Ceroid lipofuscinosis – Neuronal 4
Ceroid lipofuscinosis - Neuronal 4 (also known as Kufs disease and CLN4) is one of a group of rare inherited biochemical disorders known as neuronal ceroid lipofuscinoses (NCLs), which may also be collectively referred to as Batten disease. All these disorders affect the nervous system and typically cause worsening problems with vision, movement, and thinking ability. The different NCLs are distinguished by their genetic cause. Each disease type is given the designation "CLN," meaning ceroid lipofuscinosis, neuronal, and then a number to indicate its subtype.
There are two types of CLN4 disease: Type A and Type B. Type A causes seizures, myoclonic epilepsy (muscle jerks), dementia, ataxia (compromised muscle coordination), tremors and tics, dysarthria (speech difficulties), confusion, and psychotic behaviour. Although similar to Type A, patients with Type B do not suffer from myoclonic epilepsy or dysarthria, and they do display changes in personality. It is occasional that patients present with skin disorders causing dryness, roughness, and scaliness. The signs and symptoms of CLN4 disease typically appear around age 30, but they can develop anytime between adolescence and late adulthood. In addition, the signs and symptoms of CLN4 disease worsen over time, and affected individuals usually survive about 15 years after the disorder begins.
- Optic atrophy
- Vision impairment
- Cerebellar ataxia
- Extra-pyramidal signs
- Personality change
- Skin disorders (dryness, roughness and scaliness)
Both type A and type B of CLN4 disease are caused by mutations in two sets of different genes. Both gene sets are responsible for producing proteins and enzymes that are heavily involved in protein degradation and excretion in the cell – specifically, the nerve cell.
Mutations to the CLN6 and PPT1 genes result in CLN4 Type A. CLN6 produces proteins that facilitate fat transport throughout a cell, as well as excretion out of the cell. The PPT1 gene codes for the enzyme palmotoyl-protein thioesterase-1. This enzyme is responsible for removing the fatty-acid side chains off of proteins that have been translocated into the lysozyme. By removing the surrounding fats, palmotoyl-protein thioesterase-1 creates easier access for other enzymes to break down the rest of the protein. Fatty substance build up in the brain is a consequence of the mutated genes. The fats and proteins that build up are called lipopigments. Eventually the buildup of lipopigments results in death of the neuron cells, giving way to the phenotypic symptoms. Type A is an autosomal recessive disease, indicating that it is inherited from the parents. Each parent must carry one copy of the mutation, however the recessive designation indicates that with only one copy, the parents are not affected, and do not show any symptoms.
CLN4 Type B is caused by mutations to the DNAJC5 and CTSF genes. This form of CLN4 is autosomal dominant, meaning that only one copy of each mutated gene is enough for the disease to manifest. When there is a mutation in the DNAJC5 gene, it affects the production of a cysteine string protein (CSP) that is coded within DNAJC5. CSP aids in transmitting signals through the nerves found in the brain. When the CTSF gene is mutated, it cannot produce Cathepsin F - an enzyme that cuts proteins in the lysozyme. By cutting proteins, Cathepsin F can modify the function of the proteins as well as help break them down. Similar to Type A, when both DNAJC5 and CTSF are non-functional, it results in the incomplete breakdown of proteins. Once again, lipopigments build up and brain function is decreased as the neuron cells die.
The diagnostic challenges posed by patients with CLN4 disease are two-fold. Firstly, their clinical presentation can mimic several other rare causes of progressive myoclonic epilepsy or dementia with motor deterioration. Secondly, unlike other forms of NCL, extra-neural accumulation of the hallmark lipopigments is unreliable for confirming a diagnosis of CLN4 disease. This diagnosis is most reliably confirmed by invasive brain biopsy.
The diagnosis of an NCL is increasingly based on assay of enzyme activity and molecular genetic testing. In unusual cases diagnosis relies on electron microscopy (EM) of biopsied tissues. The diagnostic testing strategy in a proband depends on the age of onset. Mutations in the DNAJC5 gene, which has a key role in synaptic transmission, are a known cause of autosomal dominant CLN4 disease. This gene encodes for cysteine string protein (CSP-α), which is located on pre-synaptic vesicles and enables the formation of SNARE-complexes – the key mediators of pre-synaptic vesicular fusion and exocytosis at the synaptic cleft. Causative mutations reduce synaptic levels of CSP-α, therefore impairing synaptic transmission.
The signs and symptoms of CLN4 disease typically appear around age 30, but they can develop anytime between adolescence and late adulthood. In addition, the signs and symptoms of CLN4 disease worsen over time, and affected individuals usually survive about 15 years after the disorder begins.
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.