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Neuronal Ceroid Lipofuscinosis Type 3

CLN3


Presentation

  • Median age at presentation to the reporting paediatrician: 7 years 9 months.[adc.bmj.com]
  • Additionally, a review of the literature concerning the ocular and systemic manifestations of the various ceroid lipofuscinoses is presented.[ncbi.nlm.nih.gov]
  • Furthermore, these two cases had CLN5 mutation which usually presents as vLINCL and presented with typical phenotype of CLN5. Case 3 had a different granular inclusion body.[pediatricneurosciences.com]
  • The condition may be diagnosed through clinical symptoms and special tests including studies that look at samples of the skin to identify patterns present in CLN3.[diseaseinfosearch.org]
  • 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.[dovepress.com]
Difficulty Walking
  • People with this form of CLN8 disease have increasing difficulty walking and coordinating movements (ataxia), eventually becoming immobile.[icdlist.com]
Nightmare
  • 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.[dovepress.com]
Nocturnal Awakening
  • 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.[dovepress.com]
Tachycardia
  • Holter monitoring showed not only bradycardia but also slow and fast ectopic atrial rhythms, sinus arrests and complex ventricular ectopic activity including ventricular tachycardia. In the younger patient the findings were less severe.[karger.com]
Drooling
  • At last follow-up (8 years), he had drooling saliva, he was wheel chair bound with deterioration in his speech, cognition, motor skills, and fully dependent for his needs. His visual acuity (VA) was 6/18 in each eye with normal fundi.[pediatricneurosciences.com]
Aggressive Behavior
  • These include anxious and depressed mood, aggressive behavior, and hallucinations, and even psychotic symptoms.[dovepress.com]
  • Psychiatric problems (such as aggressive behavior and sleep problems) have also been reported. Rare cases of JNCL have also been described in which eye involvement is not a striking feature.[orpha.net]
  • The psychiatric symptoms include anxiety, aggressive behavior, depression, hallucinations and psychotic symptoms. Female patients with JNCL have more difficult psychiatric problems than their male counterparts 12 .[scielo.br]
Visual Hallucination
  • Case 3 An 11-year-10-month-old Caucasian boy with normal perinatal and neurodevelopmental history was referred to us with 3-year history of progressive visual loss and visual hallucinations.[pediatricneurosciences.com]
Onset at 2 to 4 Years
  • Late infantile with CLN2 mutation manifests with onset between 2 and 4 years and symptoms of epilepsy, cognitive decline, ataxia, visual failure, and death in between 9 and 18 years.[pediatricneurosciences.com]
Mental Deterioration
  • The typical early signs are loss of muscle coordination (ataxia) and seizures along with progressive mental deterioration. This form progresses rapidly and ends in death between ages 8 and 12.[brainfoundation.org.au]
  • The early symptoms are followed by epilepsy and progressive physical and mental deterioration. Batten disease gene maps to chromosome 16p12.1. 56 chromosome haplotype defined by alleles at the d16s299 is shared by 73% of batten disease chromosomes.[icd10data.com]
  • deterioration and fits and is invariably fatal, usually in the early 20s.[eyewiki.aao.org]
  • Hirvasniemi A, Lang H, Lehesjoki AE, Leisti J (1994) Northern epilepsy syndrome: An inherited childhood onset epilepsy with associated mental deterioration. J Med Genet 31: 177-182.[omicsonline.org]
  • Patients experience a progressive and profound loss of neurons in the central nervous system that generally is associated with increasingly severe epileptic seizures, visual failure, ataxia, mental deterioration, and early death.[clinchem.aaccjnls.org]
Dystonia
  • Treatment Treatment Options: Treatment is primarily symptomatic for sleep disorders, seizures, psychoses, malnutrition, dystonia and spasticity.[disorders.eyes.arizona.edu]
  • Neurologic examination showed disorientation for time and space, impairment of short- and long-term memory, dysarthria, oromandibular dystonia, and naming deficit. A pendular nystagmus was present.[catalog.coriell.org]
  • Louis (296) Pharmacogenetics (280) Los Angeles (264) Houston (244) Hybrids (242) San Antonio (221) Arkansas (201) Dystonia (185) Chicago (180) UCLA Research Institute (175) Repository Linkage Families (164) CMD Specific (154) Venezuelan Huntington Disease[coriell.org]
Myoclonic Jerking
  • Also typical are short, sharp muscle contractions called myoclonic jerks. Initial signs of this disorder include delayed psychomotor development with progressive deterioration, other motor disorders, or seizures.[brainfoundation.org.au]
Slurred Speech
  • At last follow-up at 11 years, he was wheelchair bound but could walk with support, had severe visual impairment and slow and slurred speech. He was totally dependent for all his daily activities.[pediatricneurosciences.com]
Learning Difficulties
  • Presenting symptoms were visual failure 40 (85%), developmental delay/learning difficulties 28 (60%), behavioural problems 17 (36%), seizures 10 (21%), memory loss 8 (17%), extrapyramidal signs 6 (13%) and gait disturbance/ataxia 5 (11%).[adc.bmj.com]

Workup

  • 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[eyewiki.aao.org]
Generalized Epileptiform Discharges
  • Electroencephalogram (EEG) showed bilateral synchronous generalized epileptiform discharges. Electroretinogram (ERG) was absent and visual evoked potential (VEP) was normal.[pediatricneurosciences.com]
Ventricular Hypertrophy
  • 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.[dovepress.com]
  • In the elder patient, echocardiography revealed ventricular hypertrophy with slowed ventricular relaxation.[karger.com]
  • In their early 20s, ventricular hypertrophy was a frequent finding. [ 1 ] COMMENT. Juvenile neuronal ceroid lipofuscinosis (JNCL, Batten disease), caused by mutations in the CLN3 gene and failure to respond to oxidative stress (Tuxworth RJ.[pediatricneurologybriefs.com]

Treatment

  • Although there currently is no treatment for this condition, making the correct diagnosis is important for appropriate low-vision management, educational planning, and genetic counseling.[ncbi.nlm.nih.gov]
  • Management and treatment Treatment is supportive only and should consist of palliative care with administration of anticonvulsive drugs; as well as educational, psychological, and psychiatric management.[orpha.net]
  • Treatment is specific to the symptoms present in the affected individual, but often includes teams of pediatricians, neurologists, eye doctors, physical therapists, and psychiatrists.[diseaseinfosearch.org]
  • There is no effective treatment for CLN3. A major impediment to the testing of potential therapeutic interventions is the lack of well-defined outcome measures.[clinicaltrials.gov]

Prognosis

  • Prognosis The prognosis for JNCL is severe but life expectancy varies with some patients surviving to the fourth decade. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Prognosis Affected children suffer increasing mental impairment, worsening seizures, and progressive loss of sight and motor skills. Eventually, children with Batten disease become blind, bedridden and demented.[brainfoundation.org.au]
  • Early recognition of cardiac involvement may have led to early intervention with medication but it is difficult to speculate if this would have impacted on his overall morbidity or prognosis.[academic.oup.com]
  • […] replacement, gene therapy, neural stem cell therapy, or small-molecule pharmaceuticals. [23] Greater understanding of the pathogenesis of Batten’s Disease will likely elucidate different targets along the disease cascade to establish future treatments. [27] Prognosis[eyewiki.aao.org]

Etiology

  • Etiology JNCLs are transmitted in an autosomal recessive manner and mutations in the following genes may result in JNCL with a classic and/or variant phenotype: PPT1 (designated CLN1 ; 1p32), TPP1 (11p15; designated CLN2 ), CLN3 (16p12), CLN8 (8p23; responsible[orpha.net]
  • Neuronal Ceroid Lipofuscinoses: Background, Etiology, Epidemiology [Internet]. [cited 2017 Jun 29]. Available from: Aungaroon G, Hallinan B, Jain P, Horn PS, Spaeth C, Arya R.[eyewiki.aao.org]

Epidemiology

  • Summary Epidemiology Worldwide prevalence is unknown.[orpha.net]
  • Screening, diagnosis and epidemiology of Batten disease. Expert Opinion on Orphan Drugs. 2014 Sep 1;2(9):903–10. Anderson GW, Smith VV, Brooke I, Malone M, Sebire NJ.[eyewiki.aao.org]
  • […] outcome within a decade,and a characteristic fingerprint profile inclusions in different cells,including the variant form with granular osmiophilic deposits (GROD) Relevant External Links for CLN3 Genetic Association Database (GAD) CLN3 Human Genome Epidemiology[genecards.org]
Sex distribution
Age distribution

Pathophysiology

  • In Finnish and non-finnish europeans, the estimated frequencies are 1/558 and 1/380, whereas in Latinos and USA it is estimated to be 1/1169 and 1/506. [4] Pathophysiology Genetic The pathophysiology of JNCL has been further elucidated with genetic and[eyewiki.aao.org]
  • Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test Neuronal ceroid lipofuscinoses (NCLs) are a subset of lysosomal storage diseases that involve defective cellular processing of[mayocliniclabs.com]
  • There were 14 cases where pathophysiological findings suggested LINCL but the specimens had detectable pepinase activity and there were no mutations found.[clinchem.aaccjnls.org]

Prevention

  • In mice carrying a PPT1 mutation, NtBuHA prevented neuronal cell loss, mitigated behavioral deterioration and increased survival rates.[natureasia.com]
  • The levels of impairment defined in the table after 369.9 are based on the recommendations of the WHO Study Group on Prevention of Blindness (Geneva, November 6-10, 1972; WHO Technical Report Series 518), and of the International Council of Ophthalmology[genedx.com]
  • Figure 2 Tunicamycin prevents glycosylation of OS... Figure 5 Immunoprecipitation experiments indicate... Figure 4 The mature form of OSTα is glycosylated ... Figure 3 Membrane expression of OSTα requires the...[sprout038.sprout.yale.edu]
  • However, these treatments did not prevent the fatal outcome of the disease. Prognosis Affected children suffer increasing mental impairment, worsening seizures, and progressive loss of sight and motor skills.[brainfoundation.org.au]
  • (19977) NIGMS Human Genetic Cell Repository (10711) ADA Repository (3221) NHGRI Sample Repository for Human Genetic Research (1975) NIA Aging Cell Culture Repository (1503) HD Community Biorepository (179) Autism (73) Centers for Disease Control and Prevention[coriell.org]

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