Childhood-onset Myasthenia Gravis Research Articles

Pathophysiology of Childhood-Onset Myasthenia: Abnormalities of Neuromuscular Junction and Autoimmunity and Its Background.

The pathophysiology of myasthenia gravis (MG) has been largely elucidated over the past half century, and treatment methods have advanced. However, the number of cases of childhood-onset MG is smaller than that of adult MG, and the treatment of childhood-onset MG has continued to be based on research in the adult field. Research on pathophysiology and treatment methods that account for the unique growth and development of children is now desired. According to an epidemiological survey conducted by the Ministry of Health, Labour and Welfare of Japan, the number of patients with MG by age of onset in Japan is high in early childhood. In recent years, MG has been reported from many countries around the world, but the pattern of the number of patients by age of onset differs between East Asia and Western Europe, confirming that the Japanese pattern is common in East Asia. Furthermore, there are racial differences in autoimmune MG and congenital myasthenic syndromes according to immunogenetic background, and their pathophysiology and relationships are gradually becoming clear. In addition, treatment options are also recognized in different regions of the world. In this review article, I will present recent findings focusing on the differences in pathophysiology.

Clinical Features, Treatment, and Prognostic Factors of Childhood-Onset Myasthenia Gravis in a Large Chinese Cohort

BackgroundTo describe the clinical features of patients with childhood-onset myasthenia gravis (MG) (CMG) and explore predictors affecting the treatment outcomes. MethodsA retrospective observational cohort analysis of 859 patients with CMG with disease onset before age 14 years was performed at Tongji Hospital. ResultsPatients in the pubertal-onset group (n = 148) had a worse disease course than those in the prepubertal group (n = 711), including a higher incidence of generalized MG (GMG) at presentation, generalization of ocular MG (OMG), and more severe Myasthenia Gravis Foundation of America (MGFA) classification. All patients were initially treated with pyridostigmine, 657 with prednisone, and 196 with immunosuppressants (ISs). However, 226 patients were resistant to prednisone treatment. Multivariate analysis revealed that thymic hyperplasia, higher MGFA class, disease duration before prednisone administration, and thymectomy before prednisone administration were independent predictors of prednisone resistance. At the last visit, 121 of the 840 patients with OMG had developed GMG after a median of 10.0 years from symptom onset and 186 patients (21.7%) achieved complete stable remission (CSR). In multivariable analysis, age at onset, thymic hyperplasia, prednisone, and IS treatment were associated with generalization, whereas age at onset, disease duration, anti-acetylcholine receptor antibodies (AChR-ab), MGFA class II, short-term prednisone treatment, and IS treatment were associated with CSR. ConclusionsThe majority of patients with CMG have mild clinical symptoms and favorable outcomes, especially those with earlier onset age, shorter disease duration, and negative AChR-ab. In addition, early prednisone and ISs are shown to be effective and safe for most patients with CMG.

Clinical characteristics and outcome predictors of a Chinese childhood-onset myasthenia gravis cohort.

Myasthenia gravis is an organ-specific autoimmune disease. Currently there is no universal guidelines for childhood-onset myasthenia gravis, therefore, treatment strategies are usually based on the guidelines from adult myasthenia gravis patients. In order to contribute in the process of the development of the universal childhood-onset myasthenia gravis guideline, we have summarized the clinical characteristics, treatment strategies, outcome and the related predictors of childhood-onset myasthenia gravis. We recruited 343 childhood-onset myasthenia gravis cases who were followed up at the Department of Pediatrics, Xiangya Hospital from June, 2010 to December, 2019. The data about clinical characteristics, treatments and outcome were collected and analyzed. Among of the 343 cases, 164 cases were followed up for longer than 2 years, of whom 142 still remained with ocular myasthenia gravis at the endpoint. About the treatments, 27 cases (27/164) accepted pyridostigmine only while the rest accepted glucocorticoid and/or other immunosuppressants. At the endpoint, the proportion of optimal outcome was 66.2% in the group remaining with ocular myasthenia gravis and 31.8% in the generalized myasthenia gravis group. Multivariate logistic regression analysis revealed that generalized myasthenia gravis type and positive status of antibodies against acetylcholine receptors were the independent risk factors for poor outcome. In conclusion, our childhood-onset myasthenia gravis patients present mainly as ocular myasthenia gravis, adequate immunotherapy improve the long-term outcome, and generalized myasthenia gravis phenotype as well as positive status of antibodies against acetylcholine receptors relate to poor outcome.

Childhood-Onset Myasthenia Gravis Patients Benefited from Thymectomy in a Long-Term Follow-up Observation.

The effect of thymectomy on the treatment of childhood-onset myasthenia gravis (CMG) remains debatable. The objective of this study was to evaluate the clinical outcome and relevant prognostic factors of thymectomy for CMG patients. A total of 32 CMG patients who underwent thymectomy before 18 years of age were included in this retrospective study. Clinical state following thymectomy was assessed by quantified myasthenia gravis (QMG) scores, myasthenia gravis-related activities of daily living (MG-ADL) scores, and Myasthenia Gravis Foundation of America postintervention status. Repeated-measures analysis of variance (ANOVA) examined the changes in postoperative scores during the 5-year follow-up. Univariate logistic regression was applied to identify factors associated with short-term (1-year postoperation) and long-term (5-year postoperation) clinical outcomes. Repeated-measures ANOVA showed that QMG scores (F = 6.737, p < 0.001) and MG-ADL scores (F = 7.923, p < 0.001) decreased gradually with time. Preoperative duration (odds ratio [OR] = 0.85, 95% confidence interval [CI]: 0.73-1.00, p = 0.043), gender (OR = 0.19, 95% CI: 0.04-0.94, p = 0.041), and MG subgroup (OR = 13.33, 95% CI: 1.43-123.99, p = 0.023) were predictors for 1-year postoperative prognosis. Shorter disease duration (OR = 0.82, 95% CI: 0.70-0.97, p = 0.018) and generalized CMG (OR = 6.11, 95% CI: 1.06-35.35, p = 0.043) were found to have more favorable long-term results. Our results suggest that thymectomy is effective in treating CMG. Thymectomy could be recommended for CMG patients, especially for patients in the early course of GMG.

Long-Term Improvement in a Chinese Cohort of Glucocorticoid-Resistant Childhood-Onset Myasthenia Gravis Patients Treated With Tacrolimus.

ObjectivesTo evaluate the long-term outcome of tacrolimus for childhood-onset myasthenia gravis (CMG) with an inadequate response to glucocorticoids, and investigate factors associated with favorable outcomes following tacrolimus treatment.MethodsA retrospective, observational cohort study was performed for CMG patients who had not improved satisfactorily after sufficient prednisone therapy for at least 8 weeks. All patients were given tacrolimus in doses of 2–3 mg for more than 6 months. The primary efficacy outcome was assessed using the prednisone dose, quantitative MG (QMG), and MG-activity of daily living (ADL) scores. The participants were divided into improved and unimproved groups based on changes in QMG scores to investigate the risk factors that affected tacrolimus efficacy.ResultsA total of 149 glucocorticoid resistant CMG patients were finally enrolled in our study, with 113 (75.8%) responding well to tacrolimus (defined as minimal manifestation status or better). One month after initiating tacrolimus, there was a noticeable improvement in prednisone dose, QMG, and ADL scores, which continued to improve throughout the study. More importantly, the prednisone was eventually stopped in 89 of the patients (78.8%). Thymus type [odds ratio (OR) = 3.156, 95% confidence interval (CI) 1.427–6.978; P = 0.005] and pre-intervention status (OR = 0.284, 95%CI 0.109–0.741; P = 0.010) were independent predictors of tacrolimus efficacy after controlling for confounding factors in multiple logistic regression.ConclusionThe majority of glucocorticoid-resistant CMG patients have a good long-term prognosis after adding tacrolimus. Thymus type and pre-intervention status can serve as potential predictors affecting the efficacy of tacrolimus.

P-NJ005. Clinical profile and outcome of childhood-onset Myasthenia gravis

Introduction . Myasthenia gravis (MG) is an autoimmune disease with peak incidence in fourth decade. Childhood-onset MG is uncommon. We aim to describe the clinical profile and outcome of childhood-onset MG. Methods . Retrospective chart review of 27 patients (M:F 13:14) with childhood-onset MG seen in a single neurology unit between 2000 and 2019. Diagnosis was established by decremental response in repetitive nerve stimulation, response to neostigmine, and/or antibody positivity. Congenital Myasthenic syndromes were excluded. Results . Demographic and clinical features included: mean onset-age of 12.81±4.63 years, mean symptom-duration of 23.63±36.49 months, ptosis (100%), ophthalmoplegia (63%), facial weakness (55.55%), chewing difficulty (40.74%), dysphagia (48.14%), dysarthria (14.81%), neck weakness (25.92%), shoulder-girdle weakness (44.44%), pelvic-girdle weakness (48.14%), and respiratory weakness (14.81%). Myasthenia Gravis Foundation of America (MGFA) grade at first evaluation was I (n = 11), IIa (n = 7), IIb (n = 2), IIIa (n = 4), IIIb (n = 2), and IVb (n = 1). Two patients developed myasthenic crisis during course of illness. Associated illnesses included seizure disorder (n = 2), diabetes (n = 1), hypothyroidism (n = 1), and psychiatric illnesses (n = 4). Acetylcholine receptor antibody was positive in 12 patients while MuSK was positive in one patient. Chest computed tomography (CT) showed thymic hyperplasia in 12 patients and was normal in 6 patients. Thymectomy was performed in 9 patients (hyperplasia in 7, normal histology in 2). Time from MG onset to initiation of pyridostigmine was 13.80 ± 27.83 months and mean maximum dose of pyridostigmine was 172.22 ± 127.50 mg/day. Immunosuppressants administered in 22 patients included intravenous immunoglobulin (n = 3), plasma exchange (n = 5), steroids (n = 22), azathioprine (n = 4), mycophenolate (n = 2), methotrexate (n = 3), cyclophosphamide (n = 2), and rituximab (n = 1). Of 20 patients with follow- up details, remission was achieved in 17, of which 12 could stop pyridostigmine. Conclusion . In our cohort, majority had mild-moderate MG and myasthenic crises were uncommon. Treatment response was good. Remission was achieved in majority and in many of them, pyridostigmine was discontinued.

Efficacy of tacrolimus therapy for patients with childhood-onset myasthenia gravis

Efficacy of tacrolimus therapy for patients with childhood-onset myasthenia gravis

S7-4. Clinical characteristics of patients with juvenile childhood-onset myasthenia gravis

S7-4. Clinical characteristics of patients with juvenile childhood-onset myasthenia gravis

Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis.

ObjectiveThe incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear.MethodsWe investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored.ResultsIn our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live‐attenuated Japanese encephalitis vaccine (LA‐JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA‐JEV similar to the AChR‐α subunit, and immunization with a synthesized protein containing this peptide reproduced the MG‐like phenotype in mice.InterpretationOur results describe the immunological profile of CMG. Immunization with LA‐JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA‐JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386–400

Long-term outcome of 424 childhood-onset myasthenia gravis patients.

The objective of this study was to describe the clinical characteristics, outcome and factors that may affect the outcome of childhood-onset myasthenia gravis (CMG) patients in China. We have followed up 424 patients with CMG for at least 5 years at Tongji Hospital. At the end of follow-up, the outcome of all the patients was measured according to MGFA Post-intervention Status. In this study, the patients have been followed up for 9.8 ± 5.4 years. The mean onset age was 5.4 ± 3.6 years. Ocular myasthenia gravis (OMG) was the major type of CMG within 2 years after onset (95%). Thymic hyperplasia was found in 116 patients, and thymoma was confirmed in 6 patients. Acetylcholine receptor antibodies were elevated in 69.5% of the patients. All the patients were routinely treated. Thymectomy was performed in 34 patients (8.0%). At the end of follow-up, seventy-one patients (16.7%) were significantly improved, 66 patients (15.6%) remained unchanged, 53 patients (12.5%) were worsened, and 234 patients (55.2%) were exacerbated. Importantly, fifty OMG patients (12.4%) had transformed into generalized myasthenia gravis (GMG) over 2 years after onset. Thymectomy did not effectively reduce the transformation from OMG to GMG. However, GMG cases significantly benefited from the surgery. This study indicated that the cases with autoimmune CMG account for over 50% in Chinese MG population. The long-term follow-up discloses that CMG patients have a low percentage of improvement, and a high percentage of worsening and exacerbation. The treatment should not be withdrawn too early after the patients obtain complete stable remission. More studies are needed to gain better control of CMG symptoms.

Childhood-Onset Myasthenia Gravis With Thymoma

Juvenile myasthenia gravis is an acquired, autoimmune disease occurring before age 16 years. Thymoma is exceedingly rare in children, especially in association with juvenile myasthenia gravis. We describe a 14-year-old boy with juvenile myasthenia gravis and thymoma. He presented with difficulties chewing and swallowing, nasal speech, and fluctuating weakness of the leg muscles. Neurologic examination revealed masticatory and bulbar muscle weakness with nasal speech, proximal muscle weakness, fatigability of the arms and legs, and distal muscle weakness of the legs. A diagnosis of juvenile myasthenia gravis was confirmed by a positive neostigmine test, a decremental response on repetitive nerve stimulation, and increased titers of serum anti-acetylcholine receptor antibodies. The patient received anticholinesterases, corticosteroids, azathioprine, and thymectomy. A pathohistologic analysis of the thymus gland indicated thymoma, Masaoka grade II. After 2 years of an unstable disease course, remission was achieved. Because only 10 cases of thymoma-associated myasthenia gravis are described in the pediatric population, this report offers an important contribution to a better understanding of this rare association.

HLA-DQA1*03:02/DQB1*03:03:02 is strongly associated with susceptibility to childhood-onset ocular myasthenia gravis in Southern Han Chinese

ObjectiveOur aim was to investigate the correlation between onset age, clinical features and HLA-DQA1/DQB1 genetic variability in myasthenia gravis (MG) patients in Southern Han Chinese. Methods205 MG patients and 100 controls were genotyped for HLA-DQA1 and -DQB1 using sequence-based typing (SBT) and analyzed for haplotype frequencies. Anti-acetylcholine receptor (AChR) autoantibodies were measured in all, and muscle-specific tyrosine kinase (MuSK) antibodies were tested in AChR antibody negative patients. ResultsHLA-DQA1/DQB1 haplotypes showed association only with childhood-onset MG. Haplotype DQA1*03:02/DQB1*03:03:02 (DQ9) was positively associated with the childhood-onset MG, while haplotype DQA1*02:01/DQB1*02:02 and DQA1*05:01:01/DQB1*02:01:01 (DQ2) were negatively associated with this group. Childhood-onset ocular MG patients had an extremely high phenotype frequency of DQ9 haplotype (90.1% of patients, 34.0% of controls, p≤0.0001, OR=17.8). ConclusionsThe childhood-onset ocular MG in Southern Han Chinese may present a particular subgroup of distinct genetic background. Its correlation to the HLA haplotype DQA1*03:02/DQB1*03:03:02 might explain the phenotypic difference of MG between Han Chinese and Caucasians.

Childhood-onset myasthenia gravis: the analysis of influencing factors of therapeutic effect and prognosis

Though myasthenia gravis (MG) is a typical autoimmune disorder, there was some controversy on the treatment of the childhood-onset MG. By observing the efficacy of different therapies, the authors analyzed the affecting factors of prognosis in childhood-onset MG. The retrospective data of 155 patients with childhood-onset MG (age of MG onset was less than 15 years) were collected from Department of Neurology, Beijing Tongren Hospital (January 2000 - February 2010). The patients were non-randomly divided according to their treatment into 3 groups (glucocorticoid, thymectomy and glucocorticoid combined with thymectomy groups). Postintervention status meeting the criteria of Myasthenia Gravis Foundation of America (MGFA) "complete stable remission, CSR", "pharmacologic remission, PR", "minimal manifestations, MM", or "Improved, I" was regarded as desirable response, which was used as primary indicator of observation. The authors assessed the efficacy of three therapies and analyzed the influencing factors of prognosis by using Chi-square test and Logistic regression. At 3 months of treatment, glucocorticoid group showed the highest effective rate. At the end of 1 year or 2 years of treatment, glucocorticoid combined with thymectomy group showed the highest effective rate respectively. The generalization rate of MG at 2 years, 10 years and 20 years in childhood-onset ocular MG patients were 4.3%, 10.7%, and 41.5%, respectively. Of patients with generalization of MG, 48.1% occurred within 2 years, 92.6% within 20 years. Univariate analysis showed that in childhood-onset ocular MG patients, variables such as age at onset (> 10 years), LG-MG and with chronic fatigue were significantly associated with general MG conversion. Whereas multivariate analysis showed that patients with age at onset (> 10 years) and chronic muscle fatigue were apt to convert to generalized MG. Glucocorticoid appeared to have an effect that leads to early remission of symptoms in childhood-onset MG patients and glucocorticoid combined with thymectomy appeared to have better long-term effect. For those childhood-onset ocular MG patients with longer course of disease, older age of onset, chronic fatigue, or LG-MG, physicians should try to prevent the generalization of MG by immunosuppressive therapies.

Benefits of FK 506 for refractory eye symptoms in a young child with ocular myasthenia gravis

Recently, there have been many reports on the efficacy and safety of tacrolimus (FK506) treatment for adult patients with intractable generalized myasthenia gravis (MG). There have also been a few reports of successful FK506 therapy in patients with severe childhood-onset generalized MG involving a myasthenic crisis. Herein, we report the efficacy of FK 506 for refractory ocular symptoms in a 3-year-old girl with ocular type MG. Ptosis and alternating strabismus had appeared at 10 months of age. No bulbar signs, respiratory failure or generalized muscle weakness had been seen during her course. Her ocular symptoms had persisted despite repeated steroid pulse therapy, high dose oral prednisolone and thymectomy. Adverse effects of steroids, including obesity, growth retardation, osteoporosis, cataracts and hyperlipidemia, gradually worsened. After obtaining written informed consent from her parents, we started oral tacrolimus at a dose of 0.5 mg/day and her symptoms resolved completely within 3 weeks at a maximum dose of 2.5 mg/day. No adverse effects, such as renal failure or glucose intolerance, were seen. FK506 treatment allowed the steroid dose to be reduced, eliminating its adverse effects. In patients with intractable childhood-onset MG with ocular manifestations, FK506 is an alternative to steroid therapy or thymectomy.

Myasthenia gravis: presentation and outcome in 104 patients managed in a single institution

BACKGROUND AND OBJECTIVESFew studies have attempted to delineate the clinical profile of myasthenia gravis (MG) among people of Arab ancestry. Therefore, we sought to clarify the clinical profile, the outcome of treatment and the role of thymectomy in non-thymomatous MG in Saudi Arabia.PATIENTS AND METHODSWe retrospectively studied 104 patients followed over a mean period of 7.2 years (range, 1 to 22 years) at the King Khaled University Hospital, Riyadh, Saudi Arabia. Disease outcomes were compared among thymectomized and non-thymectomized patients according to the post-intervention status criteria of the Myasthenia Gravis Foundation of America (MGFA).RESULTSAge of onset was 22.5±9.3 years (mean±SD) in females and 28.2±15.9 years in males, with peaks in the second and third decades among females and the third and fourth decades among males. At diagnosis, a majority of patients had moderate generalized weakness, equivalent to MGFA class III severity. After medical treatment with or without thymectomy, 9.6% of all patients had achieved complete stable remission, 3.8% had pharmacological remission, 27.9% had minimal manifestations, 23.1% were improved, 20.2% were unchanged and 15.4% were worse. Only thymectomized patients without a thymoma achieved remission, a significant benefit over those who had no thymectomy (P=.02).CONCLUSIONMG presents at a younger age among Saudi Arabs compared to other racial groups. Thymectomy conferred significant benefits towards achievement of remission.

A study of the factors inducing the development of childhood-onset myasthenia gravis using CDR3 spectratyping analysis of the TCR repertoire

Myasthenia gravis (MG) is an autoimmune disease. AChR-specific autologous helper T (Th) cells are essential to the pathogenesis of MG. Factors correlated with the development of childhood-onset MG are unknown. In longitudinal studies, we found TCR Vβ 2/5.1/6/7 usage in the development or relapse phases, but not in the remission phase. We also found that TCR Vβ 8/9/13.1/15/18/20 usage persisted. The polyclonally expanded TCR Vβ 2/5.1/6/7 by CDR3 spectratyping was found to be associated with the development of disease. These data suggest that in patients with childhood-onset MG, stimuli such as superantigens induced by a preceding infection, which cause development of the polyclonal pattern in TCR Vβ families, play an important role in the development of the disease.

Successful treatment of a 2-year-old girl with intractable myasthenia gravis using tacrolimus

We used tacrolimus to successfully treat a patient with childhood-onset oropharyngeal myasthenia gravis (MG). A girl (2 years, 5 months old) with oropharyngeal MG responded partially to treatment including pyridostigmine bromide, intravenous immunoglobulin, and prednisolone (2 mg/kg/day) for 7 weeks, but this resulted in worsening of her eye symptoms. By contrast, tacrolimus at 2 mg/day resulted in complete remission of the MG, which made it possible to reduce the dose of prednisolone. This is a rare report of the use of tacrolimus as an effective treatment for patients with intractable childhood-onset MG.

A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan

To investigate the correlation between clinical features and HLA DR/DQ genetic variability in myasthenia gravis (MG), we evaluated HLA DR/DQ allele frequencies in 87 Japanese patients with childhood-onset disease. HLA genotypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303 were significantly higher in patients than in healthy controls ( P c < 0.0001, RR = 5.5; P c < 0.0001, RR = 8.5, for two genotypes, respectively). Patients who had a significantly higher likelihood of the HLA types DRB1*1302/DQA1*0102/DQB1*0604 or DRB1*0901/DQA1*0301/DQB1*0303 belonged to the latent general type (LG) of MG; this is clinically ocular type, but shows myasthenic electromyographic findings in extremity muscles. The LG type of MG was observed in 78% of patients exhibiting the clinically ocular type; this group comprised approximately 75% of patients with childhood-onset MG. These date suggest that LG type of MG may present a particular subset of childhood-onset MG, which is associated with the specific HLA subtypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303.

A variant of childhood-onset myasthenia gravis: On HLA typing and clinical characteristics in Japan

A variant of childhood-onset myasthenia gravis: On HLA typing and clinical characteristics in Japan

HLA antigens in Japanese patients with myasthenia gravis.

HLA antigens in 104 Japanese patients and 41 families with myasthenia gravis (MG) were investigated. The frequencies of DR9 and DRw13 were significantly increased in the patients who developed MG before 3 yr of age. The DQw3 antigen was positive for all the patients that developed MG before 15 yr with only one exception. All the examined cases that developed MG before 3 yr (including this DQw3 negative patient) had the same DQA and DQB DNA restriction fragments. These HLA frequencies decreased as the age of onset increased, and no significant association was observed in adult-onset MG. No patients had B8, DR3, and DQw2. The relative risk was higher for the DR9/DRw13 heterozygotes (37.4) than for DR9 (16.4) or DRw13 (7.1) in the childhood-onset MG. Statistical analysis suggested that DR9 and DRw13 (or DQw1 and DQw3) act synergistically in the disease development. Family study revealed diverse DR9 haplotypes. The most frequent DRw13 haplotype was Bw44-BFF-C4A3B1-DRw13-DQw1, which may be evolutionarily related to the caucasian B8-DR3-DQw2 haplotype. These results showed that MG in early childhood in Japanese individuals is genetically different from that in adulthood and that in caucasians.