A diagnostic confidence scheme for <scp>CLN3</scp> disease

Masten, Margaux C.; Corre, Camille; Paciorkowski, Alex R.; Vierhile, Amy; Adams, Heather; Vermilion, Jennifer; Zimmerman, Grace; Augustine, Erika F.; Mink, Jonathan W.

doi:10.1002/jimd.12429

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…It will fall to future work to determine what the perceptual and cognitive implications of this breakdown are [ 10 ] [ 11 ] [ 70 ]. However, prior work has shown that weakened ability to sustain information in sensory memory can reflect cognitive deterioration in various clinical conditions [ 42 ] [ 45 ] [ 46 ]. It will also be of significant interest to further investigate the duration-evoked MMN at even slower presentation rates.…”

Section: Discussionmentioning

confidence: 99%

“…All participants with CLN3 disease underwent detailed phenotypic assessment, accompanied by detailed medical history questionnaires completed by their caregivers. All had clinically definite CLN3 disease [ 46 ] . Symptom severity was measured using a disease-specific instrument, the Unified Batten Disease Rating Scale (UBDRS) [ 8 ] [ 9 ] and severity stage was assigned using the CLN3 Staging System ( CLN3 SS) [ 7 ].…”

Section: Methodsmentioning

confidence: 99%

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Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

Brima,

Freedman,

Prinsloo

et al. 2023

Preprint

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Background: We interrogated auditory sensory memory capabilities in individuals with CLN3disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of “duration” processing, a critical cue in speech perception. Given decrements in speech and language skills associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. Methods: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. Results: Data from individuals with CLN3 disease (N=21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N=41; ages 6-26 years). Conclusions: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

Brima,

Freedman,

Prinsloo

et al. 2023

Preprint

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“…NCLs are classified as congenital, infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL) NCLs according to the clinical presentation age of the disorder [Masten et al, 2021].…”

Section: Discussionmentioning

confidence: 99%

CLN3-Associated NCL Case with a Preliminary Diagnosis of Niemann Pick Type C

et al. 2022

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Introduction: Neuronal ceroid lipofuscinoses (NCLs) are a broad class of inherited lysosomal storage disorders. Known mutations in at least 13 different genes can result in NCL with variable ages of onset, symptoms, and pathologic findings. Generally, these patients experience cognitive and motor decline, seizures, visual impairment, and premature death. Pathologically, NCL patients display heterogeneous histologic abnormalities, but consistently exhibit neuronal loss, reactive gliosis, and lysosomal accumulation of autofluorescent storage material or lipopigment. Juvenile-onset NCL has been classically referred to as Batten disease. By far the most prevalent NCL is CLN3-associated disease. It is an autosomal recessive condition that is usually caused by mutations in the ceroid-lipofuscinosis, neuronal 3 (CLN3) gene. CLN3 encodes battenin, a ubiquitously expressed transmembrane protein of unknown function that is associated with cellular homeostasis and neuronal survival. The initial clinical symptom of CLN3-associated NCL is central vision loss, which is usually detected between 4 and 9 years of age. Seizures typically begin early in the second decade of life, and affected individuals rarely live beyond their mid-20ies. Case Presentation: Herein, we describe a 16-year-old patient with CLN3-related juvenile NCL with a preliminary diagnosis of Niemann Pick Type C disease. The proband showed characteristic clinical signs, including epilepsy, ataxia, psychomotor regression, dementia, and visual impairment with an unusual elevation of lyso-sphingomyelin-509 (LysoSM-509; 812 nmol/L, normal 1–33 nmol/L). A homozygous NM_001042432.2(CLN3):c.233dup (p.Thr80fs) variant was detected at exon 4 of CLN3. Diagnosis of NCL was difficult due to the pronounced elevation of LysoSM-509. Discussion: LysoSM-509 is a biomarker which is elevated especially in Niemann Pick Type C. We can consider that a high LysoSM-509 level might be also an indicator of NCL, especially NCL type 3.

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Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN)

Brima,

Freedman,

Prinsloo

et al. 2024

J Neurodevelop Disord

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Background We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of “duration” processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. Methods We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. Results Data from individuals with CLN3 disease (N = 21; range 6–28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6–26 years). Conclusions Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

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A diagnostic confidence scheme for CLN3 disease

Cited by 3 publications

References 41 publications

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

CLN3-Associated NCL Case with a Preliminary Diagnosis of Niemann Pick Type C

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN)

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