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. 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.
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. 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. 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.
The pathophysiology of JNCL Batten disease has been further elucidated with genetic and molecular advancements.
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. 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. Approximately 67 different mutations have been identified in Batten disease. The most common mutation in CLN3 is the 1.02 kb deletion resulting in a truncated battenin with residual function. 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.
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. 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 These autoantibodies target a region of GAD that is different from the anti-GAD antibodies seen in Type 1 diabetes or stiff person syndrome. 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.
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. In CLN3 deficient murine models, microglia expressed higher levels of sialoadhesin, a adhesive molecule that promotes neuroinflammation and perturbation of the nervous system.
Typically, the first signs of juvenile onset Batten disease are rapid vision loss, followed by seizures, ataxia, and psychiatric symptoms. 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. Specifically, electron microscopy allows for visualization of the curvilinear inclusions and fingerprint profiles in lysosomal vacuoles, which are characteristic of Batten disease.
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.
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.
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.
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).
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. This morphology can be independent of the type of CLN3 mutation causing the JNCL. Fundus autofluorescence levels imaging shows a relatively dark fovea and normal or diffusely subnormal autofluorescence.
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. Pattern ERG is usually undetectable due to severe macular dysfunction.
Differentials include cone-rod dystrophy, inherited retinal dystrophy like Stargardt disease, optic neuropathy, metabolic diseases, and mitochondrial disease.
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.
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. Appropriate staging of CLN3 associated Batten disease has potential applications for future clinical trials.
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. 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.
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. Polyunsaturated fatty acids have also been shown to reverse the lysosomal storage and accumulation in cultured lymphoblasts from JNCL patients, 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.
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. In 2017, enzyme replacement therapy with cerliponase alfa (Brineura), became the first globally approved treatment for CLN2 Batten disease.
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. There are currently several on-going phase I/II clinical trials of AAV for the treatment of CLN6 Batten disease.
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. 
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. Greater understanding of the pathogenesis of Batten’s Disease will likely elucidate different targets along the disease cascade to establish future treatments.
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.
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)
- Batten Disease Support and Research Association (BDSRA)
- National Institute of Neurological Disorders and Stroke: Batten Disease Fact Sheet
- NCL Resource – A Gateway for Batten Disease
- Children Living with Inherited Metabolic Diseases (CLIMB)
- Children’s Brain Disease Foundation
- National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
- National Organization for Rare Disorders (NORD)
- Genetics Home Reference
- Foundation Fighting Blindness
- Clinical Trials
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