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S M Huson

Publications and source records attributed to S M Huson.

At least 19 recordsLinked to original sources
PubMed2006

An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation.

Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (<20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA-->ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.

Adolescent↗
PubMed2005

Management of the patient and family with neurofibromatosis 2: a consensus conference statement.

A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10-12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.

Adult↗
PubMed2002

Service provision of complex mutation analysis: a technical and economic appraisal using dystrophin point mutation analysis as an example.

Duchenne muscular dystrophy (DMD) results from mutations in the dystrophin gene. One-third of cases arise from point mutations, which are heterogeneous and difficult to detect. The aims of this study of dystrophin point mutation analysis were to assess its technical feasibility in a routine diagnostic laboratory, and to estimate its costs and clinical benefits. The methods used were a laboratory based study using reverse transcription-polymerase chain reaction (RT-PCR) and a protein truncation test, and a mathematical model to estimate costs and clinical benefits. None of the cases analyzed had an identifiable dystrophin deletion or duplication. They were 12 males affected with DMD and two obligate female carriers; two female carriers of known dystrophin point mutations were also analyzed. Point mutations were detected in six out of 12 males, but in none of the female carriers. Assuming a sensitivity of 50% the model predicts significant clinical benefits of point mutation analysis over linkage analysis, including a reduction in the number of prenatal diagnoses (by 0.77 per family), terminations of pregnancy (by 0.18 per family), and terminations of unaffected fetuses (by 0.16 per family). The mean cost of point mutation analysis to prevent the termination of an unaffected fetus is 6220 US dollars.

Dystrophin↗
PubMed2001

The clinical and diagnostic implications of mosaicism in the neurofibromatoses.

Neurofibromatosis type 1 and type 2 both occur in mosaic forms. Mosaicism results from somatic mutations. Early somatic mutations cause generalized disease, clinically indistinguishable from nonmosaic forms. Later somatic mutation gives rise to localized disease often described as segmental. In individuals with mosaic or localized manifestations of neurofibromatosis type 1 (segmental neurofibromatosis type 1), disease features are limited to the affected area, which varies from a narrow strip to one quadrant and occasionally to one half of the body. Distribution is usually unilateral but can be bilateral, either in a symmetric or asymmetrical arrangement. Patients with localized neurofibromatosis type 2 have disease-related tumors localized to one part of the nervous system; for example a unilateral vestibular schwannoma with ipsilateral meningiomas or multiple schwannomas in one part of the peripheral nervous system. The recognition of mosaic phenotypes is important. Individuals with the mosaic form, even with a generalized phenotype, are less likely to have severe disease. They also have lower offspring recurrence risk than individuals with the nonmosaic form. The mosaic forms of neurofibromatosis provide a good example of the effects of somatic mutation. It is increasingly recognized that mild and unusual forms of many dominantly inherited disorders are caused by the same mechanism.

Humans↗
PubMed2001

Pigmentary anomalies in ataxia--telangiectasia: a clue to diagnosis and an example of twin spotting.

A 6-year-old girl with consanguineous parents presented with a history of progressive ataxia and patchy, segmental pigmentary changes, some reminiscent of Blaschko's lines. There was no evidence of oculocutaneous telangiectases or signs of immunodeficiency. A clinical diagnosis of ataxia--telangiectasia (AT) was suggested and confirmed by the presence of a low serum IgA, raised alpha-fetoprotein and chromosomal rearrangements of chromosomes 7 and 14. This case of AT is unique for having hypopigmentation and hyperpigmented patches adjacent to each other, which is a feature that has been described as 'cutis tricolor', and is unusual for having pigmentary skin changes, some in the lines of Blaschko without telangiectases. Clinicians should be aware that a diagnosis of AT may be made in the absence of telangiectases.

Ataxia Telangiectasia↗
PubMed2000

Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34.

Ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome [AOA]; MIM 208920) is an autosomal recessive disorder characterized by ataxia, oculomotor apraxia, and choreoathetosis. These neurological features resemble those of ataxia-telangiectasia (AT), but in AOA there are none of the extraneurological features of AT, such as immunodeficiency, neoplasia, chromosomal instability, or sensitivity to ionizing radiation. It is unclear whether these patients have a true disorder of chromosomal instability or a primary neurodegenerative syndrome, and it has not been possible to identify the defective gene in AOA, since the families have been too small for linkage analysis. We have identified a new family with AOA, and we show that the patients have no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that AOA in this family is a true primary cerebellar ataxia. We have localized the disease gene, by linkage analysis and homozygosity mapping, to a 15.9-cM interval on chromosome 9q34. This work will ultimately allow the disease gene to be identified and its relevance to other types of autosomal recessive cerebellar ataxias to be determined.

Acid Anhydride Hydrolases↗
PubMed2000

Asymptomatic maternal myasthenia as a cause of the Pena-Shokeir phenotype.

We report six sibs with arthrogryposis multiplex congenita and a Pena-Shokeir phenotype, born to a healthy woman who was discovered to have asymptomatic myasthenia gravis (MG). This is the first report of anti-acetylcholine receptor (AChR) antibodies causing fetal akinesia/hypokinesia sequence in the offspring of an asymptomatic mother.

Abnormalities, Multiple↗
PubMed2000

Teratogen update: maternal myasthenia gravis as a cause of congenital arthrogryposis.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is defined as nonprogressive congenital contractures that generally result from lack of fetal movement in utero. AMC is a feature of many congenital disorders caused by genetic, environmental, or other factors. One rare cause of AMC is maternal myasthenia gravis (MG). This is an autoimmune disorder, caused by antibodies to the nicotinic acetylcholine receptor (AChR), and resulting in weakness of voluntary muscles. In 10-15% of babies born to MG mothers, transient signs of MG are noted after placental transfer of anti-AChR antibodies. In a few cases, AMC predominates. METHODS: We review the role of antibodies to AChR in MG and in AMC associated with maternal antibodies to AChR. RESULTS: In anti-AChR antibody-associated AMC, fetal or neonatal death is common; other deformities or CNS abnormalities are common as well. The condition usually recurs in each pregnancy unless the mother is treated for MG, but some mothers are asymptomatic. The maternal antibodies cross the placenta and block the function of the fetal isoform of the AChR leading to fetal paralysis. Injection of maternal plasma into pregnant mice results in AMC in mouse fetuses. Some women with recurrent AMC in their babies have no detectable anti-AChR suggesting the presence of antibodies to other fetal muscle or neuronal proteins. CONCLUSIONS: Although rare, anti-AChR-associated AMC is potentially treatable and can be diagnosed by a routine antibody test. The mouse model can be used to investigate the role of these and other maternal antibodies in causing congenital conditions.

Animals↗
PubMed2000

Focal amyotrophy in neurofibromatosis 2.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by bilateral vestibular schwannomas and other CNS tumours including meningiomas and spinal schwannomas. Occasionally, peripheral neuropathy occurs in these patients but this is the first report of focal amyotrophy. Clinical, electrophysiological, and imaging data from four NF2 patients seen at a specialist neurofibromatosis clinic over a 4 year period are described in whom symptomatic focal amyotrophy preceded the diagnosis of NF2. Two presented with wasting and weakness of a single muscle group, several years before NF2 was diagnosed. In one patient a mononeuritis multiplex was the presenting feature of NF2, and in one patient focal wasting and weakness developed after the diagnosis of NF2 was made. In none of the four cases could a focal peripheral nerve or root neurofibroma be identified despite extensive imaging with MRI, and the limitations of neuroimaging for identifying a structural cause in patients with NF2 with a focal peripheral nerve lesion is discussed. It is likely that NF2 may affect peripheral nerve structures in a manner distinct from a compressive schwannoma.

Adolescent↗
PubMed1999

A novel point mutation in X-linked adrenoleukodystrophy presenting as a spinocerebellar degeneration.

X-linked adrenoleukodystrophy (ALD) usually presents in childhood as severe cerebral demyelination accompanied by axonal loss or in adults as a progressive spinal cord syndrome (adrenomyeloneuropathy). Rarely, patients present with adult onset spinocerebellar ataxia. We performed mutation analysis in a family with several members who had this rare phenotype and identified a single nucleotide deletion in exon 2 of the ALD gene. This is the first mutation analysis to be reported in this unusual phenotypic variant of ALD and the first deletion to be reported in exon 2.

Adrenoleukodystrophy↗
PubMed1999

The neurofibromatoses. An overview.

The last two decades have seen clinical and molecular delineation of the different forms of neurofibromatosis. Differentiation of these forms is not just an academic exercise: their natural history, management and genetic counselling are quite different. Of the numerical classifications of neurofibromatosis proposed in the past, only neurofibromatosis type 1 (Nf1) and neurofibromatosis type 2 (Nf2) are now well delineated clinically and have been shown to be distinct at the molecular level. For both forms of neurofibromatosis, patients with clinical generalised disease have been demonstrated to be mosaic at the molecular level, and features of segmental or mosaic Nf1 and Nf2 have been delineated. Other reported forms of neurofibromatosis are rarer; they include Watson syndrome, hereditary spinal neurofibromatosis, familial intestinal neurofibromatosis, autosomal dominant café-au-lait spots alone, autosomal dominant neurofibromas alone, and schwannomatosis, the latter believed to be a variant of Nf2. Further delineation is needed for individuals having overlapping features of Noonan's syndrome and neurofibromatosis (the so-called Noonan/neurofibromatosis syndrome) and the syndrome of "multiple naevi, multiple schwannomas and multiple vaginal leiomyomas". In this article we review the forms of neurofibromatosis which we believe are true clinical entities. Particular attention is given to the neurological manifestations of neurofibromatosis.

Humans↗
PubMed1999

Family history taking and genetic counselling in primary care.

OBJECTIVES: We aimed to evaluate the feasibility and acceptability of taking routine family histories and subsequent counselling. METHODS: The study was set in primary care in the UK. The subjects were patients between the ages of 20 and 34 years registered at one general practice. Patients were invited by letter to attend a clinic in their GP surgery, run by a GP and health visitor. A family history was constructed and counselling undertaken for any identified problems. A telephone survey of a sample of nonattenders was also performed. The outcome measures were attendance rate, patient views, patient anxiety as measured by the short form of the Spielberger State-Trait Anxiety Inventory and referrals to secondary care. RESULTS: In total, 16.1% patients attended the clinic; 40.3 % had a family history of at least one disease with a possible genetic component. Anxiety levels fell immediately after the consultation and rose to pre-clinic levels at 12 weeks. The clinic generated three referrals to secondary care and a further seven patients who were counselled by the investigators following advice from a consultant geneticist. CONCLUSIONS: It is possible to take detailed family histories and provide genetic counselling advice in primary care with minimal training of clinical primary care staff. The service is acceptable to patients, does not induce anxiety and has little effect on numbers of patients referred.

Adult↗
PubMed1999

Unusual clustering of brain tumours in a family with NF1 and variable expression of cutaneous features.

Neurofibromatosis type 1 (NF1) is one of the commonest autosomal dominant disorders in man. It is characterised by café au lait spots, peripheral neurofibromas, Lisch nodules, axillary freckling, skeletal dysplasia, and optic glioma. Symptomatic brain tumours occur in 1.5-2.2% of patients with NF1. We report here a family where seven members developed brain tumours. Of these, three have a clinical history strongly suggestive of NF1, while two do not fulfil diagnostic criteria for the disorder. A splice site mutation in exon 29 of the NF1 gene was found in these two subjects. This lesion is thought to be disease causative since it creates a frameshift and a premature termination of the neurofibromin protein. Different hypotheses to explain the unusual recurrence of brain tumours in this family, such as the nature of the mutation or cosegregation of other predisposing genes, are discussed.

Adolescent↗