Jansky-Bielschowsky disease
Jansky-Bielschowsky disease (JBD) is a rare, inherited neurodegenerative disorder classified as a late-infantile form of neuronal ceroid lipofuscinosis (NCL). It typically manifests between the ages of two and four with symptoms such as seizures, ataxia, and cognitive decline, leading to significant motor and mental impairment. The disease is caused by mutations in the TPP1 gene, which results in a deficiency of the enzyme tripeptidyl peptidase I, essential for degrading certain proteins in brain cells. JBD is most common in families of Northern European and Scandinavian descent, with a global incidence estimated at 0.36–0.46 per 100,000 live births. Diagnosis involves a combination of clinical evaluations, biochemical assays, and genetic testing to identify the specific mutation. Although there is currently no cure, the FDA-approved treatment Brineura (cerliponase alfa) has shown promise in slowing disease progression. Management focuses on alleviating symptoms and improving quality of life. The condition progresses rapidly, often resulting in significant disability and a shortened lifespan, with affected children typically becoming chairbound by age six and facing life-threatening complications before reaching adulthood.
Jansky-Bielschowsky disease
ALSO KNOWN AS: Classic late infantile neuronal ceroid lipofuscinosis; late infantile CLN2/TPP1 disorder; late infantile Batten disease; CLN2 disease
DEFINITION Jansky-Bielschowsky disease (JBD) is the classic late-infantile form of a group of rare, inherited neurodegenerative disorders known as neuronal ceroid lipofuscinoses (NCL), characterized by accumulation of autofluorescent lipopigment in neurons and other cell types. This form begins between two and four years of age with seizures, then progresses rapidly to motor and mental impairment.
Risk Factors
Family history is an important risk factor. The disease is encountered worldwide, with an incidence of 0.36–0.46 per 100,000 live births, but it is most common in families of Northern European and Scandinavian ancestry. The prevalence of late-infantile NCL is unknown, but that the global prevalence of all forms of NCL, collectively, is estimated to be 1 in 100,000. In Finland NCLs affect about 1 in 12,500 people.
Etiology and Genetics
Neuronal ceroid lipofuscinoses with childhood onset are inherited in an autosomal recessive manner. The parents of an affected child are carriers of a mutant allele (obligate heterozygotes) and asymptomatic. Each of their children has a 25 percent chance of having the disease (homozygote), a 50 percent chance of carrying the gene without displaying the disease phenotype, and a 25 percent chance of not carrying the gene and not having the disease.
The gene responsible for the classic late infantile form is tripeptidyl peptidase I or TPP1 (formerly ceroid lipofuscinosis, neuronal 2 or CLN2). This 6.7 kilobase-pair gene with thirteen exons and twelve introns has been mapped to chromosome 11p15.4. It encodes for lysosomal tripeptidyl-peptidase 1 (TPP1), a pepstatin-insensitive acid that removes tripeptides from the of small proteins and several peptide hormones. Three common mutations are a GC in the invariant AG of the 3′ splice junction of 5; an exon 6 CT causing a premature stop; and an exon 10 GC missense mutation.
Cases of late infantile NCL with no TPP1 mutations have been reported for a small percentage of cases. Variants of this are associated with other genetic mutations involving PPT1 (CLN1), CLN5, CLN6, CLN8, and MFSD8. In 2013 GeneReviews listed CTSD mutations as a rare cause of late-infantile NCL., and also reported that in Finland, mutations in CLN5 are responsible for a major proportion of the nation's late-infantile NCL cases.
The relationship among NCL genetic defects, storage material accumulation, and tissue damage is still poorly understood. Lysosomal deposition of lipopigment (composed of lipid and protein) is evident in many tissues and organs, but the most prominent degeneration involves neural cells. Alterations in the CLN2 gene lead to a misfolding of the precursor peptidase, resulting in abnormal post-translational processing and lysosomal targeting of tripeptidyl-peptidase. The lack of normal enzymatic activity affects the ability of brain cells to remove and recycle proteins. Neuropathologic examination shows atrophy of cerebral and cerebellar cortices, with loss of neurons and retinal cells. The central nervous system and retina display characteristic autofluorescent curvilinear storage bodies.
Biochemical analysis of the deposits, performed for research purposes, indicates they contain hydrophobic ATP synthase complex subunit c, part of the normal inner mitochondrial membrane and a putative substrate of the affected enzyme. The inability of neurons to degrade neuropeptides, such as neuromedin B, might also contribute to the disease pathogenesis.
Symptoms
During the first twenty-four months of life, mental and motor development are normal, although slow speech development and mild clumsiness have been noted. The condition is manifested between two and four years of age, with myoclonic (most often) or tonic-clonic seizures, and ataxia. Developmental delay, cognitive decline, and visual impairment are common. Extrapyramidal and pyramidal signs are present.
Screening and Diagnosis
The diagnosis strategy combines clinicopathologic data with biochemical and genetic testing. Essays of TPP1 activity are clinically available and can be employed as an initial step. If these are abnormal, then molecular for TPP1 is performed to identify the family-specific mutation and for potential prenatal diagnosis. Electron microscopic studies performed on skin, conjunctiva or skeletal muscle biopsies, as well as heparinized whole blood (lymphocytes), reveal characteristic curvilinear bodies in TPP1-deficient patients. Immunohistochemical examination can be used to highlight the enzymatic levels.
Magnetic resonance imaging confirms the cerebral and cerebellar atrophy. Electroencephalogram, electroretinogram, and visual evoked potentials show distinct abnormalities.
Treatment and Therapy
At present, there is no cure for this disease. The major goal of treatment is to reduce muscular discomfort, control seizures, and monitor vision impairment, using a multidisciplinary approach. Palliative treatment for behavioral disturbances, malnutrition, and gastroesophageal reflux is available. Research efforts employ augmentation, gene transfer, and stem cell transplantation to mitigate the enzymatic defect.
In 2017, the FDA approved Brineura (cerliponase alfa), the first specific treatment for Jansky-Bielschowsky disease. Brineura's active ingredient is a recombinant form of human TPP1, the enzyme lacked by individuals suffering from Jansky-Bielchosky disease. It is administered directly into the patient's cerebrospinal fluid. This novel treatment, when applied to children three years of age or older, significantly slowed the loss of walking ability associated with the disorder.
Prevention and Outcomes
Genetic counseling can be pursued by individuals with relevant family history. Carrier testing is available for known parental mutations. If the proband has a demonstrated TPP1 enzymatic deficiency or a detected gene mutation, is feasible. Preimplantation genetic diagnosis can be performed in research or clinical settings.
Complications include blindness, spasticity, intellectual disability, and malnutrition. This late infantile form progresses rapidly. The affected children become chairbound by the age of four to six years. Death occurs before or during the second decade of life.
Bibliography
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