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Biomedical subjects

D R Johns

Publications and source records attributed to D R Johns.

At least 55 records · Page 3Linked to original sources
PubMed1993

Leber's hereditary optic neuropathy. Clinical manifestations of the 15257 mutation.

BACKGROUND: Leber's hereditary optic neuropathy is associated with four known pathogenetic mutations of mitochondrial DNA (mtDNA) at nucleotide positions (np) 11778, 3460, 15257, and 14484. METHODS: The authors collected clinical data from 12 visually symptomatic patients from seven different pedigrees with the 15257 mutation and compared these data with previously published clinical features of the 11778 and 3460 mutations. RESULTS: The authors' results indicate that these three groups of patients are similar in most clinical characteristics evaluated. However, patients with the 15257 mutation are more likely to experience significant recovery of visual acuity than patients with the 11778 mutation (25% versus 4% of eyes; P < 0.001). Patients with the 15257 mutation who also have an associated mutation at np 15812 are less likely to recover vision than those without this association (P = 0.001). Patients with the 15257 mutation also have a higher incidence of spinal cord and peripheral neurologic symptoms (42%) than patients with the other pathogenetic mutations. CONCLUSIONS: The phenotypic expression of the 15257 mutation differs from the 11778 and 3460 mutations and is affected by the presence of an associated mutation at np 15812. This is the first clinical evidence to support the concept of multiple simultaneous mtDNA mutations producing additive deleterious effects in patients with Leber's hereditary optic neuropathy. The clinical differences between the various genotypes associated with Leber's hereditary optic neuropathy have implications for risk factor management and visual prognosis and, thus, underscore the importance of molecular genetic testing in patients with suspected Leber's hereditary optic neuropathy.

Adolescent↗
PubMed1993

MELAS syndrome masquerading as herpes simplex encephalitis.

Herpes simplex encephalitis (HSE) is commonly treated empirically with acyclovir without confirmatory brain biopsy. Three consecutive adults with molecularly verified mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome presented with, and were treated for, apparent HSE. MELAS syndrome in adults may present as an atypical, recurrent form of HSE and should be added to the list of neurologic diseases that can mimic HSE.

Adolescent↗
PubMed1993

Association of the 11778 mitochondrial DNA mutation and demyelinating disease.

Leber's hereditary optic neuropathy is a maternally inherited disorder most commonly associated with a mitochondrial DNA mutation at nucleotide position 11778. We report four patients, including a man and a black woman, with the 11778 mutation, who have optic neuropathy and clinical or paraclinical evidence of demyelinating disease. These data support an association of this mitochondrial DNA mutation with demyelinating disease that has a marked female predominance.

Adult↗
PubMed1993

Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON).

Pathogenetic mutations in mtDNA are found in the majority of patients with Leber hereditary optic neuropathy (LHON), and molecular genetic techniques to detect them are important for the diagnosis. A false-positive molecular genetic error has adverse consequences for the diagnosis of this maternally inherited disease. We found a number of mtDNA polymorphisms that occur adjacent to known LHON-associated mutations and that confound their molecular genetic detection. These transition mutations occur at mtDNA nt 11779 (SfaNI site loss, 11778 mutation), nt 3459 (BsaHI site loss, 3460 mutation), nt 15258 (AccI site loss, 15257 mutation), nt 14485 (mismatch primer Sau3AI site loss, 14484 mutation), and nt 13707 (BstNI site loss, 13708 mutation). Molecular genetic detection of the most common pathogenetic mtDNA mutations in LHON, using a single restriction enzyme, may be confounded by adjacent polymorphisms that occur with a false-positive rate of 2%-7%.

Base Sequence↗
PubMed1992

An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy.

A mitochondrial DNA mutation at nucleotide position 14,484 was found in 14 independent probands with Leber hereditary optic neuropathy and in 0/250 controls. The 14,484 mutation, which changes methionine-64 to valine in a conserved domain of the ND-6 gene, occurred in association with a mitochondrial DNA haplotype that includes the 13,708 secondary mutation in 10/14 probands. An associated mutation at nucleotide position 3,394, which changes conserved tyrosine-30 to histidine in the ND-1 gene, was observed in 5/14 probands positive for the 14,484 mutation, all of whom harbored the same mitochondrial DNA haplotype. Multiple mitochondrial DNA mutations may interact in the pathogenesis of Leber hereditary optic neuropathy and the 13,708 secondary mutation appears to play a central role in this process.

Base Sequence↗
PubMed1992

Ophthalmic involvement in myo-neuro-gastrointestinal encephalopathy syndrome.

We studied the clinical, histopathologic, neuroradiologic, biochemical, and genetic profile of a patient with the myo-neuro-gastrointestinal encephalopathy syndrome, a recently described multisystem mitochondriopathy characterized by blepharoptosis and ophthalmoparesis. The patient had severe intestinal pseudo-obstruction and a mixed demyelinating and axonal neuropathy. Abnormal collections of mitochondria in nerve and muscle as well as diffuse white matter disease were present. Cytochrome oxidase activity in muscle mitochondria was reduced. No mitochondrial DNA deletions were detected.

Adult↗
PubMed1992

Leber's hereditary optic neuropathy. Clinical manifestations of the 3460 mutation.

Leber's hereditary optic neuropathy is associated with three different point mutations of mitochondrial DNA that appear to be pathogenetic for the disease. These mutations affect nucleotide positions 3460, 11,778, and 15,257. We reviewed the clinical characteristics of 12 visually symptomatic patients from nine families with the 3460 mutation and compared them with previously published characteristics of symptomatic patients with the 11,778 mutation. The patients with the 3460 mutation were similar to the patients with the 11,778 mutation in most clinical parameters. However, the patients with the 3460 mutation had a higher incidence of visual recovery (20% vs 4%, P = .001), a higher percentage of pedigrees with more than one affected family member (78% vs 43%, P = .011), and a greater frequency of tobacco and alcohol abuse. The difference in visual prognosis between these two mutations and the need for modification of possible risk factors provide added significance to genetic testing for Leber's hereditary optic neuropathy.

Adolescent↗
PubMed1992

Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation.

Five patients with Leber's hereditary optic neuropathy (LHON) and the 11778 mitochondrial mutation spontaneously recovered 20/40 or better visual acuity in at least one eye after months to years of legal blindness. The patients ranged in age from 9 to 45 years, and the duration of visual loss before recovery ranged from several months to 5.9 years. These patients constitute only about 4% of the 136 affected LHON patients we have studied who also had the 11778 mutation in their mitochondrial DNA. Thus, even though the visual prognosis for most patients with LHON and the 11778 mutation is poor, a few individuals do recover near-normal vision in at least one eye even years after the initial visual loss.

Adolescent↗
PubMed1991

Cytochrome b mutations in Leber hereditary optic neuropathy.

New mutations were discovered in the apocytochrome b gene in Leber hereditary optic neuropathy probands who did not harbor either of the two known Complex I mutations (positions 3,460 and 11,778). A mutation at position 15,257 was found in eight independent probands which changed a highly conserved aspartate to asparagine, was not found in controls, and appears to be pathogenetically significant. The 15,257 mutation occurred in association with a known synergistic mutation at position 13,708 in 7/8 probands and in association with a new apocytochrome b mutation at position 15,812 in 4/8 probands. Mutations in Complex III genes may be involved in Leber hereditary optic neuropathy and multiple, simultaneous mutations occur frequently.

Amino Acid Sequence↗
PubMed1991

Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy has been linked to a mitochondrial DNA mutation at position 11,778 in the ND-4 gene in 50% of families. Three alternative mutations in Complex I genes at positions 4,216 (ND-1), 4,917 (ND-2), and 13,708 (ND-5) were discovered in 11,778- Leber families. The 4,917 and 13,708 mutations appear pathogenetically significant and were observed in 36% (4,917 mutation) and 43% (13,708 mutation) of 11,778- Leber probands. Multiple, simultaneous mutations were noted. Mutation of distinct, functionally related Complex I genes is the central pathogenetic feature of Leber's hereditary optic neuropathy.

Amino Acid Sequence↗
PubMed1991

Molecular insight into the asymmetric distribution of pathogenetic human mitochondrial DNA deletions.

Pathogenetic human mitochondrial DNA deletions occur very rarely in the minor region between the origins of replication. In order to understand the molecular basis of this asymmetry, we analyzed the structure of such a 4.680 kilobase deletion (position 471 - 5151). Directly repeated sequences (12/13 nucleotides) are present in the deletion junction, both promoters of heavy chain replication and both ribosomal RNA genes are deleted, and the 5' extent further narrows the absolute limits of mitochondrial DNA deletions. Several factors are identified that may contribute to the paucity of minor region deletions.

Base Sequence↗
PubMed1991

Cerebrovascular complications of inflammatory bowel disease.

There is an increased incidence of central nervous system thromboembolic events in young patients with inflammatory bowel disease. A 33-yr-old woman previously diagnosed with pseudotumor cerebri suffered superior sagittal and transverse sinus thromboses during a severe flare of ulcerative colitis. These were documented on contrast computed tomographic (CT) and magnetic resonance imaging (MRI) scans. Stroke may be more common in patients with ulcerative colitis than in patients with Crohn's disease; arterial disease is more prevalent than venous and dural sinus disease, and is correlated with an active phase of inflammatory bowel disease. It is difficult to assess whether there is a relationship to concurrent steroid use, and a consistent relationship to duration of inflammatory bowel disease or to other extraintestinal manifestations is not apparent.

Acute Disease↗
PubMed1990

Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy.

Albright's hereditary osteodystrophy is an autosomal dominant disorder characterized by a short stature, brachydactyly, subcutaneous ossifications, and reduced expression or function of the alpha subunit of the stimulatory G protein (Gs alpha) of adenylate cyclase, which is necessary for the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger. We identified a unique Gs alpha protein in erythrocytes from two related patients with Albright's hereditary osteodystrophy and reduced Gs alpha bioactivity. The Gs alpha variant was recognized by a carboxyl terminal-specific Gs alpha antiserum but not by polyclonal antiserums specific for the amino terminus of Gs alpha. To investigate the molecular basis for this structurally abnormal Gs alpha protein, we studied the Gs alpha gene by restriction-endonuclease analysis. DNA from the two patients had an abnormal restriction-fragment pattern when digested with Ncol, which was consistent with loss of an Ncol restriction site in exon 1 of one Gs alpha allele. Amplification of a 260-base-pair region that includes exon 1 of the Gs alpha gene and direct sequencing of the amplified DNA revealed an A-to-G transition at position +1 in one Gs alpha allele from each of the two patients. This mutation converts the initiator ATG (methionine) codon to GTG (valine), blocking initiation of translation at the normal site. Translation of the abnormal Gs alpha messenger RNA would result in the synthesis of a truncated Gs alpha molecule lacking the amino terminus. We conclude that in at least some patients with Albright's hereditary osteodystrophy, the disease is caused by a single-base substitution in the Gs alpha gene and is thus due to an inherited mutation in a human G protein.

Adenylyl Cyclases↗