Lipofuscinoses 

[MIM 204 200204 500256 730600 143609 055610 127]

(Ceroid-lipofuscinoses)

Group of Lysosomal Storage Disease. Generally autosomal recessive transmission. Prevalence: 1/12500. Intralysosomal accumulation of lipofuscin and ceroid . Nine varieties (13 genes) have been described: all combine progressive dementia, loss of vision, seizures and motor problems. They were conventionally classified according to their time of onset and the order of appearance of the symptoms. Their genetic and allelic heterogeneity required the development of a new classification (table) which takes into account the responsible gene and the age at the onset of the symptoms.


Three deficient enzymes have been identified so far:

-        palmitoyl-protein thioesterase (PPT-1 gene on 1p32)

-        tripeptidyl-peptidase (TPP-1 gene on 11p15)

-        cathepsin (CTSD gene on 11p15.5)


Phenotype

proportion

gene

age of onset

first symptoms

congenital

rare

SDLC

perinatal period

microcephaly, seizures

infantile

frequent

rare

classic

frequent in Finland

PPT-1

KCTD7

TPP-1

CLN5

6 mo-2 yr


2-4 years

4-7 years

cognitive decline, loss of vision

seizures

late infantile

rare

rare variant

rare variant

very rare variant

rare variant

frequent classic

rare classic

CLN6

MSFD8

CLN8

SDLC

PPTP-1

CLN3

PPT-1

18 mo-8 yr


3 - 7.5 yr



4-10 yr

cognitive decline, convulsions,

loss of vision


juvenile

rare

rare

rare

TPP-1

CLN9

ATP13A2


neuropsychiatric disorders

northern epilepsy

frequent in Finland

CLN8

5-10 years

seizures, cognitive decline, sometimes loss of vision

adult

rare

Kufs disease

CTSD, PPT-1, CLN3, CLN5, CLN6, CTSF, GRN

15-50 years

type A: cognitive decline, epilepsy

type B: behavior disorders

autosomal dominant adult

unknown

Parry disease

DNAJC5




The best-known are:

-        Haltia-Santavuori type [Hagberg-Santavuori-Haltia] (chromosome 13q31.32): onset between 4 and 7 years of age; epilepsy, polymyoclonia, ataxia, dementia

-        late infantile Finnish type  [MIM 256 731, 601 780], CLN5: onset between 4.5 and 7 years of age

-        late infantile form CLN 6: loss of vision and seizures are the initial symptoms

-        CLN7: vision loss and seizures are the initial symptoms

-        CLN8: earlier: onset between 2 and 6 years of age


Experimental treatment: selenium-rich diet; studies of phase 1 of  intracerebral and intraventricular transplantation of cerebral stem cells in children with infantile or late-infantile forms. For the CLN2 form: intracerebroventricular injections (through an Ommaya's reservoir) of cerliponase-alpha to slow the evolution. Risk of fever, vomiting or anaphylactic reaction.


Anesthetic implications:

epilepsy, behavioral disorders. If case of CLN3 mutation: preoperative cardiac evaluation, early in adolescence: disorders of intracardiac conduction, ventricular hypertrophy ? .

Treatment of epilepsy: carbamazepine, phenytoin and lamotrigine may aggravate epilepsy; valproic acid can cause excessive sedation.

For the infantile form, risk of hypothermia and sinus bradycardia under anaesthesia, especially as soon as clinical signs of the disease are present.


References : 


Updated: March 2020