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Article: Ethical Issues in Care and Treatment of Neuronal Ceroid Lipofuscinoses (NCL)-A Personal View.

Kohlschütter, Alfried

2021 Volume 12, Page(s) 692527

Abstract: The management of Neuronal Ceroid Lipofuscinoses (NCL), a group of genetic neurodegenerative disorders mainly affecting brain and retinas, raises difficult questions for physicians and other professionals in research, pharmaceutical industry, and public ... ...

Abstract	The management of Neuronal Ceroid Lipofuscinoses (NCL), a group of genetic neurodegenerative disorders mainly affecting brain and retinas, raises difficult questions for physicians and other professionals in research, pharmaceutical industry, and public health. Ethical problems in medicine cannot be solved by rational deliberation or by following formal rules. Two topics of ethical issues in the field of NCL are presented here. One group relates to the care of individual patients and centers on a life with dementia at a young age. Advanced care planning for the end of life and the use of life-prolonging measures require challenging assumptions in the best interest of a patient. A second group of questions relates to new treatments. Impressive novel putative causal therapies, such as enzyme replacement for CLN2 disease, may be only disease-modifying and carry the risk of changing a deadly disease of short duration into one with prolonged survival and poor quality of life. The wish for better therapeutic interventions in life-limiting diseases has to take such risks, but more experience is needed before definite conclusions can be drawn. The appropriateness of presymptomatic screening for a severe disease, e.g., must be carefully evaluated to avoid the disastrous experience made with the rash start of newborn screening for Krabbe disease. The ethical issues described and commented in the article reflect the personal experience of a pediatrician who has studied clinical and research questions in NCL for four decades. They should alert various professionals to the necessity of taking their own decisions in situations that are caused by rare progressive brain diseases of young persons, as typified by the NCL.
Language	English
Publishing date	2021-06-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2021.692527
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Article ; Online: Ethical Issues in Care and Treatment of Neuronal Ceroid Lipofuscinoses (NCL)–A Personal View

Alfried Kohlschütter

Frontiers in Neurology, Vol

2021 Volume 12

Abstract	The management of Neuronal Ceroid Lipofuscinoses (NCL), a group of genetic neurodegenerative disorders mainly affecting brain and retinas, raises difficult questions for physicians and other professionals in research, pharmaceutical industry, and public health. Ethical problems in medicine cannot be solved by rational deliberation or by following formal rules. Two topics of ethical issues in the field of NCL are presented here. One group relates to the care of individual patients and centers on a life with dementia at a young age. Advanced care planning for the end of life and the use of life-prolonging measures require challenging assumptions in the best interest of a patient. A second group of questions relates to new treatments. Impressive novel putative causal therapies, such as enzyme replacement for CLN2 disease, may be only disease-modifying and carry the risk of changing a deadly disease of short duration into one with prolonged survival and poor quality of life. The wish for better therapeutic interventions in life-limiting diseases has to take such risks, but more experience is needed before definite conclusions can be drawn. The appropriateness of presymptomatic screening for a severe disease, e.g., must be carefully evaluated to avoid the disastrous experience made with the rash start of newborn screening for Krabbe disease. The ethical issues described and commented in the article reflect the personal experience of a pediatrician who has studied clinical and research questions in NCL for four decades. They should alert various professionals to the necessity of taking their own decisions in situations that are caused by rare progressive brain diseases of young persons, as typified by the NCL.
Keywords	dementia ; genetic ; lysosomal storage disease ; children ; palliative medicine ; disease-modifying therapy ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	170
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article: Demenz bei Kindern: Was muss ich davon wissen?

Kohlschütter, Alfried

Kinderärztliche Praxis

2020 Volume 91, Issue Sonderh. Kinderdemenz, Page(s) 3

Language	German
Document type	Article
ZDB-ID	209040-5
ISSN	0023-1495
Database	Current Contents Medicine

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Article: Lysosomal leukodystrophies: Krabbe disease and metachromatic leukodystrophy.

Kohlschütter, Alfried

Handbook of clinical neurology

2013 Volume 113, Page(s) 1611–1618

Abstract: Genetic deficiencies of lysosomal catabolic pathways lead to storage disorders with multiple organ abnormalities or to degeneration of purely nervous structures. Krabbe disease and metachromatic leukodystrophy are caused by metabolic errors concerning ... ...

Abstract	Genetic deficiencies of lysosomal catabolic pathways lead to storage disorders with multiple organ abnormalities or to degeneration of purely nervous structures. Krabbe disease and metachromatic leukodystrophy are caused by metabolic errors concerning lipids of neural membranes. They are characterized by demyelination of the central nervous system and, variably, the peripheral nerves. Their clinical presentation is a relentlessly progressive motor and mental deterioration starting at any age between infancy and adolescence. MRI demonstrates characteristic lesions of brain white matter. In Krabbe disease, deficient galactocerebroside β-galactosidase activity causes accumulation of lipids in "globoid" macrophages and of psychosine, which is toxic to oligodendrocytes. Diagnosis depends on demonstration of the enzyme deficiency. Experimental treatment is limited to hematopoietic stem cell transplantation, which can favorably alter the course of disease in certain situations. In metachromatic leukodystrophy, deficient activity of arylsulfatase A, or lack of a cofactor, causes accumulation of sulfatide in various tissues and diffuse demyelination. Symptoms are neurological, but gallbladder dysfunction may be present. Diagnosis depends on demonstrating the enzyme deficiency and elevated urinary sulfatide. In a rare variant, multiple sulfatases are deficient. Stem cell transplantation may prevent disease progression in selected cases. Enzyme replacement is being evaluated, and gene therapies are being developed.
MeSH term(s)	Brain/pathology ; Cerebroside-Sulfatase/genetics ; Child ; Child, Preschool ; Galactosylceramidase/genetics ; Humans ; Infant ; Leukodystrophy, Globoid Cell/diagnosis ; Leukodystrophy, Globoid Cell/enzymology ; Leukodystrophy, Globoid Cell/genetics ; Leukodystrophy, Metachromatic/diagnosis ; Leukodystrophy, Metachromatic/enzymology ; Leukodystrophy, Metachromatic/genetics ; Magnetic Resonance Imaging
Chemical Substances	Cerebroside-Sulfatase (EC 3.1.6.8) ; Galactosylceramidase (EC 3.2.1.46)
Language	English
Publishing date	2013
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	0072-9752
ISSN	0072-9752
DOI	10.1016/B978-0-444-59565-2.00029-0
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Article ; Online: Evaluating experimental treatment of leukodystrophies.

Kohlschütter, Alfried

Developmental medicine and child neurology

2011 Volume 53, Issue 9, Page(s) 781

MeSH term(s)	Humans ; Leukodystrophy, Metachromatic/therapy ; Outcome Assessment (Health Care) ; Stem Cell Transplantation/methods
Language	English
Publishing date	2011-06-27
Publishing country	England
Document type	Comment ; Journal Article
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/j.1469-8749.2011.04022.x
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Article ; Online: Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses.

Kohlschütter, Alfried / Schulz, Angela / Bartsch, Udo / Storch, Stephan

CNS drugs

2019 Volume 33, Issue 4, Page(s) 315–325

Abstract: The neuronal ceroid lipofuscinoses comprise a group of neurodegenerative lysosomal storage disorders caused by mutations in at least 13 different genes and primarily affect the brain and the retina of children or young adults. The disorders are ... ...

Abstract	The neuronal ceroid lipofuscinoses comprise a group of neurodegenerative lysosomal storage disorders caused by mutations in at least 13 different genes and primarily affect the brain and the retina of children or young adults. The disorders are characterized by progressive neurological deterioration with dementia, epilepsy, loss of vision, motor disturbances, and early death. While various therapeutic strategies are currently being explored as treatment options for these fatal disorders, there is presently only one clinically approved drug that has been shown to effectively attenuate the progression of a specific form of neuronal ceroid lipofuscinosis, CLN2 disease (cerliponase alfa, a lysosomal enzyme infused into the brain ventricles of patients with CLN2 disease). Therapeutic approaches for the treatment of other forms of neuronal ceroid lipofuscinosis include the administration of immunosuppressive agents to antagonize neuroinflammation associated with neurodegeneration, the use of various small molecules, stem cell therapy, and gene therapy. An important aspect of future work aimed at developing therapies for neuronal ceroid lipofuscinoses is the need for treatments that effectively attenuate neurodegeneration in both the brain and the retina.
MeSH term(s)	Animals ; Brain/drug effects ; Humans ; Neuronal Ceroid-Lipofuscinoses/drug therapy ; Retina/drug effects ; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/therapeutic use
Chemical Substances	Small Molecule Libraries
Language	English
Publishing date	2019-03-15
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	1203800-3
ISSN	1179-1934 ; 1172-7047
ISSN (online)	1179-1934
ISSN	1172-7047
DOI	10.1007/s40263-019-00620-8
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Article ; Online: Frühzeitige Diagnose einer seltenen Krankheit bei Kindern durch bessere Kommunikation zwischen Eltern, niedergelassenen Ärzten und spezialisierten Zentren.

Kohlschütter, Alfried / van den Bussche, Hendrik

Zeitschrift fur Evidenz, Fortbildung und Qualitat im Gesundheitswesen

2019 Volume 141-142, Page(s) 18–23

Abstract: The correct and early diagnosis of a rare disease in children is of particular importance in regard to the frequently fateful consequences for young families. Even well-known rare diseases are diagnosed with unacceptable delay in many countries. After ... ...

Title translation	Early diagnosis of a rare disease in children through better communication between parents, physicians and academic centers.
Abstract	The correct and early diagnosis of a rare disease in children is of particular importance in regard to the frequently fateful consequences for young families. Even well-known rare diseases are diagnosed with unacceptable delay in many countries. After decades of studying medical histories with delayed diagnoses and the respective literature, we describe the often severe aftereffects of a late diagnosis. We point out the underlying problems on the part of the physicians involved, of the affected families and of the health system in Germany, in particular with respect to the many emerging centers for rare diseases, most of which are associated with academic institutions. We gained the impression that the cause of delayed diagnoses is frequently not a lack of expertise or other resources, but inefficient communication between parents, practitioners and expert centers. We consider two approaches as promising and practicable: (1) strengthening the parents' competence and role in the dialogue with their doctors, an important element of which is obtaining written information on the state of the diagnostic process in language understandable to the parents; (2) definition of binding requirements for centers officially dedicated to the diagnosis of rare diseases and to research into unknown conditions. Many of our observations and deliberations in the pediatric field should be equally applicable to adults.
MeSH term(s)	Adult ; Child ; Communication ; Early Diagnosis ; Germany ; Humans ; Parents/psychology ; Physician-Patient Relations ; Rare Diseases/diagnosis
Language	German
Publishing date	2019-03-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2412512-X
ISSN	2212-0289 ; 1865-9217
ISSN (online)	2212-0289
ISSN	1865-9217
DOI	10.1016/j.zefq.2019.02.008
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Article ; Online: Ophthalmologische Manifestationen bei neuronalen Ceroid-Lipofuszinosen (NCL) : NCL als Erkrankungen von Retina und Gehirn – Rolle der Augenärzte.

Atiskova, Yevgeniya / Kohlschütter, Alfried / Spitzer, Martin Stephan / Dulz, Simon

Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft

2020 Volume 118, Issue 2, Page(s) 113–118

Abstract: Background: Neuronal ceroid lipofuscinoses are hereditary lysosomal storage diseases, which lead to a progressive neurodegeneration of the brain and retina. Visual loss can be the initial symptom but can also occur later in the course of the disease.: ...

Title translation	Ophthalmological manifestations of neuronal ceroid lipofuscinoses (NCL) : NCL as diseases of brain and retina-the role of ophthalmologists.
Abstract	Background: Neuronal ceroid lipofuscinoses are hereditary lysosomal storage diseases, which lead to a progressive neurodegeneration of the brain and retina. Visual loss can be the initial symptom but can also occur later in the course of the disease. Objective: The aim of this article is to provide ophthalmologists with an overview of the characteristic ocular alterations and the general disease course of the 13 currently known various forms of NCL. Material and methods: The findings from predominantly clinical articles are reviewed and summarized. Results and conclusion: Retinal degeneration plays a crucial role in this group of neurodegenerative diseases. In several forms visual decline is the initial clinical symptom in affected patients. Therefore, the ophthalmologist is the first medical expert consulted. An early diagnosis is crucial for the future personal and family planning but is also important regarding upcoming therapeutic strategies, which might be much more effective in patients with early stage disease. When the presence of retinal degeneration due to an NCL disease is suspected an immediate genetic diagnostic confirmation and collaboration with neuropediatricians is recommended.
MeSH term(s)	Brain ; Humans ; Neuronal Ceroid-Lipofuscinoses/diagnosis ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/therapy ; Ophthalmologists ; Retina ; Vision Disorders/diagnosis ; Vision Disorders/etiology
Language	German
Publishing date	2020-12-13
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1105167-x
ISSN	1433-0423 ; 0941-293X
ISSN (online)	1433-0423
ISSN	0941-293X
DOI	10.1007/s00347-020-01282-4
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Article ; Online: First Recognized Patient with Genetic Vitamin E Deficiency Stable after 36 Years of Controlled Supplement Therapy.

Kohlschütter, Alfried / Finckh, Barbara / Nickel, Miriam / Bley, Annette / Hübner, Christoph

Neuro-degenerative diseases

2020 Volume 20, Issue 1, Page(s) 35–38

Abstract: Introduction: Familial isolated deficiency of vitamin E (VED or AVED; MIM #277460) is a progressive neurodegenerative disorder resembling Friedreich ataxia. It is caused by the deficiency of α-tocopherol transfer protein that prevents patients from ... ...

Abstract	Introduction: Familial isolated deficiency of vitamin E (VED or AVED; MIM #277460) is a progressive neurodegenerative disorder resembling Friedreich ataxia. It is caused by the deficiency of α-tocopherol transfer protein that prevents patients from retaining vitamin E. Oral vitamin E supplements are an accepted treatment, but detailed dosage recommendations and reports on long-term therapeutic results are scarce. Methods: The first patient with VED was discovered at our institution at the age of 12 years and has since been followed with clinical, neurophysiological, neuroradiological, and biochemical investigations to his present age of 52 years. For the last 36 years, the patient has scrupulously followed a custom-made high-dose vitamin E supplement regimen that we devised on the basis of studies of his metabolism of vitamin E. Results: Over the long period of observation, the patient has remained in good general health and has not shown progression of neurological symptoms and signs. His vitamin E plasma levels were always moderately above the normal range. During short interruptions of vitamin E supplements, vitamin E levels fell rapidly, even after years of massive supplementation. Discussion: In this VED patient, a specified and carefully controlled high-dose vitamin E therapy has prevented any recognizable progression of the neurodegenerative process over more than 3 decades of observation.
MeSH term(s)	Adolescent ; Adult ; Ataxia/drug therapy ; Ataxia/genetics ; Child ; Dietary Supplements ; Humans ; Male ; Middle Aged ; Time Factors ; Vitamin E/therapeutic use ; Vitamin E Deficiency/drug therapy ; Vitamin E Deficiency/genetics ; Young Adult
Chemical Substances	Vitamin E (1406-18-4)
Language	English
Publishing date	2020-07-03
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2143569-8
ISSN	1660-2862 ; 1660-2854
ISSN (online)	1660-2862
ISSN	1660-2854
DOI	10.1159/000508080
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Article: CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis).

Kohlschütter, Alfried / Schulz, Angela

Pediatric endocrinology reviews : PER

2016 Volume 13 Suppl 1, Page(s) 682–688

Abstract: CLN2 disease is an inherited metabolic storage disorder caused by the deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). The disease affects mainly the brain and the retina and is characterized by progressive dysfunction of the central ... ...

Abstract	CLN2 disease is an inherited metabolic storage disorder caused by the deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). The disease affects mainly the brain and the retina and is characterized by progressive dysfunction of the central nervous system, leading to dementia, epilepsy, loss of motor function and blindness. The classical late infantile type begins at around three years of age with epilepsy and/or a standstill of psychomotor development, followed by a rapid loss of all abilities and death in childhood. A late onset form in a small proportion of patients starts at the age of 4 to 10 years, but also leads to severe neurological deterioration. The deficiency of TPP1 causes the lysosomal accumulation of a material called ceroid lipofuscin. The natural substrate of TPP1 is not known, nor is the connection between storage process and neurodegeneration, which is characterized by loss of neurons. Among various experimental approaches to treatment, enzyme replacement therapy (ERT) and gene therapy have developed remarkably. Enzyme delivery through the cerebrospinal fluid led to wide distribution of enzyme activity in the brain and to attenuated neuropathology and disease progression in a TPP1-deficient mouse model as well as in a natural TPP1-deficient dog model. Safety of the intrathecal delivery, pharmacokinetics, and tissue distribution of the administered enzyme studied in non-human primates were encouraging, and a phase I/II clinical trial for intraventricular ERT in CLN2 patients is ongoing. A second approach uses intracerebral injection of viral vectors containing normal coding segments of the CLN2 gene. In a CLN2 mouse model, this procedure resulted in cerebral enzyme expression, reduced brain pathology and increased survival. A small number of patients have been treated the same way using an AAV2-vector for gene transfer to the brain. Although there were no serious adverse events unequivocally attributable to the vector used, there were some serious adverse effects, and a clinical benefit was not clearly evident under the conditions of the experiment. A phase I/phase II study using a AAVrh10 vector is presently recruiting patients.
MeSH term(s)	Aminopeptidases/genetics ; Aminopeptidases/therapeutic use ; Animals ; Bone Marrow Transplantation ; Brain/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/therapeutic use ; Disease Models, Animal ; Enzyme Replacement Therapy ; Epilepsy/physiopathology ; Genetic Therapy ; Humans ; Infusions, Intraventricular ; Injections ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/physiopathology ; Neuronal Ceroid-Lipofuscinoses/therapy ; Psychomotor Disorders/physiopathology ; Serine Proteases/genetics ; Serine Proteases/therapeutic use
Chemical Substances	Serine Proteases (EC 3.4.-) ; Aminopeptidases (EC 3.4.11.-) ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (EC 3.4.14.-) ; tripeptidyl-peptidase 1 (EC 3.4.14.9)
Language	English
Publishing date	2016-06
Publishing country	Israel
Document type	Journal Article ; Review
ZDB-ID	2434390-0
ISSN	1565-4753
ISSN	1565-4753
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