Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN).

BACKGROUND: Neurodegeneration associated with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders in which disruption of cellular mechanisms leads to accumulation of iron in the basal ganglia. This group includes patients with recently discovered mutations in the PLA2G6 gene encoding a calcium-independent phospholipase A2 enzyme that catalyzes the hydrolysis of glycerophospholipids. Previously, children with PLA2G6 mutations have been diagnosed with several different disorders and we wished to better define the phenotype of PLA2G6- associated neurodegeneration. METHODS: Detailed review of the clinical and genetic features of 14 and radiologic features of 13 of these patients with PLA2G6 mutations was undertaken. RESULTS: Median age of symptom presentation was 14 months. One third of the cohort presented following an intercurrent illness. The children had progressive cognitive and motor skill regression, with evidence of axial hypotonia, four limb spasticity, bulbar dysfunction, and strabismus. All patients developed cerebellar ataxia and dystonia. Most patients had optic atrophy. Brain imaging demonstrated cerebellar cortical atrophy and gliosis in all patients. Changes consistent with increased iron deposition were identified in the globus pallidus and substantia nigra. Novel corpus callosum changes are also reported. CONCLUSION: We describe a cohort of patients with PLA2G6-associated neurodegeneration (PLAN). Although patients with PLAN have previously been diagnosed with infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome, they display a characteristic clinical and radiologic phenotype. PLA2G6 mutational analysis will negate the need for more invasive diagnostic procedures such as tissue biopsy.

Micro syndrome in Muslim Pakistan children.

OBJECTIVE: To date, Micro syndrome has been reported in only three children from one family. We describe an additional 14 children from 11 families. DESIGN: Retrospective case series. PARTICIPANTS: Fourteen children from 11 families attending one of five British hospitals. MAIN OUTCOME MEASURES: The following features were documented: pre- and postoperative eye findings, electrophysiologic analysis, systemic abnormalities, development, neuroimaging, genealogy, geographic origin of family. RESULTS: We expand and modify the description of ocular and electrophysiologic findings in Micro syndrome. The eye findings of microphakia, microphthalmos, characteristic lens opacity, and atonic pupils were the presenting feature in all infants and were the most reliable diagnostic signs in the immediate postnatal period. Cortical visual impairment, microcephaly, and developmental delay were not always detectable initially; they developed in all children by 6 months of age. Microgenitalia were a useful diagnostic clue in affected males only. Therefore, eye features were more consistently useful in determining diagnosis than dysmorphology or brain imaging. The families of all the children originate from the Muslim population of Northern Pakistan. Inheritance is likely to be autosomal recessive. CONCLUSIONS: Micro syndrome usually presents to the ophthalmologist, who may be able to make the diagnosis on the basis of characteristic eye findings combined with ethnic origin. Initially, the nature and severity of nonophthalmic features are not apparent. Early diagnosis of the underlying condition is important to guide management of the cataracts, glaucoma, and developmental delay. It is helpful for the family and medical staff to be aware of the low level of vision that develops despite optimal ophthalmic intervention. Genetic counseling extending into the wider family is particularly important in view of the high rate of consanguinity.

Craniofacial dyssynostosis: a further case report.

I describe a boy with lambdoid craniosynostosis, severe global developmental delay, epilepsy, oculomotor dyspraxia, very thin corpus callosum, and minor anomalies. The phenotype is in keeping with a diagnosis of craniofacial dyssynostosis. This autosomal recessive condition was first described in 1976 and was originally predicted to be relatively common in those of Spanish descent. However, there have been no further reports of the condition. This case is remarkably similar to those previously described, but has the additional finding of a neuronal migration defect.

A new lethal autosomal recessive skeletal dysplasia with associated dysmorphic features.

We report a fetus noted on routine ultrasonography at 21 weeks gestation to have a skeletal dysplasia with reduced ossification of shortened long bones and normal sized ribs. The consanguineous parents elected to continue the pregnancy and spontaneous labour occurred at 33 weeks gestation. The child died in the neonatal period. At necropsy, the main skeletal features were abnormal vertebrae with variation in shape and size, and ossification centres, short angulated long bones with distorted metaphyses and multiple abnormalities and fusions of the phalanges and metacarpals. In addition there was hydrops fetalis, a 'digit like' appendage overlying the left biceps muscle, a small chest with pulmonary hypoplasia and facial dysmorphism. In a subsequent pregnancy the fetus was noted at 13 weeks gestation to have nuchal translucency and bilaterally short femora. The fetus progressively developed hydrops fetalis and intrauterine death occurred at 22 weeks gestation. Post mortem examination revealed features very similar to the previous sibling. We suggest that this a new lethal osteochondrodysplasia syndrome. Recurrence in female siblings and parents who are double first cousins, strongly indicate autosomal recessive inheritance.

Fragile X syndrome is less common than previously estimated.

In 1986, a population study of school children in the city of Coventry gave an overall prevalence in males and females for fragile X syndrome of 1/952. The 29 children diagnosed as having fragile X syndrome in this study have been re-evaluated with molecular diagnostic techniques. Eighteen of the original 29 children have been found not to have the expansion of the FMR1 gene associated with fragile X syndrome. Revised prevalence figures have been calculated giving rise to an overall prevalence figure of 1/2720 (range 1/2198-1/3089). If the four children lost to follow up are also assumed not to have the fragile X syndrome, the revised prevalence figure was 1/5714 (range 1/4762-1/6349). Clinical review of boys with severe mental retardation from this and a subsidiary study show that the clinical features of head circumference greater than the 50th centile, testicular volume greater than the 50th centile, and IQ between 35 and 70 remain helpful in distinguishing boys with fragile X syndrome from those who have non-specific mental retardation.

Genotype-phenotype correlation between position of constitutional APC gene mutation and CHRPE expression in familial adenomatous polyposis.

Mutations in the adenomatous polyposis coli (APC) gene are responsible for the disease familial adenomatous polyposis (FAP), a dominantly inherited predisposition to colorectal cancer. The most common extra-colonic manifestation is congenital hypertrophy of the retinal pigment epithelium (CHRPE), expressed in up to 90% of FAP kindreds. Chain-terminating APC mutations were characterised in 26 unrelated FAP patients. Results show that CHRPE expression is determined by the length of truncated protein product. CHRPE is therefore the first extracolonic manifestation of FAP to be shown to be under the control of the APC mutation site and should facilitate the detection of constitutional APC mutations in FAP kindreds.

Primary gastrointestinal non-Hodgkin's lymphoma: a review of 175 British National Lymphoma Investigation cases.

A retrospective analysis was performed upon 175 patients with Non-Hodgkin's Lymphoma involving the gastrointestinal tract and entered into BNLI trials and studies between 1974-1988. Malignant histiocytosis of the intestine (MHI), which was present in 16 patients, was associated with a survival of less than 25% at 18 months, and probably accounted for the poor survival of patients with jejunal involvement. Histopathological evidence of tumour origin from mucosa-associated lymphoid tissue (MALT) was found in 50% of patients with gastric involvement and in 27% of those with intestinal involvement. The overall survival of the series as a whole was 44% at 10 years. Multivariate analysis identified evidence of tumour origin from MALT as the only factor to attain prognostic significance in patients with gastric involvement, and clinical stage and the presence of MHI as the only factors to attain prognostic significance in patients with intestinal involvement. It is suggested that there is a need for a large multicentre prospective study of GIT lymphoma.

Percutaneous insertion of subclavian Hickman catheters.

We have assessed the percutaneous insertion of Hickman catheters implanted directly into the subclavian vein; 116 catheters were inserted in 86 patients. The catheters were all inserted by members of the haematology staff. The majority of the catheters were inserted under local anaesthetic in a haematology ward with filtered positive pressure ventilation. X-ray screening was not routinely used. The average patient age was 45 years and the average platelet count was 155 x 10(9)/l. Sixty-seven per cent of the catheters either remain in situ or have been removed electively or at death. The remainder have been removed for a variety of reasons (infection 10%, suspected infection 8%, accidental dislodgement 7%, thrombosis 4%, catheter blockage 3%, catheter fracture 0.9%). The only complication specific to direct subclavian puncture was pneumothorax (4%). This disadvantage may be offset by rapid insertion, a cosmetically superior result and the avoidance of surgical and operating theatre time.

Correlation between tumorigenicity and altered glycosylation of a "leukocyte common" antigen in human lymphoid cell lines.

Five human lymphoblastoid cell lines which have become tumorigenic, as judged by transplantability into immunosuppressed mice, have been compared with earlier, non-tumorigenic stocks of the same cultures, recovered from liquid nitrogen. Analysis of the cell surface glycoproteins by SDS-PAGE, electro-transfer to cellulose nitrate and "blotting" with radioiodinated lectins, reveals an increase in the molecular weight of one band from around 190 kd to 220 kd, in each case coinciding with the acquisition of the tumorigenic phenotype. Probing the electrotransfers with a monoclonal antibody demonstrates that the altered glycoprotein is a member of the "leukocyte common antigen" family. The increase in molecular weight is due to the addition of carbohydrate residues which are removed by treatment with neuraminidase and endoglycosidase. Screening a larger number of lymphoid cell lines, including those derived from Burkitt's lymphoma, shows an excellent correlation between tumorigenicity and altered molecular weight of a leukocyte common antigen.

Locus of control in obesity: predictors of success in a jaw-wiring programme.

One hundred and thirty-three obese women were administered a modified version of the Reid-Ware Locus of Control questionnaire prior to jaw wiring. The factorial structure of the questionnaire was examined, and found to be primarily a unidimensional measure of internal and external locus of control, with two subscales. Total score had greatest predictive validity in terms of the four criteria of success of weight loss while wired, percentage weight loss of wiring weight, weight gain over six months, and compliance with the treatment régime. Twenty items of the scale predicted success on one or more of these criteria of success, and are presented as an abbreviated locus of control scale with a higher degree of validity than the original scale.