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Sunday, 20 June 2004
Tuesday, 23 November 2004
Neuronal ceroid lipofuscinosis:
Batten Disease, or neuronal ceroid lipofuscinosis (NCL), is a rare condition characterized by progressive mental deterioration (dementia), epilepsy and vision loss. It results when lipofuscin, a substance made of fat and protein, builds-up in brain cells and causes them to die off. Batten disease was named after the British pediatrician who first described it in 1903. There are four main types of NCL: infantile, late-infantile, juvenile and adult. The term Batten originally referred to the juvenile type of NCL but it is now used for all forms of NCL. For 50 years it was thought to be a variant of Tay-Sachs disease (another brain storage disorder) until it was proven to be a genetically distinct disorder.
: Batten Disease is an autosomal recessive disease – an inherited genetic disorder where two defective genes are necessary to manifest symptoms. The parents of the affected child are healthy but each carries a copy of the defective gene. If both parents are carriers, about 25% of their children will develop the disease. A subtype of Adult NCL (Parry’s disease) is inherited as an autosomal dominant disorder. In this case, only a single copy of the gene is necessary to manifest symptoms and one of the patient’s parents is usually affected.
One to seven in 100,000 children in the United States have Batten Disease. The disorder is most common in Finland, where 1% of the population is thought to be carriers of the defective gene. It is not contagious or preventable.
Signs and Symptoms
There are four types of NCL that tend to appear at different ages and have different degrees of severity. Infantile NCL (Santavuori-Haltia disease) typically appears between 6 months to 2 years of age. Children initially show irritability, clumsiness, hypotonia (loss of muscle tone), and seizures. They develop cerebral atrophy (loss of brain cells), resulting in microcephaly (small head size). Loss of cells in the back of the eye (retina) leads to vision loss. Infantile NCL causes the most rapid progressive mental deterioration of all NCL types.
Late Infantile NCL (Jansky-Bielschowky disease) begins around 2 to 4 years of age. Children typically present with myoclonic seizures (brief sharp muscle contractions). Other types of seizures, such as generalized tonic-clonic or absence seizures, can also occur. These children lose muscle coordination (a symptom called ataxia). Severe cerebral atrophy and retinal cell loss occur as in Infantile NCL. Blindness develops from 4 to 6 years of age. Parkinson disease-type abnormal movements, such as tremor, muscle slowing, falling and muscle rigidity also occur. Mental deterioration is progressive and rapid.
Juvenile NCL (Batten or Spielmeyer-Vogt-Sjogren disease) presents between 5 to 8 years of age. The first symptom is blindness. Moderate cerebral atrophy occurs, resulting in gradual decline of mental function after 8 to 14 years of age. Seizures are less common, but can occur and may be of different types. Speech problems, such as stuttering, are common. Behavioral problems and sleep disturbance also develop. Juvenile NCL progresses less rapidly.
Adult NCL (Kufs or Parry’s disease) begins between 30 and 40 years of age. Symptoms are milder and progress is slowest. Blindness occurs in Kufs but not in Parry’s disease. Dementia and seizures are also common.
Several other variants of NCL have been described, including Finnish, Gypsy/Indian, Turkish, and Northern epilepsy. Each has been linked to a specific gene.
Seven genes have been identified in Batten Disease: CLN1, CLN2, CLN3, CLN5, CLN6, CLN7 and CLN8. Mutations in these genes result in the accumulation of compounds called lipofuscins, or lipopigment, in the cells. Lipo refers to fat and pigment refers to the greenish yellow color of the substance viewed under a special microscope using ultraviolet light. These substances build up in the cells of the brain, eye, skin, muscle, and other tissues and are useful in diagnosis. Different genes cause the different types of Batten Disease. CLN1, on chromosome 1, makes an enzyme called PPT1. Mutations of this gene are associated with Infantile NCL. CLN2 on chromosome 11 makes an enzyme called TPP1. Mutations are associated with Late-infantile NCL. CLN3 on chromosome 16 is linked to Juvenile NCL. CLN5 on chromosome 13 is found in the Finnish variant. CLN8 on chromosome 8 is found in the Northern epilepsy variant. The proteins made by CLN3, 5, and 8 have not yet been identified. CLN4 is associated with adult NCL. CLN6 on chromosome 15 is linked to the Gypsy/Indian variant. CLN7 is associated with the Turkish variant.
The diagnosis is considered in children who present with the three clinical features of Batten disease: vision loss, dementia and epilepsy. Evaluation by a neurologist, a doctor specializing in diseases of the brain and nervous system, is necessary. A CT scan or MRI of the brain is critical to find brain atrophy. An ophthalmologist (eye doctor) can detect loss of cells and optic nerve atrophy within the eye. Recently, blood tests assessing PPT1 and TPP1 levels have become available; however they are available on a research basis only. Electroencephalogram (EEG) is a special test where wires placed on the scalp record the brain’s electric activity. This aids in defining the type of seizure. Electric studies of the eyes - visual-evoked potential (VEP) and electroretinogram (ERG) - can evaluate the eye abnormalities. However, the most effective tool in diagnosing Batten disease is to look for NCL deposits using a very powerful electron microscope (EM). EM studies can be performed on blood or on a small piece of tissue biopsied from the skin/muscle/eye/rectum.
The shape of the lipofuscin deposits help determine which form the patient has. Sand-like deposits (Gravel or sand-like granular osmophilic deposits, GRODs) are found in Infantile NCL. Comma-shaped curvilinear and rectilinear deposits are seen in Late-infantile NCL. Fingerprint-like deposits, as well as white blood cells that appear to have holes in them, are characteristic of Juvenile NCL. DNA testing for a specific gene mutation is available on a research basis. Carrier screening and prenatal diagnosis in a family with an affected child is also possible. Consultation with a geneticist is recommended.
No specific treatment or cure is available for Batten Disease. Bone marrow transplant (replacing the blood making cells of the body) has not had much success. Vitamin E and Selenium supplementation may by slightly helpful for some people, especially for Finnish patients. Seizure control is at the crux of treatment for Batten disease currently. Depending on the type of seizures, an antiepileptic drug will be selected by the child’s neurologist. Antiepileptic drugs, such as valproic acid, lamotrigine, and clonazapam are commonly used.
In addition, treating the many complications of Batten disease can significantly improve the child’s quality of life. These conditions are acid reflux disease (severe heartburn), pneumonia, muscle rigidity, behavioral problems, hyperactivity, depression, and insomnia. Physical and occupation therapy may help children retain mobility.
Research is being done to find a treatment by enzyme or gene replacement.
Life span is usually shortened by Batten disease. The younger the onset of symptoms, the more severe the course of disease, leads to an earlier possible death. In Infantile NCL, children live to 5-10 years of life. In Late-infantile NCL, death occurs between ages 8 and 12 years. In Juvenile NCL, children die in their early 20-30s. Life expectancy is shortened for adults with NCL as well.
Connect with other parents
In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.
Batten Disease Support and Research Association (BDSRA)
Well constructed family support and research site.
National Institute of Neurological Disorders and Stroke (NINDS)
NIH site with links to current studies.
Batten Disease Family Association
Family support site.