Neuronal ceroid lipofuscinoses


Neuronal ceroid lipofuscinoses

Description, Causes and Risk Factors:

Abbreviation: NCL

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited diseases characterized by deterioration of intellectual and motor abilities, seizures, vision loss, and decreased life expectancy. They involve defects in a variety of enzymes responsible for breaking down or moving substances, called lipofuscins, within cells. Symptoms associated with the NCLs are due to a toxic build-up of lipofuscins in the cells and tissues of the body, particularly in the brain.

NCLs are relatively frequent group of inherited disorders. They occur world-wide with varying incidence. In Europe the incidence is 1.2-1.6/100,000 live births. Cumulative incidence was 1.61/100,000 live births but 0.87/100,000 for JNCL and 0.73 for the infantile NCL. The highest reported incidence is in Europe (1:50,000 live birth).

The NCLs are a group of diseases that may be inherited in an autosomal recessive or autosomal dominant pattern that can be caused by mutations in several different genes. In an autosomal recessive form of NCL, an individual who inherits one copy of a disease-causing mutation in one of these genes is a "carrier" and does not usually have related health problems. An individual who inherits two disease-causing mutations in the same gene, one from each parent, is expected to be affected with an NCL. For example, a child with two PPT1 mutations would have an NCL, but a child with one PPT1 mutation and one CLN3 mutation would only be a carrier.

If both members of a couple are carriers of an autosomal recessive form of NCL in the same gene, the risk of having an affected child is 25% in each pregnancy; therefore, it is especially important that the reproductive partner of a carrier be offered testing.

The NCLs are subdivided into several subtypes according to age of onset, clinical course and ultrastructural features of the storage material. The three main childhood varieties include infantile NCL (INCL) or (CLN1), late-infantile NCL (LINCL) or (CLN2) and juvenile NCL (JNCL) or (CLN3).

Molecular genetics of these three subtypes was recently clarified.

    In the first subtype, INCL there are mutations in genes encoding a lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1) with locus CLN1 on chromosome 1p32. This type is associated with predominance of granular inclusions in biopsied material.

  • The second subtype, LINCL is caused by mutations in CLN2 gene which encodes a lysosomal enzyme tripeptidyl peptidase 1 (TPP1) with locus on chromosome 11p15.

  • The third subtype, JNCL is caused by mutations in gene encoding a 438-aminoacid membrane protein (CLN3 on chromosome 16p12.1) commonly related to 1.02kb deletion.

Symptoms:

Symptoms may include:

    Abnormally increased muscle tone or spasm (myoclonus).

  • Blindness or vision problems.

  • Dementia.

  • Lack of muscle coordination.

  • Intellectual disability.

  • Movement disorder (choreoathetosis)

  • Seizures.

  • Unsteady walk (ataxia).

The younger the person is when the disease appears, the greater the risk for disability and early death. Those who develop the disease early can have vision problems that progress to blindness, and problems with mental function that get worse. If the disease starts in the first year of life, death by age 10 is likely.

Diagnosis:

The diagnosis is usually madebased on demonstration of autoflourescent lysosomallipopigment in rectal biopsies and skin biopsies.With recent advances in molecular genetics,diagnosis of certain subtypes is possible, withoutthe need for invasive procedures like rectalbiopsies. Thus, prenatal diagnosis became anoption.

Tests include:

    Autofluorescence (a light technique).

  • EEG.

  • Electron microscopy of a skin biopsy.

  • Electroretinogram.

  • Genetic testing.

  • MRI or CT scans of the brain.

  • Tissue biopsy.

Treatment:

No specific treatment is available for these diseases.

    Seizures should be treated with standard anticonvulsants.

  • A study regarding the safety and preliminary efficacy of central nervous system stem cell transplantation in patients with PPT1 or TTP1 deficiency is currently ongoing.

  • Bone marrow transplant has been tried in animal models as well as a few infants with disappointing results.

  • Vitamin E, other antioxidants, and selenium have been tried without significant efficacy.

  • Replication deficient adeno-associated virus gene transfer vector (AAV2-mediated CLN2 gene transfer) has been studied in mice, rats, and nonhuman primates with CLN2.

  • Studying this in children is of interest.

NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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