Most of the infants with Infantile Neuronal Ceroid Lipofuscinosis appear to develop normally up to 6 months of age after birth. After 6 months, slowly they start developing indifference to the surroundings. Their reflexes to stimuli show an unusual delay or are often completely absent. There is mental retardation as they lose coordination in their activities; skillful tasks are difficult to be performed. They lose ability to speak, to reason out and there is deterioration in their previously acquired skills of activity.
In these children the brain development begins to cease and they develop microcepahaly. Children also suffer from recurrent attacks of seizures. In addition, they also have neuromuscular abnormalities such as cerebellar ataxia in which the voluntary movements are poorly coordinated. Hence, there is a loss of balance while walking and maintaining posture becomes difficult. The child is unable to stand or walk by himself. Moreover abnormal involuntary movements of hands are observed.
As the disease progresses the child develops generalized muscle weakness and loss of muscle tone (hypotonia). Later, there are muscular spasms and rigidity of the entire body. The most important feature of this disease is the involvement of the eyes. There is narrowing of the retinal vessels, macular pigmentation which is accumulation of yellowish-gray pigmentation on the macula densa.There is retinal degeneration. The child experiences visual disturbances and impairment. This is due to optic nerve atrophy. In majority of the cases studied, it was found that eventually the child losses his vision completely by the end of 1-2 years. The neurodegeneration is continued and there is a complete loss of brain activity. The child soon becomes completely immobile, there are sudden spasms in the muscles, reflexes are exaggerated, light or no response to stimuli. This finally culminates into death .
Entire Body System
Camp & Sandra L. [nature.com]
Medline Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, Hoffman SL, Peltonen L. 1995. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376 : 584 – 587. [onlinelibrary.wiley.com]
Camp LA, Verkruyse LA, Afendis SJ, Slaughter CA, Hofmann SL. Molecular cloning and expression of palmitoyl-protein thioesterase. J Biol Chem 1994;269:23212–9 6. [journals.lww.com]
Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, et al. Mutations in the palmitoyl protein thicesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 1995;376:584-7. (2.) [thefreelibrary.com]
Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, HoVman SL, Peltonen L. 1995. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376: 584â587. Prenat. [docslide.com.br]
Unable to Stand
Entire body system Unable to Stand The child is unable to stand or walk by himself. Moreover abnormal involuntary movements of hands are observed. [symptoma.com]
There is narrowing of the retinal vessels, macular pigmentation which is accumulation of yellowish-gray pigmentation on the macula densa.There is retinal degeneration. The child experiences visual disturbances and impairment. [symptoma.com]
On ophthalmological inves- tigation, depigmentation of the macula with granular pigmentation in the peripheral retina was found with Finnish late infantile FP/CL CLN5 Variant late infantile FP/CL CLN6 1 Variant late infantile FP/CL CLN7 Variant late infantile [docslide.com.br]
[symptoma.com] psychiatrical Psychomotor Retardation It is characterized by rapid deterioration with psychomotor retardation, loss of speech, seizures, ataxia, blindness, hypotonia, microcephaly, and occasional convulsions. [symptoma.com]
It is characterized by rapid deterioration with psychomotor retardation, loss of speech, seizures, ataxia, blindness, hypotonia, microcephaly, and occasional convulsions. Mapped to chromosome 1p32. [icd10data.com]
Seizures (6 patients) and psychomotor retardation (1 patient) were the initial symptoms in the INCL group. All the patients in the group of LINCL had the usual findings. [scielo.br]
[…] deterioration, ataxia, and epileptic seizures [ncbi.nlm.nih.gov] Seizures may be drops, vacant spells or motor seizures with violent jerking of the limbs and loss of consciousness. [symptoma.com]
Seizures may be drops, vacant spells or motor seizures with violent jerking of the limbs and loss of consciousness. Seizures may be controlled by medicines for several months but always recur, becoming difficult to control. [checkorphan.org]
The loss of granule neurons and GABAergic interneurons followed in each corresponding cortical region, before the onset of seizure activity. [ncbi.nlm.nih.gov]
There are over 200 inherited disorders that are associated with seizures and prompt identification and intervention is crucial for a positive outcome. [books.google.com]
Clinical manifestations include seizures, progressive mental and motor deterioration, myoclonus, visual failure, dementia and premature death. [alliedacademies.org]
By 4-5 years the children usually have myoclonic jerks of their limbs and head nods. They may have difficulties sleeping and become distressed around this time, often for no obvious reason. Vision is gradually lost. [checkorphan.org]
CLN1 disease is characterized by delays in reaching developmental milestones (developmental delays), twitching or jerking of muscles (myoclonic jerks), seizures, and mild to moderate intellectual disability. [rarediseases.org]
Myoclonic Jerks Myoclonus, also described as myoclonic jerks, are rapid, involuntary muscle contractions. Some people regularly experience one or two myoclonic jerks when falling asleep without any progression to a seizure. [verywellhealth.com]
Also typical are short, sharp muscle contractions called myoclonic jerks. Initial signs of this disorder include delayed psychomotor development with progressive deterioration, other motor disorders, or seizures. [katwasabi.com]
[icd10data.com] Cerebellar Ataxia We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia. [symptoma.com]
We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia. [Indexed for MEDLINE] Free full text [ncbi.nlm.nih.gov]
ataxia, bulbar symptoms, and extrapyramidal and pyramidal signs, but without retinal lesions and rapidly progressive dementia. [icd10data.com]
Abnormal Involuntary Movement
[icd10data.com] Abnormal Involuntary Movement Moreover abnormal involuntary movements of hands are observed. As the disease progresses the child develops generalized muscle weakness and loss of muscle tone (hypotonia). [symptoma.com]
The first symptom is motor clumsiness, followed by progressive visual failure, mental and motor deterioration and later by myo- clonus and seizures. [docslide.com.br]
Skin biopsies are done which have specific findings for the particular type of NCL. In Infantile NCL, GRODs, curvilinear bodies (CB), and fingerprint profiles (FP) are seen .
EEG shows disorganized spike and slow wave complexes, loss of posterior dominant rhythm characteristic in infantile form to eye opening.
MRI shows cerebral and cerebellar atrophy, elevated glial marker, and high amount of lactate in grey and white matter.
DNA testing has been used to identify NCLs like Infantile NCL , localizes GROD (granular osmiophilic deposits) of CLN-1 .
Histological studies of Infantile NCL show neuronal loss. In late onset NCL, there are vacuolated lymphocytes observed. For juvenile onset NCL, along with neuronal loss there is extensive gliosis and complete loss of purkinje cells. In adult onset variant, findings include neuritis due to distension of axon hillock seen in III layer.
Enzyme assays are the best diagnostic tests for the condition. The PPT enzyme levels are measured from a sample of a dried blood spot taken on a filter paper, and if the enzyme activity is less than 5% of normal, Infantile Neuronal Ceroid Lipofuscinosis is confirmed.
NCLs are fatal disease. There is no specific treatment for NCL, however a palliative treatment is given to arrest the progress of the neuronal damage. The goal of the treatment is to provide the nervous cells and tissue with adequate amounts of the deficient enzyme PPT. This can be acquired through stem cell transplants which are being explored currently. Enzyme therapy of virally mediated CLN1 gene has improved neurological condition and gene replacement treatment by using injection of AAV2-PPT1 has increased the enzyme levels. Experiments show that these methods help to slow the progress of the nerve damage.
Besides these, symptomatic treatment is given to control convulsions like lamotrigine, valroic acid derivatives. Spasticity and rigidity is controlled by muscle relaxants such as baclofen and benzodiazepine derivatives. A drug named Flupirtine has proved to protect PPT1-deficient cells from apoptosis. In a particular experiment, a PPT1 deficiency infected mice was treated with CLN1 gene and it showed neurogical improvement. This therapy is also being thought of to use for humans.
Infantile Neuronal Ceroid Lipofuscinosis is an incurable disease. Hence the prognosis is bad. Children deteriorate progressively. They develop degenerative symptoms. The child can survive from 2 to 5 years barely after the diagnosis.
There are 8 CLN genes that undergo mutations (CLN 1-8) due to an enzyme deficiency called palmitoyl protein thioesterase-1 (PPT1). The most commonly affected genes in pediatric age group are CLN 1, 2 and PPT 1 found in lysosomes of the cells of lipopigments leading to cellular destruction  . This enzyme normally removes the fatty acids from the cells so that they can be used for energy, but due to the gene mutation there is a deficiency of the enzyme which in turn causes an increase in the accumulation of the fatty acids.
Palmitoyl protein thioesterase-1 has a variety of other cellular functions such as endocytosis, vesicle trafficking, apoptosis and forming synapses.
Clinical database reveals that the actual incidence of Infantile Neuronal Ceroid Lipofuscinosis is seen in children. Studies over past 10 years with the help of molecular genetics for confirmation of clinical diagnosis have concluded that the epidemiology of NCLs has got a worldwide distribution more over in specific geographical areas .
On further investigation it was found that, the incidence of childhood onset Infantile Neuronal Ceroid Lipofuscinosis in Italy is less as compared to other European countries  . It is estimated that 2 to 4 live births of every 100,000 are affected with this disease.
Neuronal Ceroid Lipofuscinosis is an inherited autosomal recessive disorder. In this, an individual who carries both of the diseased mutated genes will manifest the symptoms. Depending on the age, symptoms and morphology, it is classified into four major types.
These are Infantile Neuronal Ceroid Lipofuscinosis (NCL) in which the defective gene is NCL1, late infantile NCLs in which the defective gene is NCL2, juvenile NCLs in which the defective gene is NCL3 and adult NCLs in which the defective gene is NCL4 . The lipopigments that accumulate in the nerve cells, muscles, skin and tissues throughout the body, form and resemble different shapes such as curvilinear bodies or comas or fingerprints bodies or granular osmophilic deposits (GROD). These are important references for diagnosis on histological examination .
The possibility of prevention of NCL can be expected by newborn screening and treatment. Prenatal diagnosis and genetic counseling has a vital role in the prevention of NCLs. DNA analysis provides reliable information about carriers for NCLs.
Infantile Neuronal Ceroid Lipofuscinosis (NCL) is a genetic disorder affecting the nervous system fatal in character. It is also known as Batten disease. It occurs due to degeneration of neuronal cells leading to progressive decline in mental and motor capacities, retinal degeneration, epilepsy and microcephaly .
In this disorder, there is accumulation of autofluoroscent lipopigments which replicate lipofuscin and ceroid in the nerve cell; hence it is named as Neuronal Ceroid Lipofuscinosis, first introduced by Zeman and Dyken in 1969 . Studies reveal the importance of prenatal diagnosis in prevention of this disease.
Infantile Neuronal Ceroid Lipofuscinosis is an inherited autoimmune recessive disorder. It is found in children who inherit 2 defective genes from their parents. A child who has only one copy of defective gene is normal and is the carrier for NCL. They may have children suffering from this disorder but do not manifest any symptoms themselves.
In Infantile Neuronal Ceroid Lipofuscinosis, there is a deficiency of an enzyme called palmitoyl protein thioesterase-1 (PPT1) which leads to genes mutations. The specific gene that is involved in Infantile Neuronal Ceroid Lipofuscinosis is CLN 1 gene. This gene acts on the nervous system which involves the brain and other structures called spinal cord, putamen, and thalamus.
Infantile Neuronal Ceroid Lipofuscinosis affects infants. They are born healthy and develop normally up to 6 months from birth, but after 6 months their mental development comes to a halt. Later by one year age, there are signs of further decline and child fails to thrive. They remain bedridden and get repeated attacks of convulsions. There are muscular spasms. The most important part of the body affected in almost every case is the eye. There is retinal degeneration, the optic nerve undergoes atrophy, and there is a complete visual loss. The child is completely mentally retarded, he loses his ability to think and reason.
Deposits of lipopigments are found in the nerve cells, skin, muscles and various tissues of the body; hence the diagnosis can be very well obtained from the histology reports of these specimens. The specimens show characteristic forms of coma (curvilinear bodies), finger prints inclusions etc which are peculiar features in diagnosing INCL.
CT scans and MRI shows nerve damage, areas of atrophy. There is no specific treatment for this disease as there is a progressive degeneration and outcome is fatal. However, recent studies link stem cell replacement and gene therapy to arrest the nerve damage and hence increase the period of life expectancy of the child. Apart from this, certain muscles relaxants, anti convulsion treatments are given periodically to the child.
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