Based on the recent report a continuous spectrum of CLN8-associated phenotypes exists rather than a sharp distinction between EPMR and vLINCL. Therefore, the clinical discussion will be conducted, considering the broader phenotype.
Congenital NCL8 (cNCL8)
The case of cNCL8 was described in an Argentinian child born with severe hypotonia. Since birth, there were signs of psychomotor delay, and language was never developed. At the age of 3, seizures (generalized tonic-clonic) started. After three years, myoclonus and ataxia arose, with an MRI study showing cerebellar atrophy. At 12, the child died.
On a side note, the NCL10 disease is the second NCL type known to present congenital form.
Late infantile NCL variant (vLINCL)
Patients with vLINCL phenotype manifest signs of disease around the fifth year of age. Moreover, from the beginning, it progresses rapidly, so patients are losing their movement ability in two to four years.
Seizures
Most patients present generalized tonic-clonic seizures with disease onset. Additionally, myoclonus often occurs. One report described a Turkish origin patient with the status dystonicus as a first sign of disease at 5.
Cognitive decline
As the disease progresses rapidly it usually severely affects cognitive functions. Patients mostly display delay of speech.
Cerebellar atrophy
Cerebellar atrophy is detected with MRI studies in all symptomatic patients. It usually affects both cerebellar hemispheres and vermis. Clinical symptoms include ataxia, gait imbalance, and dysarthria.
Visual disturbance
All patients have retinal pathology leading to visual loss. The vision acuity starts to deteriorate rapidly with disease onset (typically near the fifth year of age). The outcome is usually severe. Studies reported that retinal degeneration could be detected in the peripheral retina and macular area. Moreover, often optic nerve atrophy is also present.
On a side note, ocular manifestations of NCL are most commonly observed with NCL3 patients. They, however, have probably some differences in their pathophysiology. For example, reports of the CLN8-/- murine models found more marked thinning of the outer retina than CLN3-/- murine models studies, where thinning of the inner retina was dominating.
Atypical late infantile NCL (aLINCL)
Some of the described patients do not present the classic vLINCL or EMPR phenotype. Due to the presence of retinal pathologies, most likely they should be treated as atypical vLINCL manifestations.
The symptoms arise at the range of 5-16 years of age and are progressing slower than in vLINCL patients. Usually, epilepsy is the first sign of disease. Seizures can be generalized, but also partial seizures are observed. Myoclonus is typically absent. Infancy psychomotor development may be delayed, and the cognitive outcome is better than in vLINCL patients. Both cerebellar atrophy and accompanying clinical signs (ataxia, abnormal gait, speech impairment) can develop in some cases.
Progressive epilepsy with mental retardation (EPMR)
EPMR manifests a little later than vLINCL, at the age of 7-9, with a normal development period up until epilepsy occurs. The disease progression rate is slow, and young adults often are still able to walk. The patients may reach 50 or 60 years of age.
Seizures
EPMR usually presents with generalized tonic-clonic seizures around the age of 5-10. The seizures occur once every one or two months in the beginning. Then their frequency rises, having its peak in puberty. In adulthood, epilepsy is often less severe, however still present. The seizures in one-third of cases may also manifest as complex focal seizures. Myoclonus is uncommon.
Cognitive decline
Unfortunately, within a few years from seizures onset, cognitive deterioration begins. Even with clinical suppression of seizures, the treatment is not disease-modifying, so cognitive decline continues. As a result, most patients are moderately/profoundly intellectually disabled in adulthood.
Cerebellar atrophy
Neurological symptoms develop with the disease progression, such as cerebellar atrophy. Thus, cerebellar ataxia and dysarthric speech are arising.
Visual disturbance
Usually, patients do not present evident ocular pathology, but in some visual acuity decrease (without distinct retinal pathology) may occur. Probably mild optical nerve atrophy develops, as the VEP study results are abnormal in such patients.
CLN8