Infantile Neuronal Ceroid Lipofuscinosis

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

PPT1, TPP1, CLN6, ATP13A2, CLN3, TAC1, PPP5C, PPT2, GFAP, HRAS, MYCL, NPHS1, CASP3, GAP43, RPS6KB1, SCP2, STXBP1, DPYSL2, VIM, CASP4, SIRT1, CAPN3

Drugs

Adeno-associated viral vector serotype 9 containing the human CLN1 gene, Brivaracetam, Gemfibrozil

Adeno-associated viral vector serotype 9 containing the human CLN1 gene, Brivaracetam, Gemfibrozil, Recombinant self-complementary adeno-associated viral vector serotype 9 containing the human CLN3 gene, recombinant self-complementary adeno-associated viral vector serotype 9 (AAV9) containing the human CLN3 gene, recombinant self-complementary adeno-associated viral vector serotype 9 containing the human CLN6 gene

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Infantile neuronal ceroid lipofuscinosis (INCL) is a form of neuronal ceroid lipofuscinosis (NCL; see this term) characterized by onset during the second half of the first year of life and rapid mental and motor deterioration leading to loss of all psychomotor abilities.

Epidemiology

Infantile NCL occurs worldwide but is most common in Finland with a prevalence of around 1/190,000 and incidence of 1/20,000 live births. The disorder is less frequent in other Scandinavian countries with a prevalence of below 1/1,000,000 in Sweden and Norway.

Clinical description

After an initial period of normal development, the disorder manifests after six months of age when mental development reaches a plateau and then starts to deteriorate, accompanied by motor dysfunction. The deterioration of mental abilities is accompanied by seizures, spasticity and loss of vision. Brain atrophy results in slower than normal growth of the head circumference and microcephaly. Stiffness and irritability may also be noted. Psychomotor abilities deteriorate rapidly and children fail to thrive leading to a vegetative state within several months.

Etiology

INCL is inherited in an autosomal recessive manner and is caused by mutations in the PPT1 gene (designated CLN1; 1p32) encoding the lysosomal enzyme palmitoyl-protein thioesterase 1.

Diagnostic methods

Diagnosis is based on clinical findings from neurologic and ophthalmologic examinations and development assessments, and measurement of activity of palmitoyl-protein thioesterase 1 in leukocytes, dry blood samples or cultured skin fibroblast cells. The diagnosis can be confirmed by molecular analysis. Pathologic studies reveal the presence of autofluorescent lysosomal granular osmophilic deposits (GRODs) with characteristic accumulation of saposins A and D.

Differential diagnosis

The differential diagnosis should include other early-onset progressive neurologic diseases, including infantile Krabbe disease, early-stage Rett syndrome and gangliosidosis (see these terms).

Antenatal diagnosis

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

Genetic counseling should be provided to affected families.

Management and treatment

There is no curative treatment. Management consists of palliative care including administration of anticonvulsive drugs and treatment of severe spasticity with muscular relaxants. Oral opiates or fentanyl-containing plasters can be helpful for management of painful spastic crises occurring later in the disease course. Stem cell therapy may provide an alternative treatment for INCL in the future.

Prognosis

The prognosis is severe but life expectancy is variable, depending on the use of supportive measures such as gastrostomy feeding.