Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights

Abstract

The present review is focused on juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) due to a mutation in CLN3. Functional vision impairment occurring around 5–6 years of age is the first symptom in more than 80% of patients. Approximately 2 years later (though sometimes simultaneously), obvious signs of cognitive impairment appear. Behavior problems can occur in advance, especially in boys. These include anxious and depressed mood, aggressive behavior, and hallucinations, and even psychotic symptoms. Following the teens, severe dementia is present, including loss of memory, attention, and general reasoning abilities, as well as loss of independent adaptive skills such as mobility, feeding, and communicating. Sleep abnormalities, such as settling problems, nocturnal awakenings, and nightmares, are reported in more than half of patients. The vast majority, if not all, patients develop seizures, starting at approximately 10 years of age. Generalized tonic–clonic seizure occurs as the only type of seizure in approximately half of patients, and in combination with partial seizures in a third of patients. There seems to be no difference in seizure severity according to sex or genotype, and there is great variation in seizure activity among patients. Soon after diagnosis, patients begin to have slight ataxic symptoms, and at adolescence extrapyramidal symptoms (rigidity, bradykinesia, slow steps with flexion in hips and knees) occur with increasing frequency. Chewing and swallowing difficulties emerge as well, and food intake is hampered in the late teens. Disabling periodically involuntary movements may occur as well. A progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus-node dysfunction, ultimately leading to severe bradycardia and/or other conduction abnormalities, starts in the mid-teens. Patients are usually bedridden at 20 years of age, and death usually occurs in the third decade of life.

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…RD is an early consequence of lysosomal storage diseases, especially in neuronal ceroid lipofuscinoses (NCL) [251], also called Batten disease, an early-onset neurodegenerative disease with other systemic features such as dementia and epilepsy [252]. NCL may be caused by disruption of genes encoding lysosomal enzymes (Ppt1 and Cln5) and membrane proteins (Mfsd8) as well as ER membrane (Cln6 and Cln8) and secretory pathway (Grn) proteins, and is characterized by a common lysosomal accumulation of ceroid.…”

Juvenile Batten Disease (CLN3): Detailed Ocular Phenotype, Novel Observations, Delayed Diagnosis, Masquerades, and Prospects for Therapy

“… 16 , 17 Retinal examination often shows a bull’s-eye maculopathy, temporal optic disc pallor, peripheral retinal pigment epithelial disturbance (including bone spicule formation), and retinal vascular attenuation. 9 , 18 , 19 , 20 In one study, fundus imaging showed widespread atrophy of the retinal pigment epithelium (RPE) in 93% (n=24) of cases of confirmed CLN3 disease. 21 However, because these retinal findings overlap with selected pathological hallmarks of more common disorders, including retinitis pigmentosa, Stargardt disease, and other inherited retinal diseases, 22 , 23 , 24 the early diagnosis of JNCL often results in significant diagnostic challenge.…”

“…22 , 27 , 28 As the disease progresses to more advanced stages, the ERG shows significantly reduced cone responses and no recordable rod-specific responses. 18 Cognitive and behavioral impairment, in particular mood, memory, and attention (e.g., inability of the child to recall and accomplish 3-step commands), usually appears approximately 2 years after the onset of visual decline; however, these features may be present at first onset or occasionally in advance of visual symptoms, highlighting the importance of careful directed history in suspected cases. 16 , 17 Magnetic resonance imaging may show cerebral and cortical atrophy with demyelination.…”

A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface

“…However, we did confirm no difference in POS phagocytic capability and microvilli density between CLN3 heterozygote carriers and healthy subjects with no CLN3 defect. Furthermore, though gene-corrected lines were not included in this study, as the CLN3 mutation investigated here leads to homozygous 966 bp deletion spanning exon 7 and 8 83 , making it challenging for genome editing/CRISPR correction, we utilized WT-CLN3 overexpression in CLN3 disease hiPSC-RPE cells to investigate the role of CLN3 in POS phagocytosis. The correction of CLN3 mutation in CLN3 disease hiPSCs and introduction of CLN3 mutation in control hiPSC-RPE cells will be valuable tools to further investigate CLN3 function and CLN3 disease pathophysiology.…”

“…Fibroblasts from CLN3 disease patients harboring the homozygous 966 bp deletion spanning exon 7 and exon 8 83 and unaffected controls, heterozygote family members, and unrelated healthy subjects with no known history of retinal disease, were reprogrammed to hiPSCs using non-integrating episomal plasmid vectors in accordance with a previously published protocol 37 . Specifically, using the nucleofection kit for primary fibroblast (Lonza), fibroblasts (~60,000) were electroporated with 1 µg each of pCXLE-hOCT4-shP53, pCXLE-hSK, pCXLE-hUL plasmids (Addgene plasmid #27077, 27078, 27080) in a nucleofector 2b device (Lonza, Program T-016).…”