Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

Mole, Sara; Anderson, Glenn; Band, Heather; Berkovic, Samuel F.; Cooper, Jonathan D.; Holthaus, Sophia-Martha kleine; McKay, Tristan R.; Medina, Diego L.; Rahim, Afidah Abdul; Schulz, Angela; Smith, Alexander J.

doi:10.1016/s1474-4422(18)30368-5

Cited by 151 publications

(180 citation statements)

References 85 publications

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“…Mutations in the CTSF gene result in NCL type 13 (CLN13, OMIM ID: 615362), an adult-onset form of NCL, also known as type B Kufs disease [43,[134][135][136][137]. Patients with CLN13 exhibit mental and motor deterioration in late adulthood [51]. To date, nine mutations with recessive inheritance are known to cause CLN13: six missense mutations (p.Gln321Arg, p.Gly458Ala, p.Ser480Leu, p.Tyr231Cys, p.Ile404Thr, and p.Cys326Phe), a nonsense mutation c.416C > A (p.S139*), a frameshift mutation (p.Ser319Leufs*27), and a mutation preventing the correct splicing of CTSF mRNA (c.213 + 1G>C) [134][135][136][137].…”

Section: Gene Deficiency Biological Effect Referencesmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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Section: Gene Deficiency Biological Effect Referencesmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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“…Fourteen NCLs or NCL‐like phenotypes have been identified . Common symptoms occur over different time courses according to subtype, and include seizures; visual, cognitive, and motor decline; and onset of dementia, before death during childhood or adolescence …”

mentioning

confidence: 99%

Paediatric‐onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis

Dozières‐Puyravel

Nasser

Elmaleh‐Bergès

et al. 2019

Develop Med Child Neuro

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Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low‐frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low‐frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. What this paper adds Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.

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“…*We have not outlined similar gene therapy or cellular therapy trials that have already been completed with negative results or may be in a preliminary stage, for example with other subtypes of ceroid lipofuscinosis …”

Section: Disease‐modifying and Disease‐specific Therapiesmentioning

confidence: 99%

“…Tyrosine hydroxylase deficiency can present with akinesia, hypotonia, and oculogyric crises in infancy, and patients can become dyskinetic at low doses, but, on slow increasing regimens, may respond impressively, typically requiring higher doses than *We have not outlined similar gene therapy or cellular therapy trials that have already been completed with negative results or may be in a preliminary stage, for example with other subtypes of ceroid lipofuscinosis. 68 AADC, aromatic acid decarboxylase; AAV, adeno-associated virus; AGS, Aicardi-Goutieres syndrome.…”

Section: Dopaminergic Therapiesmentioning

confidence: 99%

Current therapies and therapeutic decision making for childhood‐onset movement disorders

2019

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Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early‐onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease‐modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease‐modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha‐adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of “disease‐specific” therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood‐onset movement disorders. © 2019 International Parkinson and Movement Disorder Society

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Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

Cited by 151 publications

References 85 publications

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Paediatric‐onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis

Current therapies and therapeutic decision making for childhood‐onset movement disorders

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