Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease).

OBJECTIVE: To use the Unified Batten Disease Rating Scale (UBDRS) to measure the rate of decline in physical and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease, a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002; during that time, the scale has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in quantitatively assessing clinical outcomes in research trials. METHODS: We administered the UBDRS to 82 subjects with JNCL genetically confirmed by CLN3 mutational analysis. Forty-four subjects were seen for more than one annual visit. From these data, the rate of physical impairment over time was quantified using multivariate linear regression and repeated-measures analysis. RESULTS: The UBDRS Physical Impairment subscale shows worsening over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This deterioration correlates with functional capability and is not influenced by CLN3 genotype. CONCLUSION: The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to quantify the rate of progression of physical impairment in subjects with JNCL in clinical trials.

Altered arginine metabolism in the central nervous system (CNS) of the Cln3-/- mouse model of juvenile Batten disease.

BACKGROUND: Juvenile neuronal ceroid lipofuscinoses (JNCL) or juvenile Batten disease is a recessively inherited childhood neurodegenerative disorder resulting from a mutation in CLN3, which encodes a putative lysosomal protein of unknown function. AIM: Recent evidence suggests that a disruption in CLN3 function results in altered regulation of arginine transport into lysosomes, and may influence intracellular arginine levels. We sought to investigate the possible consequences of arginine dysregulation in the brain of the Cln3(-/-) mouse model of JNCL. METHODS: Using a combination of enzyme assays, metabolite profiling, quantitative reverse-transcription polymerase chain reaction and Western blotting, we analysed the activities and expression of enzymes involved in arginine metabolism in the cerebral cortex and cerebellum of Cln3(-/-) mice over several developmental time points. RESULTS: We report subtle, but significant changes in the activities of enzymes involved in the citrulline-NO recycling pathway, and altered regulation of neuronal nitric oxide synthase in the cortex and cerebellum of Cln3(-/-) mice. In addition, a significant decrease in arginine transport into cerebellar granule cells was observed, despite an apparent upregulation of the cationic amino acid transporter-1 transporter at the cell surface. Our results provide further evidence that CLN3 function and arginine homeostasis are intricately related, and that cellular mechanisms may act to compensate for the loss of this protein. CONCLUSIONS: This and other studies indicate that CLN3 dysfunction in JNCL may result in multiple disturbances in metabolism that together contribute to the pathophysiological processes underlying this disease.

Distinct patterns of serum immunoreactivity as evidence for multiple brain-directed autoantibodies in juvenile neuronal ceroid lipofuscinosis.

Autoantibodies to glutamic acid decarboxylase (GAD65) have been reported in sera from the Cln3(-/-) mouse model of juvenile neuronal ceroid lipofuscinosis (JNCL), and in individuals with this fatal paediatric neurodegenerative disorder. To investigate the existence of other circulating autoreactive antibodies, we used sera from patients with JNCL and other forms of neuronal ceroid lipofuscinosis (NCL) as primary antisera to stain rat and human central nervous system sections. JNCL sera displayed characteristic patterns of IgG, but not IgA, IgE or IgM immunoreactivity that was distinct from the other forms of NCL. Immunoreactivity of JNCL sera was not confined to GAD65-positive (GABAergic) neurons, but also stained multiple other cell populations. Preadsorption of JNCL sera with recombinant GAD65 reduced the intensity of the immunoreactivity, but did not significantly change its staining pattern. Moreover, sera from Stiff Person Syndrome and Type I Diabetes, disorders in which GAD65 autoantibodies are present, stained with profiles that were markedly different from JNCL sera. Collectively, these studies provide evidence of the presence of autoreactive antibodies within multiple forms of NCL, and are not exclusively directed towards GAD65.

A clinical rating scale for Batten disease: reliable and relevant for clinical trials.

BACKGROUND: Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neurodegenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic interventions. OBJECTIVE: To develop a clinical rating instrument to assess motor, behavioral, and functional capability in JNCL. METHODS: A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted kappa statistics. RESULTS: Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was 6.1 +/- 1.6 years, and the mean duration of illness was 9.0 +/- 4.4 years. The ICCs for the domains were as follows: motor = 0.83, behavioral = 0.68, and functional capability = 0.85. CONCLUSIONS: The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.

Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease.

The pathogenic mechanisms underlying Batten disease are unclear. Patients uniformly possess autoantibodies against glutamic acid decarboxylase (GAD) that are predominantly reactive with a region of GAD (amino acids 1 to 20) distinct from subjects with autoimmune type 1 diabetes or stiff-person syndrome. Batten patients did not possess autoantibodies against other type 1 diabetes-associated autoantigens and human leukocyte antigen genotypes revealed no specific associations with this disease.