Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including 'cerebral palsy'.

The mitochondrial DNA (mtDNA) mutation 8993 is an important cause of Leigh's encephalopathy. A family is reported where other affected members have presented with non-specific delayed development or cerebral palsy. The diagnosis should be considered not only in children with Leigh's encephalopathy, but also in those with mild neurological dysfunction (including cerebral palsy) if there is a pigmentary retinopathy or a family history of neurological or ophthalmological disease. There was some correlation in this family between the disease severity and the proportion of mutant mtDNA in the blood. This mutation appears to segregate to high levels of mutant mtDNA rapidly within pedigrees and the mother of a severely affected child has a high risk of having further children with a high proportion of mutant mtDNA and a severe phenotype.     

Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype.

The classical form of severe spinal muscular atrophy (SMA type 1; Werdnig-Hoffmann disease) has a very consistent clinical phenotype that is well recognized by paediatricians. It usually presents at birth or within the first few months of life. There is general hypotonia, with axial and limb weakness; the legs are affected more than the arms and proximal muscles more than distal, leaving residual spontaneous activity in the feet and in the forearms and hands. Facial muscles are spared so that the infant usually has a bright normal expression. The intercostal muscles are always affected, whereas the diaphragm is spared, allowing adequate spontaneous respiratory activity until the infants are precipitated into respiratory failure by an incidental respiratory infection, or aspiration. With rare exception they die by 2 years of age with a median around 7 months and with about 80% of the children dying by the time they are 1 year old. There is a consistent homozygous deletion in exons 7 and 8 of the telomeric copy of the survival motor neuron (SMN) gene.In the current issue of the journal, MacLeod and her colleagues have documented five cases of more severe spinal muscular atrophy, with a history of diminished fetal movements in utero and presenting at birth with asphyxia and severe weakness.     

Type 2 Gaucher disease: the collodion baby phenotype revisited

The association of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45), and congenital ichthyosis was first noted a decade ago. Subsequently, a null allele type 2 Gaucher mouse was generated that also exhibited ichthyotic skin, confirming that the skin disorder and enzyme deficiency were directly related. This paper details the clinical and molecular characterisation of 6 cases of type 2 Gaucher disease presenting with the collodion baby phenotype. The identified mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q), as well as alleles resulting from recombination with the nearby glucocerebrosidase pseudogene. There is significant genotypic heterogeneity in this rare subset of patients with type 2 Gaucher disease. Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis in the newborn period.     

Rotavirus infections in childhood: studies using a molecular biology method (gene electrophoresis)

During a 15-month period all children below 16 years admitted to the Children's Hospital in St. Gallen with acute diarrheal disease were studied for rotavirus (RV) infection. Stool samples from control patients without gastrointestinal disease were investigated for RV shedding in order to detect RV carriers or asymptomatically infected children. RV was detected by electrophoresis of RV genomic dsRNA in 154 children. 119 (58%) of 205 patients hospitalized because of diarrhea were RV associated, 25 children became symptomatically ill during their hospitalization, and in 10 (1%) of 954 control patients RV could be found. During the winter 1983/1984 two epidemic peaks of RV associated diarrhea were noted, whereas in the summer period RV related disease occurred only sporadically. The peak incidence of RV infection was in the age group between 10 and 12 months. After the 3rd year of life RV infection only rarely required hospitalization. During this study period 8 different genomic RNA patterns of RV were found. The number of patients within these 8 RV types, however, is too small to allow definite correlations between epidemiological or clinical features and selected electrophorotypes. The possibility to perform refined epidemiological and clinical analyses of RV infection by genomic dsRNA electrophoresis offers important advantages when compared to other RV detection systems. In addition, this method has proven to be fast, simple and reliable.     

罕见ICF综合征1例临床表型和分子遗传学分析

目的探讨免疫缺陷、着丝粒不稳定和面部异常(ICF)综合征的临床特征和遗传特点。方法回顾分析1例ICF综合征患儿的临床资料和基因检测结果。结果男性患儿,4岁,有反复感染;面部特征为圆脸、眼距稍宽、下颌尖、鼻梁稍扁、内眦赘皮明显、耳位低。免疫学检测示IgA缺如。基因测序发现患儿DNMT3B基因存在一个纯合错义突变c. 2506 GA,父母为杂合携带者,确诊为ICF综合征I型。结论 DNMT3B基因突变可引发ICF综合征,基因检测有助于提高此类罕见病的诊断。     

X linked agammaglobulinaemia with a 'leaky' phenotype.

Typical X linked agammaglobulinaemia (XLA) is characterised by absence of immunoglobulin production and lack of mature B cells. The gene responsible for XLA has recently been identified, and codes for a B cell tyrosine kinase, BTK. A family affected by a B cell immunodeficiency, which is less severe than classical XLA, is described but they had a pedigree suggestive of X linked inheritance. Demonstration of a mutation in the BTK gene confirms that this is a mild form of XLA.     

Expanding the phenotype of alveolar capillary dysplasia (ACD)

OBJECTIVES: To define the phenotype of congenital alveolar capillary dysplasia (ACD) as a first step toward mapping the responsible gene(s). STUDY DESIGN: Analysis of pathology reports and microscopic slides of 23 subjects with ACD and sequence analysis of two candidate genes. RESULTS: Our review of the pre- and postmortem records delineates both the natural history of this condition and the associated anomalies. Our collection of families corroborates the likely autosomal recessive nature of this condition in some families and provides additional data for genetic and prenatal counseling. Anomalies of many organ systems were detected either in the prenatal period or during the hospital course. However, some major anomalies were not detected until postmortem examination. Left-right asymmetry and gastrointestinal malrotation emerge as important, previously recognized but underappreciated phenotypic features of ACD. Finally, we used sequence analysis to exclude mutations in the coding region of two candidate genes, bone morphogenetic protein type II receptor (BMPR2) and endothelial monocyte-activating polypeptide II (EMAP II), as candidates for ACD. CONCLUSIONS: Understanding the clinical spectrum of ACD and the cloning of an "ACD gene" both have implications for counseling, for prenatal testing, and for understanding the molecular pathophysiology of ACD and other organ malformations that are associated with this condition.     

Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including 'cerebral palsy'

The mitochondrial DNA (mtDNA) mutation 8993 is an important cause of Leigh's encephalopathy. A family is reported where other affected members have presented with non-specific delayed development or cerebral palsy. The diagnosis should be considered not only in children with Leigh's encephalopathy, but also in those with mild neurological dysfunction (including cerebral palsy) if there is a pigmentary retinopathy or a family history of neurological or ophthalmological disease. There was some correlation in this family between the disease severity and the proportion of mutant mtDNA in the blood. This mutation appears to segregate to high levels of mutant mtDNA rapidly within pedigrees and the mother of a severely affected child has a high risk of having further children with a high proportion of mutant mtDNA and a severe phenotype.     

Glioneuronal phenotype in a diencephalic pilomyxoid astrocytoma.

We report the presence of divergent populations of cells in a hypothalamic/chiasmatic pilomyxoid astrocytoma of an 11-month-old male, exhibiting differential immunohistochemical localizations for glial fibrillary acidic protein (GFAP) and synaptophysin. The tumor cells were negative for Neu-N and neurofilament protein. Ultrastructurally, the tumor comprised 2 cell types, one with features attributable to a neuronal phenotype alongside cells exhibiting an overt astroglial phenotype. This composite organization was confirmed by confocal microscopy, which revealed 2 distinct, albeit tightly interwoven, populations of GFAP and synaptophysin-labeled tumor cells. Our results indicate that a subset of the so-called pilomyxoid astrocytomas of the hypothalamic/chiasmatic region may represent phenotypically mixed glioneuronal neoplasms distinct from the pilocytic astrocytomas.     

The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome

BACKGROUND: Although physical features, including loss of hand skills, deceleration of head growth, spasticity and scoliosis, are cardinal features of Rett syndrome (RS), a number of behavioural features are also associated with the disorder, including hand stereotypies, hyperventilation and breath holding. No study has tested the specificity of these behavioural features to individuals with RS, compared to individuals with severe to profound mental retardation (SMR). METHOD: A novel checklist of characteristic RS behavioural and emotional features, the Rett Syndrome Behaviour Questionnaire (RSBQ), was developed to test the type and specificity of behavioural features of RS against those found in girls with SMR. RESULTS: After controlling for the effects of RS-related physical disabilities, the RSBQ discriminated between the groups. Some aspects of the behaviours found to be specific to RS are included in the necessary or supportive RS diagnostic criteria, notably hand behaviours and breathing problems. Additional behavioural features were also more frequently reported in the RS than the SMR group, including mood fluctuations and signs of fear/anxiety, inconsolable crying and screaming at night, and repetitive mouth and tongue movements and grimacing. CONCLUSIONS: Full validation of the scale requires confirmation of its discriminatory power and reliability with independent samples of individuals with RS and SMR. Further delineation of the specific profile of behaviours seen in RS may help in identification of the function of the MECP2 gene and in improved differential diagnosis and management of individuals with RS.     

The Kabuki (Niikawa-Kuroki) syndrome: further delineation of the phenotype in 29 non-Japanese patients

The Kabuki (Niikawa-Kuroki) syndrome was reported in 1981 by Niikawa et al. [19] and Kuroki et al. [15] in a total of ten unrelated Japanese children with a characteristic array of multiple congenital anomalies and mental retardation. The syndrome is characterized by a distinct face, mild to moderate mental retardation, postnatal growth retardation, dermatoglyphic and skeletal abnormalities. In Japan, the syndrome appears to have an incidence of about 132 000 newborns. Outside of Japan, a growing number of patients have been recognized. Clinical data are presented on 29 Caucasian patients; the patients were diagnosed over a relatively short period of time, indicating that the incidence outside of Japan is probably not lower than in Japan. A literature review of 89 patients (60 Japanese and 29 non-Japanese) is given. In 66% of the non-Japanese patients serious neurological problems were present, most notably hypotonia and feeding problems (which were not only related to the cleft palate); this was not reported in the Japanese patients. Inheritance is not clear. Most patients are isolated, sex-ratio is equal. The syndrome can be recognized in patients with cleft (lip/)palate, with mild to moderate developmental delay and in young children with hypotonia and/or feeding problems. In counselling parents, the designation Kabuki syndrome seems to be more appropriate than Kabuki make-up syndrome.