Yuji Oto

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.

Growth hormone secretion and its effect on height in pediatric patients with different genotypes of Prader–Willi syndrome†

There have been multiple reports regarding the growth hormone (GH) secretion in patients with Prader–Willi syndrome (PWS). However, none have compared GH secretion in children with deletion group to those with maternal uniparental disomy (UPD). We evaluated the GH secretion in pediatric patients with PWS. Seventy‐six patients with a deletion (n = 55) or UPD (n = 21) were studied. The secretion of GH by insulin stimulation in the patients with UPD (3.6 ± 2.2 ng/ml) was significantly lower than those with deletions (peak GH level: 11.1 ± 8.6 ng/ml; P = 0.0013). We also compared the response to GH replacement therapy. Yearly improvements in height standard deviation score (SDS) were similar in the two groups (first year SDS: 0.47 ± 0.47, deletion; 0.68 ± 0.26, UPD; P = 0.14).

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 cm2. 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.

Exacerbation of BMI after cessation of growth hormone therapy in patients with Prader–Willi syndrome

Long‐term treatment with growth hormone (GH) in patients with Prader–Willi syndrome (PWS) improves not only height velocity, height standard deviation score, and final height, but also the degree of obesity and body composition abnormalities. Anecdotally, PWS patients tend to suffer from severe obesity and its complications after cessation of GH therapy. However, there have been no studies to investigate changes in body mass index (BMI) and adipose tissue distribution after cessation of GH therapy in young PWS patients. Therefore, we investigated changes in the BMI‐standard deviation score (SDS) and adipose tissue distribution after cessation of GH therapy in PWS patients. We evaluated 14 PWS patients. BMI‐SDS was calculated at 0, 6, 12, 18, and 24 months before and after cessation of GH treatment. We also evaluated subcutaneous adipose tissue (SAT) (cm2) and visceral adipose tissue (VAT) (cm2) area in 8 of the 14 study patients with single slice abdominal computed tomography at the level of the umbilicus. The BMI‐SDS significantly increased at 6, 12, 18, and 24 months after cessation of GH therapy (P = 0.039, P = 0.008, P = 0.003, P = 0.003, respectively). There was a tendency toward increases in VAT at 12 and 24 months after cessation of GH therapy, but the increases did not reach statistical significance (P = 0.062, P = 0.125, respectively). Therefore, cessation of GH therapy in PWS patients worsened BMI. To maintain good body composition and prevent complications of obesity, long‐term use of GH in adult PWS patients may be advisable.

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/cm2 to 0.9035 ± 0.0465 g/cm2 (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.

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.

Pyruvate Improved Insulin Secretion Status in a Mitochondrial Diabetes Mellitus Patient

CONTEXT Mitochondrial diabetes is a rare form of diabetes mellitus accounting for up to 1% of all diabetes. Pyruvate therapy has been reported to be a potential therapeutic choice for patients with mitochondrial diseases. CASE DESCRIPTION Water-based sodium pyruvate solutions (0.5 g/kg, thrice daily) were administrated orally to a 32-year-old Japanese male with mitochondrial diabetes and myopathy caused by m.14709T>C mutation. At the age of 20 years, he was diagnosed with diabetes mellitus and started insulin therapy. He tested negative for islet cell and glutamic decarboxylase antibodies. To evaluate favorable therapeutic improvements, we measured the lactate and pyruvate levels in plasma and cerebrospinal fluid; urinary C-peptide, glycated hemoglobin, and glycoalbumin levels; and total daily insulin dose (TDD). The patient experienced no side effects such as diarrhea because of pyruvate therapy. His urinary C-peptide level improved from 4.3 to 17.2 μg/d after 1 day and to 30.2 μg/d after 6 months of pyruvate therapy. TDD decreased from 33 to 20 U/d after 6 months of pyruvate therapy, but the lactate levels of plasma and cerebrospinal fluid and the lactate/pyruvate ratio did not change. CONCLUSIONS Sodium pyruvate improved insulin secretion and resulted in decreased TDD in a patient with mitochondrial diabetes. Pyruvate therapy may be a potential therapeutic choice for patients with mitochondrial diabetes. Clinical trials involving a larger number of patients and long-term evaluation of the therapy are necessary to clarify the efficacy of pyruvate therapy.

Characterization of diabetes mellitus in Japanese prader-willi syndrome.

Prader-Willi syndrome (PWS) is frequently associated with marked obesity and diabetes mellitus (DM). Although the overall frequency of DM in PWS ranges from 7–20%, there is only limited data available on Japanese patients. This study evaluated five factors associated with DM in PWS: 1) frequency, 2) age of onset, 3) risk factors, 4) long-term complications and 5) treatment. Sixty-five patients, ranging in age from 10 to 53 yr, were studied retrospectively. The frequency of DM in patients over 10 yr of age was 26.2% (17/65 patients). The age of DM onset ranged from 10 to 29 yr with a median age of 15 yr. The body mass index (BMI) was significantly higher in the DM group in comparison with the non-DM group. The number of patients using growth hormone (GH) in the DM group was significantly lower than the number that did not. Proteinuria (urinary excretion of albumin/creatinine at spot collection: U-Alb/Cr ≥300 mg/gCr) was observed in 1/17 patients (5.9%), microalbuminuria (U-Alb/Cr 30–300 mg/gCr) was observed in 4/17 patients (23.5%) and nonproliferative retinopathy was observed in 2/17 patients (11.8%). Among oral hypoglycemic agents, alpha-glucosidase inhibitors (α-GI) were most often used in our patients (10/17, 58.8%). Eleven out of 17 patients (64.7%) had been treated with insulin.

Partial lipodystrophy in patients who have undergone hematopoietic stem cell transplantation during childhood: an institutional cross-sectional survey

Abstract. Partial lipodystrophy (PD), a condition similar to metabolic syndrome without obesity, is one of the late complications of hematopoietic stem cell transplantation (HSCT) performed during childhood. We aimed to investigate the prevalence and risk factors of PD. A cross-sectional survey was performed in a children’s hospital, targeting patients treated for a malignancy or hematological disorder, and who were disease-free for > 24 mo. PD was defined as gluteal lipoatrophy and lipohypertrophy of the cheeks or neck associated with diabetes and/or fatty liver disease. In total, 65 patients were enrolled. Six patients (9.2%) were judged to have PD, all of whom had received 10–14 Gy total body irradiation. Compared with the patients without PD, patients with PD were older at investigation (P < 0.01), had a longer elapsed time following HSCT (P < 0.01), had more frequent disease recurrence (P < 0.05), and were more likely to have undergone multiple HSCT (P < 0.05). In addition, they had higher blood pressure and showed higher levels of low-density lipoprotein-cholesterol and triglycerides, whereas their adiponectin levels were significantly lower. In conclusion, a large number of patients developed PD following HSCT, with unfavorable metabolic profiles at a later age, especially when they experienced a complex disease course.

Gender Differences in the Behavioral Symptom Severity of Prader-Willi Syndrome

Objectives. This study measured gender differences in Prader-Willi syndrome (PWS) in regard to the severity of behavioral symptoms. Methods. The Food Related Problem Questionnaire (FRPQ), the Aberrant Behavior Checklist Japanese Version, the Childhood Routines Inventory, the Pervasive Developmental Disorders Autism Society Japan Rating Scale, and Japanese ADHD-RS were administered to PWS patients (45 males aged 6 to 58 and 37 females aged 6 to 45). To examine the effects that gender and genotype have on the severity of each symptom, two-way ANOVAs were conducted. Results. Significant interactions were found only in regard to FRPQ scores, such as FRPQ total score (F(1, 78) = 8.43, p < 0.01). The FRPQ of male deletion (DEL) individuals was higher than that of female DEL and male mUPD. The FRPQ of male maternal uniparental disomy (mUPD) was lower than that of female mUPD. Conclusions. In terms of problem behaviors, routines, autistic behaviors, and hyperactivity, no significant differences were found. Food-related behaviors in DEL were more severe in males, although those in mUPD were less severe in males.