The term neuronal ceroid lipofuscinosis is used to describe various forms of a hereditary and as yet incurable metabolic disease of the central nervous system and retina. All ten forms of the disease have in common that ceroid, a waxy metabolic product, and lipofuscin, which contains fat and protein, are deposited in the nerve cells and cause a gradual loss of function. Certain forms of the disease occur in infancy or childhood and lead to complete loss of cognitive and motor abilities via gradual blindness, epilepsy, and dementia.
What is neuronal ceroid lipofuscinosis?
Ten different variants of the hereditary disease neuronal ceroid lipofuscinosis (NCL, also CLN), which is incurable to date, are known, some of which manifest in infancy and toddlerhood, others only in adulthood. All forms of the disease are characterized by typical ceroid and lipofuscin deposits in the nerve cells and in the retina. Ceroid is a substance reminiscent of wax and lipofuscin is a protein- and fat-containing brownish substance. Both are intermediate waste products of cellular metabolism that are normally further processed or removed and excreted. The deposits in the nerve cells and in cells of the retina cause a gradual loss of function, which is initially manifested by a reduction in vision and brain performance in the cognitive and motor areas. The different forms of NCL are designated NCL1 through NCL10 according to the order of their discovery. While the onset of most forms of the disease is limited to a typical age in each case, the onset of a few forms, such as CLN1, can occur in late infancy or even adulthood. In addition to typing and designating neuronal ceroid lipofuscinosis as NCL1 to NCL10, verbal designations are also commonly used to refer either to its discoverers or to the respective age, such as infantile, juvenile, or adult NCL.
Causes
Only gene mutations can be considered as causative agents of the various forms of neuronal ceroid lipofuscinosis. The loci of the mutated genes that are “responsible” as triggers of each individual manifestation of the disease are not all located on the same chromosome, but affect several different chromosomes. This means that the metabolic processes involved are complex and multi-step conversions, each of which may be disrupted and lead to similar disease manifestations. With the exception of NCL4 (adult NCL), which is inherited in an autosomal dominant manner, all other forms of the disease are inherited in an autosomal recessive manner. This means that in no form of the disease are sex chromosomes X or Y involved and that both partners must have the same mutation allele of the gene in question for the disease to occur. Only in NCL4 is it sufficient for the onset of the disease if either the male or female has the mutated gene (autosomal dominant inheritance).
Symptoms, complaints, and signs
The clinical pictures of all ten known forms of neuronal ceroid lipofuscinosis proceed in a similar form and sequence. Increasing visual loss with deposits of ceroid and lipofuscin in retinal cells characterize the initial symptoms and signs of the disease. The visual impairment progresses progressively and leads, for example, in juvenile NCL to complete blindness after one to two years. At the same time, affected individuals show cognitive and motor impairments that intensify as the disease progresses and can trigger hallucinations and epileptic seizures. The disease is always accompanied by dementia – even in the case of affected babies or young children. All signs and symptoms increase over the course of the disease in a time frame of about 10 to 15 years and ultimately lead to death, because there is as yet no cure for the disease.
Diagnosis and disease progression
The final determination on the presence of a form of neuronal ceroid lipofuscinosis is always accompanied by a very poor prognosis, so the diagnosis should be appropriately confirmed. Different investigations are considered for the different forms of NLC.Should an initial suspicion arise due to non-specific symptoms such as declining vision, dementia symptoms and epileptic seizures and if NCL disease is known within the family, the suspicion should be confirmed or discarded by a clear diagnosis. Reliable evidence is provided by an ocular examination of the retina for fuscin and ceroid deposits. Tissue samples can also be taken, which can be examined microscopically for deposits. Other important clues are provided by the activity of certain lysosomal enzymes. In the presence of NLC10, the congenital form of NLC that is active from birth, decreased activity of cathepsin D is considered a definite indication of NLC10 disease. Magnetic resonance imaging (MRI) is the main imaging modality available, which can clearly identify, for example, the degradation of brain matter. Ultimately, examination of specific genes for the presence of the mutations that cause the disease leads to final certainty.
Complications
In this disease, patients may suffer from various symptoms and limitations. For this reason, a general course cannot usually be predicted. However, limitations in the motor and cognitive abilities of the affected person occur, so that the patients are considerably restricted in their everyday life and in many cases are also dependent on the help of other people. Most of those affected suffer from visual impairment, which increases in the course of the disease. In the worst case, complete blindness can result. Children and adolescents in particular can suffer from severe psychological symptoms or depression as a result of the blindness. Epileptic seizures also occur with this disease and reduce the quality of life. In the worst case, this can lead to the death of the affected person. Likewise, most patients suffer from dementia and hallucinations. The life expectancy of the affected person is considerably reduced by the disease. Unfortunately, treatment of the disease is not possible. The individual symptoms can be alleviated. However, there is no complete cure of the disease.
When should one go to the doctor?
When epileptic seizures, visual disturbances, and other classic signs of neuronal ceroid lipofuscinosis are noticed, a visit to the doctor is recommended. These rare brain degeneration disorders progress rapidly and require early evaluation by a physician. Persons suffering from the above-mentioned complaints without any other cause are best advised to make an appointment with a neurologist. He or she can narrow down the possible ailments and make a diagnosis on the basis of various physical examinations. Since neuronal ceroid lipofuscinosis is hereditary, a diagnosis may be possible even before birth, provided there is an appropriate family history. At the latest, the condition can be detected during newborn screening. If this is not the case, the parents must consult the doctor when the signs of the disease mentioned at the beginning appear. In addition to the family doctor and neurologist, various specialists such as the ophthalmologist or an orthopedist may be involved in the treatment. A physiotherapist must also be consulted. Neuronal ceroid lipofuscinosis is chronic and therefore always requires close medical monitoring.
Treatment and therapy
To date, there are no known therapies that lead to a cure of any form of NLC. This means that treatments that relieve individual symptoms as best as possible are the main options. In addition, palliative measures gain importance in the advanced stages of the disease. In juvenile and late juvenile forms of NLC, which are not readily recognized in the early years because of normal childhood development, psychotherapeutic treatment is also important as children and adolescents become aware of the loss of their cognitive and motor abilities.
Outlook and prognosis
The prognosis of neuronal ceroid lipofuscinosis is unfavorable. The disease is characterized by a progressive course. The causative disorder is found in a mutation of human genetics. Current legislation prohibits scientists and researchers from using treatments that involve altering human genetics.Therefore, the treating physicians focus on an early diagnosis as well as the use of treatment measures that lead to a containment of the disease progression. In addition, any symptoms that occur should be alleviated as best as possible in order to achieve an improvement in the quality of life. A cure is impossible for any of the known forms of the disease according to the current status. Those affected show symptoms of varying severity. Patients are dependent on daily help and support in everyday life, as they are unable to cope with the tasks involved on their own. The disease is accompanied by severe disturbances, which are located in the motor and mental areas. In addition, irregularities and impairments of sensory perception are to be expected. Blindness is common. Ultimately, the disease is associated with a reduction in average life expectancy. Due to this difficult course of the disease, the patient and his relatives experience states of strong emotional stress. The risk for the additional onset of a mental disorder is therefore increased.
Prevention
Preventive measures that could prevent or delay the onset of NLC are not (yet) known. Whether genetic testing should also be performed on healthy family members if the disease occurs within the family is ultimately left to each individual after intensive consideration.
Follow-up
There are several forms of neuronal ceroid lipofuscinosis. They differ in terms of their course as well as their prognosis. To date, no variant of neuronal ceroid lipofuscinosis is curable. Therefore, follow-up care in the true sense is usually neither necessary nor possible. In most cases, affected children must be closely monitored throughout their lives. Depending on the form of the disease and the chosen therapeutic approach, different measures for follow-up and control are necessary. In some variants of neuronal ceroid lipofuscinosis, affected individuals die within hours or days of birth. They are usually cared for in the neonatal intensive care unit until their demise. Affected parents can seek psychotherapeutic help as part of follow-up care if needed. Because neuronal ceroid lipofuscinosis is a hereditary disease, they should seek genetic counseling. This is highly advisable, especially if there is an existing desire to have children. There is often a risk that future additional children will be affected by the disease. Few forms of neuronal ceroid lipofuscinosis can be treated with medication. Strict medical control is necessary in these cases. In addition, there are experimental procedures that are expected to lead to a complete cure. However, because of their novelty, no statements can yet be made about future follow-up.
What you can do yourself
Neuronal ceroid lipofuscinosis is essentially incurable. However, this does not mean that there are no ways to manage everyday life with the disease well. First of all, it should be ensured that available drug therapies are taken up. By taking medication regularly, symptoms such as seizures or spasticity can be avoided or at least reduced. Often, feeding with the help of a tube is helpful. It is advisable to find out about the advantages and disadvantages of artificial feeding at an early stage so that action can be taken quickly if necessary. Neuronal ceroid lipofuscinosis has not yet been fully researched. Therefore, it may be beneficial, for oneself but also for others, to participate in ongoing studies. In this way, cures and new therapeutic methods may be found. In the long term, this could improve the quality of life of patients. Experimental approaches should not be categorically excluded. An openness to the latest research regarding neuronal ceroid lipofuscinosis could, in the long run, significantly improve the lives of patients with the disease. In addition, consideration should be given to seeking psychological help. The loss of abilities with full consciousness can be very difficult for patients. To counteract and prevent depression and other psychological stresses, active work should be done with the help of an experienced psychotherapist.
