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Biomedical subjects

B D Lake

Publications and source records attributed to B D Lake.

At least 37 records · Page 2Linked to original sources
PubMed1997

Light and electron microscopic studies on subunit c in cultured fibroblasts in late infantile and juvenile Batten disease.

Immunohistochemical and ultrastructural studies were undertaken to determine whether accumulation of subunit c of mitochondrial ATP synthase could be detected microscopically in fibroblasts cultured from patients with late infantile and with juvenile Batten disease. Cells were grown for five weeks with and without colchicine to inhibit cell division, and were studied grown on slides, as cytospin preparations or as centrifuged pellets. The two different immunohistochemical detection methods used (peroxidase/DAB and immunogoldsilver) gave different results, but neither method indicated any accumulation of subunit c. There was no ultrastructural or electronhistochemical evidence of storage. The published biochemical results which give apparently conflicting evidence of excess amounts of subunit c in cultured fibroblasts can be explained by quantitative differences and sensitivity of the detection methods.

ATP Synthetase Complexes↗
PubMed1997

Bone marrow transplantation in late infantile Batten disease and juvenile Batten disease.

Two patients, one each with LINCL and JNCL, underwent BMT in an attempt to alter the course of their disease. The LINCL patient received two transplants, one when asymptomatic, which was rapidly rejected, and a second BMT at age 3 years 9 months when the EEG had become abnormal. He has deteriorated in the following 2 years and now has only a few words, limited vision and feeding difficulties. Only two major seizures have occurred, but minor seizures are frequent. Although he is less severely affected than his sister at the same age, it is difficult to know if BMT has had any effect. The most significant difference is the relative mildness of seizure activity. The JNCL patient, transplanted at 8 years, when her visual problems had already started, is still in mainstream school, has good speech and good quality of life at age 9 1/2 years. No regression has been found, but EEG changes are now present and her vision has further deteriorated. The effect of BMT, if any, will not become apparent for several years in the more slowly progressive JNCL.

Adolescent↗
PubMed1997

Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes 11p15 and 15q21-23.

The childhood neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative disorders characterised by progressive visual failure, neurodegeneration, epilepsy and the accumulation of an autofluorescent lipopigment in neurones and other cells. Three main subtypes have been identified according to age of onset, clinical features and ultrastructural morphology. These are infantile NCL (INCL; CLN1), classical late infantile NCL (LINCL; CLN2) and juvenile NCL (JNCL; CLN3). Several atypical forms of late infantile NCL (LINCL) have also been described including a Finnish variant LINCL (CLN5). The CLN2 gene has been excluded from the CLN1, CLN3 and CLN5 loci. A genome search was initiated using a homozygosity mapping strategy in five classical LINCL and two variant LINCL consanguineous families. A common region of homozygosity was identified on chromosome 11p15 in two of the classical families. Analysis of a further 33 classical LINCL families supported linkage in this region (Zmax = 3.07 at theta = 0.06 at D11S1338). A common region of homozygosity was also observed on chromosome 15q21-23 in the two variant LINCL families. Extension of the analysis to include a further seven families of identical ultrastructural phenotype established linkage to this region (Zmax = 6.00 at theta = 0.00 at D15S1020).

Child, Preschool↗
PubMed1997

Salla disease--rare or underdiagnosed?

Salla disease is described in two English children. Eighty-seven of the 89 cases so far reported come from Finland. It may be genuinely rare outside Finland or possibly underdiagnosed. Although a lysosomal disorder, it lacks many of their more characteristic features. Deterioration, for example, in the paediatric age range is rare. The clinical features are, however, consistent and specific. Definitive diagnosis is achieved by demonstrating increased amounts of free sialic acid in cultured skin fibroblasts. If the colorimetric method in widespread use is employed for this, a false negative result may be obtained. High-pressure liquid chromatography is sufficiently sensitive. It is possible therefore that Salla disease is under-reported, both from lack of clinical awareness and from lack of appropriate laboratory confirmation.

Child↗
PubMed1996

Deficiency of respiratory chain complex I is a common cause of Leigh disease.

We reviewed the clinical features and etiologies of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of all pedigrees, and in 74% of the 19 pedigrees with pathologically proved Leigh disease. Isolated deficiency of respiratory chain complex I was found in 7 patients, though the complex was only assayed in 25 patients, making this the second most common biochemical abnormality after complex IV deficiency. Mutations at residue 8993 of mitochondrial DNA were found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid.

Blotting, Southern↗
PubMed1996

A form of juvenile Batten disease with granular osmiophilic deposits.

The clinical, neurophysiological and pathological features of a patient who presented with the clinical features of juvenile Batten disease, yet who had storage of granular osmiophilic deposits (GROD) on ultrastructural examination of biopsy and postmortem tissues is described. The ultrastructural features are those usually found in the infantile form of Batten disease. The postmortem study showed marked neuronal storage of a lipofuscin-like material in an atrophic brain without loss of myelin. The cerebellum showed almost complete loss of Purkinje cells and loss of the granule cells. No accumulation of subunit c of mitochondrial ATP synthase was found. The clinical and neurophysiological findings are compared with those of the classical juvenile form and with those of the few reported cases of juvenile Batten disease with GROD. The importance of correct classification of patients with Batten disease and its impact on the molecular genetic studies is emphasised. The pathogenesis of this form of the disease is considered to be similar to that for infantile Batten disease.

Adolescent↗
PubMed1996

First trimester DNA-based exclusion of recessive dystrophic epidermolysis bullosa from chorionic villus sampling.

A 28-year-old woman, who previously had had a child affected with the hereditary blistering skin disorder, recessive dystrophic epidermolysis bullosa, presented at 7 weeks' gestation for prenatal diagnosis. Genomic DNA, obtained from her, her husband (who is a first cousin), their unaffected child, and their previously affected child, was used to screen all 118 exons of the type VII collagen gene (COL7A1) by polymerase chain reaction (PCR) amplification followed by heteroduplex analysis of the PCR products. Established common polymorphisms within the NC-1 region of COL7A1 were informative for both the normal maternal and paternal alleles. In addition, a putative homozygous mutation, a G to C transversion at nucleotide position 7708, was identified in the affected child. This substitution converts a glycine residue (GGT) within the Gly-X-Y region of the type VII collagen triple helix into an arginine residue (CGT), and leads to the creation of a new MnlI restriction site. Both parents and the healthy sibling were shown to be clinically normal heterozygous carriers of this mutation. A chorionic villus biopsy was performed at 10 weeks' gestation and DNA was extracted from the villi. Assessment of informative intragenic markers, and the putative mutation, revealed that the fetus had inherited both the normal maternal and paternal COL7A1 alleles. Thus, first trimester DNA-based prenatal diagnosis predicts that this child is neither affected with recessive dystrophic epidermolysis bullosa, nor is an unaffected carrier of this genodermatosis.

Base Sequence↗
PubMed1995

Tissue and cellular distribution of subunit c of ATP synthase in Batten disease (neuronal ceroid-lipofuscinosis).

The major protein component of the storage bodies in the late infantile (LIB) and juvenile (JB) forms of Batten diseases is subunit c of ATP synthase (subunit c). Ultrastructurally the stored material may appear as curvilinear bodies, fingerprint profiles, or a mixture of both, dependent upon the form of Batten disease and the cell type. The mnd/mnd mouse, an animal model for Batten disease, also stores subunit c and has loosely stacked lamellae within the neurons of the brain and in other cells and tissues. Using a range of tissue samples, immunolocalization, using avidin-biotin techniques at the LM level and postembedding immunogold-labelling (5 nm) with silver enhancement at the EM level, were used to investigate specific subunit c immunoreactivity. Subunit c storage was displayed in a number of cells, including neurons, muscle cells, adipocytes, macrophages, endothelial and some epithelial cells, and exocrine and endocrine cells. By EM, subunit c was localized to all curvilinear-type storage bodies, but to nowhere else within the cell. It was not present over fingerprint profiles, the characteristic storage pattern of neurons within the JB gut, possibly due to steric factors. Preliminary studies in the mnd mouse showed subunit c immunoreactivity localized to storage profiles seen ultrastructurally in neurons of the brain, and liver and heart cells. We suggest that accumulation and distribution of subunit c within a variety of cell types, and its consistent absence in others, may be related to the particular cell type's longevity and its metabolic demand.

Animals↗
PubMed1995

Late-infantile Batten disease: purification of the subunit c of the mitochondrial ATP synthase from storage material.

The accumulation of subunit c of the mitochondrial ATP synthase in late-infantile neuronal lipofuscinosis (LINCL) and juvenile neuronal lipofuscinosis (JNCL) is well documented. The purification of the subunit from diverse sources has been reported previously, although not from the brain of Batten disease patients. This proteolipid has now been purified from late-infantile Batten disease brain. The procedures used were an original combination of the conventional solubilisation, differential centrifugation, organic solvent extractions, preparative gel electrophoresis, and FPLC. Gel filtration of the purified protein indicated molecular mass equal to or greater than 2 x 10(6) Da; however, electrophoresis of this pure protein suggested a molecular mass of approximately 3,500 Da, which is a characteristic of subunit c. The pure protein may be solubilised in aqueous buffer containing < 1% lithium dodecyl sulphate (LDS). The protein binds dicyclohexylcarbodiimide (DCCD) and shows immunoreactivity to antibodies raised against ovine storage bodies.

Blotting, Western↗
PubMed1995

Bone marrow transplantation in Batten disease (neuronal ceroid-lipofuscinosis). Will it work? Preliminary studies on coculture experiments and on bone marrow transplant in late infantile Batten disease.

Lymphocytes from a patient with preclinical late infantile Batten disease were cultured alone and with lymphocytes from donors, and the fate of the curvilinear inclusions characteristic of the disease was monitored by electron microscopy. There was no evidence of transfer of deficient enzyme or factor that might have caused removal of the stored material, and the curvilinear profiles remained in the cultured cells without signs of degradation. Cells stimulated to divide with phytohaemaglutinin did not exhibit storage in culture suggesting that storage is a function of the age of the cell. The patient received a bone marrow transplant at 2 7/12 years while still clinically unaffected, and the effect on lymphocytes and cells in skin and rectal biopsies was monitored by electron microscopy over a period of 9 months until the donor marrow became displaced by the host cells. He has had one seizure and now has neurophysiological evidence of late infantile Batten's disease. Bone marrow transplant may have no effect on material already stored but might prevent further build-up and halt the onset of the clinical symptoms although very recent studies on early (fetal) transplants in sheep with a form of Batten disease have shown no benefit.

Bone Marrow Transplantation↗
PubMed1995

Junctional epidermolysis bullosa and pyloric atresia: a distinct entity. Clinical and pathological studies in five patients.

Junctional epidermolysis bullosa (JEB) associated with pyloric atresia (PA) is a distinct entity which is inherited as an autosomal recessive disorder. We describe five patients with this association; four died in the neonatal period and one is still alive at 4 years of age. The cutaneous lesions in these patients are identical or similar to those in other JEB subtypes. Urinary tract involvement is part of the syndrome and presents a problem for long-term survival. Using the monoclonal antibody GB3 we investigated skin biopsies from three of our patients and showed normal expression in all of them, unrelated to the outcome of their disease. This indicates that the GB3 monoclonal antibody is without prognostic significance in this syndrome. It is clear that JEB with PA is a distinct entity. The molecular basis as yet is unknown.

Antigens, Surface↗
PubMed1995

Use of type VII collagen gene (COL7A1) markers in prenatal diagnosis of recessive dystrophic epidermolysis bullosa.

Generalised recessive dystrophic epidermolysis bullosa (EB) is a severe inherited disease in which patients suffer from blistering and scarring of the skin and mucous membranes after minor mechanical trauma. Tight genetic linkage has been established to the type VII collagen gene (COL7A1) at 3p21, with no evidence of locus heterogeneity. Several COL7A1 mutations have now been identified in recessive dystrophic EB patients. Prenatal diagnosis has been performed by examination of a fetal skin biopsy taken at about 16 weeks' gestation, and relies on identification of characteristic ultrastructural and immunohistochemical changes. We have now achieved a first trimester prenatal diagnosis using intragenic and flanking COL7A1 markers in a pregnancy at risk for recessive dystrophic EB. Segregation of the informative markers predicted the baby would be an unaffected carrier. The pregnancy continued to term and a healthy baby was born, confirming this result.

Collagen↗
PubMed1995

The natural history of human dermatosparaxis (Ehlers-Danlos syndrome type VIIC).

Dermatosparaxis (Ehlers-Danlos syndrome type VIIC) has only recently been identified in human subjects. Although well documented in animals, to date only three human cases have been recorded, all aged 2 years or under. We document a 15-year-old girl with this newly recognized condition to emphasize the remarkable similarity of physical signs in all four cases. The striking skin fragility which attends the phenotype is highly distinctive, so that the diagnosis may be suspected on clinical grounds. The confirmatory diagnostic procedures are discussed.

Adolescent↗
PubMed1994

Neutral lipid storage disease. Case report and lipid studies.

A 9-year-old boy of Greek-Cypriot origin had been diagnosed at the age of 3 years as suffering from non-bullous ichthyosiform erythroderma. However, he also had hepatomegaly and abnormal liver function tests, biochemical evidence of myopathy, early cataracts, and lipid vacuoles in white blood cells and basal keratinocytes. A diagnosis of neutral lipid (triglyceride) storage disease was confirmed by lipid studies on cultured fibroblasts.

Child↗
PubMed1994

Antigenic expression of integrin alpha 6 beta 4 in junctional epidermolysis bullosa.

Integrin alpha 6 beta 4 is a major component of hemidesmosomes, considered to play a central role in the adhesion of basal epidermal cells to the underlying dermis. It is therefore of considerable interest in the study of the aetiology of inherited blistering disorders. We have examined the immunohistochemical characteristics of skin from 16 patients with epidermolysis bullosa using two antibodies directed against epitopes on the beta 4 subunit of alpha beta 4 integrin (G71, 3E1), one antibody directed against an epitope on the alpha 6 subunit (GoH3), GB3 an antibody for nicein, and LH7.2, an anticollagen type VII antibody. All 10 patients with junctional epidermolysis bullosa showed markedly reduced or no immunoreactivity with G71. These patients included two with GB3-positive junctional epidermolysis bullosa associated with pyloric atresia, and four with other subtypes. By contrast, five patients with dystrophic epidermolysis bullosa and one patient with epidermolysis bullosa simplex showed normal immunoreactivity with G71. In this study, G71 is shown to have a high specificity and sensitivity for the diagnosis of junctional epidermolysis bullosa. Immunoreactivity with 3E1 and GoH3 was normal in most patients, consistent with published reports showing normal immunoreactivity with other beta 4 and alpha 6 subunit antibodies. The data suggest a modification of the beta 4 subunit of integrin alpha 6 beta 4 at the dermo-epidermal junction in junctional epidermolysis bullosa.

Antibodies↗