.1093/med/9780197549469.003.0050
The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited lysosomal storage disorders that share similar pathological and clinical features. They are characterized by accumulation of autofluorescent storage material within the lysosome and the death of neurons. Clinical presentation includes medically refractory epilepsy, visual failure, and motor and cognitive decline, usually beginning in childhood and ending in premature death. Each NCL is caused by mutations in a single gene and is associated with a typical age of onset and disease progression. However, all NCL also have a broader age of onset and disease course. Considerable expertise has been developed in the care and management of patients. There is one treatment in the clinic and others are in development.
The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of at least 13 inherited lysosomal storage disorders that share similar pathological and clinical features. Clinical presentation includes medically refractory epilepsy, visual failure, and motor and cognitive decline, usually beginning in childhood and ending in premature death. The NCL are severe progressive degenerative disorders.
Historically, the NCLs were classified according to age at onset of symptoms and the ultrastructural morphology of the storage material (Table 50–1)—for example, infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL). Some were also named after those who first described them in the literature. As each NCL is caused by mutations in a single gene, which is important to know for gene-focused therapeutic development, this has led to development of a disease nomenclature based on the gene defect augmented with age of presentation (Williams and Mole, 2012). There is one treatment in the clinic, and others are in development.
Correlation between Genotype and Phenotype in NCL.
The genetic basis of 13 different forms of NCL is known. All forms of NCL display a classic recessive Mendelian inheritance with asymptomatic heterozygous carrier parents, with the exception of autosomal dominant adult-onset CLN4 disease (Mole and Cotman, 2015). As monogenic disorders, each is in effect a separate disease entity.
The disease-causing genes fall into several categories (Cárcel-Trullols, Kovács, 2015; Huber and Mathavarajah, 2018; Mole and Cotman, 2015): encoding soluble lysosomal proteins, mostly enzymes (CLN1, CLN2, CLN5, CLN10, CLN11, CLN12, CLN13 diseases), membrane proteins that may be expressed in the lysosome (CLN3, CLN7 diseases) or elsewhere in the endosomal-lysosomal system, membrane proteins expressed in the endoplasmic reticulum (CLN6, CLN8 diseases), and proteins working elsewhere in the cell (CLN4, CLN14). It is unlikely that further NCL genes will be identified unless they cause disease in countries where little genetic analysis has so far been undertaken.
Each gene is generally associated with a classic phenotype due to loss of protein function, which gives a typical age of onset and disease progression. However, all NCL also have a broader age of onset and disease course. The increasing implementation of next-generation sequencing panels and exome sequencing in diagnosis is leading to more diagnoses of patients with NCL and increasing recognition of these broader phenotypes (Table 50–1).
Many different disease-causing mutations (>500) have now been identified in each “CLN” gene. The most prevalent mutations are the 1 kb deletion in CLN3 and two mutations in CLN2 (Mole and Cotman, 2015). A comprehensive database of the mutations is available (www.ucl.ac.uk/ncl-disease) as are reviews of mutation (e.g., CLN2; Gardner, Bailey, 2019). In combination with data collected in disease registries such as DEM-CHILD (https://www.ejpn-journal.com/article/S1090-3798(15)30049-0/pdfr) (Nickel, Simonati, 2018; Schulz, Ajayi, 2018) and application of disease rating scales (Kwon, Adams, 2011; Marshall, de Blieck, 2005; Steinfeld, Heim, 2002), correlations can be drawn to predict disease prognosis. There is also increasing information available toward frequency of mutations or disease in specific ethnic groups. As understanding of the phenotypic spectrum increases, there is overlap with other rare and common diseases, such as retinal dystrophies. This may indicate shared disease mechanisms (Cotman, Mole, 2015).
Later onset forms of disease may have a more protracted overall course, and some classic clinical features may be when disease is caused by “milder” mutations that do not completely abolish protein function (Table 50–1) (Berkovic, Staropoli, 2016). There are some mutations that are associated with a specific disease phenotype. These include a missense mutation in CLN8 and the 1 kb intragenic deletion that underlies the most common form of NCL, juvenile CLN3 disease (Mole and Cotman, 2015). The age at which first symptoms appear can guide toward which gene may be mutated.
NCL are considered collectively to be the most common inherited neurodegenerative disorder of childhood. NCL diseases occur worldwide, though some forms were originally reported in certain geographical regions, and some are enriched in or absent from certain regions due to historical population (genetic) bottlenecks.
Incidence and prevalence rates are not reported worldwide. Incidence rates are probably more robust than estimated prevalence rates and generally reported between 1 in 14,000 (Iceland) up to 1 in 100,000 (Mole, Williams, 2011). The most common NCL in Northern Europe and the United Kingdom are juvenile CLN3 disease and late infantile CLN2 disease, but all types are present.
There is normal psychomotor development before onset of first NCL symptoms, apart from congenital CLN10 disease (Schulz, Kohlschutter, 2013). Age at disease onset ranges from birth to adulthood for most genes, for some even as late as >60 years (Table 50–1). The different forms of NCL share clinical features, but the age and order that symptoms appear, and the rate of disease progression varies between the different genetic forms (Nita, Mole, 2016; Schulz, Kohlschutter, 2013).
The main symptoms are the combination of at least two of dementia, epilepsy, motor deterioration, and visual loss (Schulz, Kohlschutter, 2013).
In addition to genetic and allelic heterogeneity, there is clinical variability between and within families (Lebrun, Moll-Khosrawi, 2011). The number of phenotypes for NCL diseases is growing with widest age of onset for NCLs caused by lysosomal enzyme deficiencies (Table 50–1) (Mole and Cotman, 2015). Without disease-modifying treatment, all NCL are degenerative.
The first presentation of disease varies between the different classic forms of NCL. There may be some periods of plateau in the disease process. For infantile CLN1 disease (age of onset: 6–24 months) there is slowing of psychomotor development and then developmental regression, followed by seizures and vision loss; for late infantile CLN2 disease (age of onset: 2–5 years), first presentation is often language delay and seizures followed by progressive loss of acquired psychomotor abilities, onset of epilepsy, and then vision loss (Schulz, Kohlschutter, 2013). Diagnosis can be delayed in a period of regression is considered a side effect of antiepileptic drugs. For juvenile CLN3 disease (age of onset: 5–7 years), following rapid loss of vision, there is a delay before dementia and behavior changes and then loss of motor skills and epilepsy in the early teenage years. For those individuals presenting early in life, disease progression is usually more rapid than in those presenting later.
In recessive adult phenotypes (>16 years but typically around age 30 years), there is not usually visual loss, and patients present with progressive myoclonus epilepsy or dementia with motor decline (Berkovic, Staropoli, 2016).
Symptoms occur beyond the central nervous system (CNS). For example, cardiac involvement has been reported in adolescent and adult patients with CLN3 disease (Dilaveris, Koutagiar, 2014; Østergaard, Rasmussen, 2011) and can be treated, for example, fitting a pacemaker has improved psychomotor abilities (Lebrun, Moll-Khosrawi, 2011).
Motor signs can include ataxia (including dysmetria and dysarthria), dysphagia, myoclonus, chorea, tremor, and dystonia, especially in classic infantile and late infantile patients (Schulz, Kohlschutter, 2013). In juvenile CLN3 disease, Parkinsonism is observed. There are some stereotypical movements in various types with late infantile and juvenile age of onset (Schulz, Kohlschutter, 2013).
Some mutations underlie wider disease phenotypes beyond those typically considered as NCL (Table 50–1). These may overlap with other diagnoses. One of the clinical hallmarks might be more predominant with others missing. In a rare type of CLN2 disease (autosomal recessive spinocerebellar ataxia type 7) the primary phenotype is ataxia, and there is no accompanying epilepsy or vision loss (Sun, Almomani, 2013). A particular mutation causes a type of juvenile CLN2 disease where survival is into the fourth decade (Kohan, Carabelos, 2013). Some mutations in CLN3 are associated with isolated nonsyndromic retinal degeneration only (Ku, Hull, 2017), or visual failure, seizures, and cardiac involvement, but over decades no motor deterioration (Cortese, Tucci, 2014). Homozygous mutations in GRN cause an NCL presenting at around 20 years with visual failure, seizures, and ataxia, whereas heterozygous mutations in this gene are a common cause of frontotemporal lobar degeneration with TDP-43 inclusions at a later age (Mole and Cotman, 2015; Smith, Damiano, 2012).
In the early stages of disease brain, magnetic resonance imaging (MRI) can be normal or might show some unspecific signs, such as periventricular intensity changes in the early stages of CLN2 disease (Dyke, Sondhi, 2016). MRI is not sensitive or specific for early diagnosis; however, it can be used to monitor progression of brain changes (Dyke, Sondhi, 2016; Lobel, Sedlacik, 2016).
The electroencephalogram (EEG) can help for earlier diagnosis. Characteristic posterior spike waves following low-frequency photic stimulation in a young child with new onset of seizures should trigger testing for CLN2 disease (Albert, Yin, 2016; Specchio, Bellusci, 2017). Photosensitivity with low-frequency stimulation is also found in CLN6 disease, especially in those with adult onset (Canafoglia, Gilioli, 2015; Lv, Zhang, 2018; Ozkara, Gunduz, 2017). A characteristic “flat EEG” occurs in advanced stages of infantile CLN1 disease, as the early abnormalities disappear. Antiepileptic drugs will not lead to normalization of EEG findings as these are due to the underlying neurometabolic disease (Schulz, Kohlschutter, 2013). Monitoring by EEG may also be useful for detecting signs of encephalitis occurring as a rare consequence of antiepileptic drugs such as valproate in advanced late infantile CLN2 disease (Johannsen, Nickel, 2016) or an allergic reaction to new treatments.
Clinical symptoms usually precede the profound neuronal loss of NCL. The degree varies between NCL forms, and it is widespread and progressive, resulting in cortical grey matter and cerebellar atrophy, and secondary ventricular enlargement (Anderson, Goebel, 2013; Radke, Stenzel, 2015). The thalamus is also severely affected (Anderson, Goebel, 2013; Radke, Stenzel, 2015). Atrophy of the cerebellum can be evident in the latter stages of all NCLs (Baker, Levin, 2017; Dyke, Sondhi, 2016; Lobel, Sedlacik, 2016). Neuronal cell loss in the retina begins with the photoreceptor outer segments, before the inner segments, nerve cell bodies, and ganglionic layer. This occurs early in CLN3 disease (Dulz, Wagenfeld, 2016; Preising, Abura, 2017) and after other symptoms for other types of NCL (Anderson, Goebel, 2013; Schulz, Kohlschutter, 2013). Loss of neurons and brain atrophy may not be as pronounced in adult-onset NCL (Anderson, Goebel, 2013; Radke, Stenzel, 2015). Lipopigment storage material accumulates in all types of NCL, in macrophages, neurons, and some somatic tissues, including vascular endothelial and smooth muscle cells (Anderson, Goebel, 2013). Lipopigments also accumulate in the CNS with age or other conditions (Berkovic, Staropoli, 2016).
The NCLs can be regarded as lysosomal storage diseases (LSDs) because autofluorescent ceroid lipopigment accumulates in lysosomes; unlike other LSDs, this is not the substrate of a defective enzyme for each type of NCL and therefore not disease-specific. The material is a mix of components; its main protein components being either subunit c of mitochondrial ATP synthase or sphingolipid activator proteins A and D (saposins A and D). Other molecules are also present (Elleder, Sokolova, 1997; Palmer, Barns, 1986; Palmer, Fearnley, 1989; Tyynela, Palmer, 1993).
Before genetic diagnosis became possible, diagnosis of NCL relied on the combination of clinical presentation, age of onset, and ultrastructural morphologies of the storage material revealed by electron microscopy (EM). There are characteristic NCL ultrastructural morphologies (Table 50–1; Anderson, Goebel, 2013). These are granular osmiophilic deposits (GRODs) first observed in patients diagnosed with infantile CLN1 disease, where onset of symptoms is in the first or second year of life; curvilinear bodies (CLs) first observed in patients with late infantile CLN2 disease, and fingerprint profiles (FPs), together with vacuolated lymphocytes, seen under light microscopy, that are distinctive for patients with classic juvenile CLN3 disease. As more NCLs were recognized, more complex patterns of storage were observed, with a mixture of FPs and CLs, or condensed FPs, or rectilinear profiles (RLs) observed in patients with late infantile CLN5, CLN6, CLN7, CLN8 diseases. Some EM patterns are strongly associated with a particular gene (e.g., GROD and CLN1), and others vary according to age of onset or disease severity rather than underlying genetic defect. EM pathology, now using skin biopsy or white-cell buffy coat, is still useful to confirm an NCL diagnosis when a clear genetic diagnosis is elusive.
Although the genetic basis of NCL, including mutations, are known, understanding of how these mutations affect the encoded protein function and integrate with homeostatic molecular pathways at a cellular and subcellular level is incomplete (Butz, Chandrachud, 2020). Clearly all NCL genes have an impact on lysosomal homeostasis.
Some NCL genes are conserved in unicellular or simple organisms, indicating their fundamental function within eukaryotic cells. Many are lysosomal enzymes, involved in the degradation and recycling of cell components. From their location in the endoplasmic reticulum CLN6 and CLN8 proteins may contribute to the transport of lysosomal enzymes to the Golgi complex en route to the lysosome; deficiency in either protein leads to lysosomal enzyme deficiency. CLN5 protein may also help in the transport of NCL proteins all the way to the lysosome. Whether neuronal cells die solely due to their intrinsic cell defects arising from protein insufficiency or because the supporting astrocytes are functionally deficient is being studied.
CLN1 encodes the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1) (Vesa, Hellsten, 1995). PPT1 acts mainly in the lysosome, but possibly also in synaptic vesicles, removing fatty acyl groups from modified cysteines in proteins (Camp and Hofmann, 1993). There are two widespread mutations, one in the Finnish population, where the disease was first described. Mutations in PPT1 are associated with disease whose onset ranges from classic infantile to adult (Table 50–1). Loss of residues in the catalytic triad cause infantile disease due to low levels of detectable enzyme activity. Later onset or a more protracted disease course is usually associated with missense mutations.
CLN2 encodes the lysosomal enzyme, tripeptidyl peptidase I (TPP1) (Sleat, Donnelly, 1997), a deficiency of which leads to cases of classic late infantile CLN2 disease. TPP1 cleaves tripeptides from the amino terminus of small polypeptides. There are two widespread mutations, and there is one mutation more frequent in Canada. Most TPP1 mutations cause classic late infantile CLN2 disease. Missense changes have been associated with more protracted disease or later onset.
Classic juvenile CLN3 disease is caused by mutations in CLN3, encoding a conserved membrane protein with no significant similarities to proteins of known function (Consortium, 1995). CLN3 resides in endosomes/lysosomes and possibly the Golgi compartment of non-neuronal cells, and in the synaptic vesicles of neuronal cells (Haskell, Carr, 2000). A 1 kb intragenic deletion found worldwide accounting for approximately 90% of the affected alleles, with most patients compound heterozygous or homozygous for this deletion (Mitchison, O’Rawe, 1995). Studies showed that this mutant protein retains some of its function (Kitzmuller, Haines, 2008; Minnis, Townsend, 2021), but many mutant proteins may be retained within the ER.
CLN4/ DNAJC5 encodes cysteine-string protein alpha (CSPα), a cytoplasmic protein that forms a complex at the presynapse to chaperone the synaptic SNARE protein SNAP-25, facilitating the formation of synaptic SNARE complexes, which are necessary for the fusion of synaptic vesicles with the plasma membrane (Naseri, Sharma, 2021). There are only three known disease-causing mutations. All cause disease that is dominantly inherited with onset in adulthood. Adult-onset NCL is caused by mutations in a variety of genes, some of which also cause onset in childhood (see Table 50–1).
CLN5 encodes a soluble lysosomal glycoprotein thought to interact with some NCL proteins, perhaps facilitating their trafficking. Mutations cause disease from late infancy up to adult onset.
CLN6 encodes an ER membrane protein (Mole, Michaux, 2004; Wheeler, Sharp, 2002). Three CLN6 mutations are enriched in specific populations—in Costa Rica, Portugal, and Newfoundland. There is a very wide range in the age of onset for CLN6 disease, from late infancy up to adulthood (Kufs type A phenotype with no visual failure).
CLN7 encodes a 12-transmembrane major facilitator superfamily domain 8-containing lysosomal protein (MFSD8) (Siintola, Topcu, 2007). As a member of the major facilitator superfamily of transporter proteins, MFSD8 probably acts as a transporter of as yet unknown substrate(s). Two common mutations are known—in Roma patients, and in Italy. Phenotypic disease variation occurs, including adult onset.
CLN8 encodes an ER membrane protein (Lonka, Kyttala, 2000; Ranta, Zhang, 1999). CLN8 is a member of the TLC (TRAM-LAG1-CLN8) protein family that has a role in sensing, biosynthesis, and metabolism of lipids or protection of proteins from proteolysis (Winter and Ponting, 2002). There is a missense mutation in Finland, missense p.Arg24Gly, that causes CLN8 disease, EPMR, a protracted disease that is not associated with myoclonus or visual failure. Most mutation combinations cause disease with onset in late infancy, although occasionally a slightly milder phenotype arises.
CLN10 encodes CTSD, an aspartyl protease of the pepsin family (Metcalf and Fusek, 1993), that cleaves peptide bonds flanked by bulky hydrophobic amino acids to mediate protein degradation, but its activity is not restricted to the lysosome (Benes, Vetvicka, 2008). The catalytic site contains two aspartic acid residues (Asp97 and Asp294), one on each chain of CTSD. No common mutations have been recognized in CLN10 disease. All mutations that completely abolish the enzymatic activity of CTSD correlate with the severest CLN10 disease, present congenitally. Milder mutations are associated with juvenile or teenage/early adult onset.
CLN11/GRN encodes the glycoprotein, progranulin, that can be proteolytically cleaved following secretion to produce smaller peptides, granulins A–G, and intermediate forms. Progranulin is probably a multifunctional protein, with the granulins are also likely to be bioactive. Their activities fall into three broad categories: growth factor-like, modulation of immune responses, and neuronal effects (Cenik, Sephton, 2012). Heterozygous mutations in GRN cause frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) but compound heterozygous mutations can cause adult-onset NCL (Smith, Damiano, 2012).
CLN13/CTSF encodes a lysosomal cysteine protease. Mutations cause adult-onset NCL (CLN13 disease, adult Kufs type B) (Smith, Dahl, 2013).
The remaining genes affect fewer patients, with some being described in only one or a few families diagnosed with NCL, and most patients given other diagnoses.
CLN12/ATP13A2 encodes a 10-transmembrane lysosomal protein, a lysosomal type 5 P-type ATPase. ATP13A2 may regulate intracellular cation homeostasis and neuronal integrity, or protect cells against α-synuclein misfolding and toxicity. Mutations in ATP13A2 generally cause Kufor–Rakeb syndrome (KRS), a rare form of autosomal recessive juvenile or early-onset, levodopa-responsive migrostriatal–pallidal–pyramidal Parkinsonism, that is part of a larger group neurodegeneration with brain iron accumulation (NBIA). One family who are homozygous for a missense mutation were diagnosed with a juvenile-onset NCL presenting with learning difficulties (Bras, Verloes, 2012).
CLN14/KCTD7 encodes a potassium channel tetramerization domain-containing protein 7 (Staropoli, Karaa, 2012; Stogios, Chen, 2007). KCTD7 protein is located in the cytoplasm, and at the plasma membrane, and may function to modulate transporter subunits. KCTD7 may modulate the resting plasma membrane potential and contribute to neuronal signalling. Mutations in KCTD7 have been described in three infantile diseases, infantile progressive myoclonic epilepsy, opsoclonus-myoclonus ataxia-like syndrome, and infantile NCL in one family.
Clinical severity and presentation of NCL differ even for those caused by mutations in the same gene, which can lead to diagnostic delays. Delay in expressive language development is the first sign of regression of psychomotor function in 83% of classic late infantile CLN2 disease and could enable earlier diagnosis (Nickel, Simonati, 2018). Children with a combination of language acquisition delay and new onset of seizures should be tested for CLN2 disease (Nickel, Simonati, 2018; Williams, Adams, 2017). Epilepsy is therapy-resistant in almost all NCL patients, with especially high seizure frequency and severity in late infantile CLN2 disease up until late disease stages (Williams, Adams, 2017). However, in infantile CLN1 disease, seizure frequency tends to decrease in the later disease stages and in patients with classic juvenile CLN3 disease seizures are infrequent with only mild worsening with increasing age (Augustine, Adams, 2015; Johannsen, Nickel, 2016). Therapy with more than two anticonvulsants may result in increased side effects rather than reduction of seizures (Schulz, Kohlschutter, 2013). Some anticonvulsants are particularly recommended—valproate and lamotrigine for CLN2 and CLN3 diseases (Augustine, Adams, 2015; Williams, Adams, 2017); others (e.g., carbamazepine, gabapentin, phenytoin, vigabatrin) may have negative effects, for example, exacerbating myoclonic seizures in patients with CLN2 or CLN3 disease (Augustine, Adams, 2015; Mole, Williams, 2011; Williams, Adams, 2017). Also, as disease progresses, anticonvulsive drugs that have been tolerated and effective might cause new side effects and should be reconsidered critically if symptoms of the disease worsen (Johannsen, Nickel, 2016).
Diagnostic strategies vary according to the age of the patient and can be guided by diagnostic algorithms (Schulz, Kohlschutter, 2013).
New comprehensive approaches are changing the former investigations and order of diagnostic tests. Protocols for enzymatic and genetic testing are widely available, making rapid genetic and biochemical diagnosis of most forms of NCL increasingly straightforward (Table 50–2).
Brief Clinical Descriptions and Diagnostic Tools for Typical NCL Types.
Enzyme testing can rapidly confirm deficiencies of CTSD, PPT1, and TPP1 using saliva, blood samples, and dried blood spots. These enzyme assays should always be applied in cases with an unusual presentation or later onset, and all diagnoses should be supported by DNA sequencing and mutation analysis where possible.
New DNA technologies allow testing for many genes in a single step regardless of the presentation (e.g., NCL genes are part of panels designed to interrogate genes underlying a larger group of syndromic and nonsyndromic inherited epilepsies). This more readily provides a genetic diagnosis for clinically milder or variant phenotypes.
A common feature of CLN3 disease is vacuolated lymphocytes which can be visualized by blood film examination (Anderson, Smith, 2005). Ultrastructural examination of a skin biopsy or blood sample remains helpful for confirmation of NCL disease for atypical forms that have not been confirmed as enzyme deficiencies or received a genetic diagnosis (Table 50–1). Extracerebral storage is readily detected in childhood NCLs but not necessarily in NCL presenting in adulthood (Berkovic, Staropoli, 2016).
There is an urgency in making an NCL diagnosis now that disease-modifying treatments are available or in the pipeline. Biomarkers that follow disease progression and allow the effectiveness of therapies to be monitored are likely to emerge in the near future.
Carrier detection is not possible by histology and is unreliable by enzyme assay; it should always be based on mutation analysis.
Prenatal diagnosis can be offered to families with a history of NCL disease, and particularly where the genetic subtype of the index case had been defined precisely. Preimplantation genetic diagnosis (Shen, Cram, 2013) or a combination of enzyme assay and mutational analysis, perhaps with ultrastructural examination of chorionic villus samples obtained at 12–15 weeks gestation, can provide a rapid diagnosis.
Disease-modifying treatment currently available in the clinic is only for CLN2 disease (see below). Medical care and practical management of children, young people, and young adults with NCL is therefore aimed at minimizing disease symptoms and retaining skills to maintain their quality of life for as long as possible. There is much collective specialist knowledge and experience available (Schulz, Kohlschutter, 2013), for example, CLN2 disease (Mole, Schulz, 2021; Williams, Adams, 2017). As supportive care has improved, many with CLN3 disease now survive into their twenties or thirties. There are some sex differences (Adams, Augustine, 2011; Cialone, Adams, 2012).
Seizure management in the NCLs can be challenging as it is resistant to therapies. This requires that children and young people are reviewed regularly by experts. Some NCLs have high seizure frequency and severity, for example, late infantile CLN2 disease up until the late disease stages (Williams, Adams, 2017). In others seizure frequency may decrease, for example, in the later stages of infantile CLN1 disease; and in others they are infrequent, for example, juvenile CLN3 disease seizures, with only mild worsening with increasing age (Augustine, Adams, 2015; Johannsen, Nickel, 2016). Using more than two anticonvulsants may cause increased side effects rather than reduction of seizures (Schulz, Kohlschutter, 2013). Some anticonvulsants are particularly effective—valproate and lamotrigine for CLN2 and CLN3 diseases (Augustine, Adams, 2015; Williams, Adams, 2017); others have been observed to have negative effects, exacerbating myoclonic seizures in patients with CLN2 or CLN3 disease (e.g., carbamazepine, gabapentin, phenytoin, vigabatrin) (Augustine, Adams, 2015; Mole, Williams, 2011; Williams, Adams, 2017). As disease progresses, anticonvulsive drugs that have previously been effective might cause new side effects and should therefore be reconsidered if the disease worsens (Johannsen, Nickel, 2016).
The effects of medications should be monitored closely and drug regimens modified appropriately. Informed and expert multidisciplinary and interagency working is essential to support NCL families. NCL is progressive; therefore, interventions, whether medical or educational, should be discussed and agreed with the family and all their supporting teams and services.
Therapy will need to address the consequences of both CNS and peripheral disease and begin as early as possible before first symptoms appear. The current main translational approaches for the NCL are gene therapies, enzyme replacement therapies, cell-based therapies, and drug approaches (Kohlschutter, Schulz, 2019; Mole, Anderson, 2019; Specchio, Ferretti, 2021). The type of therapeutic approach is linked to the underlying defective protein. The blood–brain barrier is a challenge, for example, for drug approaches. Treatments given directly into the brain are unlikely to provide therapeutic benefit for the NCL-related retinal degeneration or peripheral pathologies.
At present, there is no curative or disease-modifying treatment available for the majority of NCL patients, and clinical care is limited to symptom control and supportive approaches.
For one specific form of NCL, CLN2 disease, the defective lysosomal enzyme, TPP1, can be delivered directly into the brain where it is effective at attenuating the progression of the disease (Markham, 2017; Schulz, Ajayi, 2018). Already affected children treated with this enzyme replacement therapy (ERT) have a significantly slower disease progression or stabilization as measured by a clinical rating scale assessing motor and language function. Children are now being treated prior to symptom onset, which emphasizes the importance of early diagnosis. This will be lifelong treatment. Specifically, TPP1 is administered as a recombinant proenzyme using a surgically fitted Rickham or Ommaya device into the lateral cerebral ventricles every 2 weeks, over 4 h at a dose of 300 mg protein (Schulz, Ajayi, 2018). The delivered enzyme is recognized by receptors on the surface of cells and taken into the cell and trafficked to the lysosome.
The same enzyme replacement approach might be suitable for other types of NCL caused by mutations in lysosomal enzymes (Table 50–1) and, with adaptions, may be able to correct systemic disease.
Current experimental therapy options for NCL being tested in animal models include small molecule therapy, neuroprotection and immunomodulation, stem cell therapy, and gene therapy; some have reached phase I/II clinical trials in patients, and these are summarized in Table 50–3.
Clinical Trials Assessing Treatment of Neuronal Ceroid Lipofuscinoses (https://clinicaltrials.gov/).
For enzyme-deficient forms of NCL, therapeutic approaches aim at using the principle of cross-correction and providing a working enzyme delivered directly or provided by grafted stem cells or following gene therapy. Treatment options for forms of NCL that are caused by defects in membrane proteins are challenging. For some, overexpression may be toxic. Potential treatment options include gene augmentation strategies, immunomodulatory therapies, neuroprotection, or small-molecule therapies. Patients with atypical milder and adult-onset forms may particularly benefit from new treatments (Berkovic, Staropoli, 2016).
Greater efficacy in animal disease models has been shown if experimental therapy is initiated early in disease progression. Combined therapeutic strategies that target both CNS and visceral manifestations of disease may provide better outcomes. A natural history database (Dementia in Childhood; Schulz, Ajayi, 2018) provides a cohort of untreated patients to compare the efficacy of a clinical trial.
The genetic basis of the NCLs is now established, with the underlying genes identified, although all functions are not known, limiting understanding of disease mechanisms. Correlation of genotype with clinical phenotype has broadened definition of NCL. Therapeutic development beyond current palliative treatments is underway. The first approved treatment is for CLN2 disease which delivers recombinant protein directly into the brain at regular intervals.
For long-term clinical benefit treatment for the NCLs must begin early before any symptoms, which requires rapid and earlier diagnosis. Diagnosis is improving with advances in DNA-based approaches which may allow future newborn screening (Barcenas, Xue, 2014; Khaledi, Liu, 2018).
International cooperation is enabling collection of natural history data for all NCL types and genotype-phenotype data through databases. This increases understanding of the genetic spectrum as well as provides necessary control data for use in future clinical trials as well as data that (Schulz, Ajayi, 2018).
Work is still needed to understand the molecular basis and disease mechanism of the NCLs, and develop the means to assess the effectiveness of any new treatment at a molecular level. New pharmacological treatments may then be able to target pathways close to the underlying defect. Treatment for the NCLs must reach the most vulnerable cells in the brain and eye, and address the burden of disease outside the CNS.
The author thanks clinicians, scientists, and families who participate in the NCL Disease Registry and NCL Mutation Database and have shared their expertise over many years, allowing more comprehensive understanding of this group of diseases. SM also acknowledges the support of UCL and the Medical Research Council that provides funding to the MRC Laboratory for Molecular Cell Biology University Unit at UCL (award code MC_U12266B) toward lab and office space.
Sara Mole (ORCID:0000-0003-4385-4957) reports support by Biomarin for maintaining the NCL mutation database.
This is an open access publication, available online and distributed under the terms of a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International licence (CC BY-NC-ND 4.0), a copy of which is available at https://creativecommons.org/licenses/by-nc-nd/4.0/. Subject to this license, all rights are reserved.
Your browsing activity is empty.
Activity recording is turned off.
See more...
