Perinatal and neonatal characteristics of Prader-Willi syndrome in Japan.

BACKGROUND: Prader-Willi syndrome (PWS) is suspected at birth if extreme hypotonia, difficulty in feeding, hypogonadism, and failure to thrive are present. Genetic diagnosis of PWS can generally be made within the first few months of life; however, a delayed diagnosis of PWS is frequently reported. Although the clinical characteristics of perinatal and neonatal patients with PWS have been reported, there are no such reports on the clinical characteristics of these patients in Japan. METHODS: This retrospective, single-center study involved 177 Japanese patients with PWS and their medical data regarding the perinatal and neonatal periods were evaluated. RESULTS: The median maternal age at birth was 34 years; 12.7% of the mothers had a history of assisted reproductive technology (ART). Of the mothers, 13.5% reported polyhydramnios and 4.3% had oligohydramnios. Decreased fetal movement during pregnancy was reported by 76% of the mothers. A total of 60.5% of patients were born by cesarean section. Genetic subtypes included deletions (66.1%), uniparental disomy (31.0%), imprinting defects (0.6%), and other or unknown subtypes (2.3%). The median birth length was 47.5 cm and the median birthweight was 2476 g. Of the 160 patients, 14 (8.8%) were classified as small for gestational age. Most patients had hypotonia (98.8%), and 89.3% required gavage feeding at birth. Breathing problems, congenital heart disease, and undescended testis were noted in 33.1%, 7.0%, and 93.5% of patients, respectively. CONCLUSION: In our study, higher rates of ART, polyhydramnios, decreased fetal movements, cesarean section, hypotonia, feeding difficulties, and undescended testis were observed in PWS.

Differences in sleep architecture between left and right temporal lobe epilepsy.

To investigate whether seizure lateralization affects sleep macrostructure in patients with left and right temporal lobe epilepsy (TLE), as rapid eye movement (REM) sleep is shorter in patients with right hemispheric cerebral infarction than with left. We retrospectively analyzed data from 16 patients with TLE (6 men and 10 women aged 34.9 ± 11.4 years) who underwent polysomnography as well as long-term video electroencephalography. Ten patients were diagnosed with left TLE and six patients with right TLE. Sleep stages and respiratory events were scored based on the American Academy of Sleep Medicine criteria. Sleep and respiratory parameters were compared between the patient groups. Percentage of REM stage sleep was significantly (p < 0.05) lower in patients with left TLE (median 8.8 %, interquartile range 5.5-13.8 %) than in patients with right TLE (median 17.0 %, interquartile range 14.1-18.3 %). The other parameters showed no significant differences. Shorter REM sleep in patients with left TLE sharply contrasts with the previous report of shorter REM sleep in patients with right cerebral infarction. Laterality of the irritative epileptic focus versus destructive lesion may have different effects on the sleep macrostructures.

Testosterone replacement therapy to improve secondary sexual characteristics and body composition without adverse behavioral problems in adult male patients with Prader-Willi syndrome: an observational study.

Prader-Willi syndrome (PWS), a complex genetic disorder, arises from suppressed expression of paternally inherited imprinted genes on chromosome 15q11-q13. Characteristics include short stature, intellectual disability, behavioral problems, hypogonadism, obesity, and reduced bone and muscle mass. Testosterone replacement (TR) remains controversial due to concerns regarding behavioral problems. To evaluate the effects of TR on secondary sexual characteristics, body composition, and behavior in adult males with PWS, 22 male PWS patients over the age of 16 with behavioral scores of less than grade 4 on the Modified Overt Aggression Scale (MOAS) underwent monthly intramuscular TR (125 mg). Pubertal change, body composition and behavior were evaluated before and after 24 months of therapy. Serum testosterone, LH, and FSH did not change. Increased pubic hair was observed in 16 of 22 patients (72.7%). Percent body fat decreased from 47.55 ± 2.06% to 39.75 ± 1.60% (n = 18) (P = 0.018). Bone mineral density increased from 0.8505 ± 0.0426 g/cm(2) to 0.9035 ± 0.0465 g/cm(2) (n = 18) (P = 0.036), and lean body mass increased from 18093.4 ± 863.0 g to 20312.1 ± 1027.2 g (n = 18) (P = 0.009). The MOAS was unchanged, from 4.5 ± 2.0 at the beginning of the study to 3.0 ± 1.7 at the end of study indicating no increase in aggression. No behavioral problems were observed. Based on this pilot study, TR with 125 mg monthly is a potentially safe and useful intervention for adult males with PWS.

Characterization of fat distribution in Prader-Willi syndrome: relationships with adipocytokines and influence of growth hormone treatment.

Marked anthropometric changes are seen in Prader-Willi syndrome (PWS). Emaciation is observed during infancy, whereas severe obesity is found in older children and adults. Growth hormone (GH) treatment modifies the anthropometric changes in PWS patients. In this study, we examined changes in the body composition of 51 PWS patients (age range, 6-54 years; median, 16.5 years), with a focus on the amount of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), VAT/SAT ratio, and serum levels of adipocytokines (adiponectin, leptin, and resistin). The relationships between VAT, SAT, and adipocytokines, and lipid abnormalities and type 2 diabetes in 24 patients with obese PWS were also evaluated. With increasing age, SAT and VAT both increased markedly, but in 18 patients receiving GH treatment, VAT remained low at ≤30 cm(2) . In the GH-completed patients (n = 19), VAT and SAT increased with age to levels similar to those in non-GH-treated patients (n = 14). In the obese group, adiponectin decreased as VAT increased (r = -0.35, P = 0.11). Leptin (r = 0.67, P < 0.001) and resistin (r = 0.45, P = 0.04) showed positive correlations with SAT. Total cholesterol, low-density lipoprotein, and triglyceride levels correlated negatively with adiponectin (r = -0.59, r = -0.56, r = -0.56, respectively, P < 0.05) and hemoglobin A1c (r = -0.42, P = 0.08). To maintain lower VAT and prevent cardiovascular disease risk factors, GH treatment may be advisable even in adult patients with PWS.

Scoliosis in Prader-Willi syndrome: effect of growth hormone therapy and value of paravertebral muscle volume by CT in predicting scoliosis progression.

Growth hormone (GH) therapy is now widely given to Prader-Willi syndrome (PWS) patients to encourage growth in body height and to prevent obesity. Scoliosis, one of the complications in this syndrome, is thought to be accelerated in parallel with a rapid increase in body height, especially during adolescence. To determine whether GH therapy aggravates scoliosis and to identify any factor which might predict the progression of scoliosis, we studied 35 (22 males and 13 female) PWS patients between the ages of 2-16 years on GH therapy whose scoliosis was followed with spinal X-rays every 6 months. Thirteen (37.1%) of 35 patients had scoliosis with a Cobb angle of over 10°. Scoliosis was unchanged in five patients (14.3%), became worse in six (17.1%) and improved in two (5.7%). All 22 (62.9%) of 35 patients who did not have scoliosis did not develop scoliosis with GH therapy. Since abnormal paraspinal muscle development was thought to induce scoliosis, we measured cross-sectional areas of paraspinal muscles by using one slice CT scan at the level of the umbilicus at the level of L4. Since there was a delay in the increase in total paravertebral muscle area and prolonged asymmetry in patients with progressive scoliosis, both were thought to be useful predictors of progressive scoliosis in PWS patients with GH therapy.

[Three cases of Fanconi syndrome associated with valproate sodium treatment].

Valproate sodium (VPA) is a commonly used antiepileptic drug. However, various side effects, including liver dysfunction, thrombocytopenia, anorexia, hyperammonemia, and pancreatitis have been reported in association with the administration of VPA. Recently, renal Fanconi syndrome associated with VPA treatment has occasionally been reported. However, the mechanisms and detailed characteristics of this adverse effect remain unknown. We herein report three cases of Fanconi syndrome associated with VPA treatment. All of these patients were severely disabled children, who had been previously treated with multiple antiepileptic drugs, and also required tube feeding. The possible risk factors of Fanconi syndrome in these three cases were similar to those previously reported in the literature. In addition, all three patients developed Fanconi syndrome after the onset of bacterial infections. Before developing Fanconi syndrome, hypouricemia was observed in all three and an increased urinary level of beta2 microglobulin (beta2MG) was also noted in one of the patients. None of these patients had hypophosphatemia. Two patients had an appropriate serum VPA level, while the other had an inappropriately high level. We therefore recommend that severely disabled children receiving multiple antiepileptic drugs and tube feeding be periodically checked for urinary beta2MG and uric acid, especially during the course of any infectious episodes.

Successful treatment of Gaucher disease type 1 by enzyme replacement therapy over a 10-year duration in a Japanese pediatric patient: A case report.

The prevalence of Gaucher disease (GD) in Japan is much lower than that in Western countries; therefore, data on Japanese pediatric patients with GD type 1 are currently limited. The present study reports on the case of a Japanese pediatric patient with GD type 1 who was diagnosed when she presented with hepatosplenomegaly, thrombocytopenia and slight anemia at the age of 2 years. Serology tests revealed high levels of acid phosphatase (ACP) and angiotensin-converting enzyme (ACE). A bone marrow biopsy revealed the presence of Gaucher cells. Abdominal MRI indicated huge hepatosplenomegaly. Erlenmeyer flask deformity was observed on X-ray examination. MRI of the femora featured a high-intensity area within the diaphysis region. The enzymatic activity of leukocyte ß-glucosidase, the measurement of which is necessary for a definitive diagnosis of GD, had decreased to 186.7 nmol/h/mg (reference range, 1,424.0-2,338.0 nmol/h/mg). Based on these results, the patient was clinically diagnosed with GD. Glucocerebrosidase gene analysis identified the compound heterozygote mutation of F213I (c.754T>A) on exon 7 and L444P (c.1448T>C) on exon 11. Enzyme replacement therapy (ERT) along with an intravenous infusion of 60 U/kg of imiglucerase every other week was initiated following diagnosis. Hemoglobin levels and the platelet count gradually improved and normalized after two years. ACP and ACE levels, biomarkers of the progression of GD, also improved. Abdominal MRI at six months after the initiation of ERT revealed a decrease in the size of the liver and spleen, which normalized after 1 year. Conversely, MRI of the femora indicated no improvement in the high-intensity area within the diaphysis region for 10 years.

[Clinical characteristics of four patients with temporal lobe epilepsy associated with elevated anti-GAD antibodies].

Anti-glutamic acid decarboxylase (GAD) antibodies are known to be associated with insulin-dependent diabetes mellitus (IDDM), stiff-person syndrome, and other neurological symptoms including temporal lobe epilepsy (TLE), known as autoimmune epilepsy. We treated four patients with TLE who had elevated titers of serum anti-GAD antibody (anti-GAD-Ab), higher than 100 U/ml. Three of the four patients started to have epileptic seizures in their 5th or 6th decade. Characteristic symptoms suggesting encephalitis or encephalopathy were absent at onset of these symptoms, which led to delayed diagnosis. All four patients developed two or three of cerebellar ataxia, neuropsychological impairment, and IDDM, by several years or decades after onset of TLE, even after seizure freedom in two patients. These abnormalities were indicators for suspecting the involvement of anti-GAD-Ab in the pathogenesis. Anti-GAD-Ab levels in the cerebrospinal fluid (CSF) were measured, which detected elevated CSF/serum anti-GAD-Ab ratio (≥ 1.0), suggesting intrathecal anti-GAD-Ab synthesis, in three of the four patients. The TLE symptoms were somewhat prolonged, but three of the four patients eventually achieved seizure freedom after immunotherapies with combinations of two or three anti-epileptic drugs. Serum anti-GAD Ab is recommended to be measured in patients with middle-aged onset TLE. Moreover, immune-modulating therapies including steroid pulse and intravenous immunoglobulin therapies could have ameliorated neurological complications, even in the chronic phase.

Earlier tachycardia onset in right than left mesial temporal lobe seizures.

OBJECTIVE: To clarify whether the presence and timing of peri-ictal heart rate (HR) change is a seizure lateralizing sign in patients with mesial temporal lobe epilepsy (mTLE). METHODS: Long-term video EEGs were retrospectively reviewed in 21 patients, 7 men and 14 women aged 13 to 67 years, diagnosed as mTLE with MRI lesions in the mesial temporal structures (hippocampal sclerosis in 20 cases, amygdala hypertrophy in 1 case). Seventy-seven partial seizures without secondary generalization were extracted. Peri-ictal HR change was compared between 29 right seizures (9 patients) and 48 left seizures (12 patients). RESULTS: HR abruptly increased in all 29 right seizures and 42 of 48 left seizures. Onset time of HR increase in relation to ictal EEG onset was significantly earlier in right seizures than in left seizures (mean ± SD, -11.5 ± 14.8 vs 9.2 ± 21.7 seconds; p < 0.0001). Time of maximum HR was also significantly earlier in right seizures than in left seizures (36.0 ± 18.1 vs 58.0 ± 28.7 seconds; p < 0.0001). Maximum HR changes from baseline showed no significant difference between right and left seizures (47.5 ± 19.1 vs 40.8 ± 20.0/min). CONCLUSIONS: Significantly earlier tachycardia in right than left mTLE seizures supports previous hypotheses that the right cerebral hemisphere is dominant in the sympathetic network. No HR change, or delayed tachycardia possibly due to seizure propagation to the right hemisphere, may be a useful lateralizing sign of left mTLE seizures.

Electro- and magneto-encephalographic spike source localization of small focal cortical dysplasia in the dorsal peri-rolandic region.

OBJECTIVE: Small focal cortical dysplasia (FCD) may be ambiguous or overlooked on magnetic resonance (MR) imaging. Source localization of EEG and magnetoencephalography (MEG) spikes was evaluated to confirm the diagnosis of small FCD. METHODS: This study included 6 epilepsy patients with a single small lesion on MR imaging suggesting FCD within a single gyrus among 181 consecutive epilepsy patients admitted to our epilepsy monitoring unit over 27 months. Stereotypical interictal spikes were detected on simultaneous EEG and MEG recordings and the onset-related source of averaged spikes was estimated. RESULTS: All 6 patients had unique clinical characteristics as follows: leg sensori-motor seizures in 5 patients and eye version in 1 patient; a small MR imaging lesion suggesting FCD in the dorsal peri-rolandic region, which had been overlooked until our evaluation; and both EEG and MEG dipoles were estimated adjacent to the MR imaging lesion. CONCLUSIONS: Source localization of EEG and MEG spikes can confirm the diagnosis of FCD based on a single small MR imaging lesion, which was overlooked by previous examination of MR images. SIGNIFICANCE: Examination of MR images should be based on spike source localization as well as seizure semiology to identify subtle MR imaging abnormalities.

Congenital generalized lipodystrophy type 4 with muscular dystrophy: clinical and pathological manifestations in early childhood.

A boy with congenital generalized lipodystrophy type 4 with muscular dystrophy presented in infancy with delay in motor milestones and a persistent elevation of CK. There was no associated mental retardation. He was followed up to 3 years and 11 months; he had a homozygous c.696_697insC mutation in polymerase I and transcript release factor (PTRF). He started to walk at 2 years and 6 months although he did not have mental retardation. Insulin resistance appeared at 3 years and 11 months of age. PTRF immunostaining positivity was absent in the muscle but caveolin-3 was preserved in the sarcolemma at 16 months of age. Secondary deficiency of caveolins may be closely associated with disease progression.

Time-varying inter-hemispheric coherence during corpus callosotomy.

OBJECTIVE: Corpus callosotomy limits the bilateral synchrony of epileptic discharges. However, the instantaneous changes in bilateral synchrony during corpus callosotomy are unclear. The present study investigated how and when bilateral synchrony is suppressed in the anterior and then posterior steps of corpus callosotomy. METHODS: Intra-operative scalp electroencephalography (EEG) was recorded simultaneously with surgical video for six patients who underwent total corpus callosotomy for medically intractable drop attacks. The time-varying EEG inter-hemispheric coherence was quantified by wavelet transform coherence and trend analysis. RESULTS: The 4-13 Hz coherence decreased after corpus callosotomy in five patients. Significant decrease in coherence was observed only during the posterior step of callosal sectioning in three patients, but throughout both steps in two patients. CONCLUSIONS: Decrease in inter-hemispheric coherence is not always correlated with the stages of callosal sectioning. Inter-hemispheric coherence is decreased during the final stage of corpus callosotomy and the effect is maximized after sectioning is completed. SIGNIFICANCE: Various patterns of coherence decrease suggest individual variations in the participation of the corpus callosum in the genesis of bilateral synchrony. Time-varying inter-hemispheric EEG coherence is useful to monitor the physiological completeness of corpus callosotomy.

Complete remission of seizures after corpus callosotomy.

OBJECT: Corpus callosotomy is usually intended to alleviate-not to achieve total control of-epileptic seizures. A few patients experience complete seizure control after callosotomy, but the associated clinical factors are unknown. The object of this study was to investigate clinical factors associated with long-term seizure remission after total corpus callosotomy in patients with infantile or early childhood onset epilepsy. METHODS: Thirteen consecutive patients with infantile or early childhood onset epilepsy underwent 1-stage total corpus callosotomy for alleviation of seizures. Their age at surgery ranged from 1 year and 5 months to 24 years (median 7 years). Eleven patients had West syndrome at the onset of disease, and the other 2 had Lennox-Gastaut syndrome. All patients suffered from spasms, axial tonic seizures, or atonic seizures. Six patients had proven etiology of epilepsy, including tuberous sclerosis, polymicrogyria, trauma, and Smith-Magenis syndrome. The association between postoperative seizure freedom and preoperative factors including age at surgery, no MRI abnormalities, proven etiology, and focal electroencephalographic epileptiform discharges was examined. RESULTS: Postoperative seizure freedom was achieved in 4 of 13 patients for a minimum of 12 months. All 4 patients had no MRI abnormalities and no identified etiology. None of the 8 patients with MRI abnormality, 6 patients with known etiology of epilepsy, or 4 patients aged older than 10 years at surgery achieved seizure freedom. Two of the 7 patients with focal electroencephalographic abnormalities became seizure free. Absence of MRI abnormalities was significantly associated with postoperative seizure freedom (p < 0.01). CONCLUSIONS: Complete seizure remission is achieved after total corpus callosotomy in a subgroup of patients with intractable epilepsy following West syndrome or Lennox-Gastaut syndrome. One-stage total corpus callosotomy at a young age may provide a higher rate of seizure freedom, especially for patients with no MRI abnormalities and no identified etiology of epilepsy.