Late Infantile Neuronal Ceroid Lipofuscinosis

Synonyms

8

Overview

Late infantile neuronal ceroid lipofuscinosis (also known as LINCL, Jansky-Bielschowsky and late infantile CLN2/TPP1 disorder) is part of a group of progressive degenerative neurometabolic disorders known as the ceroid lipofuscinosis neuronal (CLNs). The CLNs are characterized by an abnormal accumulation of lipopigments, which are substances made up of fats and proteins within the brain’s nerve cells, eyes, skin, muscle, and other tissues throughout the body. CLN2 causes nerve cells, found in the brain, retina, and central nervous system, to die. Symptoms typically begin between ages 2 and 4. Early signs may include loss of muscle coordination (ataxia) and seizures that do not respond to drugs. This form progresses rapidly and ends in death between ages 8 and 12. The condition is caused by mutations in the CLN 2 gene which lead to deficient activity of the TPP1 enzyme.

Symptoms

The list of signs and symptoms mentioned in various sources for late infantile neuronal ceroid lipofuscinosis includes the symptoms listed below:

  • Myoclonic seizures
  • Developmental delay
  • Impaired motor abilities
  • Impaired intelligence
  • Progressive dementia
  • Hyperkinesia
  • Cerebellar ataxia
  • Seizures
  • Reduced muscle tone
  • Small head
  • Vision loss
  • Blindness
  • Progressive mental retardation

Causes

The gene called CLN2 lies on chromosome 11.  CLN2 disease is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the CLN2 gene, and both parents are unaffected carriers.  The gene was discovered in 1998.  CLN2 normally directs production of a lysosomal enzyme called tripeptidyl peptidase1 or TPP1.  A deficiency of TPP1 results in abnormal setorage of proteins and lipids in neurons and other cells and impaired cellular function.  The cells cannot function as they should and symptoms develop.

Mutations in the TPP1 gene cause CLN2 disease. The TPP1 gene provides instructions for producing an enzyme called tripeptidyl peptidase 1. This enzyme is found in cell structures called lysosomes, which digest and recycle different types of molecules. Tripeptidyl peptidase 1 breaks down protein fragments, known as peptides, into their individual building blocks (amino acids).

Mutations in the TPP1 gene greatly reduce or eliminate the production or activity of the tripeptidyl peptidase 1 enzyme. A reduction in functional enzyme results in the incomplete breakdown of certain peptides. CLN2 disease, like other CLNs, is characterized by the accumulation of proteins or peptides and other substances in lysosomes. These accumulations occur in cells throughout the body; however, nerve cells seem to be particularly vulnerable to their effects. The accumulations can cause cell damage leading to cell death. The progressive death of nerve cells in the brain and other tissues leads to the signs and symptoms of CLN2 disease.

Individuals who are diagnosed with CLN2 disease later in childhood likely have TPP1 gene mutations that result in the production of an enzyme with a small amount of normal function. Protein function in these individuals is higher than in those who have the condition beginning earlier in childhood. As a result, it takes longer for peptides and other substances to accumulate in the lysosomes and damage nerve cells.

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person's medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The resources presented below provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources: The diagnosis is usually made by enzyme (TPP1) and genetic (CLN2) tests on blood samples.  Occasionally a skin biopsy may be necessary.  Curvilinear bodies (CVB) are the characteristic storage body at the electron microscope level. 

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Prognosis

Children are healthy and develop normally for the first few years of life.  Towards the end of the second year, developmental progress may start to slow down.  Some children are slow to talk.  The first definite sign of the disease is usually epilepsy.  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.  Children tend to become unsteady on their feet with frequent falls and gradually skills such as walking, playing and speech are lost.  Children become less able and gradually skills such as walking, playing and speech are lost.  Children become less able, and increasingly dependent.  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.  By the age of 6 years, most will be completely dependent on families and carers for all of their daily needs.  They may need a feeding tube and their arms and legs may become stilff.  Some children get frequent chest infections.  Death usually occurs between the ages of 6 and 12 years (but occasionally later).

Treatment

Treatment of manifestations: Treatment is currently symptomatic and palliative only. Seizures, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, depression and anxiety, spasticity, Parkinsonian symptoms, and dystonia can be effectively managed. Antiepileptic drugs (AEDs) should be selected with caution. Benzodiazepines may help control seizures, anxiety, and spasticity. Trihexyphenydate may improve dystonia and sialorrhea. Individuals with swallowing problems may benefit from placement of a gastric (G) tube.

Surveillance: Routine medical management of children and young adults with complex neurodisability will be relevant to all those affected by CLN, and may include surveillance for swallowing difficulties and recurrent aspiration and radiograph surveillance of hip joints and spine.

Agents/circumstances to avoid: Carbamazepine and phenytoin may increase seizure activity and myoclonus and result in clinical deterioration; lamotrigine may exacerbate seizures and myoclonus.

Genetic counselling: The CLNs are inherited in an autosomal recessive manner with the exception of adult onset, which can be inherited in either an autosomal recessive or an autosomal dominant manner.

Autosomal recessive CLN. The parents of a child with an autosomal recessive form of CLN are obligate heterozygotes, and therefore carry one mutated allele. Heterozygotes have no symptoms. At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known.

Prenatal testing for pregnancies at increased risk is possible if the proband has documented deficient enzyme activity or if the pathogenic variant(s) have been identified in the family.

New drug therapy: On 27th of April 2017, the FDA approved treatment for CLN2. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2).

Brineura is an enzyme replacement therapy. Its active ingredient (cerliponase alfa) is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease. Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a specific surgically implanted reservoir and catheter in the head (intraventricular access device). Brineura must be administered under sterile conditions to reduce the risk of infections, and treatment should be managed by a health care professional knowledgeable in intraventricular administration. The recommended dose of Brineura in pediatric patients 3 years of age and older is 300mg administered once every other week by intraventricular infusion, followed by an infusion of electrolytes. The complete Brineura infusion, including the required infusion of intraventricular electrolytes, lasts approximately 4.5 hours. Pre-treatment of patients with antihistamines with or without antipyretics (drugs for prevention or treatment of fever) or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion.

Please discuss with your health practitioner on benefits/risks of treatment options.

Resources

GHR; PubMed; FDA