Topological Structural Brain Connectivity Alterations in Aspartylglucosaminuria: A Case-Control Study.

BACKGROUND AND PURPOSE: We investigated global and local properties of the structural brain connectivity networks in aspartylglucosaminuria, an autosomal recessive and progressive neurodegenerative lysosomal storage disease. Brain connectivity in aspartylglucosaminuria has not been investigated before, but previous structural MR imaging studies have shown brain atrophy, delayed myelination, and decreased thalamic and increased periventricular WM T2 signal intensity. MATERIALS AND METHODS: We acquired diffusion MR imaging and T1-weighted data from 12 patients with aspartylglucosaminuria (mean age, 23 [SD, 8] years; 5 men), and 30 healthy controls (mean age, 25 [SD, 10] years; 13 men). We performed whole-brain constrained spherical deconvolution tractography, which enables the reconstruction of neural tracts through regions with complex fiber configurations, and used graph-theoretical analysis to investigate the structural brain connectivity networks. RESULTS: The integration of the networks was decreased, as demonstrated by a decreased normalized global efficiency and an increased normalized characteristic path length. In addition, the average strength of the networks was decreased. In the local analyses, we found decreased strength in 11 nodes, including, for example, the right thalamus, right putamen, and, bilaterally, several occipital and temporal regions. CONCLUSIONS: We found global and local structural connectivity alterations in aspartylglucosaminuria. Biomarkers related to the treatment efficacy are needed, and brain network properties may provide the means for long term follow-up.

Brain magnetic resonance imaging of siblings from families with two or more children with learning or intellectual disabilities and need for full-time special education.

BACKGROUND: Several factors are involved in determining a child's need for special education (SE). Thus, the value of brain magnetic resonance imaging (MRI) for subjects with learning and intellectual disabilities is uncertain. PURPOSE: To evaluate the usefulness of MRI in the diagnostic process of siblings with learning and intellectual disabilities and need for full-time SE. MATERIAL AND METHODS: Altogether, 119 siblings (mean age 11.9 years) from families in which two or more children attended/had previously attended full-time SE underwent prospective brain MRI. SE grouping included three levels, from specific learning disabilities (level 1) to global intellectual disabilities (level 3). Forty-three controls (level 0, mean age 12.0 years) attended mainstream education groups. Signal intensity and structural abnormalities were analyzed, and areas of the cerebrum, posterior fossa, corpus callosum, vermis and brain stem, and diameters of the corpus callosum were measured. In analyses, all area measurements were calculated in proportion to the total inner skull area. RESULTS: Abnormal finding in MRI was more common for siblings (n=62; 52%) in SE (58% for level 3; 49% for level 2; 35% for level 1) than for controls (n=13; 16%). The siblings showed enlarged supra- (P<0.001) and infratentorial (P=0.015) cerebrospinal fluid (CSF) spaces and mild corpus callosum abnormalities (P=0.003) compared to controls. Siblings in SE had smaller inner skull area than controls (P<0.001). Further, the relative area of the mesencephalon (P=0.027) and the diameter of the body of the corpus callosum (P=0.015) were significantly smaller than in controls. In binary logistic regression analysis, enlarged supratentorial CSF spaces increased the probability of SE (odds ratio 4.2; P=0.023). CONCLUSION: Subjects with learning and intellectual disabilities commonly have more MRI findings than controls. Enlarged supratentorial CSF spaces were a frequent finding in siblings in full-time SE.

White matter hyperintensities on T2-weighted MRI images among DNA-verified older familial hypercholesterolemia patients.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder, causing an increased risk of coronary heart disease (CHD) if untreated. Silent brain infarctions and white matter hyperintensities (WMHIs) observed on T2-weighted magnetic resonance images (MRI) are associated with increased risk for stroke and myocardial infarction. Age is a strong predictor of WMHIs. PURPOSE: To use MRI to assess the presence of clinically silent brain lesions in older FH patients, and to compare the occurrence and size of these lesions in older FH patients with middle-aged FH patients and healthy controls. MATERIAL AND METHODS: A total of 43 older (age >or= 65 years) FH patients with the same FH North Karelia mutation, living in Finland, were identified. In this comprehensive cohort, 1.5 T brain MRI was available for 33 individuals (age 65-84 years, M/F 9/24, mean duration of statin treatment 15.3 years). This group was divided into two age categories: 65-74 years (FHe1 group, n=23) and 75-84 years (FHe2 group, n=10). Infarcts, including lacunas, and WMHIs on T2-weighted images were recorded. Data from brain MRI were compared to those of a group of middle-aged FH patients with CHD (n=19, age 48-64 years) and with middle-aged healthy controls (n=29, age 49-63 years). RESULTS: Only two (6%) of the older FH patients had clinically silent brain infarcts detected by MRI. The amount of large WMHIs (>5 mm in diameter) was similar in the FHe1 group compared with the groups of middle-aged FH patients and healthy controls, even though the FHe1 group was 13 years older. The total amount of WMHIs and the amount of large WMHIs were greatest in the FHe2 group. CONCLUSION: FH patients aged 65 to 74 years receiving long-term statin treatment (15 years) did not have more WMHIs on brain MRI compared to middle-aged FH patients and healthy controls.

Susceptibility-Weighted Imaging Findings in Aspartylglucosaminuria.

BACKGROUND AND PURPOSE: Aspartylglucosaminuria is a rare lysosomal storage disorder that causes slowly progressive, childhood-onset intellectual disability and motor deterioration. Previous studies have shown, for example, hypointensity in the thalami in patients with aspartylglucosaminuria on T2WI, especially in the pulvinar nuclei. Susceptibility-weighted imaging is a neuroimaging technique that uses tissue magnetic susceptibility to generate contrast and is able to visualize iron and other mineral deposits in the brain. SWI findings in aspartylglucosaminuria have not been reported previously. MATERIALS AND METHODS: Twenty-one patients with aspartylglucosaminuria (10 girls; 7.4-15.0 years of age) underwent 3T MR imaging. The protocol included an SWI sequence, and the images were visually evaluated. Thirteen patients (6 girls, 7.4-15.0 years of age) had good-quality SWI. Eight patients had motion artifacts and were excluded from the visual analysis. Thirteen healthy children (8 girls, 7.3-14.1 years of age) were imaged as controls. RESULTS: We found a considerably uniform distribution of decreased signal intensity in SWI in the thalamic nuclei in 13 patients with aspartylglucosaminuria. The most evident hypointensity was found in the pulvinar nuclei. Patchy hypointensities were also found especially in the medial and anterior thalamic nuclei. Moreover, some hypointensity was noted in globi pallidi and substantia nigra in older patients. The filtered-phase images indicated accumulation of paramagnetic compounds in these areas. No abnormal findings were seen in the SWI of the healthy controls. CONCLUSIONS: SWI indicates accumulation of paramagnetic compounds in the thalamic nuclei in patients with aspartylglucosaminuria. The finding may raise the suspicion of this rare disease in clinical practice.

Topological Alterations of the Structural Brain Connectivity Network in Children with Juvenile Neuronal Ceroid Lipofuscinosis.

BACKGROUND AND PURPOSE: We used diffusion MR imaging to investigate the structural brain connectivity networks in juvenile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease of childhood. Although changes in conventional MR imaging are typically not visually apparent in children aged <10 years, we previously found significant microstructural abnormalities by using diffusion MR imaging. Therefore, we hypothesized that the structural connectivity networks would also be affected in the disease. MATERIALS AND METHODS: We acquired diffusion MR imaging data from 14 children with juvenile neuronal ceroid lipofuscinosis (mean ± SD age, 9.6 ± 3.4 years; 10 boys) and 14 control subjects (mean ± SD age, 11.2 ± 2.3 years; 7 boys). A follow-up MR imaging was performed for 12 of the patients (mean ± SD age, 11.4 ± 3.2 years; 8 boys). We used graph theoretical analysis to investigate the global and local properties of the structural brain connectivity networks reconstructed with constrained spherical deconvolution-based whole-brain probabilistic tractography. RESULTS: We found significantly increased characteristic path length (P = .003) and decreased degree (P = .003), which indicated decreased network integration and centrality in children with juvenile neuronal ceroid lipofuscinosis. The findings were similar for the follow-up MR imaging, and there were no significant differences between the two acquisitions of the patients. In addition, we found that the disease severity correlated negatively (P < .007) with integration, segregation, centrality, and small-worldness of the networks. Moreover, we found significantly (P < .0003) decreased local efficiency in the left supramarginal gyrus and temporal plane, and decreased strength in the right lingual gyrus. CONCLUSIONS: We found significant global and local network alterations in juvenile neuronal ceroid lipofuscinosis that correlated with the disease severity and in areas related to the symptomatology.

Reorganization of the composition of brain oscillations and their temporal characteristics during opioid withdrawal.

Majority of the opioid-dependence and withdrawal studies are dominated with many inconsistencies and contradictions. One of the reasons for such inconsistencies may be methodological while performing EEG analysis. To overcome methodological limitations, in the present study we examined the composition of electroencephalographic (EEG) brain oscillations in broad frequency band (0.5-30 Hz) in 13 withdrawal opioid-dependent patients and 14 healthy subjects during resting condition (closed eyes). The exact compositions of brain oscillations and their temporal behaviour were assessed by the probability-classification analysis of short-term EEG spectral patterns (SPs). It was reported that early withdrawal had a generalized effect: the activity in all EEG channels was affected nearly equally. EEG of withdrawal patients was characterized by (a) different dominant SP types (had unique SP types which describe beta-frequency band), (b) increased number of SP types observed in each EEG channel, (c) a larger percentage of alpha(2)-, beta- and poly-rhythmic activity, and by a smaller percentage of delta-, - and alpha(1)-rhythmic activity, (d) predominantly right-sided asymmetry and (e) longer periods of temporal stabilization for alpha- and beta-brain oscillations and by shorter periods of temporal stabilization for -activity when compared with control subjects. When taken together, these findings suggest a considerable reorganization of composition of brain oscillations, which reflects a disorganization process and an allostatic state with neuronal activation in EEG of opioid withdrawal patients.

Bilateral pulvinar signal intensity decrease on T2-weighted images in patients with aspartylglucosaminuria.

BACKGROUND: Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal disease caused by deficiency of aspartylglucosaminidase. A thalamic T2 signal intensity decrease is associated with lysosomal diseases. PURPOSE: To investigate thalamic signal intensity in AGU by performing a retrospective review of brain magnetic resonance (MR) imaging studies of AGU patients. MATERIAL AND METHODS: A total of 25 MR examinations were available for 11 patients aged between 3 and 32 years (four patients underwent bone marrow transplantation). Of these, 13 examinations were performed after bone marrow transplantation. Five patients had from two to six examinations, and six patients had one examination each. In every patient, the diagnosis of AGU was confirmed by blood and urine tests. Eighteen examinations were performed with a 1.0T imager including dual spin-echo T2 and proton density (PD) axial and coronal images, and 10 examinations also included T1-weighted images. Seven examinations were performed with a 1.5T imager including turbo spin-echo axial and coronal T2-weighted images and axial fluid-attenuated inversion recovery (FLAIR) images; three examinations included T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo (3D MPRAGE) images. The signal intensity of the thalamus and pulvinar in every sequence was compared to that of the putamina. RESULTS: In AGU, thalamic alterations were first detectable on T2-weighted images (25 examinations in 11 patients) from the age of 3 years 6 months, showing decreased signal intensity in 21 of 24 examinations. T1-weighted images (13 examinations) showed slightly increased thalamic signal intensity in five out of seven examinations from the age of 7 years, and PD images (19 examinations) showed decreased signal intensity from the age of 16 years (three examinations). The pulvinar showed decreased signal intensity on spin-echo T2-weighted images for 14 of 18 examinations or on FLAIR sequences for seven of seven examinations from the age of 6 years and 6 months, both in patients with and without bone marrow transplantation, but no pulvinar alterations were observable on T1 and PD images. CONCLUSION: In AGU, the thalamus is affected. Pulvinar changes are visible only on T2-weighted images, and these may be the first changes reported in the group of lysosomal diseases.

Global and Widespread Local White Matter Abnormalities in Juvenile Neuronal Ceroid Lipofuscinosis.

BACKGROUND AND PURPOSE: Juvenile neuronal ceroid lipofuscinosis is a progressive neurodegenerative lysosomal storage disease of childhood. It manifests with loss of vision, seizures, and loss of cognitive and motor functions leading to premature death. Previous MR imaging studies have reported cerebral and cerebellar atrophy, progressive hippocampal atrophy, thalamic signal intensity alterations, and decreased white matter volume in the corona radiata. However, conventional MR imaging findings are usually normal at younger than 10 years of age. The purpose of our study was to investigate whether diffusion MR imaging could reveal changes in white matter microstructure already present at a younger age. MATERIALS AND METHODS: We investigated global and local white matter abnormalities in 14 children with juvenile neuronal ceroid lipofuscinosis (mean age, 9.6 ± 3.4 years; 10 boys) and 14 control subjects (mean age, 11.2 ± 2.3 years; 7 boys). Twelve patients underwent follow-up MR imaging after 2 years (mean age, 11.4 ± 3.2 years; 8 boys). We performed a global analysis using 2 approaches: white matter tract skeleton and constrained spherical deconvolution-based whole-brain tractography. Then, we investigated local microstructural abnormalities using Tract-Based Spatial Statistics. RESULTS: We found globally decreased anisotropy (P = .000001) and increased diffusivity (P = .001) in patients with juvenile neuronal ceroid lipofuscinosis. In addition, we found widespread increased diffusivity and decreased anisotropy in, for example, the corona radiata (P < .001) and posterior thalamic radiation (P < .001). However, we found no differences between the first and second acquisitions. CONCLUSIONS: The patients with juvenile neuronal ceroid lipofuscinosis exhibited global and local abnormalities in white matter microstructure. Future studies could apply more specific microstructural models and study whether these abnormalities are already present at a younger age.

Thalami and corona radiata in juvenile NCL (CLN3): a voxel-based morphometric study.

Juvenile neuronal ceroid lipofuscinosis (CLN3) is characterized by progressive cerebral atrophy. The purpose of this study was to re-evaluate the three-dimensional magnetic resonance (3D-MR) images of patients with CLN3 using voxel-based morphometry (VBM) to achieve a detailed understanding of the affected brain regions. T1-weighted 3D-MR images of 15 patients with CLN3 (age range: 12-25 years, mean age 17.6 years) and 15 age- and sex-matched controls were analyzed using VBM. VBM showed strikingly focal alterations in the brains of CLN3 patients: the gray matter volume was significantly decreased in the dorsomedial part of the thalami of CLN3 patients. In addition, the volume of the white matter was significantly decreased in the corona radiata, containing cortical efferents and afferents in the transition between the internal capsule and the subcortical white matter. These data suggest that the dorsomedial part of the thalamus and the corona radiata may have a central, previously unrecognized role in the pathogenesis of CLN3.

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.

Statin-treated familial hypercholesterolemia patients with coronary heart disease and pronounced atherosclerosis do not have more brain lesions than healthy controls in later middle age.

BACKGROUND: Clinically silent brain lesions detected with magnetic resonance imaging (MRI) are associated with increased risk for stroke, while stroke risk is controversial in familial hypercholesterolemia (FH). PURPOSE: To determine whether the occurrence and size of clinically silent brain lesions in FH patients with coronary heart disease (CHD) is higher than in neurologically healthy controls without CHD. MATERIAL AND METHODS: Brain MRI (1.5T) was performed on 19 DNA-test-verified FH patients with CHD and on 29 cardiovascularly and neurologically healthy controls, all aged 48 to 64 years. All patients were on cardiovascular medication. Intracranial arteries were evaluated by MR angiography. Infarcts, including lacunas, and white matter T2 hyperintensities (WMHI), considered as signs of small vessel disease, were recorded. A venous blood sample was obtained for assessment of risk factors. Carotid and femoral intima-media thicknesses (IMT), assessed with ultrasound, were indicators of overall atherosclerosis. RESULTS: On intracranial MR angiography, three patients showed irregular walls or narrowed lumens in intracranial carotid arteries. No silent infarcts appeared, and no differences in numbers or sizes of WMHIs between groups were recorded. Patients had greater carotid and femoral IMTs, and a greater number of carotid and femoral plaques. Cholesterol-years score, level of low-density lipoprotein (LDL) cholesterol, and level of high-sensitivity C-reactive protein (hsCRP) of the FH-North Karelia patients were higher than those of the controls, while the level of high-density lipoprotein (HDL) cholesterol in controls was higher. CONCLUSION: FH patients with CHD and adequate cardiovascular risk-factor treatment showed no difference in the amount or size of clinically silent brain lesions compared to controls, despite patients' more severe atherosclerosis.

Monitoring the CNS pathology in aspartylglucosaminuria mice.

Aspartylglucosaminuria (AGU) is a recessively inherited lysosomal storage disorder caused by the deficiency of the aspartylglucosaminidase (AGA) enzyme. The hallmark of AGU is slowly progressing mental retardation but the progression of brain pathology has remained uncharacterized in humans. Here we describe the long-term follow-up of mice carrying a targeted AGU-mutation in both alleles. Immunohistochemistry, histology, electron microscopy, quantitative magnetic resonance imaging (MRI) and behavioral studies were carried out to evaluate the CNS affection of the disease during development. The lysosomal storage vacuoles of the AGA -/- mice were most evident in central brain regions where MRI also revealed signs of brain atrophy similar to that seen in the older human patients. By immunohistochemistry and MRI examinations, a subtle delay of myelination was observed in AGA -/- mice. The life span of the AGA -/- mice was not shortened. Similar to the slow clinical course observed in human patients, the AGA -/- mice have behavioral symptoms that emerge at older age. Thus, the AGU knock-out mice represent an accurate model for AGU, both histopathologically and phenotypically.

Decreased striatal dopamine transporter density in JNCL patients with parkinsonian symptoms.

OBJECTIVE: To explore whether striatal dopamine transporters are involved in juvenile neuronal ceroid lipofuscinosis (JNCL) with extrapyramidal signs. METHODS: Seventeen patients with JNCL entered the study (mean age, 15 years; age range, 10 to 31 years). For clinical evaluation, the authors used the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). For studying the density of dopamine transporters in the striatum, they employed iodine-123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl) tropane as a SPECT tracer. The SPECT images were evaluated visually, and tracer accumulation was semiquantified from transverse slices as striatum-to-cerebellum activity ratios. MRI (1.5-T) signal intensities of the striatum were measured and compared with those of the thalamus. RESULTS: The mean UPDRS score was 20 (range, 2 to 41). On SPECT, the mean striatum-to-cerebellum uptake ratio was lower in patients than in control subjects (3.1 +/- 0.6 versus 6.8 +/- 1.0; p < 0.001), with the decrease being more pronounced in the putamen than in the caudate nucleus. On MRI, the mean striatum-to-thalamus signal intensity ratio was higher in patients than in control subjects (1.14 +/- 0.02 versus 1.08 +/- 0.02; p < 0.001). There was a negative correlation between uptake ratios in SPECT and UPDRS scores, and a positive correlation between the MRI ratios and UPDRS. The SPECT and MRI ratios also correlated significantly, providing additional evidence for the contributions of nigrostriatal, striatal, and thalamic dysfunction to the parkinsonian symptoms. CONCLUSIONS: The observed decrease in the striatal dopamine transporter density in JNCL offers a rational basis for a trial of dopaminergic drugs in this disease.

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.

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.

CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts.

BACKGROUND: Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a genetically heterogeneous disease characterized by a combination of systemic bone cysts and dementia. OBJECTIVE: The authors present a neurologic, neuroradiologic, and neuropathologic analysis of a series of PLOSL patients in which the diagnosis has been confirmed by molecular genetic methods. METHODS: Clinical, neurophysiologic, and imaging follow-up data on eight patients as well as autopsy samples of three patients were analyzed in this study. All eight patients were homozygous for a loss-of-function mutation in the DAP12 gene. RESULTS: In most patients, the disease debuted with pain in ankles and wrists after strain during the third decade, followed by fractures caused by cystic lesions in the bones of the extremities. Frontal lobe syndrome and dementia began to develop by age 30, leading to death by age 40. Neuroimaging disclosed abnormally high and progressively increasing bicaudate ratios and calcifications in the basal ganglia as well as increased signal intensities of the white matter on T2-weighted MR images even before the appearance of clinical neurologic symptoms. Three patients who had undergone autopsies showed an advanced sclerosing leukoencephalopathy with frontal accentuation, widespread activation of microglia, and microvascular changes. CONCLUSIONS: Although PLOSL in most patients manifests by bone fractures, some patients do not show any osseous symptoms and signs before the onset of neurologic manifestations. Consequently, patients with frontal-type dementia of unknown origin should be investigated by x-ray of ankles and wrists. The current results suggest early basal ganglia involvement in PLOSL.

Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis.

OBJECTIVE: To correlate the phenotypes with the genotypes of 10 Finnish juvenile neuronal ceroid lipofuscinosis (JNCL; late-onset Batten disease) patients who all are compound heterozygotes for the major 1.02-kb deletion in the CLN3 gene. METHODS: The mutations on the non-1.02-kb deletion chromosomes were screened in 6 patients; in the other 4 patients the mutations were known (one affecting a splice site, two missense mutations, and one deletion of exons 10 through 13). Clinical features were examined, and MRI, MRS, somatosensory evoked magnetic field (SEF), and overnight polysomnography (PSG) studies were performed. RESULTS: A novel deletion of exons 10 through 13 was found in 6 patients belonging to three families. In the patients carrying the deletions of exons 10 through 13 the clinical course of the disease was fairly similar. Variation was greatest in the time course to blindness. In these patients the mental and motor decline was slower than in classic JNCL, but more severe than in the two patients with missense mutations in exons 11 and 13. MRI showed brain atrophy in 4 patients. One patient had hyperintense periventricular white matter, otherwise brain signal intensities were normal. SEFs were enhanced in patients older than 14 years, whereas in PSG all but the youngest 6-year-old patient showed epileptiform activity in slow-wave sleep. CONCLUSIONS: JNCL can manifest as at least three different phenotypes: classic, delayed classic, and protracted JNCL with predominantly ocular symptoms. Finnish compound heterozygotes have the delayed classic or the protracted form of JNCL.

Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood?

Two brothers with severe mental retardation of unknown origin were found to share several physical anomalies, including large round head, small concave nose, downslanted palpebral fissures, and gingival hyperplasia. In addition to relative macrocephaly, magnetic resonance imaging (MRI) showed severe cerebral atrophy, especially fronto-temporally. The brothers also had a thin corpus callosum and atrophic caudate nuclei. The reduced white matter showed patchy periventricular signal intensity changes. The lateral and third ventricles were large, but the fourth ventricle was of normal size. The boys had large cisterna magna, communicating widely with the fourth ventricle, but no vermian hypoplasia. Both boys had Lennox-Gastaut spectrum type epilepsy. No chromosomal anomalies were found, despite the suggestive clinical picture. Some of the clinical findings resembled fetal alcohol effects/fetal alcohol syndrome (FAE/FAS), which was also suggested by history. Current diagnostic criteria for FAE/FAS, however, excluded full-blown FAS in these cases and failed to explain the entire clinical picture in the boys. We argue that these boys had an unidentified inherited syndrome, possibly modified by fetal alcohol exposure.

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.

Brain involvement in Salla disease.

BACKGROUND AND PURPOSE: Our purpose was to document the nature and progression of brain abnormalities in Salla disease, a lysosomal storage disorder, with MR imaging. METHODS: Fifteen patients aged 1 month to 43 years underwent 26 brain MR examinations. In 10 examinations, signal intensity was measured and compared with that of healthy volunteers of comparable ages. RESULTS: MR images of a 1-month-old asymptomatic child showed no pathology. In all other patients, abnormal signal intensity was found: on T2-weighted images, the cerebral white matter had a higher signal intensity than the gray matter, except in the internal capsules. In six patients, the white matter was homogeneous on all images. In four patients, the periventricular white matter showed a somewhat lower signal intensity; in five patients, a higher signal intensity. In the peripheral cerebral white matter, the measured signal intensity remained at a high level throughout life. No abnormalities were seen in the cerebellar white matter. Atrophic changes, if present, were relatively mild but were found even in the cerebellum and brain stem. The corpus callosum was always thin. CONCLUSION: In Salla disease, the cerebral myelination process is defective. In some patients, a centrifugally progressive destructive process is also seen in the cerebral white matter. Better myelination in seen in patients with milder clinical symptoms.