Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome

The triple A syndrome (Allgrove syndrome, OMIM #231550) is caused by autosomal recessively inherited mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. This multisystemic disease is characterised by achalasia, alacrima, adrenal insufficiency and neurological impairment. We analyse long-term clinical follow-up and results of sequencing of the AAAS gene in eight patients with triple A syndrome aged from 2 to 35?years. At the time of diagnosis, all patients presented with alacrima, neurological dysfunction, dermatological abnormalities, seven of them with adrenal insufficiency and five of them with achalasia. Sequencing of the AAAS gene identified the p.S263P mutation in five of eight patients, supporting the hypothesis that this mutation is a founder mutation in Slavic population. One of the patients is homozygous for the p.S263P mutation, two are compound heterozygous for the p.S263P and the p.G14fs mutation, two are compound heterozygous for the p.S263Pro mutation and p.S296Y mutation, two are compound heterozygous for the p.G14fs and the p.Q387X mutations and one is homozygous for the p.Q387X mutation. In the course of the follow-up time of 4-29?years, progression of existing and appearance of new symptoms developed. Although severe, many of these symptoms presented in all six young adult patients are often overlooked or neglected: postural hypotension with blurred vision and syncope, hyposalivation resulting with complete edentulosis, talocrular contractures with permanent walking difficulties and erectile dysfunction in male patients. Triple A syndrome is a progressive debilitating disorder which may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment. Conclusion: Long-term follow-up of patients with triple A syndrome revealed a variety of the clinical features involving many systems. Progressive natural course of the disease may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment.     

Epilepsy in patients with Angelman syndrome

Angelman syndrome (AS) is a neuro-behavioural, genetically determined condition, characterized by ataxic jerky movements, happy sociable disposition and unprovoked bouts of laughter in association with seizures, learning disabilities and language impairment. Most of the cases are hardly diagnosed during infancy as jerky movements, the cardinal sign, appear later in childhood.AS is caused by a variety of genetic mechanisms involving the 15q 11-13 chromosome. About 70% of cases are due to a "de novo" interstitial deletion in the long arm region, arising on the maternally inherited chromosome. The diagnosis is confirmed by methylation test or by mutation analysis of UBE3A gene. The deletion phenotype is generally linked to a more severe clinical picture in that 95% of patients manifest more severe seizures, severe mental and motor retardation, dysmorphic features and microcephaly.The pathogenesis of epilepsy in AS is still not fully understood. The presence in the commonly deleted region of a cluster of genes coding for 3 subunits of the GABAa receptor complex has lead to the hypothesis that GABA neurotransmission is involved.Epilepsy, often severe and hard to control, is present in 85% of patients within the first three years of life, although less than 25% develop seizures during the first year. It was observed that febrile seizures often precede the diagnosis. Most frequent types are atypical absences, generalized tonic-clonic, atonic or myoclonic seizures, with multiple seizure types occurring in 50% of deleted patients. There is still some doubt about the association with West syndrome.The EEG abnormalities are not themselves pathognomonic of AS and both background activity and epileptic discharges vary even in the same patient with time. Nevertheless, the existence of some suggestive patterns should facilitate the early diagnosis allowing the correct genetic counselling for the family. Some drugs seems to act better than others, Valproate, ethosuximide and clonazepam giving the best results.     

An Angelman syndrome clinic: Report on 24 patients

Objective : Angelman syndrome (AS) is a rare congenital neurodevelopmental disorder with complex genetic aetiology. Diagnosis may be difficult and there is severe life-long disability. An AS clinic was commenced in Sydney, Australia, in 1993 with the aim of gathering information about the natural history of AS, management issues and parental concerns. Methodology : Patients were referred from metropolitan Sydney, rural New South Wales and interstate. A questionnaire, history, physical examination and diagnostic tests were undertaken. Results : In the first year, 24 patients with AS were assessed. There were 11 males and 13 females, whose ages ranged from 3 to 30 years. The mean age of diagnosis was 12.8 years. The diagnosis was made by neurologists in four cases, by clinical geneticists in three cases, by paediatricians in two cases and 15 cases were diagnosed at the AS clinic. A clear history of epilepsy was obtained in 19 (79%) and in 15 of these patients the age of onset was during the first 4 years of life. An EEG had been performed in 21 patients, and in two the EEG was reported as normal. Fifteen of the patients (62.5%) could walk independently and in this cohort there was a significant sex difference in walking: 10/11 males compared to 5/13 females (P >0.01). Five patients (21%) were in full-time permanent care. Genetic testing with appropriate DNA probes from chromosome 15(q11-13), complete in 20 families, showed deletion in 12 patients (60%), uniparental disomy in 1 (5%) and no detectable abnormality in 7 (35%). Conclusions : The diagnosis of AS should be considered in any patient with severe developmental disability particularly if there is a movement disorder and lack of speech. The control of epilepsy is a major management problem. Further research is needed to establish the frequency and type of seizures, the reponse to anticonvulsants and to determine if improvement can be expected with age. The mobility of patients should be assessed regularly, to determine the most appropriate options for intervention.     

Angelman综合征8例回顾性临床分析

目的 分析Angelman综合征(AS)的临床表现、脑电图(EEG)特征以及基因结果,探讨生酮饮食(KD)对AS难治性癫(痫)的近期疗效.方法 回顾性分析2012年1月至2013年12月复旦大学附属儿科医院神经科诊断的8例AS患儿的临床表现及EEG特征,并对治疗及预后进行随访.结果 8例AS患儿中男4例,女4例.临床均(100％)表现为大笑或愉快时微笑、全面发育迟滞和运动障碍,4例患儿头围偏小或小头畸形.7例患儿(88％)有癫(痫)发作且发作形式多种,主要为肌阵挛、不典型失神、失张力和部分继发全面性发作等,癫(痫)发病年龄6个月～2岁9个月,4例(57％)有肌阵挛持续状态.EEG特征为前头部、后头部或广泛性δ及θ节律性发放,慢波多呈游走性,并夹杂棘波、棘慢波,棘慢波多在后头部突出.所有患儿采用基因组DNA甲基化特异性多重连接探针扩增技术(MS-MLPA)进行检测,其中6例患儿(75％)证实存在染色体15q11PWS/AS相关区域基因的拷贝数缺失.7例患儿为多种抗癫(痫)药物联合治疗,6例(86％)为药物难治性癫(痫),3例患儿给予KD治疗,治疗1个月时2例有效,1例无效,3个月时1例发作完全缓解,1例有效,1例无效.结论 AS具有相对特征性的临床和EEG表现,结合基因检查可帮助诊断,癫(痫)发生率高,肌阵挛持续状态多见,且多为药物难治性癫(痫),KD可作为AS难治性癫(痫)治疗的选择.     

The 'happy puppet' syndrome of Angelman: review of the clinical features.

Thirty six children with typical features of Angelman''s syndrome, including global developmental delay, ataxia, episodes of paroxysmal laughter, seizures, and microcephaly were studied. The series included three sibships of three affected sisters, two affected brothers, and two affected sisters, respectively. The facial appearance is characterised by a prominent jaw, a wide mouth, and a pointed chin. Tongue thrusting is common. The movement disorder consists of a wide based, ataxic gait with frequent jerky limb movements and flapping of the hands. Tone is variable in the limbs with normal reflexes, and the plantar responses are usually flexor. The syndrome is being diagnosed more often, and attention is drawn to its diagnostic aspects.     

Longitudinal follow-up of autism spectrum features and sensory behaviors in Angelman syndrome by deletion class

Background: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a ‘syndromic’ form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger (～6 Mb) Class I deletions of chromosome 15q11‐13. Questions remain regarding whether intellectual disability solely contributes to ASD features in AS and how ASD features in AS change over time. In this study, we used a dimensional approach to examine ASD symptom severity in individuals with AS Class I versus Class II deletions within the context of cognitive development over time. Methods: A total of 17 participants with a larger, Class I deletion and 25 participants with a smaller Class II deletion (～5 Mb) were enrolled (age range = 2–25 years; 5 years 5 months). Standardized measures of cognition, language, motor skills, adaptive skills, maladaptive behavior, autism, and sensory‐seeking behaviors/aversions were given at baseline and after 12 months. Results: Despite equivalent cognition and adaptive behavior, the results of repeated measures analyses of variance indicate that participants with Class I deletions have greater impairment in social affect (F = 8.65; p = .006) and more repetitive behaviors (F = 7.92; p = .008) compared to participants with Class II deletions. Although both groups improve in cognition over time, differences in ASD behaviors persist. Conclusions: Despite a lack of differences in cognition or adaptive behavior, individuals with Class I deletions have greater severity in ASD features and sensory aversions that remain over time. There are four genes (NIPA 1, NIPA 2, CYFIP1, and GCP5) missing in Class I and present in Class Il deletions, one or more of which may have a role in modifying the severity of social affect impairment, and level of restricted/repetitive behaviors in AS. Our results also suggest the utility of a dimensional, longitudinal approach to the assessment of ASD features in populations of individuals who are low functioning.     

Middle aortic syndrome: clinical and radiological findings.

Eight patients with the middle aortic syndrome are described. They were aged 2 months to 14 years at diagnosis; follow up was one to 11 years. Clinical presentations included asymptomatic hypertension (n = 5), severe headache, nose bleed, and chest pain (n = 1), and cardiac failure (n = 1). All had severe hypertension requiring multiple drug treatment. Diminished peripheral pulses were not helpful in the diagnosis, which is made on aortography. Associated clinical findings were Williams' syndrome (n = 3) and appreciable eosinophilia (n = 3). The differential diagnosis includes Takayasu's arteritis, fibromuscular dysplasia, and neurofibromatosis. Blood pressure was adequately controlled by medical treatment in six patients. Surgical angioplasty was performed in two. One patient remained normotensive without drug treatment 21 months after operation; the other died of sepsis and uncontrollable haemorrhage in the postoperative period. Medical treatment is satisfactory in most cases: surgery should be reserved for those in whom blood pressure cannot be controlled without unacceptable side effects of drug treatment. Although rare, the middle aortic syndrome should be considered in the differential diagnosis of hypertension when commoner causes have been excluded. Aortography is necessary for diagnosis.     

Near-miss sudden infant death syndrome: clinical findings and management

The clinical findings for 73 infants with near-miss sudden infant death syndrome (SIDS) diagnosed from 1980 to 1984 are presented. Infants who were found apparently dead and who required vigorous stimulation or mouth-to-mouth resuscitation to revive them were said to have near-miss SIDS. The most common finding was apnea, often with pallor. A repeat episode requiring resuscitation occurred in 30 (41%) infants. Six (8%) had multiple episodes requiring resuscitation. Two infants (3%) died. Prediction of subsequent attacks or outcome was impossible on clinical grounds. The controversy of definition, relationship to SIDS, and treatment is discussed.     

Long-standing fever and Angelman syndrome: report of two cases

Abstract:   An 8-month-old girl and a 20-month-old boy who presented with motor and developmental delay and long-standing fever are presented. The patients were diagnosed as Angelman syndrome with fluorescence in situ hybridization (FISH) analysis. Despite extensive clinical and laboratory examinations, no inflammatory or infectious origin for the fever was found. It was considered that the long-standing fever observed in these cases was due to hypothalamic dysfunction for thermoregulation.     

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目的分析Angelman综合征(AS)的临床及脑电图(EEG)特征,提高临床对本病早期而准确的认识。方法分析2006年1月至2009年11月北京大学第一医院儿科神经门诊、病房及EEG监测室8例经遗传学确诊的AS患儿临床及EEG特征,并对治疗及预后进行随访。结果 8例中男6例,女2例。均存在全面发育特别是语言发育延迟、运动障碍、表情快乐并伴与环境不相适应的笑,部分患儿有异常的特征性面部表现。均有癫痫发作,起病年龄为6个月至2岁,发作包括热性惊厥、不典型失神发作、部分性发作、肌阵挛发作、部分继发全面性发作,3例有癫痫持续状态。EEG监测年龄为1岁7个月至7岁,图形特征为醒睡各期前头部、后头部及广泛性δ及θ节律性阵发或连续发放,慢波在多部位之间常呈游走性,并见夹杂棘波、棘慢波,5例棘慢波以后头部突出。均经遗传学检测而确诊,其中7例为来源于母源染色体15q11-13的大片段缺失。2例影像学证实有脑白质发育异常。随访时年龄为2岁5个月至9岁3个月,随访时间1～8年。癫痫治疗主要为丙戊酸单药或联合其他抗癫痫药,3例发作控制,4例发作明显减少,1例无改善。随访时5例能独立行走但不稳,1例仅能说简单词汇,7例语言始终无发育。...     

Dyskinetic cilia syndrome: clinical,radiographic and scintigraphic findings

The clinical, electron microscopic and radiographic data of 9 patients with dyskinetic cilia syndrome (DCS) are presented. Scintigraphic evaluation of mucociliary dynamics in six patients showed evidence of dyskinesia. Ventilation and perfusion studies were performed to evaluate obstructive lung disease. Retrospectively, bronchiectasis could be detected in 77% of the patients by analysis of the chest radiograph and lung scintigraphy, and bronchography potentially avoided in the seven patients who underwent this procedure.     

Congenital smooth muscle hamartoma. Prevalence, clinical findings, and follow-up in 15 patients

Cogenital smooth muscle hamartoma is a congenital skin lesion characterized by proliferation of bundles of smooth muscle within the reticular dermis. We report on a group of 15 children with this lesion, confirmed by skin biopsy specimen, its prevalence, the occurrence of associated anomalies, and long- term follow-up. To our knowledge, this is the largest group of patients with this lesion described in the literature. The estimated prevalence is about 1:2600 live births with slight male predominance. The lesion is most frequent in the lumbosacral area (67% [10/15]) and a positive pseudo-Darier's sign is present in 80% (12/15) of patients. During the follow-up period of up to 7 years, the lesions enlarged slightly but became less prominent. No malignant transformation was observed.     

PHACE syndrome: MRI of intracerebral vascular anomalies and clinical findings in a series of 12 patients

Background  

PHACE (posterior fossa defects, haemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities) syndrome describes a constellation of abnormalities that can occur in association with segmental craniofacial infantile haemangioma.     

Aicardi-Goutières syndrome: neuroradiological findings after nine years of follow-up.

The main radiological features of Aicardi-Goutières syndrome include basal ganglia calcification, cerebral atrophy and white matter alterations. We present a case where progress of cerebral calcifications demonstrated on consecutive CT-scans later on was followed by a decrease. The MRI showed a progressive and significant loss of white matter and severe signal changes of the remaining myelin. The aetiology of the myelin changes and the transient worsening of the cerebral calcifications remains to be elucidated. It has previously been shown that the spinal fluid level of interferon-alpha decreases with age and we suggest that the biphasic course of the calcifications and the ventricular size as well as the clinical course shown in many patients with Aicardi-Goutières might favor a causal role of interferon-alpha in the disease leading to a transient microangiopathy.     

Bartter's syndrome:clinical findings,genetic causes and therapeutic approach

Backgound Bartter's syndrome(BS)is a rare group of salt losing tubulopathies due to the impairment of transport mecha-nisms at the thick ascending limb of the H...     

Cardiovascular abnormalities in Noonan syndrome: The clinical findings and treatments

The clinical findings and treatment of cardiovascular abnormalities in 33 patients with Noonan syndrome are reviewed. Major cardiovascular abnormalities were pulmonary valvular stenosis in 17 patients (51.1%), hypertrophic cardiomyopathy (HCM) in 11 (33.3%), and atrial septal defect in 9 (27.3%). Dysplastic pulmonary valve was seen in 6 (35.3%). Balloon pulmonary valvuloplasty was performed for 4 patients with dysplastic pulmonary valves. Two patients were successfully treated. Surgical treatment was performed in 13 patients, 11 alive and 2 died. Two patients with HCM and arrhythmia died suddenly. In conclusion, balloon pulmonary valvuloplasty should be the initial palliation for dysplastic pulmonary valve in Noonan syndrome, and HCM is the risk factor for sudden death in Noonan syndrome.     

Angelman综合征的临床和脑电图特征

目的 探讨儿童Angelman综合征(AS)的临床和脑电图特征,加强对本病的认识.方法 14例患儿均接受录像脑电图、头颅MRI/CT及基因学检查;11例进行了遗传代谢病相关检查(血乳酸、血氨、尿氨基酸和有机酸筛杳等);8例接受智力测查.随访时间1～3年.结果 本组就诊时年龄8个月～3岁7个月,其中男4例,女10例,他们的临床特征表现为下颌突出、嘴阔大、肤色白、毛发黄、虹膜色淡,阵发性发笑,站立不能或走路不稳,语言落后.本组中被诊断癫癎12例,其中10例出现非惊厥样癫癎持续状态;同时有肌阵挛发作、不典型失神发作、非惊厥样癫癎持续状态9例;单纯肌阵挛发作、强直阵挛发作和复杂部分性发作各1例;病初发热惊厥4例.8例患儿脑电图提示清醒及睡眠期阵发中高波幅(2.5～3 Hz)棘波、棘慢波;4例双导频繁阵发中高波幅2～3 Hz慢波,夹杂少量尖波;2例脑电图正常.全部病例均被遗传学检查确诊,其中母源性染色体15q11-13缺失12例,父源性单亲二倍体1例,印迹缺损1例.结论 AS患儿具有较为突出的临床特点及特殊面容,多数患儿具有特征性的脑电图表现.15q11-13区域存在异常是确诊的依据.