Batten Disease

From EyeWiki



Batten disease (also known as, Neuronal Ceroid Lipofuscinosis, NCL) was named after Dr. Frederick E. Batten, a British pediatrician who first discovered it. The disease is a member of a group of neurodegenerative disorders characterized by lysosomal accumulation of lipopigments. This family is known as neuronal ceroid lipofuscinoses and members are classified according to age of onset.[1] The juvenile onset form, known as Juvenile Neuronal Ceroid Lipofucinosis (JNCL) is the most common neurodegenerative disease in childhood. It is inherited in an autosomal recessive pattern. Hallmarks of JNCL include rapid vision loss due to retinal degeneration, progressive intellectual and motor deterioration, seizures, and early death.

Disease Entity

Epidemiology

Batten disease is the most common neurodegenerative disorder in childhood. It can result from mutations in 1-13 genes, and the worldwide prevalence of Batten disease is about 1 in 100,000 live births.[2] The JNCL Batten disease is caused by a mutation in the CLN3 gene which is inherited in an autosomal recessive pattern mostly in Caucasian populations. The CLN3 mutation has reported incidences that range from 0.02-4.8 per 100,000 worldwide.[3][4] With advancements in genetic analyses and databases, the carrier frequencies for the most common mutation have been estimated. In Finnish and non-Finnish europeans, the estimated frequencies are 1/558 and 1/380, whereas in Latinos and Americans it is estimated to be 1/1169 and 1/506.[5]

Pathophysiology

Genetic

The pathophysiology of JNCL Batten disease has been further elucidated with genetic and molecular advancements.

CLN3

JNCL is primarily caused by a mutation in the CLN3 gene. Discovered in 1995, the CLN3 gene is located on the short arm of chromosome 16 at position 12.1 and codes for the lysosomal and endosomal protein battenin. Battenin is 438 amino acids long and has six transmembrane domains.[6] Its precise function is currently unknown, but it is believed to facilitate endocytosis, autophagy, regulation of lysosomal pH, transport of lysosomal enzyme transporters, osmoregulation, apoptosis, cell-cycle regulation, and protein secretion.[7][8] Approximately 67 different mutations have been identified in Batten disease.[9] The most common mutation in CLN3 is the 1.02 kb deletion resulting in a truncated battenin with residual function.[10][11] As a result of diminished function, accumulation of autofluorescent ceroid material within neuronal lysosomes causes neurotoxicity and degeneration. Approximately 76% of patients with JNCL are homozygous for this mutation, whereas 22% of patients have compound heterozygosity.[6]

Autoimmune

In addition to the CLN3 mutation, there have been discoveries suggesting an autoimmune component contributes to JNCL.

Autoantigens and antibodies have been identified in patients with JNCL. Increased levels of alpha-fetoprotein are present in neural tissue.[12] It has been noted that anti-glutamic acid decarboxylase (GAD) antibodies are elevated in Batten disease. The enzyme converts glutamate to GABA. This specific antibody inhibits the GAD enzyme and leads to excess glutamate toxicity in neurons[13][14] These autoantibodies target a region of GAD that is different from the anti-GAD antibodies seen in Type 1 diabetes or stiff person syndrome.[15] However, the association between anti-GAD and JNCL has been disputed. It was shown that JNCL sera did not exclusively react with GAD65+ neurons, but also stained other cell populations. Furthermore, sera from patients with Type 1 diabetes, a disease with present anti-GAD65 antibodies, stained differently from JNCL sera. These findings suggest there are other autoreactive antibodies at play in Batten disease.[16]

The CLN3 mutation is known to affect antigen presenting cells. These cells express higher levels of CD11c which localizes to lipid rafts known to be abnormal in these cells. These same APCs also show altered cytokine secretion and increased adhesive properties.[17] In CLN3 deficient murine models, microglia expressed higher levels of sialoadhesin, a adhesive molecule that promotes neuroinflammation and perturbation of the nervous system.[18]

Diagnosis

Screening

Typically, the first signs of juvenile onset Batten disease are rapid vision loss, followed by seizures, ataxia, and psychiatric symptoms.[19] In patients presenting with such characteristic clinical features, or with reminiscent symptoms in the context of an elevated clinical suspicion (positive family history, unusual physical exam finding) diagnostic testing should be initiated.

Historically, the diagnosis of Batten disease was made based on the presenting clinical features along with histopathologic examination of skin and rectal biopsies, using electron microscopy, to determine accumulation of characteristic autofluorescent storage materials.[20] Specifically, electron microscopy allows for visualization of the curvilinear inclusions and fingerprint profiles in lysosomal vacuoles, which are characteristic of Batten disease.[21]

However, advances in genetic and biochemical understanding of Batten disease have enabled use of DNA tests for common disease alleles, allowing for less invasive and more efficient methods of diagnosis. Approximately 80% of affected individuals worldwide are homozygotes for the 1.02-kb CLN3 mutation, and nearly all of the remaining 20% are compound heterozygotes for the 1.02-kb deletion and another missense or nonsense disease-causing mutation. This can be tested for fairly rapidly, with use of a single primer extension-based DNA “minisequencing” test to detect the 1.02 kb deletion. Detection of other less common mutation variants requires nucleotide sequencing. DNA sampling can be obtained from a buccal swab.[21]

Brain imaging of patients with Batten’s Disease may show variable cerebral and cerebellar atrophy, typically apparent after the age of 10 years, as well as bilateral mild optic nerve and tract atrophy in the absence of cortical involvement. Additionally, on T2-weighted images, the thalamus can appear with abnormally low signal intensity, and the periventricular white matter with abnormally high signal intensity.[22]

Unfortunately, delay in diagnosis remains common in Juvenile Batten disease. From a case series published in 2020, the average delay in diagnosis is 2.9 years from first presentation.[23]

Ophthalmic Findings

As previously mentioned, the ophthalmic manifestations (vision loss, night blindness, photophobia, and loss of peripheral and color vision) are commonly presenting symptoms of JNCL Batten disease. A diagnostic workup is initiated based on patient presentation, however, aside from tests of gene sequencing, and electron and light microscopy, several other ophthalmic imaging modalities can be useful in confirming the diagnosis with characteristic findings. These modalities include: optical coherence tomography (OCT), fundus autofluorescence, electroretinogram (ERG), and brain imaging (CT or MRI).[22]

Usually the vision loss starts at 6.4-6.6 years of age and patients present to ophthalmologists at 5.5 to 8.5 years. This is followed within 1-9 years by neurological features (increasing frequency of seizures and gradual deterioration of cognitive and motor functions).

The child may have a tendency to keep the eye up and use the inferior peripheral field to see.

Ocular features include

  • Rotary nystagmus
  • Eccentric viewing/overlooking
  • Normal to severe pigmentary retinopathy with optic disc pallor, arteriolar attenuation, peripheral pigmentation with bone spicule formation
  • Macular mottling or typical Bull's eye maculopathy


Representative fundus images are available at https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/batten-disease.htm

OCT can reveal reduced thickness in the central and outer and inner retinal layers. There can be observed homogeneous reflectivity in the inner retinal layer. Retinal pigment epithelium may contain hyperreflective granules. Additionally, the optical reflectivity of the inner retinal layers can appear abnormally homogenous, and there can be reflectivity changes at the level of the nerve fiber later and internal limiting membrane.[23] This morphology can be independent of the type of CLN3 mutation causing the JNCL.[24] Fundus autofluorescence levels imaging shows a relatively dark fovea and normal or diffusely subnormal autofluorescence.[24]

At presentation, ERG can show a significant loss of amplitude at particularly under scotopic conditions. There is typically a greater and earlier-onset loss in b-wave amplitude compared to a-wave amplitude, resulting in a markedly reduced b:a ratio in the single flash photopic ERG. Such electronegative configuration with relative sparing of the a-wave indicates a primary lesion of the retina in the inner layers, and is in line with the inner retinal localization of the gene product for CLN3.[22] Pattern ERG is usually undetectable due to severe macular dysfunction.[23]

Differential diagnosis

Differentials include cone-rod dystrophy, inherited retinal dystrophy like Stargardt disease, optic neuropathy, metabolic diseases, and mitochondrial disease.

Staging

The Unified Batten Disease Rating Scale (UBDRS) is a global disease severity scale used to measure disease progression in all variants of Batten disease. The UBDRS consists of four categories; physical assessment (score 0–112), seizure assessment (score 0–54), behavior assessment (score 0–55), and capability assessment (score 0–14). Higher scores correspond to increased severity. The UBDRS also contains a Batten disease history section to record approximate age at onset of clinical features from a caregiver interview. The UBDRS has been shown to be a valid and reliable tool for quantifying disease severity and progression in CLN3 disease.[25]

Further staging of CLN3 associated Batten disease is based on the a disease specific staging system (CLN3SS). It consists of four stages (0–3), and is based on genetic confirmation, vision loss, presence of seizures, and loss of independent walking.[26] Appropriate staging of CLN3 associated Batten disease has potential applications for future clinical trials.

Management

Currently, no treatment is known to halt or reverse the symptoms of CLN3 associated Batten disease. The only available therapies for CLN3 associated Batten disease are symptomatic and targeted specifically at the psychiatric and neurologic manifestations of the disease.[21] Psychiatric manifestations can be managed with atypical antipsychotics as well as citalopram. Neurologic features such as seizures are treated fairly effectively with anticonvulsants such as valproic acid, carbamazepine, lamotrigine, and clonazepam; and movement disorders, such as spasticity, with baclofen and tizandine. Accompanying physical therapy, occupational therapy, speech therapy, feeding gastrostomy, suction and airway management provides further symptomatic support.[27]

In addition to symptomatic treatment, a combination of oral vitamin E and sodium selenite have been proven to have mild benefit to retarding the progression of Batten’s disease.[28] Polyunsaturated fatty acids have also been shown to reverse the lysosomal storage and accumulation in cultured lymphoblasts from JNCL patients[29], and further support the rationale for dietary supplementation in patients with this disease.

Though unclear whether autoimmunity is the disease cause or the consequence of the symptoms of Batten’s Disease, immune suppression using mycophenolate motefil (MMF) has been shown to improve motor function in patients with CLN3 -/- Batten’ Disease, and reduce circulating autoantibodies directed toward brain antigens.[30]

The majority of recent studies on the treatment of Batten disease focus on the neurodegenerative components of Batten disease caused by mutations in other CLN genes. Between 2013 and 2015, a multicenter study of 24 patients with CLN2 Batten disease evaluated effects of intra-ventricular infusion of cerliponase alfa, a recombinant proenzyme of human tripeptidyl peptidase (TPP1), and found that that this treatment results in slower rate of decline in motor and language function compared to historical controls.[31] In 2017, enzyme replacement therapy with cerliponase alfa (Brineura), became the first globally approved treatment for CLN2 Batten disease.[32]

Adeno-associated virus (AAV)- mediated gene therapy has shown promising results for Batten disease in preclinical studies. An AAV2/8 virus carrying human CLN6 delivered intravitreally to Cln6nclf mice, an established model of CLN6 disease,  showed that bipolar cell-specific expression of CLN6 successfully prevented photoreceptor loss.[33] There are currently several on-going phase I/II clinical trials of AAV for the treatment of CLN6 Batten disease.[34]

There is also on-going phase I/II clinical trials of AAV for the treatment of CLN3 associated Batten disease (NCT03770572), but preliminary results are not yet available. [35]

The major barrier that exists to effectively treating Batten’s Disease is a necessity for central nervous system (CNS) access. A number of treatments are in various stages of development, though all face the challenge of crossing the blood-brain barrier to access the CNS. These treatments largely target defects in soluble lysosomal proteins and act via enzyme replacement, gene therapy, neural stem cell therapy, or small-molecule pharmaceuticals.[27] Greater understanding of the pathogenesis of Batten’s Disease will likely elucidate different targets along the disease cascade to establish future treatments.[36]

Prognosis

Batten's disease is characterised by early visual loss followed by progressive mental deterioration and fits and is invariably fatal, usually in the early 20s.

Additional Resources

Resources for Batten Disease

  • Centers of Excellence in the US
    • Nationwide Children’s Hospital (Columbus, OH): 614-722-4629
    • Debbie (assistant for Batten Disease Clinic): 614-722-4638
    • Dr. Emily De Los Reyes (neurologist)
    • Massachusetts General Hospital (Boston, MA): 617-726-5732
    • University of Rochester Medical Center (Rochester, NY): 585-275-4762
    • Texas Children’s Hospital (Houston, TX): 832-822-1759 or 832-822-1750
  • Batten Disease Family Association (BFDA)
    • www.bdfa-uk.org.uk
  • Batten Disease Support and Research Association (BDSRA)
    • www.bdsra.org
  • NCL Resource – A Gateway for Batten Disease
    • www.ucl.ac.uk/ncl
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    • www.climb.org.uk
  • Children’s Brain Disease Foundation
    • jrider6022@aol.com
  • National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
    • www.ntsad.org

References

  1. Wisniewski KE, Zhong N, Philippart M. Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. Neurology. 2001 Aug 28;57(4):576–81.
  2. Rider JA, Rider DL. Batten disease: past, present, and future. Am J Med Genet Suppl. 1988;5:21-26
  3. Mitchison HM, O’Rawe AM, Taschner PE, Sandkuijl LA, Santavuori P, de Vos N, et al. Batten disease gene, CLN3: linkage disequilibrium mapping in the Finnish population, and analysis of European haplotypes. Am J Hum Genet. 1995 Mar;56(3):654–62.
  4. Elleder M, Franc J, Kraus J, Nevsímalová S, Sixtová K, Zeman J. Neuronal ceroid lipofuscinosis in the Czech Republic: analysis of 57 cases. Report of the “Prague NCL group.” Eur J Paediatr Neurol. 1997;1(4):109–14.
  5. Sleat DE, Gedvilaite E, Zhang Y, Lobel P, Xing J. Analysis of large-scale whole exome sequencing data to determine the prevalence of genetically-distinct forms of neuronal ceroid lipofuscinosis. Gene. 2016 Nov 30;593(2):284–91.
  6. 6.0 6.1 Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium. Cell. 1995 Sep 22;82(6):949–57.
  7. Cárcel-Trullols J, Kovács AD, Pearce DA. Cell biology of the NCL proteins: What they do and don’t do. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2015;1852(10):2242–55.
  8. Huber RJ. Loss of Cln3 impacts protein secretion in the social amoeba Dictyostelium. Cell Signal. 2017 Jul;35:61–72.
  9. Genetics of the neuronal ceroid lipofuscinoses (Batten disease) - ScienceDirect [Internet]. [cited 2017 Jul 1]. Available from: https://doi.org/10.1016/j.bbadis.2015.05.011
  10. Kitzmüller C, Haines RL, Codlin S, Cutler DF, Mole SE. A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis. Hum Mol Genet. 2008 Jan 15;17(2):303–12.
  11. Munroe PB, Mitchison HM, O’Rawe AM, Anderson JW, Boustany RM, Lerner TJ, et al. Spectrum of mutations in the Batten disease gene, CLN3. Am J Hum Genet. 1997 Aug;61(2):310–6.
  12. Castaneda JA, Pearce DA. Identification of alpha-fetoprotein as an autoantigen in juvenile Batten disease. Neurobiol Dis. 2008 Jan;29(1):92–102.
  13. Pearce DA, Atkinson M, Tagle DA. Glutamic acid decarboxylase autoimmunity in Batten disease and other disorders. Neurology. 2004 Dec 14;63(11):2001–5.
  14. Chattopadhyay S, Ito M, Cooper JD, Brooks AI, Curran TM, Powers JM, et al. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet. 2002 Jun 1;11(12):1421–31.
  15. Ramirez-Montealegre D, Chattopadhyay S, Curran TM, Wasserfall C, Pritchard L, Schatz D, et al. Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Neurology. 2005 Feb 22;64(4):743–5.
  16. Lim MJ, Beake J, Bible E, Curran TM, Ramirez-Montealegre D, Pearce DA, et al. Distinct patterns of serum immunoreactivity as evidence for multiple brain-directed autoantibodies in juvenile neuronal ceroid lipofuscinosis. Neuropathol Appl Neurobiol. 2006 Oct;32(5):469–82.
  17. Hersrud SL, Kovács AD, Pearce DA. Antigen presenting cell abnormalities in the Cln3(-/-) mouse model of juvenile neuronal ceroid lipofuscinosis. Biochim Biophys Acta. 2016 Jul;1862(7):1324–36.
  18. Groh J, Ribechini E, Stadler D, Schilling T, Lutz MB, Martini R. Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease. Glia. 2016 May;64(5):792–809.
  19. Simpson NA, Wheeler ED, Pearce DA. Screening, diagnosis and epidemiology of Batten disease. Expert Opinion on Orphan Drugs. 2014 Sep 1;2(9):903–10.
  20. Anderson GW, Smith VV, Brooke I, Malone M, Sebire NJ. Diagnosis of neuronal ceroid lipofuscinosis (Batten disease) by electron microscopy in peripheral blood specimens. Ultrastruct Pathol. 2006 Sep;30(5):373–8.
  21. 21.0 21.1 21.2 Hofmann SL, Peltonen L. 154: The Neuronal Ceroid Lipofuscinoses. In: The Online Metabolic and Molecular Bases of Inherited Disease.
  22. 22.0 22.1 22.2 Bozorg S, Ramirez-Montealegre D, Chung M, Pearce DA. Juvenile neuronal ceroid lipofuscinosis (JNCL) and the eye. Surv Ophthalmol. 2009 Jul;54(4):463–71.
  23. 23.0 23.1 23.2 Wright GA, Georgiou M, Robson AG, Ali N, Kalhoro A, Holthaus SK, Pontikos N, Oluonye N, de Carvalho ER, Neveu MM, Weleber RG, Michaelides M. Juvenile Batten Disease (CLN3): Detailed Ocular Phenotype, Novel Observations, Delayed Diagnosis, Masquerades, and Prospects for Therapy. Ophthalmol Retina. 2020 Apr;4(4):433-445
  24. 24.0 24.1 Hansen MS, Hove MN, Jensen H, Larsen M. OPTICAL COHERENCE TOMOGRAPHY IN JUVENILE NEURONAL CEROID LIPOFUSCINOSIS. Retin Cases Brief Rep. 2016 Spring;10(2):137–9.
  25. Kwon JM, Adams H, Rothberg PG, Augustine EF, Marshall FJ, Deblieck EA, Vierhile A, Beck CA, Newhouse NJ, Cialone J, Levy E, Ramirez-Montealegre D, Dure LS, Rose KR, Mink JW. Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology. 2011 Nov 15;77(20):1801-7
  26. Masten MC, Williams JD, Vermilion J, Adams HR, Vierhile A, Collins A, Marshall FJ, Augustine EF, Mink JW. The CLN3 Disease Staging System: A new tool for clinical research in Batten disease. Neurology. 2020 Jun 9;94(23):e2436-e2440
  27. 27.0 27.1 Geraets RD, Koh SY, Hastings ML, Kielian T, Pearce DA, Weimer JM. Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis. Orphanet J Rare Dis. 2016 Apr 16;11:40.
  28. Santavuori P. Neuronal ceroid-lipofuscinoses in childhood. Brain Dev. 1988;10(2):80–3.
  29. Bennett MJ, Oriack RLB, -M. BOUSTANY R. Polyunsaturated fatty acids reverse the lysosomal storage and accumulation of subunit 9 of mitochondrial F F -ATP synthase in cultured lymphoblasts from patients with Batten disease. J Inherit Metab Dis. 1997;20:457–60.
  30. Seehafer SS, Ramirez-Montealegre D, Wong AM, Chan C-H, Castaneda J, Horak M, et al. Immunosuppression alters disease severity in juvenile Batten disease mice. J Neuroimmunol. 2011 Jan;230(1-2):169–72.
  31. Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A; CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018 May 17;378(20):1898-1907
  32. Markham A. Cerliponase Alfa: First Global Approval. Drugs. 2017 Jul;77(11):1247-1249
  33. Kleine Holthaus SM, Ribeiro J, Abelleira-Hervas L, Pearson RA, Duran Y, Georgiadis A, Sampson RD, Rizzi M, Hoke J, Maswood R, Azam S, Luhmann UFO, Smith AJ, Mole SE, Ali RR. Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells. Mol Ther. 2018 May 2;26(5):1343-1353
  34. Johnson TB, Cain JT, White KA, Ramirez-Montealegre D, Pearce DA, Weimer JM. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol. 2019 Mar;15(3):161-178
  35. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03770572 (2020).
  36. Tarczyluk MA, Cooper JD. Investigative and emerging treatments for Batten disease. Expert Opinion on Orphan Drugs. 2015 Sep 2;3(9):1031–45.
  1. Neuronal Ceroid Lipofuscinoses: Background, Etiology, Epidemiology [Internet]. [cited 2017 Jun 29]. Available from: http://emedicine.medscape.com/article/1178391-overview
  2. Aungaroon G, Hallinan B, Jain P, Horn PS, Spaeth C, Arya R. Correlation Among Genotype, Phenotype, and Histology in Neuronal Ceroid Lipofuscinoses: An Individual Patient Data Meta-Analysis. Pediatr Neurol. 2016 Jul;60:42–8.e4.