Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Sep 1.
Published in final edited form as: J Child Neurol. 2013 Jul 9;28(9):1101–1105. doi: 10.1177/0883073813494268

Classification and Natural History of the Neuronal Ceroid Lipofuscinoses

Jonathan W Mink 1, Erika F Augustine 1, Heather R Adams 1, Frederick J Marshall 1, Jennifer M Kwon 1
PMCID: PMC3979348  NIHMSID: NIHMS568814  PMID: 23838030

Abstract

The neuronal ceroid lipofuscinoses represent a group of disorders characterized by neurodegeneration and intracellular accumulation of an auto-fluorescent lipopigment (ceroid lipofuscin). Together, they represent the most prevalent class of childhood neurodegenerative disease. The neuronal ceroid lipofuscinoses encompass several distinct biological entities that vary in age of onset, specific neurological phenotype, and rate of progression. In this review, we describe 9 major forms and present a classification scheme. Understanding the age of onset, clinical features, and natural history can inform rational diagnostics. Better knowledge the natural histories of these disorders is necessary to shed light on the underlying pathobiology and to develop new therapeutics.

Keywords: Batten Disease, Neurodegeneration, Blindness, Dementia, Epilepsy, Movement Disorders

The neuronal ceroid lipofuscinoses represent a group of disorders characterized by neurodegeneration and intracellular accumulation of an auto-fluorescent lipopigment. Together, they represent the most prevalent class of childhood neurodegenerative disease.1 The neuronal ceroid lipofuscinoses encompass several distinct biological entities that vary in age of onset, specific neurological phenotype, and rate of progression. Substantial progress has been made toward identifying the genetics of the neuronal ceroid lipofuscinoses and understanding the pathobiology of some forms. However, clinical recognition and diagnosis remains challenging.

The first description of a neuronal ceroid lipofuscinosis in the medical literature was by Otto Christian Stengel.2 He described a juvenile-onset disorder with blindness and progressive dementia. In 1903, Frederick Batten described a similar clinical entity and was the first to describe the neuropathology of “cerebral degeneration with macular changes.”3 In 1905, Spielmeyer4 and Vogt5 reported a similar disorder. Hence, juvenile neuronal ceroid lipofuscinosis is often referred to eponymously as Batten-Spielmeyer-Vogt disease. Within a few years, Janský6 and Bielschowsky7 described a somewhat similar disorder but with a “late-infantile” onset. This form came to be known as late-infantile neuronal ceroid lipofuscinosis or Janský-Bielschowsky disease. Subsequently, Kufs described an adult-onset disease with similar pathological characteristics but without the vision loss that was so prominent in juvenile neuronal ceroid lipofuscinosis and late-infantile neuronal ceroid lipofuscinosis.8 This came to be known as adult-onset neuronal ceroid lipofuscinosis or Kufs disease. Approximately 50 years later, a distinct infantile-onset form was described by Haltia and Santavuori.9,10 Classic infantile neuronal ceroid lipofuscinosis is also known as Haltia-Santavuori disease.

Prior to the discovery of the causative genes, the neuronal ceroid lipofuscinoses were classified primarily by age of onset and ultrastructural abnormalities found with electron microscopy. The distinctive ultrastructural patterns are granular osmiophilic deposits in infantile neuronal ceroid lipofuscinosis, curvilinear profiles in late-infantile neuronal ceroid lipofuscinosis, fingerprint bodies in juvenile neuronal ceroid lipofuscinosis, and rectilinear profiles in adult-onset neuronal ceroid lipofuscinosis.11 These 4 primary forms have common features of a neurodegenerative course with epilepsy, dementia, a movement disorder, and retinal degeneration (except adult-onset neuronal ceroid lipofuscinosis), and storage of ceroid lipofuscin in neurons. However, in additional to ultrastructural abnormalities, other features distinguish the neuronal ceroid lipofuscinoses. These include age of onset, specific clinical features, underlying cell biology and biochemistry, and rate of progression.

Several additional forms of neuronal ceroid lipofuscinosis have been described more recently with clinical and ultrastructural features that overlap those of the 4 classic forms. With the diversity of disorders now known to share some features in common with the classic neuronal ceroid lipofuscinoses, a general definition of neuronal ceroid lipofuscinosis has been proposed: “A progressive degenerative disease of the brain and, in most cases, the retina, in association with intracellular storage of material that is morphologically characterized as ceroid lipofuscin or similar.”1 Most experts in neuronal ceroid lipofuscinosis now recommend primary classification by gene (or protein), with secondary classification by age of onset and clinical features.12 However, a more extensive taxonomy has been proposed, including 7 axes: (1) affected gene (CLN gene symbol); (2) mutation diagnosis; (3) biochemical phenotype; (4) clinical phenotype; (5) ultrastructural features; (6) level of functional impairment (descriptive or using a universally recognized scoring system); and (7) other remarks (additional genetic, environmental, or clinical features).13 Although comprehensive, the 7-axis system is unwieldy for use in clinical practice and the authors have suggested combining axes 1 and 4 for routine use.

At least 9 genetic forms of neuronal ceroid lipofuscinosis have been identified. A few other diseases have been identified that show evidence of accumulation of ceroid lipofuscin, but there is some debate as to whether these are proper neuronal ceroid lipofuscinoses.14 This review is limited to the forms for which there is consensus regarding inclusion as a neuronal ceroid lipofuscinosis. These are summarized in Table 1. With the availability of molecular analysis, it has become increasingly clear that causative gene and mutation do not always predict phenotype either within or across genes. Furthermore, age of onset does not necessarily predict genotype. However, there are general guidelines about phenotype, including age of onset, that can guide rational diagnostic testing. In the following section, we discuss the diverse clinical presentations associated with specific gene defects. However, we also describe the disorders most commonly seen with each gene. With the exception of CLN4 disease, all CLNs are recessive disorders.

Table 1.

Classification of NCLs

Gene Age of Onset Chromosome Protein Ultrastructure
CLN1 Infantile, but also late-infantile, juvenile, and adult 1p32 PPT1 Granular osmiophilic deposits (GRODS)
CLN2 Late-infantile, but also juvenile 11p15 TPP1 Curvilinear profiles
CLN3 Juvenile 16p12 lysosomal transmembrane protein Fingerprint profiles
CLN4 (DNAJC5) Adult (Parry) 20q13.33 Cysteine string protein Rectilinear profiles
CLN5 Late-infantile (Finnish variant) 13q22 soluble lysosomal protein Rectilinear profiles, Curvilinear profiles, Fingerprint profiles
CLN6 Late-infantile Adult (Kufs Type A) 15q21 transmembrane protein of ER Rectilinear profiles, Curvilinear profiles, Fingerprint profiles
CLN7 Late-infantile, Turkish variant 4q28 MFSD8, lysosomal membrane protein Fingerprint profiles
CLN8 Late-infantile, Northern epilepsy 8q23 transmembrane protein of ER Curvilinear profiles
CLN10 Congenital Later onset ? 11p15 Cathepsin D GRODS?
Open in a new tab

ER, endoplasmic reticulum; GRODS, granular osmiophilic deposits; NCLs, neuronal ceroid lipofuscinoses.

CLN1 Disease

Mutations in CLN1 cause the classic infantile-onset form. The CLN1 gene codes for palmitoyl-protein thioesterase 1, a soluble lysosomal protein.15 In classic infantile neuronal ceroid lipofuscinosis, early development appears normal, but between 6 and 24 months there is rapid psychomotor regression, ataxia, myoclonus, seizures, and visual failure.16 Ultimately, patients become vegetative, with prominent spasticity. Visual failure is usually present by 2 years of age with optic atrophy retinal changes but no pigment aggregation. There is early extinction on the electroretinogram. In the early stages there is generalized cerebral atrophy, and hypointensity on T2-weighted images of thalamus and basal ganglia.17

Other mutations in CLN1 can cause later-onset and longer-duration diseases courses. All forms progress to premature death, but in general, the later the onset, the more protracted the course. There is a late-infantile variant of CLN1 disease that typically begins between 2 and 4 years of age. The clinical course is characterized by initial visual and cognitive decline followed by development of ataxia and myoclonus.18,19 A juvenile-onset form of CLN1 disease has also been described and has been referred to “juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits.”19,20 The juvenile-onset form starts between the ages of 5 years and 10 years, with cognitive decline followed by seizures (7 to 17 years), motor decline (7 to 15 years), and vision loss (10 to 14 years). The vision loss in juvenile-onset CLN1 disease occurs late compared with that seen in classic juvenile neuronal ceroid lipofuscinosis (CLN3 disease). A rarer adult-onset form of CLN1 disease has been described with onset after 18 years of age, beginning with cognitive decline and depression, followed by ataxia, parkinsonism, and vision loss.21,22

In all forms of CLN1 disease, granular osmiophilic deposits are present on electron microscopy and correlate with palmitoyl-protein thioesterase 1 deficiency. There is a rough association between age of onset and genotype; mutations predicted to cause severe truncation or loss of protein are more likely to be seen in infantile-onset cases.19,23

CLN2 Disease

CLN2 disease is the classic late infantile-onset form. The CLN2 gene codes for tripeptidyl peptidase 1, a soluble lysosomal protein.24 CLN2 disease is more homogeneous than CLN1 disease, both in age of onset and clinical phenotype. Classic CLN2 disease presents between ages 1 and 4 years, but can start as late as 6 years.25 Usually there is developmental standstill or psychomotor regression beginning in the second year of life, followed by refractory epilepsy (onset, 2 to 4 years of age). The seizures associated with CLN2 disease take multiple forms and include myoclonic, tonic, atypical absence, and tonic-clonic. Ataxia, myoclonus, and, ultimately, spastic quadriparesis follow. The myoclonus may be severe and refractory to treatment. Visual loss occurs but may be less obvious than in other forms of neuronal ceroid lipofuscinosis because of profound cognitive impairment. Retinal degeneration is most apparent in the macula, but there is no “cherry red spot.26 Electroretinograms and visual evoked potentials are abnormal. Children with onset after 4 years of age tend to have a milder course with more prominent ataxia and less prominent epilepsy.27

CLN3 Disease

CLN3 disease is the classic juvenile-onset form of neuronal ceroid lipofuscinosis. The CLN3 protein is a lysosomal transmembrane protein of unknown function. There appears to be less phenotypic heterogeneity for than for other forms of neuronal ceroid lipofuscinosis.28,29 The typical age of onset in CLN3 disease is between 4 years and 7 years, with insidious, but rapidly progressive, vision loss. Children with juvenile neuronal ceroid lipofuscinosis likely go from having normal vision to functional blindness in a matter of months, but may retain light-dark perception for several years. Cognitive decline follows (7 to 10 years of age), then behaviorial problems (8 to 10 years of age), and then seizures (10 to 12 years of age). In most patients, parkinsonism develops (11 to 13 years of age). Females have slightly later onset of vision loss but also more rapid progression than males.30,31 CLN3 disease is accompanied by a characteristic severe dysarthria that usually develops after age 10 years. Cardiac conduction abnormalities have been reported in older individuals.32

CLN4 Disease

Initially, the CLN4 designation had been reserved for classic adult-onset neuronal ceroid lipofuscinosis(NCL), or Kufs disease. However, with advances in genetic knowledge and methodology, most classic patients with adult-onset neuronal ceroid lipofuscinosis have been shown to have CLN6 mutations. There is an autosomal dominant form of neuronal ceroid lipofuscinosis, now classified as CLN4 disease, that is due to mutation in the DNAJC5 gene that codes for a cysteine string protein. This has also been referred to as “Parry disease,” named after the family in which it was first described.33 This is the only autosomal dominant form of neuronal ceroid lipofuscinosis. Onset of symptoms is after age 30 years. Clinical features include ataxia, progressive dementia, seizures, and myoclonus. There is no visual loss in CLN4 disease.

CLN5 Disease

CLN5 disease is one of the “variant” late infantile-onset forms of neuronal ceroid lipofuscinosis. It has been referred to as the “Finnish variant” due to its initial description in Finland,34 but it is not limited to families with Finnish heritage.35 The CLN5 protein is a soluble lysosomal glycoprotein of unknown function. The age of onset in CLN5 disease varies from 4 to 17 years, with a mean of 5.6 years.35 Clinical features include psychomotor regression, ataxia, myoclonic epilepsy, and visual failure, which may be a presenting sign.

CLN6 Disease

CLN6 disease is another “variant” late infantile-onset neuronal ceroid lipofuscinosis, but has recently been shown to be responsible for Type A Kufs disease. The CLN6 protein is a transmembrane protein of unknown function. Like CLN5 disease, the age of onset of CLN6 disease is highly variable, ranging from 18 months to 8 years. The clinical features include vision loss, motor developmental delay, dysarthria, ataxia, and seizures.36,37 Seizures are an early feature in CLN6 disease, occurring before 5 years in >60% of patients. Early vision loss is reported in 50% of patients with CLN6- related variant late infantile-onset neuronal ceroid lipofusinosis. There is rapid deterioration and death usually occurs between 5 years and 12 years of age.

Recently, CLN6 mutations have been shown to cause autosomal recessive Kufs disease (formerly CLN4).38 Kufs disease has been sub-classified as Type A and Type B.39 Type A begins with a progressive myoclonic epilepsy, with later development of dementia and ataxia. Type B is characterized by dementia with cerebellar and/or extrapyramidal motor symptoms. Age of onset for both forms is around 30 years. Neither form has visual loss. Type A is caused by CLN6 mutations,38 but the cause for Type B remains unknown.

CLN7 Disease

CLN7 disease is another “variant” late infantile-onset neuronal ceroid lipofuscinosis that has been referred to as the Turkish variant due to initial description in Turkish families.40 However, it is not limited to individuals with Turkish ancestry. The CLN7 protein is a lysosomal membrane protein that belongs to the “major facilitator” superfamily of transporter proteins.41 The gene for this protein has also been called MFSD8. Age of onset for CLN7 disease is typically between 2 years and 7 years. Initial symptoms are typically seizures, followed by motor decline, myoclonus, and dementia. Vision loss is usually present.

CLN8 Disease

CLN8 disease is due to mutations in a transmembrane protein of the endoplasmic reticulum of unknown function. Two forms of disease are associated with mutations of CLN8. The first is a “variant” late-infantile neuronal ceroid lipofuscinosis that was initially described in Turkish families,42 but has also been reported in other ethnic groups. Age of onset is usually 5 years to 10 years; patients initially present with seizures, followed by progressive motor and cognitive decline. Vision loss also occurs. The second form has been referred to as “Northern epilepsy,” a variant of progressive myoclonus epilepsy.43 It is also characterized by seizures with cognitive and motor decline, but there is no vision loss in this form.

CLN10 Disease

CLN10 disease is a severe congenital form of neuronal ceroid lipofuscinosis, caused by mutations in the lysosomal aspartic protease cathepsin D gene (CTSD).44 This is the earliest-onset form of neuronal ceroid lipofuscinosis. It presents in the neonatal period with microcephaly due to brain atrophy, absence of neonatal reflexes, and respiratory insufficiency. Infants with CLN10 disease rarely live more than a few days.

Summary

The neuronal ceroid lipofuscinoses represent a class of neurodegenerative disorders with most forms affecting children. They have several features in common that suggest biological similarities or perhaps functional interactions between involved genes. However, this has not been demonstrated. The clinical manifestations of the different neuronal ceroid lipofuscinoses differ in age of onset, order of progression, and specific symptoms. This variability suggests either differential expression of the causative genes within the central nervous system or differential vulnerability of different neuronal populations. Recognition of the typical age of onset is a useful starting point for understanding the different neuronal ceroid lipofuscinoses (Table 2). However, neuronal ceroid lipofuscinoses with similar ages of onset may have quite different presenting symptoms and natural histories. Quantitative study of the natural history in neuronal ceroid lipofuscinoses can be helpful to better understand the disorders and to inform the clinician’s diagnostic approach.45 Ultimately, this information is required to inform neurobiological investigations and development of outcome measures for clinical trials. With rapid advances in genetics and the improving knowledge of the clinical features of these rare diseases, meaningful therapeutics may be on the horizon.

Table 2.

Characteristic Ages of Disease Onset in the NCLs

Age of Onset NCL Gene
Congenital CLN10 (neonatal)
Infantile CLN1 (6 – 24 mos)
Late-infantile CLN1 (2 – 4 y)
CLN2 (1 – 6 y)
CLN5 (4 – 6 y)
CLN6 (18 mos – 8 y)
CLN7 (2 – 7 y)
CLN8 (5 – 10 y)
Juvenile CLN1 (5 – 10 y)
CLN3 (4 – 7 y)
CLN5 (7 – 17 y)
Adult CLN1 (> 18 y)
CLN4 (> 30 y)
CLN6 (> 25 y)
Open in a new tab

The classic forms are represented in BOLD.

mos, months; NCL, neuronal ceroid lipofuscinosis; y, years.

Acknowledgments

We gratefully acknowledge support for the collective work of the University of Rochester Batten Center, most importantly from the children and their families. We thank the Batten Disease Support and Research Association, National Institute of Neurological Disorders and Stroke (R01NS060022, K12 NS066098, U54NS065768, and K23 NS058756) for financial research support. We thank Melanie Fridl Ross, MSJ, ELS, for editing assistance.

Footnotes

Presented at the Neurobiology of Disease in Children Symposium: Batten Disease, in conjunction with the 41st Annual Meeting of the Child Neurology Society, Huntington Beach, California, October 31, 2012.

References

  • 1.Mole SE, Williams RE, Goebel HH, editors. The Neuronal Ceroid Lipofusinoses. 2nd ed. Oxford: Oxford University Press; 2011. [Google Scholar]
  • 2.Stengel OC. Beretning om et maerkeligt Sygdomstilfaelde hos fire Sødskende I Nærheden af Röraas. Eyr. 1826;1:347–352. [Google Scholar]
  • 3.Batten FE. Cerebral degeneration with symmetrical changes in the maculae in two members of a family. Trans Ophthalmol Soc UK. 1903;23:386–390. [Google Scholar]
  • 4.Spielmeyer W. Über familiäre amaurotische Idiotien. Neurol Cbl. 1905;24:620–612. [Google Scholar]
  • 5.Vogt H. Über familiäre amaurotische Idiotie und verwandte Krankheitsbilder. Mschr Psychiatr Neurol. 1905;18:161–171. [Google Scholar]
  • 6.Janský J. Dosud nepopsaný pripad familiárni amaurotické idiotie komplikované s hypoplasii mozeckovou. Sborn Lék. 1908;13:165–196. [Google Scholar]
  • 7.Bielschowsky M. Über spätinfantile familiäre amaurotische Idiotie mit Kleinhirnsymptonen. Deutsche Zeitschrift für Nervenheilkunde. 1913;50:7–29. [Google Scholar]
  • 8.Kufs H. Über eine Spätform der amaurotischen Idiotie und ihre heredofamiliären Grundlagen. Z Ges Neurol Psychiatr. 1925;95:168–188. [Google Scholar]
  • 9.Haltia M, Rapola J, Santavuori P, Keranen A. Infantile type of so-called neuronal ceroid-lipofuscinosis. 2. Morphological and biochemical studies. J Neurol Sci. 1973;18(3):269–285. doi: 10.1016/0022-510x(73)90076-2. [DOI] [PubMed] [Google Scholar]
  • 10.Santavuori P, Haltia M, Rapola J, Raitta C. Infantile type of so-called neuronal ceroid-lipofuscinosis. 1. A clinical study of 15 patients. J Neurol Sci. 1973;18(3):257–267. doi: 10.1016/0022-510x(73)90075-0. [DOI] [PubMed] [Google Scholar]
  • 11.Haltia M. The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol. 2003;62:1–13. doi: 10.1093/jnen/62.1.1. [DOI] [PubMed] [Google Scholar]
  • 12.Williams RE, Goebel HH, Mole SE, et al. NCL Nomenclature and Classification. In: Mole SE, Williams RE, Goebel HH, editors. The Neuronal Ceroid Lipofuscinoses (Batten Disease) 2nd ed. Oxford: Oxford University Press; 2011. pp. 20–23. [Google Scholar]
  • 13.Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofusicnoses. Neurology. 2012;79:183–191. doi: 10.1212/WNL.0b013e31825f0547. [DOI] [PubMed] [Google Scholar]
  • 14.Berkovic SF, Carpenter S, Andermann F, et al. Kufs' disease: a critical reappraisal. Brain. 1988;111(Pt 1):27–62. doi: 10.1093/brain/111.1.27. [DOI] [PubMed] [Google Scholar]
  • 15.Vesa J, Hellsten E, Verkruyse LA, et al. Mutations in the palmityl protein thioesterase gene causing late infantile neuronal ceroid lipofuscinosis. Nature. 1995;376:584–587. doi: 10.1038/376584a0. [DOI] [PubMed] [Google Scholar]
  • 16.Santavuori P, Haltia M, Rapola J. Infantile type of so-called neuronal ceroid-lipofuscinosis. Dev Med Child Neurol. 1974;16(5):644–653. doi: 10.1111/j.1469-8749.1974.tb04183.x. [DOI] [PubMed] [Google Scholar]
  • 17.Vanhanen SL, Puranen J, Autti T, et al. Neuroradiological findings (MRS, MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease. Neuropediatrics. 2004;35(1):27–35. doi: 10.1055/s-2004-815788. [DOI] [PubMed] [Google Scholar]
  • 18.Becker K, Goebel HH, Svennerholm L, et al. Clinical, morphological, and biochemical investigations on a patient with an unusual form of neuronal ceroid-lipofuscinosis. Eur J Pediatr. 1979;132(3):197–206. doi: 10.1007/BF00442436. [DOI] [PubMed] [Google Scholar]
  • 19.Das AK, Becerra CH, Yi W, et al. Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. J Clin Invest. 1998;102(2):361–370. doi: 10.1172/JCI3112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Wisniewski KE, Connell F, Kaczmarski W, et al. Palmitoyl-protein thioesterase deficiency in a novel granular variant of LINCL. Pediatr Neurol. 1998;18(2):119–123. doi: 10.1016/s0887-8994(97)00173-2. [DOI] [PubMed] [Google Scholar]
  • 21.van Diggelen OP, Thobois S, Tilikete C, et al. Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease. Ann Neurol. 2001;50(2):269–272. doi: 10.1002/ana.1103. [DOI] [PubMed] [Google Scholar]
  • 22.Ramadan H, Al-Din AS, Ismail A, et al. Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1. Neurology. 2007;68(5):387–388. doi: 10.1212/01.wnl.0000252825.85947.2f. [DOI] [PubMed] [Google Scholar]
  • 23.Das A. Biochemical analysis of mutations in palmitoyl-protein thioesterase causing infantile and late-onset forms of neuronal ceroid lipofuscinosis. Hum Mol Genet. 2001;10(13) doi: 10.1093/hmg/10.13.1431. [DOI] [PubMed] [Google Scholar]
  • 24.Golabek AA, Walus M, Wisniewski KE, Kida E. Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo. J Biol Chem. 2005;280(9):7550–7561. doi: 10.1074/jbc.M412047200. [DOI] [PubMed] [Google Scholar]
  • 25.Steinfeld R, Heim P, von Gregory H, et al. Late infantile neuronal ceroid lipofuscinosis: Quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002;112:347–354. doi: 10.1002/ajmg.10660. [DOI] [PubMed] [Google Scholar]
  • 26.Brodsky MC, Baker RS, Hamed LM. Pediatric Neuro-Ophthalmology. New York: Springer-Verlag; 1996. [Google Scholar]
  • 27.Taratuto AL, Saccoliti M, Sevlever G, et al. Childhood neuronal ceroid-lipofuscinoses in Argentina. Am J Med Genet. 1995;57(2):144–149. doi: 10.1002/ajmg.1320570207. [DOI] [PubMed] [Google Scholar]
  • 28.Adams HR, Beck CA, Levy E, et al. Genotype does not predict severity of behavioural phenotype in juvenile neuronal ceroid lipofuscinosis (Batten disease) Dev Med Child Neurol. 2010;52(7):637–643. doi: 10.1111/j.1469-8749.2010.03628.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kwon JM, Adams H, Rothberg PG, et al. Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease) Neurology. 2011;77(20):1801–1807. doi: 10.1212/WNL.0b013e318237f649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Cialone J, Adams H, Augustine EF, et al. Females experience a more severe disease course in Batten disease. J Inherit Metab Dis. 2012;35(3):549–555. doi: 10.1007/s10545-011-9421-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Nielsen AK, Ostergaard JR. Do females with juvenile ceroid lipofuscinosis (Batten disease) have a more severe disease course? The Danish experience. Eur J Paediatr Neurol. 2013;17(3):265–268. doi: 10.1016/j.ejpn.2012.10.011. [DOI] [PubMed] [Google Scholar]
  • 32.Ostergaard JR, Rasmussen TB, Molgaard H. Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease) Neurology. 2011;76(14):1245–1251. doi: 10.1212/WNL.0b013e31821435bd. [DOI] [PubMed] [Google Scholar]
  • 33.Boehme DH, Cottrell JC, Leonberg SC, Zeman W. A dominant form of neuronal ceroid-lipofuscinosis. Brain. 1971;94(4):745–760. doi: 10.1093/brain/94.4.745. [DOI] [PubMed] [Google Scholar]
  • 34.Santavuori P, Rapola J, Sainio K, Raitta C. A variant of Jansky-Bielschowsky disease. Neuropediatrics. 1982;13(3):135–141. doi: 10.1055/s-2008-1059612. [DOI] [PubMed] [Google Scholar]
  • 35.Xin W, Mullen TE, Kiely R, et al. CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. Neurology. 2010;74(7):565–571. doi: 10.1212/WNL.0b013e3181cff70d. [DOI] [PubMed] [Google Scholar]
  • 36.Gao H, Boustany RM, Espinola JA, et al. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet. 2002;70:324–335. doi: 10.1086/338190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Mole S, Williams R, Goebel H. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6:107–126. doi: 10.1007/s10048-005-0218-3. [DOI] [PubMed] [Google Scholar]
  • 38.Arsov T, Smith KR, Damiano J, et al. Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. Am J Hum Genet. 2011;88(5):566–573. doi: 10.1016/j.ajhg.2011.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Berkovic SF, Andermann F, Andermann E, et al. Kufs disease: clinical features and forms. Am J Med Genet Suppl. 1988;5:105–109. doi: 10.1002/ajmg.1320310614. [DOI] [PubMed] [Google Scholar]
  • 40.Topcu M, Tan H, Yalnizoglu D, et al. Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies. Turk J Pediatr. 2004;46(1):1–10. [PubMed] [Google Scholar]
  • 41.Kousi M, Siintola E, Dvorakova L, et al. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain. 2009;132(Pt 3):810–819. doi: 10.1093/brain/awn366. [DOI] [PubMed] [Google Scholar]
  • 42.Mitchell WA, Wheeler RB, Sharp JD, et al. Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8. Eur J Paediatr Neurol. 2001;5(Suppl A):21–27. doi: 10.1053/ejpn.2000.0429. [DOI] [PubMed] [Google Scholar]
  • 43.Ranta S, Lehesjoki AE. Northern epilepsy, a new member of the NCL family. Neurol Sci. 2000;21:S43–S47. doi: 10.1007/s100720070039. [DOI] [PubMed] [Google Scholar]
  • 44.Steinfeld R, Reinhardt K, Schreiber K, et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78(6):988–998. doi: 10.1086/504159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.de Blieck EA, Augustine EF, Marshall FJ, et al. Methodology of clinical research in rare diseases: Development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates. Contemp Clin Trials. 2013;35(2):48–54. doi: 10.1016/j.cct.2013.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES