Four types of lipofuscinoses have been identified, formerly defined largely by the age of onset: Santavuori-Haltia Finnish infantile type, Jansky-Bielschowsky early childhood type, Vogt-Spielmeyer juvenile type, and Kufs adult type. They have been referred to collectively as Batten disease, although that term has been applied to the juvenile form. The storage material in neuronal cytoplasm consists of two pigmented lipids, presumably ceroid and lipofuscin, which are cross-linked polymers of polyunsaturated fatty acids and have the property of autofluorescence.
Newer classifications have confused the picture and use a numbered nomenclature, NCL 1 through NCL 10; the older classification would have approximated forms 1 through 4, most due to mutations in CLN or less often, TPP1 or PPT1. All except a few adult cases are autosomal recessive and the diagnosis can be made by genetic study. The type of mutation (nonsense, frame shift, missense) also has an influence on the clinical syndrome that results (Wisniewski et al). All the infantile forms and one of the juvenile forms of the disease are due to of mutations affecting the lysosomal enzyme palmitoyl–protein thioesterase. Other lysosomal enzymes are abnormal in the remaining juvenile and in the adult forms. Each of these disorders is discussed in more detail with the other metabolic disorders that appear at each age of life.
In the infantile Santavuori-Haltia form of the disease (NCL 1, PPT1 mutation), infants from 3 to 18 months of age, after a normal period of development, undergo psychomotor regression with ataxia, hypotonia, and widespread myoclonus. There are retinal changes with extinction of the electroretinogram, slowing of the EEG with spike and slow-wave discharges, and eventually an isoelectric record. Within a few years these patients become blind, develop spastic quadriplegia and microcephaly, and succumb.
In the late infantile-juvenile Jansky-Bielschowsky type (NCL 2, TPP1 mutation), the onset of symptoms is between 2 and 4 years, after normal or slightly slow earlier development, with survival to 4 to 8 years of age. Usually the first neurologic manifestations are seizures (petit mal or grand mal) and myoclonic jerks evoked by proprioceptive and other sensory stimuli, including voluntary movement and emotional excitement. Incoordination, tremor, ataxia, and spastic weakness with lively tendon reflexes and Babinski signs, deterioration of mental faculties, and dysarthria proceed to dementia and eventually to mutism. In patients with relatively late onset, a progressive dementia is the cardinal manifestation. Visual failure may occur early in some cases because of retinal degeneration (of rods and cones) with pigmentary deposits, but in others vision is normal. The electroretinogram becomes isoelectric if vision is affected. Abnormal inclusions (translucent vacuoles) are seen in 10 to 30 percent of circulating lymphocytes, and azurophilic granules in neutrophils. High-voltage EEG spikes are induced by photic stimuli. Only in early-onset cases is there microcephaly. It is in this type of Batten disease that an intraventricularly administered enzyme replacement treatment (cerolipinase alpha) by Schulz and coworkers has met with provocative success in reducing the degree and rapidity of cognitive decline compared to historical controls, at the price of serious adverse events, many from the intraventricular catheter.
In the juvenile form (NCL 3, CLN3 mutation), visual loss, seizures and ataxia predominate. The adult Kuf type (NCL 4, CLN6 and other mutations) has manifestations that are varied, including dementia, as discussed further on.