Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood. Symptoms typically present at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. Studies on sex differences in JNCL have yielded mixed results, but parent anecdotes suggest that females experience a more precipitous disease course. Therefore, we sought to determine if sex-based differences exist in JNCL. We used data from the Unified Batten Disease Rating Scale (UBDRS), the Batten Disease Support and Research Association (BDSRA) database, and the PedsQL quality of life (QoL) survey to evaluate sex-based differences in functional independence and time from symptom onset to death. On average, females had JNCL symptom onset one year later and death one year earlier than did males. Despite a later age at onset, females had lower functional capability, earlier loss of independent function, and lower physical QoL. Future research in sex differences in JNCL may help to further understand the biological mechanisms underpinning the disease course and may point to targeted therapies.
Objective: To use the Unified Batten Disease Rating Scale (UBDRS) to measure the rate of decline in physical and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease, a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002; during that time, the scale has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in quantitatively assessing clinical outcomes in research trials. Methods:We administered the UBDRS to 82 subjects with JNCL genetically confirmed by CLN3 mutational analysis. Forty-four subjects were seen for more than one annual visit. From these data, the rate of physical impairment over time was quantified using multivariate linear regression and repeated-measures analysis. Results:The UBDRS Physical Impairment subscale shows worsening over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This deterioration correlates with functional capability and is not influenced by CLN3 genotype. Conclusion:The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to quantify the rate of progression of physical impairment in subjects with JNCL in clinical trials. Neurology The neuronal ceroid lipofuscinoses (NCLs) are degenerative, autosomal recessive storage diseases with common clinical and pathologic features, including blindness, seizures, dementia, motor decline, and lysosomal accumulation of autofluorescent material (ceroid and lipofuscin).1 The NCLs are categorized by genetic etiology. The juvenile form of neuronal ceroid lipofuscinosis (JNCL), also called Batten disease, is the most prevalent NCL. Clinically, JNCL begins with progressive visual loss between 4 and 8 years of age, followed by seizures, then loss of motor coordination and dementia between 10 and 12 years. Death occurs by the third or fourth decade. 1,2 JNCL is due to mutations of the CLN3 3 gene that encodes a ubiquitously expressed protein of unknown function localized to the lysosomal membrane 4,5 ; modeling studies suggest a role in substrate trafficking. 5,6 Most cases of JNCL are caused by an approximately 1-kb deletion in the CLN3 3,7 gene, encompassing exons 7 and 8. Approximately 74% of patients with JNCL are homozygous for this common deletion, and 22% are compound heterozygotes for this deletion and another CLN3 mutation.8 There are no mutations consistently associated with better prognosis. 8 -10 From the University of Rochester (J.M.K., H.A., P.G.R., E. With biological advances, there is hope for rational therapies to prevent, slow, or reverse the course of JNCL. We developed the Unified Batten Disease Rating Scale (UBDRS) to measure disease progression in JNCL.11 We used the UBDRS to evaluate and quantify disease burden in 82 subjects with JNCL from 2002 through 2010...
AIM To evaluate seizure phenomenology, treatment, and course in individuals with juvenile neuronal ceroid lipofuscinosis (JNCL). METHOD Data from an ongoing natural history study of JNCL were analyzed using cross-sectional and longitudinal methods. Seizures were evaluated with the Unified Batten Disease Rating Scale, a disease-specific quantitative assessment tool. RESULTS Eighty-six children (44 males, 42 females) with JNCL were assessed at an average of three annual visits (range 1–11y). Eighty-six percent (n=74) experienced at least one seizure, most commonly generalized tonic-clonic, with mean age at onset of 9 years 7 months (SD 2y 10mo). Seizures were infrequent, typically occurring less often than once every 3 months, and were managed with one to two medications for most participants. Valproate (49%, n=36) and levetiracetam (41%, n=30) were the most commonly used seizure medications. Myoclonic seizures occurred infrequently (16%, n=14). Seizure severity did not vary by sex or genotype. Seizures showed mild worsening with increasing age. INTERPRETATION The neuronal ceroid lipofuscinoses (NCLs) represent a group of disorders unified by neurodegeneration and symptoms of blindness, seizures, motor impairment, and dementia. While NCLs are considered in the differential diagnosis of progressive myoclonus epilepsy, we show that myoclonic seizures are infrequent in JNCL. This highlights the NCLs as consisting of genetically distinct disorders with differing natural history.
Objective Despite evidence of elevated risk factors for suicidal thoughts and behavior in youth with Tourette syndrome and chronic tic disorders (CTD), few studies have actually examined that relationship. This study documented the frequency and clinical correlates of suicidal thoughts and behaviors in a sample of children and adolescents with CTD (N=196; range 6-18 years old). Method Youth and parents completed a battery of measures that assessed co-occurring psychiatric diagnoses, child emotional and behavioral symptoms, and impairment due to tics or co-occurring conditions. Results A structured diagnostic interview identified that 19 youths with CTD (9.7%) experienced suicidal thoughts and/or behaviors, which was elevated compared to three youths (3%) who experienced these thoughts in a community control sample (N=100; range 6-18 years old; p = 0.03). For youth with CTD, suicidal thoughts and behaviors were frequently endorsed in the context of anger and frustration. The Child Behavior Checklist (CBCL) anxious/depressed, withdrawn, social problems, thought problems, and aggressive behavior subscales, as well as the total internalizing problems scale were associated with the presence of suicidal thoughts and/or behaviors. Suicidal thoughts and/or behaviors were significantly associated with tic symptom severity, tic-related impairment, and obsessive-compulsive, depressive, anxiety, and attention-deficit/hyperactivity disorder symptom severity. CBCL anxiety/depression scores mediated the relationship between tic severity and suicidal thoughts and behaviors. Conclusions Findings suggest that about 1 in 10 youth with CTD experience suicidal thoughts and/or behaviors, which are associated with a more complex clinical presentation and often occur in the presence of anger and frustration.
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