Congenital neuronal ceroid lipofuscinosis
Cathepsin D deficiency
Ceroid lipofuscinosis - Neuronal 10 (also known as CLN10, Congenital neuronal ceroid lipofuscinosis and Cathepsin D deficiency disease) is a rare, severe metabolic disorder that primarily affects the nervous system and is characterized by the deposits of lipopigments (lipofuscin). CLN10 involves a deficiency of cathepsin D and involves an initial period of normal development with neurodegenerative symptoms starting during the early school years.
Individuals with this condition typically show signs and symptoms soon after birth. These signs and symptoms can include muscle rigidity, respiratory failure, and prolonged episodes of seizure activity that last several minutes (status epilepticus). It is likely that some affected individuals also have seizures before birth while in the womb. Infants with CLN10 disease have unusually small heads (microcephaly) with brains that may be less than half the normal size. There is a loss of brain cells in areas that coordinate movement (the cerebellum) and control thinking and emotions (the cerebral cortex). Nerve cells in the brain also lack a fatty substance called myelin, which protects them and promotes efficient transmission of nerve impulses. Infants with CLN10 disease often die hours to weeks after birth.
In some individuals with CLN10 disease, the condition does not appear until later in life, between late infancy and adulthood. These individuals have a gradual loss of brain cells and often develop problems with balance and coordination (ataxia), loss of speech, a progressive loss in intellectual functioning (cognitive decline), and vision loss. Individuals with later-onset CLN10 disease have a shortened lifespan, depending on when their signs and symptoms first started.
- Neurodegenerative symptoms
- Progressive vision impairment
- Retinitis pigmentosa
- Cerebral atrophy
- Cerebellar atrophy
- Progressive cognitive decline
- Loss of speech
- Retinal atrophy
- Loss of motor function
- Mental retardation
- Progressive dementia
CLN10 disease is caused by mutations in the CTSD gene. The CTSD gene provides instructions for making an enzyme called cathepsin D. Cathepsin D is one of a family of cathepsin proteins that act as protease enzymes, which modify proteins by cutting them apart. Cathepsin D is found in many types of cells and is active in lysosomes, which are compartments within cells that digest and recycle different types of molecules. By cutting proteins apart, cathepsin D can break down certain proteins, turn on (activate) other proteins, and regulate self-destruction of the cell (apoptosis).
CTSD gene mutations found to cause CLN10 disease that is present at birth lead to a complete lack of cathepsin D enzyme activity. As a result, proteins and fats are not broken down properly and abnormally accumulate within lysosomes. While accumulations of these substances occurs in cells throughout the body, nerve cells appear to be particularly vulnerable to damage caused by the abnormal cell materials. Early and widespread loss of nerve cells in CLN10 disease leads to severe signs and symptoms and death in infancy.
In the later-onset cases of CLN10 disease, CTSD gene mutations likely result in the production of a cathepsin D enzyme whose function is greatly reduced but not eliminated. As a result, some proteins and fats are broken down by the enzyme, so it takes longer for these substances to accumulate in lysosomes and cause nerve cell death.
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 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.
Infants with CLN10 disease often die hours to weeks after birth. And individuals with later-onset CLN10 disease have a shortened lifespan, depending on when their signs and symptoms first started.
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; 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
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.