The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses

Gardner, Emily; Mole, Sara

doi:10.3389/fneur.2021.754045

Cited by 36 publications

(30 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, individuals with an INCL phenotype were mostly diagnosed with CLN1, LINCL cases mostly with CLN2, and JNCL cases mostly with CLN3 disease. However, the genotype/phenotype correlation is not bidirectional (3). The current nomenclature and classification of NCLs was agreed by an international panel of experts in the clinical, genetic, biological, and morphological fields, and formally established in 2012 (24).…”

Section: The Saandc Cohort Phenotypic Genetic and Demographic Distrib...mentioning

confidence: 99%

“…Morphologically, NCLs are characterized by the accumulation of undegraded lipoprotein lipofuscin-like material within lysosomes (1), which includes them in the group of lysosomal storage disorders. To date, thirteen NCL diseases have been described, named according to the affected gene (CLN1-CLN14 diseases, CLN9 disease was suggested and later removed) (3). All the proteins encoded by these genes were defined; however, the specific role of some of them, and how they lead to the lysosomal pathology, remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuronal ceroid lipofuscinosis in the South American-Caribbean region: An epidemiological overview

et al. 2022

View full text Add to dashboard Cite

Neuronal ceroid lipofuscinoses (NCLs) comprise 13 hereditary neurodegenerative pathologies of very low frequency that affect individuals of all ages around the world. All NCLs share a set of symptoms that are similar to other diseases. The exhaustive collection of data from diverse sources (clinical, genetic, neurology, ophthalmology, etc.) would allow being able in the future to define this group with greater precision for a more efficient diagnostic and therapeutic approach. Despite the large amount of information worldwide, a detailed study of the characteristics of the NCLs in South America and the Caribbean region (SA&C) has not yet been done. Here, we aim to present and analyse the multidisciplinary evidence from all the SA&C with qualitative weighting and biostatistical evaluation of the casuistry. Seventy-one publications from seven countries were reviewed, and data from 261 individuals (including 44 individuals from the Cordoba cohort) were collected. Each NCL disease, as well as phenotypical and genetic data were described and discussed in the whole group. The CLN2, CLN6, and CLN3 disorders are the most frequent in the region. Eighty-seven percent of the individuals were 10 years old or less at the onset of symptoms. Seizures were the most common symptom, both at onset (51%) and throughout the disease course, followed by language (16%), motor (15%), and visual impairments (11%). Although symptoms were similar in all NCLs, some chronological differences could be observed. Sixty DNA variants were described, ranging from single nucleotide variants to large chromosomal deletions. The diagnostic odyssey was probably substantially decreased after medical education activities promoted by the pharmaceutical industry and parent organizations in some SA&C countries. There is a statistical deviation in the data probably due to the approval of the enzyme replacement therapy for CLN2 disease, which has led to a greater interest among the medical community for the early description of this pathology. As a general conclusion, it became clear in this work that the combined bibliographical/retrospective evaluation approach allowed a general overview of the multidisciplinary components and the epidemiological tendencies of NCLs in the SA&C region.

show abstract

Section: The Saandc Cohort Phenotypic Genetic and Demographic Distrib...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuronal ceroid lipofuscinosis in the South American-Caribbean region: An epidemiological overview

et al. 2022

View full text Add to dashboard Cite

show abstract

“…It should be noted that our patient's genotype does not include the more frequent 1 kb founder deletion, which accounts for approximately 90% of the affected alleles in CLN3 patients (74% homozygous and 22% heterozygous) ( 17 , 18 ) and leads to the formation of a protein lacking exons 7 and 8, located in the second of the four luminal loops of the protein ( 19 ). On the contrary, our patient has an unusual CLN3 genotype with a deletion (c.558_559delAG) in exon 8 and a splice-site mutation (c.461-1G > C) upstream exon 7 of the CLN3 gene.…”

Section: Discussionmentioning

confidence: 99%

Cardiac magnetic resonance findings in neuronal ceroid lipofuscinosis: A case report

Todiere

Vecchia²,

Morales³

et al. 2022

Front. Neurol.

View full text Add to dashboard Cite

Cardiac magnetic resonance imaging (MRI) is an essential tool for the study of hypertrophic cardiomyopathies (HCM) and for differentiating HCM from conditions with increased ventricular wall thickness, such as cardiac storage diseases. Although cardiac MRI is already used for the diagnosis and characterization of some forms of storage diseases involving the myocardium, it has not yet been used to study myocardial involvement in neuronal ceroid lipofuscinosis (NCL). Here, we describe comprehensive cardiac MRI findings in a patient with the CLN3 form of NCL showing basal inferior interventricular septal hypertrophy with maintained indexed LV mass within reference values and low T1-native values. MRI findings support a finding of abnormal storage material within the myocardium in CLN3 disease. We recommend the possible routine use of cardiac MRI for early diagnosis of cardiac involvement in CLN3 disease (also termed juvenile NCL) and to monitor the effects of emerging CLN3 therapies on the myocardium as well.

show abstract

“…The classic form of CLN1 disease begins in infancy and can present as early as 6 months of age. However, some mutations in this gene result in more delayed presentations according to the precise mutation ( 8 , 9 ). Its clinical manifestations include sensory and motor deficits, visual impairment leading to blindness, and epileptic seizures ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep

Nelvagal¹,

Eaton²,

Wang³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

CLN1 disease is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by delivering monthly infusions of recombinant human PPT1 (rhPPT1) in PPT1-deficient mice (Cln1 −/− ), and CLN1 R151X sheep to assess scale up for translation. In Cln1 −/− mice, intracerebroventricular rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1 treated-mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1 R151X sheep, intracerebroventricular infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural magnetic resonance imaging and neuropathology. These findings demonstrate the feasibility and therapeutic efficacy of intracerebroventricular rhPPT1 enzyme replacement therapy. This represents a key step towards clinical testing of ERT in children with CLN1 disease and highlights the importance of a cross-species approach to developing a successful treatment strategy.

show abstract

The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses

Cited by 36 publications

References 83 publications

Neuronal ceroid lipofuscinosis in the South American-Caribbean region: An epidemiological overview

Neuronal ceroid lipofuscinosis in the South American-Caribbean region: An epidemiological overview

Cardiac magnetic resonance findings in neuronal ceroid lipofuscinosis: A case report

Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep

Contact Info

Product

Resources

About