Do females with juvenile ceroid lipofuscinosis (Batten disease) have a more severe disease course? The Danish experience.

BACKGROUND: Juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) is characterized by progressive visual failure starting at 4-7 years of age, followed by seizures, dementia as well as a progressive decline in motor function. The patients are typically bedridden in the late teens and death usually occurs in the third decade of life. It has been suggested, that females may have a more precipitous decline than do males. OBJECTIVE: To compare sex differences in loss of skills and age at death in an unselected population of Danish Adolescents with Batten disease. METHOD: Review of hospital records of all 35 Danish patients with JNCL born in the period 1971-2003. The records contain a continuously maintained history of the clinical course and first moments for different events, thus eliminating recall bias. RESULTS: We found that females with JNCL experienced a later age at diagnosis, but showed an earlier loss of independent functions, and died at an earlier age. CONCLUSION: Females with JNCL have a more precipitous decline than males, and die at an earlier age. Further studies are needed in order to provide possible explanations for this difference.

Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis.

PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death by around 8 months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3 mg, corresponding to 12 mg/kg or 180 U/kg for a 25 g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8 weeks of age. The treatment was surprisingly well tolerated and neither anaphylaxis nor antibody formation was observed. In mice treated from birth, survival increased from 236 to 271 days (p<0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8 weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3 months in mice treated from birth, and although this improvement persisted it was attenuated by 7 months. Outside the central nervous system, substantial clearance of autofluorescent storage material in many tissues was observed. Macrophages in spleen, liver and intestine were especially markedly improved, as were acinar cells of the pancreas and tubular cells of the kidney. These findings suggest that ERT may be an option for addressing visceral storage as part of a comprehensive approach to PPT1-related NCL, but more effective delivery methods to target the brain are needed.

Females experience a more severe disease course in Batten disease.

Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood. Symptoms typically present at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. Studies on sex differences in JNCL have yielded mixed results, but parent anecdotes suggest that females experience a more precipitous disease course. Therefore, we sought to determine if sex-based differences exist in JNCL. We used data from the Unified Batten Disease Rating Scale (UBDRS), the Batten Disease Support and Research Association (BDSRA) database, and the PedsQL quality of life (QoL) survey to evaluate sex-based differences in functional independence and time from symptom onset to death. On average, females had JNCL symptom onset one year later and death one year earlier than did males. Despite a later age at onset, females had lower functional capability, earlier loss of independent function, and lower physical QoL. Future research in sex differences in JNCL may help to further understand the biological mechanisms underpinning the disease course and may point to targeted therapies.

Comparative study of cerebellar degeneration in canine neuroaxonal dystrophy, cerebellar cortical abiotrophy, and neuronal ceroid-lipofuscinosis.

The cerebellar lesions of three dogs with canine neuroaxonal dystrophy (NAD), one dog with cerebellar cortical abiotrophy (CCA), and 4 dogs with neuronal ceroid-lipofuscinosis (NCL) were examined to understand their pathogeneses. Purkinje cell loss was most severe in the vermis of a dog with CCA, and granule cell loss was most prominent in the cerebellar hemisphere of dogs with NCL. Immunohistochemically, CD3-and HLA-DR-positive cells were most frequent in the dogs with NCL, and moderate in dogs with NAD, but not in a dog with CCA. The number of cleaved caspase 3-positive cells was prominent in a dog with CCA, but no significant in the dogs with NAD. The results indicate different pathway of neuronal loss of these canine neuronal disorders.

Occurrence of and mortality from childhood neuronal ceroid lipofuscinoses in norway.

The aim of this study was to estimate the prevalence of, incidence of, and survival from childhood neuronal lipofuscinoses in Norway. All children with neuronal ceroid lipofuscinoses living in Norway are referred to the Tambartun National Resource Centre for the Visually Impaired. We based the data collection on the medical records at Tambartun. We identified 70 children with neuronal ceroid lipofuscinoses who were born in Norway from 1957 to 1998. Seven had a diagnosis of late infantile neuronal ceroid lipofuscinoses, and 63 had the juvenile form of neuronal ceroid lipofuscinoses. In 2005, the prevalence of childhood neuronal ceroid lipofuscinoses was 8.3 per million inhabitants in Norway, and all children were diagnosed with the juvenile form. The average annual incidence rate of childhood neuronal ceroid lipofuscinoses was 1.8 per 100,000 live births using the years from 1957 to 1978 and 3.9 using the years from 1978 to 1999. The trend in incidence increased at an annual rate of about 3.3% per year (P = .001), averaged over this period. Restricted to the most recent period (1967-1998), the trend was much weaker (1.4% increase per year; P = .3), and confidence intervals included the possibility of no trend. The median age at death of children diagnosed with late infantile neuronal ceroid lipofuscinoses was 12 years (95% confidence interval 9-14) and 26 years (95% confidence interval 25-30) for children diagnosed with the juvenile form. The results did not support the hypothesis that children with neuronal ceroid lipofuscinoses born in 1975 or later lived longer than those born from 1957 to 1975 (relative risk 1.0, 95% confidence interval 0.36-2.8). Mortality was similar for both genders (hazard ratio 0.97, 95% confidence interval 0.4-2.2).

Altered flurothyl seizure induction latency, phenotype, and subsequent mortality in a mouse model of juvenile neuronal ceroid lipofuscinosis/batten disease.

PURPOSE: Juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a pediatric neurodegenerative disease characterized by vision loss, seizure activity, cognitive decline, and premature death. Discovery of the Batten disease-related gene, CLN3, led to creation of a Cln3 protein-deficient mouse model (Cln3-/-), which recapitulates some of the histopathologic characteristics of the human condition. We hypothesized that lack of Cln3 would alter seizure-related behavioral parameters. METHODS: Using flurothyl gas inhalation, we examined seizure-induction latencies in Cln3-/- mice and wildtype (wt) controls at time points that represent late neonatal, immature, mature, and aged time points. We examined latency to first myoclonic jerk (LMJ), latency to loss of posture (LOP), and subsequent mortality. RESULTS: Our results demonstrate an age-dependent alteration of seizure-induction latencies in Cln3-/-. Immature Cln-/- mice aged 35-42 days had an increased latency to both LMJ and LOP compared with age-matched wt controls. There were no significant latency differences between Cln3-/- and wt at other time points examined. Mortality after generalized seizure was high in both Cln3-/- and wt animals at late neonatal and immature developmental stages. No mortality was seen in wt mice past maturity at 6 weeks. Mature and aged Cln3-/- animals retained a vulnerability to death after seizure activity. CONCLUSIONS: These results suggest that a deficiency of Cln3 protein in the Batten model mice may result in age-dependent alteration of the neuroanatomic and biochemical substrates involved in seizure propagation and recovery. This may be important in understanding seizures, neurodegeneration, and premature death in human Batten disease.

Dietary carnitine supplements slow disease progression in a putative mouse model for hereditary ceroid-lipofuscinosis.

The childhood ceroid-lipofuscinoses are a group of autosomal recessively inherited disorders characterized by massive accumulation of autofluorescent lysosomal storage bodies in neurons as well as other cell types. The storage body accumulation is accompanied by severe degeneration of the central nervous system that results in blindness, cognitive and psychomotor degeneration, and premature death. On the basis of pathologic and biochemical criteria, a hereditary disease in the mnd mouse strain has been proposed as a model for certain types of human ceroid-lipofuscinosis. Experimental evidence suggests that the storage body accumulation in humans with juvenile and late-infantile ceroid-lipofuscinosis is linked to altered carnitine biosynthesis. On the basis of the latter observation, a study was performed to determine whether dietary carnitine supplements could slow the disease progression in the mnd mouse model. Carnitine supplementation begun at 4 weeks of age did not slow the retinal degeneration that is characteristic of this disease. It did, however, significantly elevate brain carnitine levels, slow the accumulation of autofluorescent storage bodies in brain neurons, and prolong the lifespans of the treated animals. These findings suggest that there is a link between carnitine biosynthesis and the disease pathology and indicate that carnitine supplementation may be beneficial in slowing the disease progression in humans with certain types of hereditary ceroid-lipofuscinosis.

Neuronal ceroid-lipofuscinoses in childhood.

Neuronal Childhood types of ceroid-lipofuscinoses (NCL) are reviewed. All three main types, infantile, late infantile and juvenile, are progressive encephalopathies characterized by neural and extraneural accumulation of ceroid- and lipofuscin like storage cytosomes. The pathogenesis of NCL is unknown. A disturbance of the peroxidation of polyunsaturated fatty acids and a defect in the processing and turn-over of the glycoproteins in the lysosomal membrane are those hypotheses which have been most widely investigated. Reduced membrane lipids and reduced membrane fluidity have recently been detected. Prenatal diagnosis, based on the characteristic ultrastructural findings, is possible in all types.