Brain MRI findings in aspartylglucosaminuria.

BACKGROUND AND PURPOSE: The aim of this study was to identify characteristic 3.0 T brain MRI findings in patients with aspartylglucosaminuria (AGU), a rare lysosomal storage disorder. Previous AGU patient material imaged at 1.0 and 1.5 T was also re-evaluated. MATERIALS AND METHODS: Twenty-five brain MRI examinations from 20 AGU patients were included in the study. Thirteen patients underwent a prospective 3.0 T MRI (5 male, 8 female, aged 9-45 years). Twelve examinations from nine patients (4 male, 5 female, aged 8-33 years) previously imaged at 1.0 or 1.5 T were re-evaluated. Two patients were included in both the prospective and the retrospective groups. Visual analysis of the T1- and T2-weighted images was performed by two radiologists. RESULTS: The previously reported signal intensity changes in T2-weighted images were visible at all field strengths, but they were more distinct at 3.0 T than at 1.0 or 1.5 T. These included signal intensity decrease in the thalami and especially in the pulvinar nuclei, periventricular signal intensity increase and juxtacortical high signal foci. Poor differentiation between gray and white matter was found in all patients. Some degree of cerebral and/or cerebellar atrophy and mild ventricular dilatation were found in nearly all patients. This study also disclosed various unspecific findings, including a higher than normal incidence of dilated perivascular spaces, arachnoid cysts, pineal cysts and mildly dilated cavum veli interpositi. CONCLUSION: This study revealed particular brain MRI findings in AGU, which can raise the suspicion of this rare disease in clinical practice.

Hippocampal volumes in juvenile neuronal ceroid lipofuscinosis: a longitudinal magnetic resonance imaging study.

BACKGROUND: Juvenile neuronal ceroid lipofuscinosis is an inherited, autosomal recessive, progressive, neurodegenerative disorder of childhood. It belongs to the lysosomal storage diseases, which manifest with loss of vision, seizures, and loss of cognitive and motor functions, and lead to premature death. Imaging studies have shown cerebral and cerebellar atrophy, yet no previous studies evaluating particularly hippocampal atrophy have been published. This study evaluates the hippocampal volumes in adolescent juvenile neuronal ceroid lipofuscinosis patients in a controlled 5-year follow-up magnetic resonance imaging study. METHODS: Hippocampal volumes of eight patients (three female, five male) and 10 healthy age- and sex-matched control subjects were measured from two repeated magnetic resonance imaging examinations. Three male patients did not have controls and were excluded from the statistics. In the patient group, the first examination was performed at the mean age of 12.2 years and the second examination at the mean age of 17.3 years. In the control group, the mean ages at the time of examinations were 12.5 years and 19.3 years. RESULTS: Progressive hippocampal atrophy was found in the patient group. The mean total hippocampal volume decreased by 0.85 cm³ during the 5-year follow-up in the patient group, which corresponds to a 3.3% annual rate of volume loss. The whole brain volume decreased by 2.9% per year. The observed annual rate of hippocampal atrophy also exceeded the previously reported 2.4% annual loss of total gray matter volume in juvenile neuronal ceroid lipofuscinosis patients. CONCLUSIONS: These data suggest that progressive hippocampal atrophy is one of the characteristic features of brain atrophy in juvenile neuronal ceroid lipofuscinosis in adolescence.

Subjects with intellectual disability and familial need for full-time special education show regional brain alterations: a voxel-based morphometry study.

Subjects attending full-time special education (SE) often have multifactorial background for their cognitive impairment, and brain MRI may show nonspecific changes. As voxel-based morphometry reveals regional volume differences, we applied this method to 119 subjects with cognitive impairments and familial need for full-time SE--graded into three levels from specific disorders of cognitive processes (level 1) to intellectual disability (IQ <70; level 3)--and to 43 age-matched controls attending mainstream education (level 0). Subjects in SE groups had smaller global brain white matter (WM), cerebrospinal fluid, and total brain volume than controls. Compared with controls, subjects with intellectual disabilities in SE level 3 showed greater regional gray matter volumes bilaterally in the ventral and dorsal anterior cingulate cortex and smaller regional gray matter volumes in the left thalamus and cerebellar hemisphere. Further, they had greater WM volume in the left frontoparietal region and smaller WM volumes in the posterior limbs of the internal capsules. Subjects in SE level 1 and 2 groups showed the same tendency, but the results were nonsignificant. In conclusion, compared with controls, subjects with intellectual disabilities showed in voxel-based morphometry analysis several regional brain alterations.

A 30-year follow-up of a neuronal ceroid lipofuscinosis patient with mutations in CLN3 and protracted disease course.

Reported here is the 30-year follow-up of a patient, diagnosed with juvenile neuronal ceroid lipofuscinosis, who was compound heterozygous for the common 1-kb deletion and the missense mutation p.Glu295Lys in the CLN3 gene. Visual failure was noticed at 6 years of age, but thereafter disease progression was atypical. Polyneuropathy and cerebellar signs were observed after age 20, and epilepsy and slight mental decline after age 35. From then on, there was rapid deterioration, and the patient died at age 39. This case highlights the importance of exact genotyping for disease course prediction and management.

Childhood growth and development associated with need for full-time special education at school age.

OBJECTIVE: To explore how growth measurements and attainment of developmental milestones in early childhood reflect the need for full-time special education (SE). METHODS: After stratification in this population-based study, 900 pupils in full-time SE groups (age-range 7-16 years, mean 12 years 8 months) at three levels and 301 pupils in mainstream education (age-range 7-16, mean 12 years 9 months) provided data on height and weight from birth to age 7 years and head circumference to age 1 year. Developmental screening was evaluated from age 1 month to 48 months. Statistical methods included a general linear model (growth measurements), binary logistic regression analysis (odds ratios for growth), and multinomial logistic regression analysis (odds ratios for developmental milestones). RESULTS: At 1 year, a 1 standard deviation score (SDS) decrease in height raised the probability of SE placement by 40%, and a 1 SDS decrease in head size by 28%. In developmental screening, during the first months of life the gross motor milestones, especially head support, differentiated the children at levels 0-3. Thereafter, the fine motor milestones and those related to speech and social skills became more important. CONCLUSION: Children whose growth is mildly impaired, though in the normal range, and who fail to attain certain developmental milestones have an increased probability for SE and thus a need for special attention when toddlers age. Similar to the growth curves, these children seem to have consistent developmental curves (patterns).

JNCL patients show marked brain volume alterations on longitudinal MRI in adolescence.

UNLABELLED: Juvenile neuronal ceroid lipofuscinosis (JNCL, CLN3) is an inherited lysosomal disease. We used longitudinal MRI, for the first time, to evaluate the rate of brain volume alterations in JNCL. Six patients (mean ages of 12.4 years and 17.3 years) and 12 healthy controls were studied twice with 1.5 T MRI. White matter (WM), gray matter (GM) and CSF volumes were measured from the sets of T1-weighted 3-dimensional MR images using a fully automated image-processing procedure. The brain volume alterations were calculated as percentage change per year. The GM and whole brain volumes decreased and the CSF volume increased significantly more in the patients than in controls (p-values for the null hypothesis of equal means were 0.001, 0.004, and 0.005, respectively). We found no difference in the WM volume change between the populations. In patients, the GM volume decreased 2.4 % (SD 0.5 %, p 0.0001 for the null hypothesis of zero mean change between observations), the whole brain volume decreased 1.1 % (SD 0.5 %, p = 0.003), and the CSF volume increased 2.7 % (SD 1.8 %, p = 0.01) per year. In normal controls, only the mean white matter volume was significantly altered (0.8 % increase, SD 0.7 %, and p = 0.001). CONCLUSION: We demonstrated by longitudinal MRI that the annual rate of the gray matter loss in adolescent JNCL patients is as high as 2.4 %.

Newborns at risk for special education placement: a population-based study.

OBJECTIVES: To establish the contributions of birth weight (BW), gender, socioeconomic status (SES), and parental age on risks for special education (SE) placements in school-age children. METHODS: A population-based sample of 900 school-age children attending the following full-time SE groups: at level 1, children had isolated neurodevelopmental, physical, or other impairments; at level 2, borderline to mild intellectual disability (ID); and at level 3, moderate to severe ID. Three hundred and one children enrolled in mainstream education formed the control group (level 0). For all children with siblings, we defined familiar forms of learning disorders as having a sibling in one of the SE groupings. We performed our analysis for the entire cohort as well as comparing risk factors within the familial and non-familial types of SE groupings. RESULTS: In multinomial logistic regression analysis, age of father 40 years, low BW (<2500g or <-2 SD), male sex, and parent's lower SES, all increased the probability of SE placement. In the familial forms of levels 2 and 3, the parental SES was lower and, in addition, in the level 2, the family size was bigger. Furthermore, in the non-familial form of level 2, both the low and the high (4000g) BW were more common. CONCLUSIONS: Among the known risk factors for learning disabilities (LD), our study highlighted the importance of a higher paternal age and a lower SES especially in the familial forms of LD.

Decreased T2 signal in the thalami may be a sign of lysosomal storage disease.

INTRODUCTION: Lysosomal disorders are rare and are caused by genetically transmitted lysosomal enzyme deficiencies. A decreased T2 signal in the thalamus has occasionally been reported. AIMS: Because the finding of bilateral abnormal signal intensity of the thalamus on T2-weighted images has not been systematically reviewed, and its value as a diagnostic tool critically evaluated, we carried out a systematic review of the literature. METHODS: Articles in English with 30 trios of keywords were collected from PubMed. Exclusion criteria were lack of conventional T2-weighted images in the protocol and not being a human study. Finally, 111 articles were included. The thalamus was considered affected only if mentioned in the text or in the figure legends. RESULTS: Some 117 patients with various lysosomal diseases and five patients with ceruloplasmin deficiency were reported to have a bilateral decrease in T2 signal intensity. At least one article reported a bilateral decrease in signal intensity of the thalami on T2-weighted images in association with GM1 and GM2 gangliosidosis and with Krabbe's disease, aspartylglucosaminuria, mannosidosis, fucosidosis, and mucolipidosis IV. Furthermore, thalamic alteration was a consistent finding in several types of neuronal ceroid lipofuscinosis (NCL) including CLN1 (infantile NCL), CLN2 (classic late infantile NCL), CLN3 (juvenile NCL), CLN5 (Finnish variant late infantile NCL), and CLN7 (Turkish variant late infantile NCL). CONCLUSION: A decrease in T2 signal intensity in the thalami seems to be a sign of lysosomal disease.

Diagnosis of the neuronal ceroid lipofuscinoses: an update.

For the majority of families affected by one of the neuronal ceroid lipofuscinoses (NCLs), a biochemical and/or genetic diagnosis can be achieved. In an individual case this information not only increases understanding of the condition but also may influence treatment choices and options. The presenting clinical features prompt initial investigation and also guide clinical care. The clinical labels "infantile NCL", "late infantile NCL" and "juvenile NCL", therefore remain useful in practice. In unusual or atypical cases ultra-structural analysis of white blood cells or other tissue samples enables planning and prioritisation of biochemical and genetic tests. This review describes current methods available to achieve clinical, pathological, biochemical and genetic diagnosis in children presenting with symptoms suggestive of one of the NCLs.

Hyperandrogenism in girls with juvenile neuronal ceroid lipofuscinosis.

Acne and hirsutism are common findings in girls with juvenile neuronal ceroid lipofuscinosis (JNCL). A study on their hormonal status was conducted to investigate the mechanisms underlying these symptoms. Sixteen girls with JNCL entered the study. Ten of the girls had periodic menstruation, while three were given medroxyprogesterone acetate therapy to prevent menstrual bleeding, and three had earlier undergone an ovariectomy. Ten age- and weight-matched healthy girls served as controls. Age at menarche, menstrual cycle length, acne, and hirsutism were assessed. Extensive hormonal laboratory tests were made in the early follicular phase. In addition, 1.5 Tesla magnetic resonance imaging of the lower abdomen was performed to search for structural abnormalities of the ovaries. The mean age at menarche in these JNCL patients was 11.6 years. Of the patients with periodic menstruation, four of ten had irregular (prolonged) cycles, but, in patients with regular cycles, the mean ovarian cycle was short (26 days). Hyperandrogenism, characterized by acne, hirsutism and/or hyperandrogenaemia, was found significantly more often in the patients than in the controls (p<0.01). No significant differences were found in the laboratory parameters. Polycystic ovaries were found in two of seven of the patients who menstruated, but in none of the healthy controls. Hyperandrogenism is common in patients with JNCL. In addition, there is an early menarche and signs of anovulation. The factors underlying these hormonal changes seem complex, possibly including a neurodegenerative process, the obesity associated with JNCL, and the drugs used for symptomatic treatment of the patients.