Ceroid lipofuscinosis - Neuronal 1 (also known as CLN1, Classic Infantile NCL, INCL and Santavuori-Haltia) is a rare inherited biochemical disorder involving the progressive accumulation of lipopigments (lipofuscins) in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys due to deficiency of an enzyme (protease tri-peptidyl-peptidase) needed to process it. CLN1 is often caused by a mutation in the PPT1 (palmitoyl- protein thioesterase 1) gene or more rarely from mutations in the KCTD7 (Potassium channel tetramerisation domain containing 7 ) gene. The age of onset is usually between 6-24 months.
All individuals with a ceroid lipofuscinosis neuronal disorder have progressive decline, an evolving cognitive and motor disorder, and seizures.
- seizures (epilepsy)
- progressive deterioration of cognition (dementia)
- motor function impairment
- involuntary movements
- myoclonic jerks
- vision loss
- microcephaly and deceleration of head growth
- developmental regression/standstill
- hand stereotypies
- mild to moderate deterioration of intellectual ability
- speech problems
- lost interest in playing with toys, but interest in surroundings
- moderate motor dysfunction
- retinal blindness
- psychomotor abilities deteriorate rapidly
The relation between genetic defects associated with the major CLN forms, the accumulation of storage material, and tissue dysfunction and/or damage is still unknown. Furthermore, all individuals with CLNs manifest lysosomal storage in many tissues and organs, but severe degeneration and cell loss involve mostly neuronal cells. Thus, it appears that CLN proteins may be most critical for the metabolism of neurons. It is uncertain whether this phenomenon results from the specific metabolic requirements of a neuron as a postmitotic cell, or from the properties of CLN proteins per se.
Normal gene product. PPT-1 is a globular enzyme consisting of six parallel β strands alternating with α helices organized in a structure known as the α/β hydrolast fold typical of lipases. A large insertion between β6 and β7 (amino acid residues 140-223) forms a second domain that forms most of the fatty acid-binding site. Catalytic active site residues are: Ser115, Asp233, and His289. PPT-1 is a housekeeping enzyme present in the lysosomes of many tissues. It removes long-chain fatty acids, usually palmitate, from cystine residues. Based on the results of crystallographic and molecular modeling studies of recombinant bovine PPT-1 enzyme, a mechanism has been hypothesized to explain the milder INCL phenotype in individuals with PPT1 mutations who retain low-level thioesterase activity [Bellizzi et al 2000]. Abnormal gene product. Mutations affect PPT-1 in different ways. For some the protein is truncated, lacking its catalytic site; for others critical residues, such as within the catalytic site, are absent or altered.
Normal gene product. The gene product, BTB/POZ domain-containing protein KCTD7, is a potassium channel tetramerization domain-containing protein 7. Abnormal gene product. Unknown, but different mutations cause different diseases. Only one CLN-causing pathologic allelic variant mutation has been described.
Carrier testing for relatives at risk for the autosomal recessive forms of CLN requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.
Enzymatically or genetically undefined cases. Store DNA and fibroblast cell lines and consult an CLN research scientist who may be able to access new research tests, or store samples until diagnostic tests become available.
Diagnosis through Histological findings:
Electron microscopy studies can be performed with 5-10 µL of heparinized blood (lymphocytes) or tissue biopsies (now usually of skin but previously from conjuntiva or other tissues). Can show granular osmiophilic deposits (GROD) in CLN1 disease.
Palmitoyl-protein thioesterase 1 (PPT-1) encoded by PPT1. A A fluorimetric assay for PPT-1 based on the fluorochrome 4-methylumbelliferone detects significantly reduced PPT-1 activity in leukocytes, fibroblasts, lymphoblasts, amniotic fluid cells, or chorionic villi in forms of NCL caused by PPT1mutations. Other variants/types of neuronal cerioid-lipofuscinoses can present with PPT1 gene mutations/enzymatic deficiencies but with differences in age of onset. A carrier of a mutation in PPT1 typicalls has 50% of normal enzymatic activity in the PPT-1 enzyme.
Molecular Genetic Testing:
PPT1 and KCTD7 are two genes in which mutations are known to cause infantile neuronal ceroid-lipofuscinosis. For the gene PPT1, the test methods recommended are: Targeted mutation analysis, sequence analysis, and detection/duplication analysis. For the KCTD7 gene, sequence analysis for sequence variants is recommended for detection of small intragenic deletions/insertions and missense, nonsense, and splice site mutations.
Other progressive neurologic diseases with onset from birth to age two years need to be considered. These include: hexosaminidase A deficiency, progressive leukodystrophies Rett syndrome, peroxisomal biogenesis disorders, Neimann-Pick disease types A and B (see Acid Sphingomyelinase Deficiency), and Leigh syndrome (see also Mitochondrial Disorders Overview). While some of these disorders are associated with cortical blindness, retinal involvement is rarely seen.
CLN1 disease usually presents between age six and 24 months. Onset before age six months and after age two years also occurs. Over time, seizures, loss of muscle coordination (ataxia), dementia, and very severe wasting away of brain tissue (cerebral atrophy) occur. Children with this form of NCL have a life expectancy of 5 to 10 years.
Evaluations following initial diagnosis
To establish the extent of disease in an individual diagnosed with one of the neuronal ceroid-lipofuscinoses, the following evaluations are recommended:
- Neurologic examination
- Ophthalmologic examination
- Developmental/cognitive and educational assessment
- Medical genetics consultation
Treatment of Manifestations
Symptomatic treatment can be successful in mitigating the manifestations of CLN. Seizures, sleep-related problems, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, hyperactivity and behavior problems, psychosis, anxiety, spasticity, Parkinsonian symptoms, and dystonia can be palliated.
Seizures. Antiepileptic drugs (AEDs) should be selected with caution. The stage of the disease, age of the affected individual, and quality of life are important to consider in evaluating the effectiveness of AEDs.
Lamotrigine (LTG) had a favorable effect on 23/28 individuals with JNCL, 13/19 being continued on monotherapy with 100% control, compared to 70% control for those receiving valproic acid (VPA), 60% control for VPA-clonazepam (CZP), and 60% control for LTG-CZP [Aberg et al 1999, Aberg et al 2000].
Benzodiazepines may be of benefit for seizures, anxiety, spasticity, and sleep disorders.
Trihexyphenydil improves dystonia and sialorrhea.
Individuals with swallowing problems may benefit from placement of a gastric (G) tube.
Stem cell therapy for phenotypes caused by mutations in CLN1 and CLN2 is currently in progress.
Agents/Circumstances to Avoid
Carbamazepine (CZP) and phenytoin may increase seizure activity and myoclonus in NCL and result in clinical deterioration. Lamotrigine may exacerbate seizures and myoclonus.
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