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 [10].

• Visual Impairment

  […] ceroid lipofuscinosis neuronal ceroid lipofuscinosis (nū-rŏn′ĭl), NCL One of several mostly autosomal recessive neurodegenerative disorders, characterized by regression of previously attained development, visual impairment, seizures, dementia, and early [medical-dictionary.thefreedictionary.com]

  […] loss Progressive loss of vision Progressive vision loss Progressive visual impairment Slowly progressive visual loss Vision loss, progressive Visual loss, progressive [ more ] 0000529 Rectilinear intracellular accumulation of autofluorescent lipopigment [rarediseases.info.nih.gov]

  Infantile NCL with CLN1 mutation presents with motor disturbances (ataxia, hypotonia, spasticity), visual impairment, seizures, dementia, and familial occurrence. [pediatricneurosciences.com]

• Visual Impairment

  […] ceroid lipofuscinosis neuronal ceroid lipofuscinosis (nū-rŏn′ĭl), NCL One of several mostly autosomal recessive neurodegenerative disorders, characterized by regression of previously attained development, visual impairment, seizures, dementia, and early [medical-dictionary.thefreedictionary.com]

  […] loss Progressive loss of vision Progressive vision loss Progressive visual impairment Slowly progressive visual loss Vision loss, progressive Visual loss, progressive [ more ] 0000529 Rectilinear intracellular accumulation of autofluorescent lipopigment [rarediseases.info.nih.gov]

  Infantile NCL with CLN1 mutation presents with motor disturbances (ataxia, hypotonia, spasticity), visual impairment, seizures, dementia, and familial occurrence. [pediatricneurosciences.com]

• Progressive Loss of Vision

  […] degeneration of movement 0002333 Myoclonus 0001336 Progressive visual loss Progressive loss of vision Progressive vision loss Progressive visual impairment Slowly progressive visual loss Vision loss, progressive Visual loss, progressive [ more ] 0000529 [rarediseases.info.nih.gov]

  […] decline in cognitive and motor functions, progressive loss of vision, and refractory seizures. [neurologyindia.com]

• Psychomotor Retardation

  [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]

• Abnormal Behavior

  Behavioral disturbances Behavioral problems Behavioral/psychiatric abnormalities Behavioural/Psychiatric abnormality Psychiatric disorders Psychiatric disturbances [ more ] 0000708 Showing of 16 | Last updated: 3/1/2019 Making a diagnosis for a genetic [rarediseases.info.nih.gov]

• Seizure

  […] 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]

  Myoclonic seizures don’t usually cause a complete loss of consciousness or severe shaking or jerking the way a generalized tonic-clonic seizure does. Myoclonic seizures can be preceded by an aura, or a sense that a seizure is going to happen. [verywellhealth.com]

  His seizure frequency has reduced. Otherwise the course is progressive. [annalsofian.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]

• Myoclonus

  Other features like myoclonus, ataxia and vision loss develop later in the course with optic atrophy being detectable within 2½ years of vision loss. [annalsofian.org]

  Clinical manifestations include seizures, progressive mental and motor deterioration, myoclonus, visual failure, dementia and premature death. [alliedacademies.org]

  Myoclonus can also occur due to several diseases of the spine or the nerves. Occasionally, myoclonus can occur as a result of electrolyte or hormonal changes. [verywellhealth.com]

  Clinical features include mental retardation and behavoural distubance, which may be accompanied by extrapyramidal symptoms (facial dyskinesia) and myoclonus epilepsy. [alzheimer-europe.org]

  Affected people may experience loss of muscle coordination (ataxia ), seizures that do not respond to medications, muscle twitches (myoclonus), visual impairment, and cognitive/motor decline. It occurs predominantly in the Finnish population. [rarediseases.info.nih.gov]

• Cerebellar Ataxia

  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]

  [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]

  ataxia, bulbar symptoms, and extrapyramidal and pyramidal signs, but without retinal lesions and rapidly progressive dementia. [icd10data.com]

• Dysarthria

  We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. [ncbi.nlm.nih.gov]

  Showing of 20 | Medical Terms Other Names Learn More: HPO ID 5%-29% of people have these symptoms Cerebellar atrophy Degeneration of cerebellum 0001272 Dysarthria Difficulty articulating speech 0001260 Dysdiadochokinesis Difficulty performing quick and [rarediseases.info.nih.gov]

  Some individuals experience difficulties in coordinating voluntary movements (ataxia) or difficulty speaking (dysarthria). Type B often has similar symptoms to type A. [rarediseases.org]

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 [11].

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 [10].

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 [3] [4]. 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 [5].

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 [6] [7]. 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 [8]. 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 [9].

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 [1].

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 [2]. 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.

1. Hofmann SL, Peltonen L. The Neuronal Ceroid Lipofuscinoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. NewYork: McGraw-Hill; 2001. p. 3877–94.
2. Zeman, W., Dyken, P. Neuronal ceroid-lipofuscinosis (Batten's disease): relationship to amaurotic familial idiocy. Pediatrics 44: 570-583, 1969.
3. Mole SE, Goebel HH, Williams R, editors. The neuronal ceroid lipofuscinoses (Batten disease). 2nd ed. Biomedical and Health Research. Amsterdam: IOS Press; 2009.
4. Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease) Jacqueline A. Hawkins-Salsbury, Jonathan D. Cooper, Mark S. Sands Biochemical et biophysica acta (BBA) volume 1832, issue 11 November 2013. Pages 1906–1909.
5. Williams RE: Appendix 1: NCL incidence and prevalence data. In The Neuronal Ceroid Lipofuscinoses (Batten Disease). 2nd edition. Edited by Mole SE, Williams RE, Goebel HH. Oxford: Oxford University Press; 2011:361-363.
6. Moore SJ, Buckley DJ, MacMillan A, Marshall HD et al. The clinical and genetic epidemiology of neuronal ceroid lupofuscinosis in Newfoundland. Clin Genet 2008, 74:213-222.
7. Verity C, Winstone AM, Stellitano L, Will R, et al. The epidemiology of progressive intellectual and neurological deterioration in childhood. Arch Dis Child. 2010, 95:361-364.
8. Carpenter S, Karpati G, Andermann F. A type of juvenile cerebromacular degeneration characterized by granular osmiophilic deposits. J Neurol Sci. 1973;18:67-87.
9. Sleat DE, Gin RM, Sohar I, Wisniewski K, et al. Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. Am J Hum Genet.1999;64:1511-1523.
10. Anderson GW, Smith VV, Brooke I, Malone M et al. Diagnosis of neuronal ceroid lipofuscinosis (Batten disease) by electron microscopy in peripheral blood specimens. Ultrastruct Pathol. Sep-Oct 2006;30(5):373-8.
11. Narducci N, Verga ML, Binelli S, et al. Neuronal ceroid-lipofuscinosis: a clinical and morphological study of 19 patients. Am J Med Genet. 1995;57:137-141