Childhood dementia is a neurological disorder that affects brain metabolism. Typical symptoms include retinal degeneration, epileptic seizures, visual loss, deafness, cognitive deterioration, and impaired motor functions, with a high probability of early death.

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What is Childhood Dementia?

Childhood dementia is a very rare genetic disease that occurs as a result of complex neurodenerative and metabolic diseases. Because of its rarity, there is a lack of information and awareness about this life-threatening disorder, which often leads to late or improper diagnosis and delayed onset of treatment.

Moreover, early diagnosis of childhood dementia is problematic because initial symptoms are not very specific and mostly related to other neurological disorders. Since dementia-related brain damages are irreversible, delayed diagnosis is particularly dangerous for children and often leads to premature death.

Causes of Childhood Dementia

The primary cause of childhood dementia is neuronal ceroid lipofuscinoses (NCLs), which are a group of genetic, neurodegenerative, lysosomal storage disorders inherited in an autosomal recessive manner. With a global prevalence of 7-8 per 100,000 births, NCLs are the most leading cause of childhood dementia worldwide.

NCLs are characterized by severe neurodegeneration in the central nervous system and accumulation of lipofuscin-like autofluorescent storage material in the neurons, microglia, macroglia, but also other cell types. The classification of different types of NCLs mainly depends on the affected or disease causing gene and age of disease onset. To date, 14 genes have been identified that are known to cause NCLs.

According to the age of onset and clinical manifestations, NCLs are subdivided into following types:

Congenital – it is caused by mutation in CTSD gene. The age of onset is before or around birth, and clinical manifestations are seizures and microcephaly.

Infantile (INCL) – it is caused by mutations in PPT1 and KCTD7 genes. The age of onset is 6-24 months, and typical symptoms are deterioration of cognitive and motor abilities, vision loss, and seizures.
 

Late-infantile (LINCL) – mutations in CLN2/TPP1, CLN5, CLN6, MFSD8, CLN8, CTSD, and PPT1 genes are responsible For this form of NCL, which mainly occurs in children with an age range of 2-7.5 years. Clinical characteristics include cognitive and motor abilities, vision loss, and seizures.

Juvenile (JNCL) – mutations in CLN3, PPT1, CLN2/TPP1, CLN9, and ATP13A2 genes are responsible for this form of NCL. Typical age of onset is 4-10 years, and clinical features are cognitive and motor abilities, vision loss, and seizures.

Adult forms – Kufs disease and Parry disease are two major forms that appear in adults with an age range of 15-50 years.

Among all NCLs, most prevalent forms are juvenile (CLN3 disease) and late infantile (CLN2 disease). Children suffering from classical CLN2 disease have a life expectancy of 8-12 years.       

Other Lysosomal Storage Diseases Causing Childhood Dementia

Besides NCLs, other lysosomal storage diseases such as Niemann-Pick disease type-C (NPC) and mucopolysaccharidoses are also responsible for childhood dementia. NPC is another inherited neurodenerative disorder that hits children at any age - from early infancy to the adolescence.

A genetic mutation in either NPC1 or NPC2 gene is mainly responsible for developing this disease. It occurs as a result of impaired cholesterol and lipid metabolism in the body, leading to accumulation of fatty substances in the brain, liver, spleen, and lung. The primary symptom of NPC is dementia, which usually becomes noticeable in school going children.

Dementia-related symptoms of NPC mainly include poor concentration, lack of insight, poor judgment, impaired short-term memory formation, and learning difficulties. All these symptoms collectively lead to severe cognitive and motor disabilities and premature death.

The Role of Mucopolysacchardiosis and Leukodystrophies

Mucopolysaccharidosis is another inherited disease characterized by impaired breakdown of long-chain sugar molecules such as mucopolysaccharides. This results in abnormal accumulation of sugar in the cells, blood, and connective tissue, leading to impaired motor functioning, progressive cognitive decline, and multiple organ failure. However, despite being a leading cause of childhood dementia, basic research and clinical studies concerning the association between mucopolysaccharidosis and childhood dementia are lacking.

Leukodystrophies, a group of inherited metabolic disorders affecting the brain, spinal cord, and peripheral nervous system, are also related to childhood dementia. These disorders are associated with abnormal development or destruction of myelin sheath (i.e.nerve covering) in the central nervous system, which results in progressive loss of motor control and cognitive function/development, ataxia, seizures, and premature death. Since the loss of cognitive function occurs gradually in leukodystrophies, dementia is not an early symptom in these cases.