Childhood dementia | |
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Other names | Pediatric dementia |
Specialty | Neurology, Psychiatry, Pediatrics |
Symptoms | Loss of previously acquired developmental skills, seizures, cognitive decline |
Usual onset | Childhood or adolescence |
Duration | Progressive |
Causes | Genetic disorders, neurodegenerative diseases |
Diagnostic method | Biochemical testing, genetic testing |
Treatment | Symptomatic treatment (anticonvulsants, physiotherapy, etc.) |
Prognosis | Poor (life expectancy between 9-16 years) |
Childhood dementia is a group of rare neurodegenerative conditions that lead to progressive cognitive and physical decline in children. It affects mental function, causing the loss of previously acquired developmental skills such as walking, talking, and reasoning. This umbrella term includes over 100 distinct disorders, many of which are linked to genetic causes. [1] The most common cause of childhood dementia is neuronal ceroid lipofuscinoses (NCL), a group of lysosomal storage disorders. [2]
Childhood dementia typically manifests as a gradual loss of cognitive and motor functions. Symptoms can vary depending on the specific condition but often include:
Other complications include loss of vision or hearing, respiratory issues, and bone or joint problems.
The majority of childhood dementia cases are caused by genetic mutations that lead to neurodegenerative diseases. The most frequent cause is neuronal ceroid lipofuscinoses (NCL), a family of lysosomal storage disorders. [2] Other causes include mitochondrial diseases, peroxisomal disorders, and other genetic disorders affecting brain function. [5]
Diagnosis typically involves a combination of biochemical testing and genetic testing, often performed around the age of four. Early diagnosis is crucial for managing symptoms and improving the quality of life for those affected. [1] In most cases, childhood dementia is diagnosed after developmental regression is observed.
There is no cure for most forms of childhood dementia. Treatment focuses on managing symptoms and improving quality of life. Common management strategies include:
The prognosis for childhood dementia is generally poor, with most children experiencing a significant decline in cognitive and motor function. Life expectancy varies depending on the underlying cause, but it is often significantly reduced. Studies show that only 25–29% of affected individuals survive to adulthood, and only 10% reach the age of 50. [1] The median life expectancy is around 9 years. [1]
Current estimates place the incidence of childhood dementias at 1 in 1186 births. [1] This is higher than the incidence of some well-recognised diseases, such as Cystic Fibrosis [7] (~1 in 3000-4000 births [8] ) and Spinal Muscular Atrophy (1 in 11000 births [1] [9] ).
The estimates for the prevalence are 1 in 3484 people in the general population and 1 per 1715 among children
The concept of childhood dementia gained recognition in the early 20th century with the identification of Batten disease, one of the first known forms of childhood dementia. British neurologists first described batten disease Frederick Batten in 1903. [10]
Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.
Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes. Men and women appear to be equally affected. FTD generally presents as a behavioral or language disorder with gradual onset. Signs and symptoms tend to appear in late adulthood, typically between the ages of 45 and 65, although it can affect people younger or older than this. Currently, no cure or approved symptomatic treatment for FTD exists, although some off-label drugs and behavioral methods are prescribed.
Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare lifelong genetic disease that mainly affects the brain and spinal cord. It is caused by a problem with how the body breaks down certain large sugar molecules called glycosaminoglycans (also known as GAGs or mucopolysaccharides). In children with this condition, these sugar molecules build up in the body and eventually lead to damage of the central nervous system and other organ systems.
Batten disease is a fatal disease of the nervous system that typically begins in childhood. Onset of symptoms is usually between 5 and 10 years of age. Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).
Neuronal ceroid lipofuscinosis is a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.
Infantile neuronal ceroid lipofuscinoses (INCL) or Santavuori disease or Hagberg–Santavuori disease or Santavuori–Haltia disease or Infantile Finnish type neuronal ceroid lipofuscinosis or Balkan disease is a form of NCL and inherited as a recessive autosomal genetic trait. The disorder is progressive, degenerative and fatal, extremely rare worldwide – with approximately 60 official cases reported by 1982.
Myoclonic epilepsy refers to a family of epilepsies that present with myoclonus. When myoclonic jerks are occasionally associated with abnormal brain wave activity, it can be categorized as myoclonic seizure. If the abnormal brain wave activity is persistent and results from ongoing seizures, then a diagnosis of myoclonic epilepsy may be considered.
A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16. Battenin is not clustered into any Pfam clan, but it is included in the TCDB suggesting that it is a transporter. In humans, it belongs to the atypical SLCs due to its structural and phylogenetic similarity to other SLC transporters.
Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).
Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene, also known as CLN2. TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene. Mutations in the TPP1 gene leads to late-infantile neuronal ceroid lipofuscinosis.
Ceroid-lipofuscinosis neuronal protein 6 is a protein that in humans is encoded by the CLN6 gene.
Ceroid-lipofuscinosis neuronal protein 5 is a protein that in humans is encoded by the CLN5 gene.
Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.
Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body due to a deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. This late-infantile form of the disease progresses rapidly once symptoms are onset and ends in death between age 8 and teens. The prevalence of Jansky–Bielschowsky disease is unknown; however, NCL collectively affects an estimated 1 in 100,000 individuals worldwide. Jansky–Bielschowsky disease is related to late-infantile Batten disease and LINCL, and is under the umbrella of neuronal ceroid lipofuscinosis.
Northern epilepsy syndrome (NE), or progressive epilepsy with mental retardation (EPMR), is a subtype of neuronal ceroid lipofuscinosis and a rare disease that is regarded as a Finnish heritage disease. Unlike most Finnish heritage diseases, this syndrome has been reported only in Finland. The disease is characterized by seizures in early childhood that progressively get worse until after puberty. Once the onset of seizures occurs, mental degradation is seen. This continues into adulthood, even after seizure frequency has decreased. The cause of the disease is a missense mutation on chromosome 8. The creation of a new protein occurs, and the lipid content of the brain is altered because of it. The ratio of the mutation carriers is 1:135. There is nothing that has been found to stop the progression of the disease, but symptomatic approaches, such as the use of benzodiazepines, have helped control seizures.
Kufs disease is one of many diseases categorized under a disorder known as neuronal ceroid lipofuscinosis (NCLs) or Batten disease. NCLs are broadly described to create problems with vision, movement and cognitive function. Among all NCLs diseases, Kufs is the only one that does not affect vision, and although this is a distinguishing factor of Kufs, NCLs are typically differentiated by the age at which they appear in a patient.
Cerliponase alfa, marketed as Brineura, is an enzyme replacement treatment for Batten disease, a neurodegenerative lysosomal storage disease. Specifically, Cerliponase alfa is meant to slow loss of motor function in symptomatic children over three years old with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency, a soluble lysosomal enzyme deficiency. Approved by the United States Food and Drug Administration (FDA) on 27 April 2017, this is the first treatment for a neuronal ceroid lipofuscinosis of its kind, acting to slow disease progression rather than palliatively treat symptoms by giving patients the TPP1 enzyme they are lacking.
Sara Elizabeth Mole Crowley is a Professor of Molecular Cell Biology and Provost's Envoy for Gender Equality at University College London and the Great Ormond Street Hospital. She works on diseases caused by genetic changes, in particular neurodegenerative diseases that impact children.
Erika F. Augustine is an Associate Chief Science Officer and Director of the Clinical Trials Unit at Kennedy Krieger Institute. She was previously an Associate Professor of Neurology and Pediatrics at the University of Rochester Medical Center in Rochester, New York. Augustine co-directed the University of Rochester Batten Center, and was the associate director of both the Center for Health and Technology and the Udall Center of Excellence in Parkinson's Disease Research. Augustine's clinical research and medical practice specialize in pediatric movement disorders. She leads clinical trials for Batten diseases, a group of rare pediatric neurodegenerative disorders, and she has developed a novel telemedicine model to increase the efficacy of remote care for patients with rare diseases.