Juvenile-onset neuronal ceroid lipofuscinosis with infantile CLN1 mutation and palmitoyl-protein thioesterase deficiency.

Accurate diagnosis, especially in progressive hereditary diseases, is essential for the treatment and genetic counseling of the patient and the family. Neuronal ceroid lipofuscinoses (NCL) are amongst the most common groups of neurodegenerative diseases. Infantile, juvenile, and adult-onset types with multiple genotype-phenotype associations have been described. A fluorimetric enzyme assay for palmitoyl protein thioesterase (PPT) from leukocytes and fibroblasts has been previously developed to confirm the diagnosis of infantile NCL. We describe a patient with juvenile-onset NCL phenotype with a new CLN1 mutation and deficient PPT activity. Over 40 different mutations have been found in patients with PPT deficiency, indicating that screening for known mutations is not an efficient way to diagnose this disorder. Therefore, PPT enzyme analysis should precede mutation analysis in suspected PPT deficiency, particularly in patients with granular osmiophilic deposits (GROD) or in patients who have negative ultrastructural data. The use of enzyme assay led to the diagnosis of this patient with juvenile-onset Finnish variant NCL with PPT deficiency, and we expect that greater awareness of the utility of the enzymatic assay may lead to identification of other similar cases awaiting a definitive diagnosis.

Psychiatric symptoms of children and adolescents with juvenile neuronal ceroid lipofuscinosis.

BACKGROUND: Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the most common neurodegenerative disorders in childhood and adolescence. The clinical picture includes diverse and complex psychiatric symptoms that are difficult to treat. Only symptomatic treatment is available. To improve symptomatic therapy, it is important to recognize the symptoms. The purpose of this study was to identify predominant psychiatric symptoms in patients with JNCL. METHODS: The study included 27 patients with JNCL with and without psychotropic treatment. The mean age was 15.2 (range 9-21) years. Characteristic psychiatric symptoms in this patient group were clarified by using the following standardized questionnaires filled in by parents, teachers and the patients themselves: Child Behavior Checklist (CBCL), Teacher Report Form (TRF) and Children's Depression Inventory (CDI). The symptoms were recorded for the entire study group and compared between patients with and without psychotropic treatment and between genders. RESULTS: The patients had a large number of psychiatric symptoms according to the CBCL and TRF. The most commonly reported symptoms were social, thought, attention problems, somatic complaints and aggressive behaviour. Patients receiving psychotropic medication had more psychiatric symptoms according to the CBCL and TRF. Moreover, female patients had more problems than male patients according to the CBCL. The total psychiatric symptom score was at clinical or borderline range for psychiatric disturbance in 74% of patients. The number of depressive symptoms reported by the patients themselves was low. CONCLUSIONS: JNCL patients suffer from a multitude of psychiatric symptoms. To improve drug choice and dosage, a thorough evaluation of these symptoms by standardized methods is needed before initiating treatment. Progress and possible adverse effects of treatment should be monitored on a regular basis.

Neuroradiological findings (MRS, MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease.

Infantile neuronal ceroid-lipofuscinosis (infantile CLN1) is a progressive and uniformly fatal lysosomal storage disease of the nervous system. The purpose of this study was to compare the findings of various radiological examinations of the brain in the course of infantile CLN1 in order to evaluate the relative usefulness of the methods and their potential for monitoring therapeutic interventions. We examined eight infantile CLN1 patients, 51 studies, in various stages of the disease--preclinical to late stage--with proton magnetic resonance spectroscopy (1H-MRS), MRI, and perfusion SPECT, and in addition three benzodiazepine (BZ) receptor ligand SPECT studies. Both 1H-MRS and MRI showed abnormal findings before clinical manifestations of the disease. Cortical hypoperfusion and loss of cortical BZ receptors revealed by SPECT appeared simultaneously with clinical signs. After the age of 4 years MRI and SPECT alterations progressed minimally, whereas 1H-MRS showed progressive deterioration of neurometabolism. Of the four methods used in this study, MRI proved to be the most practicable for diagnosing infantile CLN1; the final diagnosis of infantile CLN1 is confirmed by the characteristic clinical picture and DNA or PPT enzyme analysis. The combination of 1H- MRS and MRI could be most useful for monitoring therapeutic interventions.

Enlarged SI and SII somatosensory evoked responses in the CLN5 form of neuronal ceroid lipofuscinosis.

OBJECTIVES: To examine in detail the activation of the primary (SI) and secondary (SII) somatosensory cortex in CLN5, the Finnish variant of late infantile neuronal ceroid lipofuscinoses (NCL). METHODS: Somatory evoked magnetic fields were recorded with a 122-channel planar gradiometer in response to median nerve stimulation in 5 CLN5 patients (aged 8.8-16.7 years) and in 10 healthy age-matched controls. RESULTS: The first two responses from contralateral SI, N20m and P35m, were 6-20 times stronger in the patients than in the controls. The morphology of the subsequent deflections from SI was abnormal in the patients: a prominent N45m was detected, while the normally present P60m deflection was missing. In 4 patients the contra- and in two patients the ipsilateral SII responses were also enlarged. Furthermore, the SII activation was detected at shorter latency in patients than in controls. CONCLUSIONS: At SI, CLN5 is associated with a selective enhancement of the early cortical responses. We propose that the enlargement of N20m most likely reflects increased synchronous input from thalamus, whereas the altered morphology of the following responses may reflect defective interneuronal inhibition at the cortex. The enlargement of SII responses shows that the imbalance between excitation and inhibition in CLN5 extends outside the primary somatosensory areas.

Positron emission tomography shows reduced striatal dopamine D1 but not D2 receptors in juvenile neuronal ceroid lipofuscinosis.

We studied striatal dopamine D1 and D2 receptors in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) with positron emission tomography (PET) using a dopamine D1 receptor antagonist [11C]NNC 756 and a dopamine D2 receptor antagonist [11C]raclopride as ligands. The mean [11C]NNC 756 uptake value in JNCL was reduced by 15 % from the mean control value in the putamen (p < 0.01) and by 13 % in the caudate nucleus (p < 0.01). The mean [11C]raclopride uptake in JNCL patients was not significantly different from the mean of the control group either in the putamen or the caudate nucleus. Our results show a mild reduction in striatal dopamine D1 but not in D2 receptors in JNCL, indicating slightly impaired striatal neuronal function. The contribution of these changes to the extrapyramidal symptoms of the patients and their treatment deserves further studies.

Sleep and its disturbance in a variant form of late infantile neuronal ceroid lipofuscinosis (CLN5).

To examine the nature of sleep disturbance in patients with a variant form of late infantile neuronal ceroid lipofuscinosis (CLN5), we studied 12 patients (age range 7-32 years). We used a sleep questionnaire to assess sleep and its disturbances quantitatively. To identify the periodicity in the diurnal rest-activity rhythms, the motor activity level was recorded by activity monitors continuously for a 1-week period with concomitant sleep logs. In addition, whole-night polysomnographic recordings were performed. The patients under 20 years of age had an excess of nocturnal sleep (the mean of the usual duration of nighttime sleep was 10.0 hours) and frequent daytime naps. Frequent shifts of the longest sleep period into the daytime hours and fragmented diurnal rest-activity patterns with no distinct rhythm occurred in the older patients. The progressive disease may damage the internal circadian timing system and also impair the ability of patients with variant late infantile neuronal ceroid lipofuscinosis to use external time cues for synchronization of their sleep and environmental time.

Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis.

OBJECTIVE: To study the effect of allogeneic hematopoietic stem cell transplantation (SCT) on the clinical course of infantile neuronal ceroid lipofuscinosis (INCL), a lysosomal storage disease. BACKGROUND: INCL is a progressive encephalopathy with severe neuronal loss, especially in the cerebral and cerebellar cortex and retina. Autofluorescent lipopigments constitute the typical storage material in INCL. The disease is caused by recessive mutations in the palmitoyl protein thioesterase 1 (PPT1) gene. PPT1 is a depalmitoylating enzyme, which is transported to lysosomes through the mannose-6-phosphate receptor-mediated pathway, and participates in the lysosomal degradation of fatty acylated proteins. METHODS: Three patients with INCL received transplants and were followed up after SCT at the Hospital for Children and Adolescents at the University of Helsinki. The first patient rejected the first graft at the age of 7 months and had mild symptoms of INCL at the second transplantation at 11 months. The two other patients were asymptomatic when they received their transplants at the age of 4 months. RESULTS: PPT1 enzyme activity was normalized in peripheral leukocytes, but remained low in the CSF and resulted only in a mild and transient amelioration of the classic INCL. All patients who received transplants developed INCL by the age of 2 or 3 years. CONCLUSIONS: More experimental animal and cell culture studies are needed to determine the in vivo function of PPT1. SCT currently cannot be recommended as therapy for INCL.

Clinical and neuroradiological diagnostic aspects of neuronal ceroid lipofuscinoses disorders.

Early diagnosis is mandatory for avoiding further cases in families with hereditary metabolic brain disorders. This review lists the most important clinical symptoms and neuroradiological findings at the early stage of the seven most common childhood neuronal ceroid lipofuscinoses (NCL) types. In the infantile type the typical magnetic resonance imaging (MRI) findings can be seen even before the clinical signs. In the classic late infantile type (CLN2), MRI is less informative but in this and in the variant late infantile type CLN6 the characteristic neurophysiological findings are present at an early stage, although not in the Finnish variant CLN5. In the latter, the clinical diagnosis depends on ophthalmological and MRI findings. The combination of ophthalmological deficits and vacuolated lymphocytes is highly characteristic of the juvenile type (CLN3). A new NCL type, Northern epilepsy (CLN8), is also briefly reviewed.

New antidepressive and antipsychotic drugs in juvenile neuronal ceroid lipofuscinoses--a pilot study.

Patients with juvenile neuronal ceroid lipofuscinosis (JNCL) often have severe psychiatric symptoms. These are common in their mid-teens and include such symptoms as anxiety and affective and psychotic disorders. The older antidepressants and antipsychotics do not seem to be effective and often cause many adverse effects. Therefore, we wanted to try the new psychotropic drugs in Finnish patients with JNCL. We also wanted to determine the profile of these drugs in this patient group. Fourteen Finnish patients with JNCL receiving psychotropic drug treatment with citalopram, risperidone, olanzapine or quetiapine, were included. The mean age at initiation of the new psychotropic drugs was 13.8 years. Indications for treatment were psychotic symptoms, affective symptoms, anxiety and an inadequate response to other psychotropic drugs, or even adverse reactions. Information on psychiatric symptoms and current treatment was gathered from interviews and from the medical records. Indications and the clinical outcome of the treatment were determined by a consensus of the assessments by parents and physicians. The psychotropic drugs most commonly used in Finnish patients with JNCL are citalopram and risperidone. The clinical outcome was good or satisfactory in 70%. The adverse effects most commonly reported were fatigue, weight gain and aggravation of extrapyramidal symptoms. Little research has been done in this area and there are no good guidelines for treatment of psychiatric symptoms in patients with JNCL. Therefore, every patient should be treated with the safest and most commonly used drugs in the lowest possible doses.

Northern epilepsy syndrome (NES, CLN8)--MRI and electrophysiological studies.

Northern epilepsy syndrome (NES, EPMR, progressive epilepsy with mental retardation, CLN8), an inherited childhood-onset epilepsy with mental retardation, has been recently characterized to belong to the family of neuronal ceroid lipofuscinoses (NCLs). In this study, four patients (ages 26-44 years) with NES and eight healthy controls underwent magnetic resonance imaging (MRI) and electrophysiological evaluation with somatosensory evoked magnetic field (SEF) studies. The findings in NES were compared with the known findings in juvenile NCL (JNCL, CLN3) and Finnish variant late infantile NCL (vLINCLFIN, CLN5) that manifest around the same age as NES. Also postmortem MRI was performed on one brain. On the MRIs, slight to moderate cerebellar atrophy was seen in all patients, whereas only two patients had slightly enlarged cerebral sulci. None of the MRIs demonstrated signal intensity abnormalities that are commonly seen in JNCL and vLINCLFIN and are considered to reflect the Wallerian degeneration after neuronal death. Generally SEFs in NES were within normal limits, indicating that the disease had not impaired the function of the neurons on the somatosensory pathway. In conclusion, MRI imaging and SEF findings suggest that the cerebral neuronal death and dysfunction in NES are minimal compared with JNCL and vLINCLFIN.

Transdermal fentanyl therapy for pains in children with infantile neuronal ceroid lipofuscinosis.

We used infantile neuronal ceroid lipofuscinosis (INCL), in which deterioration of the central nervous system is extremely rapid, to study constant release of an opioid for pains of central origin in a metabolic disease. The effect of a transdermal fentanyl patch was studied in five children with INCL. In two of them, measurements of 17 fentanyl serum concentrations and also visual analogue pain scale were obtained during a 15-day study period. Low doses of transdermal fentanyl usually provided good pain relief for the first two days, but not for the third day, of the three-day patch change interval. Pain relief of this type seems mandatory for pains mostly of central origin.

Electroencephalography in juvenile neuronal ceroid lipofuscinosis: visual and quantitative analysis.

Fourteen patients with a confirmed diagnosis of juvenile neuronal ceroid lipofuscinosis (JNCL) (aged 6-12.5 years at the beginning of the study) were prospectively followed for 5 years. An electroencephalogram (EEG) was recorded and analysed both visually and quantitatively and a neuropsychological examination was performed once a year. In addition, a cross-sectional EEG study of 32 patients aged 5-27 years was performed. The EEG was often normal before the age of 9 years, and thereafter a progressive background abnormality and increase in paroxysmal activity took place. The EEGs were significantly slower than those of the controls, and the speed of slowing of EEG correlated to the decrease in intelligence quotients (IQ). Quantitative analysis was superior to visual analysis in detecting the deterioration of the background activity. The best parameter describing this was the fast/slow ratio. Peak frequency, percentage of theta and the fast/slow ratio correlated with IQ.

A favorable response to antiparkinsonian treatment in juvenile neuronal ceroid lipofuscinosis.

To study the effect of dopaminergic drugs on the parkinsonism in juvenile neuronal ceroid lipofuscinosis, the authors conducted an open study of 21 patients. According to the motor Unified PD Rating Scale (UPDRS) score, treatment was initiated with either levodopa (n = 10) or selegiline (n = 6). Five patients served as a control group. The UPDRS score after 1 year was compared with the score at onset. Both in the control group and in the selegiline group, the mean UPDRS score increased, whereas in the levodopa group, the mean UPDRS score decreased. The difference between the levodopa group and the control group was significant.

Studies of homogenous populations: CLN5 and CLN8.

Finland and the Finns have been the subject of numerous genetic and genealogical studies, owing to enrichment of certain rare hereditary disorders in the Finnish population. Two types of NCL have so-far been found almost exclusively in Finland: Finnish variant late infantile NCL, vLINCL (CLN5), and the Northern epilepsy syndrome or Progressive epilepsy with mental retardation, EPMR (CLN8). The first symptoms of Finnish vLINCL are concentration problems or motor clumsiness by 3 to 6 years of age, followed by mental retardation, visual failure, ataxia, myoclonus, and epilepsy. Northern epilepsy, the newest member of the NCL family with the most protracted course, is characterized by the onset of generalized seizures between 5 and 10 years of age and subsequent progressive mental retardation. Visual problems are slight and late, while myoclonus has not been observed. Both the Finnish vLINCL and Northern epilepsy are pathologically characterized by intraneuronal cytoplasmic deposits of autofluorescent granules which are Luxol fast blue-, PAS-, and Sudan black B-positive in paraffin sections. In Northern epilepsy the intraneuronal storage process and neuronal destruction are generally of mild degree but highly selective and, in contrast to other forms of childhood onset NCL, the cerebellar cortex is relatively spared. By electron microscopy the storage bodies mainly contain rectilinear complex type and fingerprint profiles in Finnish vLINCL and structures resembling curvilinear profiles in Northern epilepsy. Mitochondrial ATP synthase subunit c is the main stored protein in both disorders. Both the DCLN5 and CLN8 genes encode putative membrane proteins with yet unknown functions. Furthermore, a well studied spontaneously occurring autosomal recessive mouse mutant, motor neuron degeneration (mnd) mouse, is a homolog for CLN8.

Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease.

BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

A child with muscle-eye-brain disease. Ophthalmological and neurological characteristics.

PURPOSE: To describe a child with Muscle-Eye-Brain disease (MEB), one of three types of congenital muscular dystrophy associated with ocular abnormalities. METHODS: Case report. RESULTS: The child showed severe visual impairment due to progressive myopia and retinal degeneration, a pachygyria-type of migration disorder of the brain with a nodular cortical surface, i.e. cobblestone cortex, as well as muscular weakness and severe mental retardation. CONCLUSION: Ophthalmological assessments are important to help to diagnose and follow children with congenital muscular dystrophy.

Neuropsychological test battery in the follow-up of patients with juvenile neuronal ceroid lipofuscinosis.

The aim of the present study was to develop a neuropsychological test battery for patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and to study the development of cognitive functions during the first 5 years after diagnosis. Fourteen patients with JNCL entered the study. Nine patients were homozygous for the major mutation, whereas five were compound heterozygotes. All patients were studied annually with a special neuropsychological test battery (NEPSY) adapted from Luria's neuropsychological test, and modified for the visually handicapped; the Wechsler Intelligence Scale for Children - Revised (WISC-R) was also included. The neurological examinations were scored. Furthermore, 1.OT magnetic resonance imaging scan was performed at the beginning of follow-up and after a mean of 5 years. A decline in verbal IQ (WISC-R) during the follow-up period was found in all subjects except one compound heterozygous male. Short-term memory and digit memory span were already impaired at an early stage of the disease. Orientation to time was found to decline more than orientation to person and place. Motor speed usually became impaired after 10 years of age. Spatial orientation was impaired only in the patients homozygous for the major mutation. The test battery was found to be reliable and easy to use, and offered valuable information on the progress of the disease. It also provided important guidelines for rehabilitation.

Neuronal ceroid lipofuscinoses in childhood.

NCL disorders are progressive brain diseases with an autosomal recessive inheritance in all eleven childhood types. These occur world-wide but may be enriched in some countries. In Finland altogether about 400 patients have been diagnosed during the last forty years. The most common types are the infantile and classic juvenile forms with an incidence of 1: 20,000 and 1: 21,000, respectively Personally followed-up are patients with infantile, classic and Finnish variant late infantile and classic juvenile types. Clinical, neurophysiological and neuroimaging findings in these four NCL forms are reviewed including also management and diagnostic aspects.

Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis.

PURPOSE: To survey the characteristics of epilepsy in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and determine the antiepileptic drug (AED) treatment most suitable for these patients. METHODS: The study included 60 patients with JNCL; their mean age was 16.5 years (range 5-33). The age at onset of epilepsy, type of seizures, effect of the first AED on seizures, and the current seizure frequency and AED therapy were studied. The side effects of the AEDs were also clarified. RESULTS: Fifty of the 60 patients had epilepsy. Patients' first epileptic seizure occurred at a mean age of 10.0 years (range 5-16), the most common type being generalized seizures. As the first AED tried, valproate (VPA) and lamotrigine (LTG) appeared equally effective, with 80% of the patients responding to these AEDs. During the study year, the median seizure frequency was four seizures a year (range 0-120), and 72% of the patients had good or satisfactory seizure control (0-6 seizures a year). In the different AED therapy groups, the proportion of patients with good or satisfactory seizure control ranged from 25% to 100%. LTG in monotherapy or in combination with clonazepam (CZP) was superior to other AEDs or combinations, but VPA also seemed effective. Adverse effects leading to the discontinuation of an AED were observed in 25% of the patients, most frequently in patients receiving phenobarbital (PB). No patient receiving LTG had to discontinue the drug due to adverse effects. CONCLUSION: Epilepsy in JNCL can usually be successfully treated with the current AEDs. In Finnish patients with JNCL, treatment is based on LTG, or, secondarily, VPA. In combination therapy, CZP seems a valuable add-on AED.

Phenotype-genotype correlation in eight patients with Finnish variant late infantile NCL (CLN5).

The authors analyzed the clinical phenotype, including MRI, of eight patients with Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCLFin; CLN5; MIM256731). Although the four known mutations, including one novel mutation identified in this study, have very different consequences for the predicted polypeptide, none of them results in an atypical phenotype, as has been reported in other forms of NCL. Thus, it seems likely that each mutation severely disturbs the normal function of the CLN5 protein.