Neuronal ceroid lipofuscinosis late infantile form. Jansky-Bielschowsky Disease. Early onset Batten disease. Tripeptidyl peptidase 1 (TPP1) deficiency.
Incidence
It is an autosomal recessive hereditary lysosomal storage disorder, caused by pathogenic variants (mutations) in the TPP1 gene (also referred to as the CLN2 gene). There is no ethnic or geographic predominance for the disease. Incidence of 0.5-2.2/100.000.
Clinical Characteristics
Late infantile Neuronal Ceroid lipofuscinosis or Jansky-Bielschowsky Disease is characterized by dramatic neurological symptoms including numerous generalized seizures, myoclonic jerks, ataxia, mental deterioration and visual failure appearing over a period of months.The condition usually starts between ages 2 to 4 years after a period of normal or moderately retarded early psychomotor development. Characteristically, slow photic stimulation induced occipital spikes on the EEG. Visual as well as somatosensory evoked potentials are very large. Typical intralysosomal inclusion with curvilinear bodies can be detected on skin biopsies. Nocturnal restlessness with a markedly reduced desire for sleep may be an early sign. The first manifestation of the disease is usually seizures which rapidly increase in frequency and tends to be intractable. There are several types even in the same individual. There may be generalized tonic-clonic, myoclonic or atonic, also staring spells. Soon are associated with irregular asynchronous asymmetric myoclonic jerks that become more severe as the disease progress. The myoclonus is evoked by proprioceptive stimuli, voluntary movements or emotional excitement. Ataxia is also later present as well as involvement of corticospinal tracts. The motor disability in the child soon becomes very marked. Mental faculties deteriorate and speech becomes thick and slurred. Vision fails with time and most children are blind by the age of six years. The fundoscopic evaluation is abnormal except early in the disease. There is macular degeneration with varying degrees of discoloration and hyperpigmentation or sometimes showing diffuse pigmentary degeneration. Then optic atrophy follows. ERG becomes extinct and may be abnormal even before any clear evidence of visual loss or ophthalmoscopic change. The most important electrophysiological finding for diagnosis occur in the EEG photic stimulation. Flashes at 1 to 2/second elicit a characteristic high amplitude occipital spikes. Giant visual evoked potentials and high somatosensory evoked potentials are typical. CT scan and MRI reveal brain atrophy predominantly in the cerebellum. Hypointense areas may be seen in the thalami and putamen and hyperintense areas in the periventricular white matter. CSF is normal. There is no vacuolated lymphocytes (as they occur in the juvenile form) Death occur usually before the end of the first decade. There is a variant form almost seen in Finland which usually start late usually after the age of six to seven years. Important aspects to consider in the diagnosis are the ophthalmoscopic evaluation in ERG, EEG with slow photic stimulation and visual evoked and somatosensory evoked potential, brain MRI and EM study of skin and conjunctival biopsy revealing intralysosomal inclusions in the mesenchymal cells showing multiple small arciform lamellar structures called curvilinear bodies. There may be occasional fingerprint-like lamellar structures in some cells. For infantile (CLN1) and classic late-infantile (CLN2) there are now available white cell lysosomal enzyme assays which are both more sensitive and specific for these NCL variants. Also less invasive than a biopsy.
There is now specific treatment. Cerliponase alfa (Brineura) injection for intraventricular use is indicated to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as Tripeptidyl peptidase 1 (TPP1) deficiency. So early diagnosis is critical for children with CLN2 disease.
Precipitants
The myoclonus is evoked by proprioceptive stimuli, voluntary movements or emotional excitement.
Provocation Tests
no
Diagnostic Procedures
The most important electrophysiological finding for diagnosis occur in the EEG photic stimulation. Flashes at 1 to 2/second elicit a characteristic high amplitude occipital spikes. Giant visual evoked potentials and high somatosensory evoked potentials are typical. EM study of skin and conjunctival biopsy reveal intralysosomal inclusions in the mesenchymal cells showing multiple small arciform lamellar structures called curvilinear bodies. There may be occasional fingerprint-like lamellar structures in some cells. For infantile (CLN1) and classic late-infantile (CLN2) there are now available white cell lysosomal enzyme assays which are both more sensitive and specific for these NCL variants. Also less invasive than a biopsy. Molecular or enzymatic genetic testing can be diagnostic. On average, there is a 2 year delay from first seizure to diagnosis, but with recent free molecular testing offered to patients with early, non specific symptoms and early onset unprovoked seizures, the delay for diagnosis seems to be shortening. To contact diagnostic company for free testing call BioMarin at 1-866-906-6100 or e-mail support@biomarin-rareconnections.com.