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Considerations and Bayesian Applications in Pharmaceutical Development for Rare Diseases
Published in Mani Lakshminarayanan, Fanni Natanegara, Bayesian Applications in Pharmaceutical Development, 2019
Batten disease is a fatal rare disease of the nervous system that typically has onset of symptoms in childhood and causes worsening problems with vision, movement, and thinking ability.39,40 It is usually referring to a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), to which CLN2 disease belong. CLN2 disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency. In the late infantile form of the CLN2 disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy), and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease collectively is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.41
Inborn errors of metabolism
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Other important sphingolipidoses, almost all autosomal recessive in inheritance, include Gaucher disease, Niemann-Pick disease, metachromatic leucodystrophy and generalised gangliosidosis. Batten disease had no specific enzyme defect known until positional cloning identified one form on chromosome 16, with one particularly frequent mutation, allowing, for the first time, prenatal diagnosis for some families with this devastating disorder (see also Chapter 14). The genes involved in the other forms of Batten disease have since been identified.
Lysosomal, sterol and lipid disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Batten disease consists of a group of disorders comprising four main clinical types as well as several other variant forms. In the infantile form, there is a build-up of lipofuscins, which are composed of fats and proteins, in the body. This form is caused by a deficiency of the palmitoyl protein thioesterase (PPT) enzyme, as a result of which, storage material known as granular osmiophilic deposits (GROD) accumulates in the brain and other body tissues, leading to severe deterioration.
Progress in gene and cell therapies for the neuronal ceroid lipofuscinoses
Published in Expert Opinion on Biological Therapy, 2018
Anthony Donsante, Nicholas M Boulis
CLN4 disease has not yet been addressed in rodent or large animal models. This form of Batten disease is unique in that it is inherited in an autosomal dominant manner. Rather than causing haploinsufficiency, in vitro and in vivo data suggest that the primary problem is a gain of function resulting in protein aggregation [61,62]. Protein aggregation is a common theme in neurodegenerative disorders [63]. For CLN4, the toxicity may involve the sequestering of PPT1, resulting in a deficiency akin to CLN1 disease [64]. Knockdown or deletion of the mutant allele could be a potential route to therapy for this disease [65], as has been previously done for other proteins such as superoxide dismutase 1 in amyotrophic lateral sclerosis [66].