28 May 2024
Bagh MB, et al. J Biol Chem. 2024 Feb; 300(2):105641. ABSTRACT The ceroid lipofuscinosis neuronal 1 (CLN1) disease, formerly called infantile neuronal ceroid lipofuscinosis, is a fatal hereditary neurodegenerative lysosomal storage disorder. This disease is caused by loss-of-function mutations in the CLN1 gene, encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1 catalyzes depalmitoylation of S-palmitoylated proteins for degradation and clearance by lysosomal hydrolases. Numerous proteins, especially in the brain, require dynamic S-palmitoylation (palmitoylation-depalmitoylation cycles) for endosomal trafficking to their destination. While 23 palmitoyl-acyl transferases in the mammalian genome catalyze S-palmitoylation, depalmitoylation is catalyzed by thioesterases such as PPT1. Despite these discoveries, the pathogenic mechanism of CLN1 disease has remained elusive. Here, we report that in the brain of Cln1-/- mice, which mimic CLN1 disease, the mechanistic target of rapamycin complex-1 (mTORC1) kinase is hyperactivated. The activation of mTORC1 by nutrients requires its anchorage to lysosomal limiting membrane by Rag GTPases and Ragulator complex. These proteins form the lysosomal nutrient sensing scaffold to which mTORC1 must attach to activate. We found that in Cln1-/- mice, two constituent proteins of the Ragulator complex (vacuolar (H+)-ATPase and Lamtor1) require dynamic S-palmitoylation for endosomal trafficking to the lysosomal limiting membrane. Intriguingly, Ppt1 deficiency in Cln1-/- mice misrouted these proteins to the plasma membrane disrupting the lysosomal nutrient sensing scaffold. Despite this defect, mTORC1 was hyperactivated via the IGF1/PI3K/Akt-signaling pathway, which suppressed autophagy contributing to neuropathology. Importantly, pharmacological inhibition of PI3K/Akt suppressed mTORC1 activation, restored autophagy, and ameliorated neurodegeneration in Cln1-/- mice. Our findings reveal a previously unrecognized role of Cln1/Ppt1 in regulating mTORC1 activation and suggest that IGF1/PI3K/Akt may be a targetable pathway for CLN1 disease. Access the article here [Disruption of lysosomal nutrient sensing scaffold contributes to pathogenesis of a fatal neurodegenerative lysosomal storage disease - PubMed (nih.gov)]
Gammaldi, N. et al. Neurogenetics. 2024 Jan;25(1):39-46 ABSTRACT Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies. The DEM-AGING project aims to define molecular signatures in NCL and expedite biomarker discovery with a view to identifying novel targets for monitoring disease status and progression and accelerating clinical trial readiness in this field. In this study, we fused multiomic assessments in established NCL models with similar data on the more common late-onset neurodegenerative conditions in order to test the hypothesis of shared molecular fingerprints critical to the underlying pathological mechanisms. Our aim, ultimately, is to combine data analysis, cell models, and omic strategies in an effort to trace new routes to therapies that might readily be applied in the most common forms of dementia. Access the full article here [Dem-Aging: autophagy-related pathologies and the "two faces of dementia" - PubMed (nih.gov)]
Nayame, K. et al. Mol Cell. 2024 Feb 28:S1097-2765(24)00125-4. ABSTRACT Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models. Mechanistically, GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity. GPDs effectively inhibit the rate-limiting lysophospholipase activity of these phospholipases. Consistently, lysosomes of CLN3-deficient cells and tissues accumulate toxic lysophospholipids. Our work establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease. Access the full article here [Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease - PubMed (nih.gov)]
Sürücü Kara I, et al. J Pediatr Endocrinol Metab. 2024 Jan 23;37(3):280-288 ABSTRACT Objectives: Neuronal ceroid lipofuscinosis type 11 (NCL11) is a rare disease that presents with progressive cognitive decline, epilepsy, visual impairment, retinal atrophy, cerebellar ataxia and cerebellar atrophy. We present herein a case of NCL11 in a patient diagnosed with neuromotor developmental delay, epilepsy, bronchiolitis obliterans and hypothyroidism. Case presentation: A 4-year-old male patient was admitted to our clinic with global developmental delay and a medical history that included recurrent hospitalizations for pneumonia at the age of 17 days, and in months 4, 5 and 7. Family history revealed a brother with similar clinical findings (recurrent pneumonia, hypothyroidism, hypotonicity, swallowing dysfunction and neuromotor delay) who died from pneumonia at the age of 22 months. Computed tomography of the thorax was consistent with bronchiolitis obliterans, while epileptic discharges were identified on electroencephalogram with a high incidence of bilateral fronto-centro-temporal and generalized spike-wave activity but no photoparoxysmal response. Cranial MRI revealed T2 hyperintense areas in the occipital periventricular white matter and volume loss in the white matter, a thin corpus callosum and vermis atrophy. A whole-exome sequencing molecular analysis revealed compound heterozygous c.430G>A (p.Asp144Asn) and c.415T>C (p.Cys139Arg) variants in the GRN gene. Conclusions: The presented case indicates that NCL11 should be taken into account in patients with epilepsy and neurodegenerative diseases. Access the article here [Neuronal ceroid lipofuscinosis type 11 diagnosed patient with bi-allelic variants in GRN gene: case report and review of literature - PubMed (nih.gov)]
Geulbert, N, et al, Mol Genet Metab Rep. 2024 Feb 1:38:101060. ABSTRACT Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes. Access the full article here [Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa - PubMed (nih.gov)]
Puhl, AC, et al. ACS Omega. 2024 Feb 28;9(10):11870-11882. ABSTRACT Palmitoyl-protein thioesterase 1 (PPT1) is an understudied enzyme that is gaining attention due to its role in the depalmitoylation of several proteins involved in neurodegenerative diseases and cancer. PPT1 is overexpressed in several cancers, specifically cholangiocarcinoma and esophageal cancers. Inhibitors of PPT1 lead to cell death and have been shown to enhance the killing of tumor cells alongside known chemotherapeutics. PPT1 is hence a viable target for anticancer drug development. Furthermore, mutations in PPT1 cause a lysosomal storage disorder called infantile neuronal ceroid lipofuscinosis (CLN1 disease). Molecules that can inhibit, stabilize, or modulate the activity of this target are needed to address these diseases. We used PPT1 enzymatic assays to identify molecules that were subsequently tested by using differential scanning fluorimetry and microscale thermophoresis. Selected compounds were also tested in neuroblastoma cell lines. The resulting PPT1 screening data was used for building machine learning models to help select additional compounds for testing. We discovered two of the most potent PPT1 inhibitors reported to date, orlistat (IC50 178.8 nM) and palmostatin B (IC50 11.8 nM). When tested in HepG2 cells, it was found that these molecules had decreased activity, indicating that they were likely not penetrating the cells. The combination of in vitro enzymatic and biophysical assays enabled the identification of several molecules that can bind or inhibit PPT1 and may aid in the discovery of modulators or chaperones. The molecules identified could be used as a starting point for further optimization as treatments for other potential therapeutic applications outside CLN1 disease, such as cancer and neurological diseases. Read the full article here [Identification of New Modulators and Inhibitors of Palmitoyl-Protein Thioesterase 1 for CLN1 Batten Disease and Cancer - PubMed (nih.gov)]
Schulz A, et al. Orphanet J Rare Dis. 2024 Mar 18;19(1):125 . ABSTRACT Background: CLN3 disease (also known as CLN3 Batten disease or Juvenile Neuronal Ceroid Lipofuscinosis) is a rare pediatric neurodegenerative disorder caused by biallelic mutations in CLN3. While extensive efforts have been undertaken to understand CLN3 disease etiology, pathology, and clinical progression, little is known about the impact of CLN3 disease on parents and caregivers. Here, we investigated CLN3 disease progression, clinical care, and family experiences using semi-structured interviews with 39 parents of individuals with CLN3 disease. Analysis included response categorization by independent observers and quantitative methods. Results: Parents reported patterns of disease progression that aligned with previous reports. Insomnia and thought- and mood-related concerns were reported frequently. "Decline in visual acuity" was the first sign/symptom noticed by n = 28 parents (70%). A minority of parents reported "behavioral issues" (n = 5, 12.5%), "communication issues" (n = 3, 7.5%), "cognitive decline" (n = 1, 2.5%), or "seizures" (n = 1, 2.5%) as the first sign/symptom. The mean time from the first signs or symptoms to a diagnosis of CLN3 disease was 2.8 years (SD = 4.1). Misdiagnosis was common, being reported by n = 24 participants (55.8%). Diagnostic tests and treatments were closely aligned with observed symptoms. Desires for improved or stabilized vision (top therapeutic treatment concern for n = 14, 32.6%), cognition (n = 8, 18.6%), and mobility (n = 3, 7%) dominated parental concerns and wishes for therapeutic correction. Family impacts were common, with n = 34 (81%) of respondents reporting a financial impact on the family and n = 20 (46.5%) reporting marital strain related to the disease. Conclusions: Collectively, responses demonstrated clear patterns of disease progression, a strong desire for therapies to treat symptoms related to vision and cognition, and a powerful family impact driven by the unrelenting nature of disease progression. Access the full article here [The parent and family impact of CLN3 disease: an observational survey-based study - PubMed (nih.gov)]
Reith, RR, et al. J Vet Diagn Invest. 2024 Mar 22:10406387241239918. ABSTRACT Thirteen American Hereford cattle were reported blind with presumed onset when ~12-mo-old. All blind cattle shared a common ancestor through both the maternal and paternal pedigrees, suggesting a recessive genetic origin. Given the pedigree relationships and novel phenotype, we characterized the ophthalmo-pathologic changes associated with blindness and identified the responsible gene variant. Ophthalmologic examinations of 5 blind cattle revealed retinal degeneration. Histologically, 2 blind cattle had loss of the retinal photoreceptor layer. Whole-genome sequencing (WGS) of 7 blind cattle and 9 unaffected relatives revealed a 1-bp frameshift deletion in ceroid lipofuscinosis neuronal 3 (CLN3; chr25 g.26043843del) for which the blind cattle were homozygous and their parents heterozygous. The identified variant in exon 16 of 17 is predicted to truncate the encoded protein (p. Pro369Argfs*8) battenin, which is involved in lysosomal function necessary for photoreceptor layer maintenance. Of 462 cattle genotyped, only blind cattle were homozygous for the deletion. A query of WGS data of > 5,800 animals further revealed that the variant was only observed in related Hereford cattle. Mutations in CLN3 are associated with human juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, which results in early-onset retinal degeneration and lesions similar to those observed in our cases. Our data support the frameshift variant of CLN3 as causative of blindness in these Hereford cattle, and provide additional evidence of the role of this gene in retinal lesions, possibly as a model for human non-syndromic JNCL. Access the full article here [A recessive CLN3 variant is responsible for delayed-onset retinal degeneration in Hereford cattle - PubMed (nih.gov)]
O’Neal, M. et al. Pediatr Neurol. 2024 Mar 1:154:51-57. ABSTRACT Background: Mutations in the CLN6 gene cause late infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease of childhood onset. Clinically, individuals present with progressive motor and cognitive regression, ataxia, and early death. The aim of this study is to establish natural history data of individuals with classic, late-infantile-onset (age less than five years) CLN6 disease. Methods: We analyzed the natural history of 25 patients with late-infantile-onset CLN6, utilizing the Hamburg motor-language scale to measure disease progression. The key outcomes were CLN6 disease progression, assessed by rate of decline in motor and language clinical domain summary scores (0 to 6 total points); onset and type of first symptom; onset of first seizure; and time from first symptom to complete loss of function. Results: Median age of total motor and language onset of decline was 42 months (interquartile range 36 to 48). The estimated rate of decline in total score was at a slope of -1.20 (S.D. 0.30) per year, after the start of decline. Complete loss of both motor and language function was found to be, on average, 88.1 months (S.D. 13.5). Conclusions: To our knowledge, this is the largest international study that monitors the longitudinal natural history and progression of CLN6 disease. These data may serve as a template for future interventional trials targeted to slow the progression of this devastating disease. Access the article here [Natural History of Neuronal Ceroid Lipofuscinosis Type 6, Late Infantile Disease - PubMed (nih.gov)]
Rogers DL, et al. J AAPOS. 2024 Apr;28(2):103830 ABSTRACT Classically, peripheral vascular changes in the retina in patients with neuronal ceroid lipofuscinosis type 2 (CLN2) are described as vascular attenuation seen in the late stages of disease on the Weill Connell Ophthalmic Severity Score (WCOSS) staging system. We describe isolated, mild, peripheral vasculitis with peripheral arteriolar dropout identified by fluorescein angiography in patients with a WCOSS grade of stage 2. We believe this vasculitis represents an early vasodegenerative phase of disease that leads to the vascular attenuation seen in later stages of the disease. Access the article here [Peripheral retinal finding on fluorescein angiography in neuronal ceroid lipofuscinosis type 2 (CLN2) - Journal of the American Association for Pediatric Ophthalmology and Strabismus (JAAPOS)]
Madhana KP, et al. Metab Brain Dis. 2024 Apr;39(4):545-558 ABSTRACT Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57 kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and - 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder. Access the article here [A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis - PubMed (nih.gov)]
Hundsberger F, et al. Klin Monbl Augenheilkd. 2024 Apr;241(4):538-539. ABSTRACT Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the many types of NCLs, which are a group of inherited neurodegenerative lysosomal storage disorders. Type 3, the classic and most common form, is caused by homozygous or compound heterozygous pathogenic variants in the CLN3 gene that encodes a lysosomal transmembrane protein. This yields in unbalanced cellular homeostasis and increased neuronal loss, as the physiological protein is predicted to be a pH regulator and modulator of vesicular transport and fusion [1]. Clinical symptoms mostly present between 5?–?10 years of age and manifest as progressive vision loss and, rarely, seizures. Cognitive and behavioural impairment is thought to appear a few years after the onset of visual impairment [1]. This is, however, not always the case. The aim of this case report is to describe the unusual phenotypic presentation of juvenile NCL3 in a patient of Swiss descent. Access the article here [Thieme E-Journals - Klinische Monatsblätter für Augenheilkunde / Abstract (thieme-connect.com)]
Saleh MM, et al; Pediatr Neurol. 2024 Mar 7;155:149-155. ABSTRACT Background: Neuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population. Methods: A retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed. Results: CLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14. Conclusions: This is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families. Access the article here [Clinical and molecular characteristics of neuronal ceroid lipofuscinosis in Saudi Arabia - Pediatric Neurology (pedneur.com)]
Lourenço CM, et al. Arq Neuropsiquiatr. 2024 May; 82(5):1-8. ABSTRACT Background: Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia, seizures, movement disorders, language delay/regression, progressive visual failure, and early death. Neuronal ceroid lipofuscinosis type 2 (CLN2), caused by biallelic pathogenic variants of the TPP1 gene, is the only NCL with an approved targeted therapy. The laboratory diagnosis of CLN2 is established through highly specific tests, leading to diagnostic delays and eventually hampering the provision of specific treatment for patients with CLN2. Epilepsy is a common and clinically-identifiable feature among NCLs, and seizure onset is the main driver for families to seek medical care. Objective: To evaluate the results of the Latin America Epilepsy and Genetics Program, an epilepsy gene panel, as a comprehensive tool for the investigation of CLN2 among other genetic causes of epilepsy. Methods: A total of 1,284 patients with epilepsy without a specific cause who had at least 1 symptom associated with CLN2 were screened for variants in 160 genes associated with epilepsy or metabolic disorders presenting with epilepsy through an epilepsy gene panel. Results: Variants of the TPP1 gene were identified in 25 individuals (1.9%), 21 of them with 2 variants. The 2 most frequently reported variants were p.Arg208* and p.Asp276Val, and 2 novel variants were detected in the present study: p.Leu308Pro and c.89 + 3G > C Intron 2. Conclusion: The results suggest that these genetic panels can be very useful tools to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment for the patients. Access the article here [A needle in a haystack? The impact of a targeted epilepsy gene panel in the identification of a treatable but rapidly progressive metabolic epilepsy: CLN2 disease - PubMed (nih.gov)]
Chen B, et al. Neurol Sci. 2024 May 21. Epub ahead of print. ABSTRACT Background: Neuronal ceroid lipofuscinoses are a genetically heterogeneous group of inherited lysosomal storage disorders. Kufs disease is the predominant form of neuronal ceroid lipofuscinosis in adults, but it's rare and challenging to diagnose. Case description: The proband initially presented with cognitive deterioration and parkinsonian traits. At 35, he was admitted to hospital following a tonic-clonic seizure. Brain magnetic resonance imaging showed atrophy of the cerebral cortex and cerebellum, enlarged ventricles, and thinned corpus callosum. The proband's younger brother and sister were also affected, and the clinical phenotype within the family was consistent. Whole-exome Sequencing of the proband revealed a novel homozygous mutation in CLN6 (NM_017882: c.425A > G, p. Tyr142Cys). Co-segregation analysis revealed that two other affected individuals carried a homozygous mutation at the same locus, with both parents exhibiting heterozygous mutations of c.425A > G. Conclusion: Our study not only provides insights into the clinical presentation and development of the disease within the affected family but also expanded the mutational and phenotypical spectrum of the CLN6 gene. Access the article here [A novel homozygous CLN6 Tyr142Cys variant in a nonconsanguineous family with Kufs disease]
Specchio N, et al. PLoS One. 2024 May 22;19(5):e0302382. ABSTRACT Background: The CLN2 Clinical Rating Scale evaluates disease progression in CLN2 disease, an ultra-rare, neurodegenerative disorder with late infantile onset. To validate the Clinical Rating Scale, a comparison with the Pediatric Quality of Life Inventory (PedsQL) was conducted utilising clinical trial data investigating cerliponase alfa use in CLN2 disease. Methods: Linear regression and mixed effects models were used to investigate the relationship between the Clinical Rating Scale and PedsQL using open-label, single-arm, phase 1/2 (NCT01907087) and ongoing extension study (NCT02485899) data of 23 children with CLN2 disease treated with cerliponase alfa for ?96 weeks. Results: Correlations between the four Clinical Rating Scale domains were low. Linear mixed effects analyses showed significant correlation between PedsQL and Clinical Rating Scale (Total score or motor-language [ML] score adjusted p-values <0.05), driven by the relationship with the PedsQL Physical domain. A statistically significant relationship was identified between the Clinical Rating Scale motor domain and PedsQL (Total score: adjusted p-value = 0.048, parameter estimate [PE] = 8.10; Physical domain score: adjusted p-value = 0.012; PE = 13.79). Conclusions: Each domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients' quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease. Access the article here [Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data | PLOS ONE]
Felczak P, et al. Folia Neuropathol. 2024;62(1):21-31. ABSTRACT Case report - Neuronal ceroid lipofuscinoses (NCLs) are a growing group of neurodegenerative storage diseases, in which specific features are sought to facilitate the creation of a universal diagnostic algorithm in the future. In our ultrastructural studies, the group of NCLs was represented by the CLN2 disease caused by a defect in the TPP1 gene encoding the enzyme tripeptidyl-peptidase 1. A 3.5-year-old girl was affected by this disease. Due to diagnostic difficulties, the spectrum of clinical, enzymatic, and genetic tests was extended to include analysis of the ultrastructure of cells from a rectal biopsy. The aim of our research was to search for pathognomonic features of CLN2 and to analyse the mitochondrial damage accompanying the disease. In the examined cells of the rectal mucosa, as expected, filamentous deposits of the curvilinear profile (CVP) type were found, which dominated quantitatively. Mixed deposits of the CVP/fingerprint profile (FPP) type were observed less frequently in the examined cells. A form of inclusions of unknown origin, not described so far in CLN2 disease, were wads of osmophilic material (WOMs). They occurred alone or co-formed mixed deposits. In addition, atypically damaged mitochondria were observed in muscularis mucosae. Their deformed cristae had contact with inclusions that looked like CVPs. Considering the confirmed role of the c subunit of the mitochondrial ATP synthase in the formation of filamentous lipopigment deposits in the group of NCLs, we suggest the possible significance of other mitochondrial proteins, such as mitochondrial contact site and cristae organizing system (MICOS), in the formation of these deposits. The presence of WOMs in the context of searching for ultrastructural pathognomonic features in CLN2 disease also requires further research.. Access the article here [A current view of mitochondria damage and the diversity of lipopigment inclusions in neuronal ceroid lipofuscinose type 2 from rectal biopsy]