Childhood dementia: Infusion into the brain – DocCheck

So far, childhood dementia can only be treated symptomatically. There are no drugs that can slow the progression – but that could now change.

Elderly patients have long been associated with dementia. However, in rare cases, dementia can appear already in childhood. The frequency in Germany is about 2:100,000. The cause is the accumulation of aggregates in lysosomes.

The term neuronal ceroid lipofuscinosis (NCL) refers to a group of autosomal recessive neurodegenerative diseases characterized by myoclonic epilepsy, psychomotor delay, progressive visual loss, and premature death. NCL is the most common cause of childhood dementia. According to the NCL Foundation, there are about 700 children with NCL in Germany and about 70,000 worldwide.

NCLs are currently grouped under two main names, Batten disease and Kufs disease. Batten disease, also known as Spielmeyer-Vogt syndrome, refers to childhood NCL regardless of age of onset. In Kufs disease, NCL symptoms appear in adulthood.

Cause of enzyme deficiency

One of the most common forms is the CLN2 subtype, in which the enzyme tripeptidyl peptidase 1 (TPP1) is not formed or is formed insufficiently. All patients with NCL, except those with the congenital form (ceroid neural lipofuscinosis type 10 (CLN10)), have normal psychomotor development before the onset of symptoms. In most patients, the onset of the first recognizable symptoms of the disease is in childhood. NCL is a collection of different subtypes, but typical clinical manifestations of NCL include:

  • progressive vision loss
  • dementia
  • psychomotor inhibition
  • Failure to reach normal developmental milestones
  • developmental decline
  • behavioral problems
  • progressive cerebral atrophy
  • seizures
  • cognitive decline and motor deficits
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Cognitive decline occurs rapidly in young children, while adolescents and adults show a much slower course, allowing for normal life and education. The decline in cognitive functions takes place in two phases.

At the beginning of the disease, children’s cognitive development slows down; they learn more slowly than their peers but often stay within the normal range for some time. They level off and then begin to lose the cognitive skills they acquired in the first few months and/or years of life.

However, with CLN2 disease, many children show delayed cognitive acquisition at a very early stage; their profiles are inconsistent, the delay in expression is more pronounced than in motor. In CLN3, disease progression is generally slow and children can attend school with support for intellectual and visual demands, according to a recent review.

A neurologist is wanted

In addition to epilepsy, typical neurological manifestations of NCL include motor symptoms such as ataxia, dysphagia, myoclonus, chorea, tremor, and dystonia. These occur mainly in classic and late infantile phenotypes. Parkinsonism may also occur, especially in juvenile CLN3 disease. Many known childhood neurodegenerative diseases have similar symptoms, so late diagnosis of NCL is unfortunately common. The standard diagnostic tool for NCL is genetic testing to detect the presence of a mutated gene.

Proteins poison the CNS

Toxic concentrations of protein aggregates in the central nervous system, namely lipopigment (lipofuscin) aggregates in lysosomes, are largely responsible for the pathology of NCL. Aggregated lysosomal lipofuscin affects the neuronal cytoskeleton and cell trafficking, resulting in neuronal loss and pathological glial proliferation and activation. In all forms of NCL, lipopigment storage material accumulates in macrophages, neurons, and some somatic tissues, including vascular endothelial cells and smooth muscle cells.

Neuronal loss is extensive in most patients with NCL, leading to cortical gray matter atrophy, cerebellar atrophy, and secondary ventricular enlargement, all of which progress with disease progression. The degree of atrophy and enlargement of the ventricles varies according to the shape of the NCL. A constant hallmark of NCL is cerebral and cerebellar atrophy occurring simultaneously with enlargement of the lateral ventricles in the brain.

Studies in mouse models have shown that the thalamus and cerebellum are particularly vulnerable regions in various forms of NCL, and that somatosensory areas of the cortex are affected earlier and more severely than motor areas. Patients with NCL often suffer from sensory and motor deficits. A spinal cord injury is to blame. Both animal model studies and human autopsy studies suggest that spinal cord pathology occurs with high frequency in many types of NCL.

Vision loss is common

Most patients with NCL experience progressive vision loss. This required a detailed study of the visual pathway. In many forms of NCL, extensive retinal degeneration is also often accompanied by degeneration of the optic nerve. Because most of the proteins in NCL are widely distributed in various tissues and cell types, deficiency can also affect other organ systems in the body. Heart and intestinal problems may occur.

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A new therapy option

For adults with dementia, such as Alzheimer’s disease, there are a number of medications available that can slow the progression. Treatment of NCL is purely symptomatic.

The active substance cerliponase alfa has been approved since 2017 for late-onset infantile neuronal ceroid lipofuscinosis type 2 (NCL2) and is intended to slow the progression of the disease. Cerliponase alfa is a recombinant form of human TPP1. Thanks to enzyme replacement therapy, the storage substances that trigger CLN2 can be broken down. The drug delays neurological symptoms and prolongs the patient’s life – but has no effect on visual functions.

As approved, cerliponase alfa is given once every two weeks by intracerebroventricular infusion. This means that the drug must be administered directly to the brain to bypass the blood-brain barrier. A copy of the enzyme prevents the formation of ceroid lipofuscins, which can lead to cell death. The data situation is currently not very extensive. A study of eight young children noted cessation of neurological symptoms. However, the development gives hope that progress can be made in other forms of NCL as well.

Image source: BUDDHI KUMAR SHRESTHA, unsplash

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