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Late infantile neuronal ceroid lipofuscinosis

Orpha number ORPHA168491
Synonym(s) Jansky-Bielschowsky disease
LINCL
Late infantile NCL
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Childhood
ICD-10
  • E75.4
ICD-O -
OMIM
UMLS
  • C0022340
MeSH -
MedDRA -
SNOMED CT
  • 14637005

Summary

Late infantile neuronal ceroid lipofuscinoses (LINCLs) are a genetically heterogeneous group of neuronal ceroid lipofuscinoses (NCLs; see this term) typically characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy, and vision loss through retinal degeneration.

LINCLs have been reported in populations with diverse ethnic origins with the highest prevalence being reported in Finland (around 1/385,000), estimates of below 1/1,000,000 in other Scandinavian counties and an annual incidence at birth of at least 1/200,000 in Germany.

The initial clinical symptoms are motor or/and cognitive decline or epilepsy but the mean age of onset and speed of progression may vary depending on the underlying genetic defect. Patients with classic LINCL generally present with a standstill of mental development or the onset of severe epilepsy around the third year of life. The disorder progresses to complete loss of almost all motor and mental capacities before school age. As visual loss is not a prominent finding in the early stages of the disease course, it is frequently not recognized. Several variant forms have also been described in the literature (vLINCL) in which the mean ages of onset generally vary from 2-7 years and which commonly manifest with severe epilepsy followed by cognitive and motor decline and vision loss.

LINCLs are transmitted in an autosomal recessive manner and mutations in the following genes may result in LINCL with a classic and/or variant phenotype: PPT1 (designated CLN1; 1p32), TPP1 (11p15; designated CLN2 and responsible for the majority of cases of cLINCL), CLN5 (13q22), CLN6 (15q21), MFSD8 (designated CLN7), CLN8 (8p23) and CTSD (designated CLN10; 11p15.5).

The diagnostic strategy for patients presenting with LINCL should include enzymatic testing for deficiencies in palmitoyl-protein thioesterase 1, tripeptidyl-peptidase 1 and cathepsin D, present in patients with PPT1, TPP1 and CTSD mutations, respectively. When these tests are negative, skin biopsy material should be examined by electron microscopy to search for the presence of storage material with autofluorescent ceroid lipopigments. If these pigments are present, molecular genetic analysis can be used to identify rare mutations in the other disease-causing genes and confirm the diagnosis.

The differential diagnosis should include inborn errors of metabolism and inflammatory brain diseases.

Prenatal diagnosis is possible on the basis of enzymatic analysis or molecular genetic testing if the mutation in the family has already been identified.

Genetic counseling should be provided to affected families.

There is no curative treatment. Management consists of palliative care including administration of anticonvulsive drugs, treatment of spasticity with muscular relaxants and gastronomy feeding in the later stages of the disease. Stem cell therapy may provide an alternative treatment for some forms of LINCL in the future.

The prognosis is poor with most children becoming severely disabled by mid-childhood. Most patients do not survive to reach adulthood.

Expert reviewer(s)

  • Pr Alfried KOHLSCHÜTTER

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Detailed information

Clinical genetics review
  • EN (2013)
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