Neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive degenerative brain diseases characterized clinically by a decline of mental and other capacities, epilepsy, and vision loss through retinal degeneration, and histopathologically by intracellular accumulation of an autofluorescent material, ceroid lipofuscin, in the neuronal cells in the brain and in the retina.


Introduction
As a group, the Neuronal ceroid lipofuscinoses (NCLs) form the most common inherited progressive childhood encephalopathies, with an incidence of between 1 and 5 per 100000 live births in different countries, while prevalence is estimated between 1 and 3 per million. 1 Accumulation of intracellular autofluorescent storage material and neurodegeneration are features of this heterogenous group of diseases, which lead to visual impairment, epilepsy, motor disorders and cognitive deterioration.
Adult presentation is very uncommon, and knowledge of adult forms is very limited compared to the childhood forms. NCLs show recessive inheritance, except for the extremely uncommon autosomal dominant adult form, of which only a few families have been reported. This dominant adult NCL form is the subject of this thesis.
The scanty literature on dominant adult NCL is reviewed below, but in this chapter we will also briefly review the knowledge of the different childhood NCLs and recessive adult NCL (Kufs' disease), as a background to further chapters on the dominant adult form.
Several excellent monographs on NCL provide more detailed information on this topic 2 3 4 5 .

Classification
Classically, distinction of different forms of NCL was based on age at onset 6 16 We will now present a short review of all human NCL forms, using the genetic classification as an index.

MIM 256730
The

MIM 204500
Mutations in CLN2 on chromosome 11p15 which cause loss of tripeptidyl peptidase 1 (TPP1, a lysosomal exopeptidase that sequentially removes tripeptides from the N termini of polypeptides), lead to classic lateinfantile NCL (Jansky-Bielschowsky disease). More than 65 mutations are reported 13 . Electronmicroscopy of storage material shows curvilinear bodies, which are rich in subunit C of mitochondrial ATP synthase (SCMAS). LINCL usually has an onset between 1 and 5 years of age.
Prevalence in the USA is around 200 children. 20 These children have progressive myoclonic seizures, ataxia, blindness and psychomotor regression that invariably results in death around age 8 to 12 years.

MIM 204200
Batten disease (a name which is also confusingly used for all NCLs), or

IV-3
He had a first seizure at the age of 32. Cognitive deterioration with apraxia and dysgraphia, myoclonus, epilepsy and absent tendon reflexes were seen. EEG showed bilaterally symmetrical spikes and waves. He

IV-5
She had an epileptic seizure at age 30, shaking clumsy hands, progressive epilepsy, ataxia, severe action induced myoclonus, speech problems and mask face. EEG showed bilaterally rhythmic bursts.

IV-7
She had limited medical records, which mention clumsy hands at age 32, epilepsy, myoclonus, ataxia and delusions. EEG was abnormal. She died at the age of 39 years old.

IV-13
At 31 years of age he had an epileptic seizure, followed by myoclonus, impaired speech, ataxia, decreased tendon reflexes in the legs.

IV-15
She had non-fluent speech at 33 years of age, and myoclonus. EEG Age of onset was between 32 and 40. Seven patients died at an age between 41 and 58. Seizures, dementia and movement disorders were common, but no retinal pathology was seen.
Some patients were reported in more detail: V-3 had an abnormal EEG before occurrence of cognitive decline, dyskinesias, dystonia, and hip girdle muscle weakness.
IV-1 had jerks dementia, mask face and seizures.
IV-2 had seizures, memory loss, aphasia, mask face and myoclonus. In patient E3, ultrastructure of PAS positive storage material in neurons showed GRODs, which were also found in the skin.

MIM 609055
This is a putative gene, postulated to explain two Serbian sisters and two German brothers with a clinical history characteristic for juvenile NCL, but with curvilinear inclusions, fingerprint profiles, and granular osmiophilic deposits in neurons, lymphocytes, and conjunctival cells.
Enzyme screening and sequencing of the coding regions of other NCL genes was negative. CLN9 is mainly studied in fibroblasts, which have a distinctive phenotype of rapid growth and increased apoptosis and diminished levels of ceramide, dihydroceramide, and sphingomyelin.
CLN9 protein may be a regulator of dihydroceramide synthase. 56

MIM 610127
Only a few patients with this rare disorder have been reported, all with similar clinical and neuropathological findings. Cathepsin D is a lysosomal aspartic protease involved in protein degradation, but it may also regulate apoptosis 58  Cathepsin D deficiency should be considered as a possible diagnosis in microcephalic neonates, who present with seizures at or before birth. 59 In a prematurely born infant with microcephaly and hypertonia, a mutation in the cathepsin D gene was found 60 . He died after 2 days.
Storage material composed of GRODs with saposin D was found in neurons and astrocytes.