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D R Johns

Publications and source records attributed to D R Johns.

At least 37 records · Page 2Linked to original sources
PubMed1996

Clinical spectrum of mitochondrial diseases.

Mitochondrial diseases include myopathies and multisystem disorders. They are characterized by morphologic and biochemical abnormalities of mitochondria. Their genetic characteristics-maternal inheritance, heteroplasmy, mitotic segregation, and threshold effect-are unique. The clinical phenotypes are considerably heterogeneous, but the clinical presentation in many cases is characteristic or suggestive. We review the clinical features of the most prevalent mitochondrial encephalomyopathy syndromes, their molecular genetic basis, isolated clinical symptoms, and uncommon presentations. Molecular genetic diagnosis is available for the common syndromes and has revolutionized their diagnosis. Future therapeutic advances, based on the precise genetic etiology, are anticipated. Mitochondrial dysfunction may be a more frequent pathogenetic mechanism than the prevalence of the classic mitochondrial syndromes would indicate, as there is an association between the accumulation of mitochondrial DNA mutations in postmitotic tissues and neurologic and systemic degenerative diseases.

Animals↗
PubMed1995

The ophthalmologic manifestations of mitochondrial disease.

The cardinal eye manifestations of mtDNA diseases are ophthalmoplegia, optic neuropathy, and pigmentary retinopathy. A number of other eye structures may also be affected in these disorders and the ophthalmologist is in a unique position to detect and interpret these findings. The presence of these ophthalmologic manifestations may be the first clue that the patient has an underlying mitochondrial disease with the eye as the initial or most prominently affected organ. The phenotypic manifestations of mitochondrial disease are protean and variable, and there are no clear-cut, minimal features that define these disorders. The possibility of a mitochondrial disorder should be raised when any of the mitochondrial eye manifestations (Table 1) are present, either alone or in concert with the neurological and systemic (Table 2) manifestations of mitochondrial disease. A maternal family history of an ophthalmologic, neurological, or systemic illness is also compatible with a mitochondrial disorder. The ophthalmologist should not loose sight of the fact that mitochondrial disorders have systemic manifestations and implications, even when the primary manifestations are ocular. Detection of and proactive intervention into comorbid features (eg, diabetes mellitus, hearing loss, heart block) is an important component.

DNA Mutational Analysis↗
PubMed1995

MR of the brain in mitochondrial myopathy.

PURPOSE: To determine the spectrum of MR findings in patients with mitochondrial myopathy and correlate them with central nervous system symptoms and signs. METHODS: We performed a prospective evaluation of the MR findings of eight patients with mitochondrial myopathy (three with Kearns-Sayre syndrome and five with chronic progressive external ophthalmoplegia), six of whom had central nervous system symptoms or signs (ataxia, sensorineural hearing loss, or cognitive dysfunction). RESULTS: All six patients with neurologic symptoms or signs had multiple abnormal MR findings, whereas patients without neurologic symptoms had either normal MR findings (one patient) or the solitary finding of cortical atrophy (one patient). Abnormal MR findings consisted of cerebral cortical atrophy (seven patients), cerebellar atrophy (six patients), and hyperintense signal abnormalities on T2-weighted images within the cerebral white matter (three patients), cerebellar white matter (one patient), basal ganglia (three patients), brain stem (one patient), and thalamus (one patient). In two patients, the cerebral white matter signal abnormalities were primarily peripheral and involved the arcuate fibers. All patients with ataxia had abnormal cerebellar findings on MR imaging, but there was poor correlation between other neurologic features and MR findings. CONCLUSIONS: Cerebral and cerebellar atrophy are the most common MR findings in Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia. White matter and deep gray nuclei abnormalities, presumed to result from the diffuse spongiform encephalopathy reported in these patients, can also be seen. Patients with abnormal neurologic findings typically have multiple abnormalities on MR imaging, which frequently do not correlate with specific symptoms.

Adult↗
PubMed1994

Cuban epidemic optic neuropathy. Mitochondrial DNA analysis.

OBJECTIVE: To search for mitochondrial DNA (mtDNA) mutations previously associated with Leber's hereditary optic neuropathy (LHON) in patients with an optic neuropathy that appeared in epidemic form in Cuba. METHODS: Twelve Cuban patients underwent a comprehensive neuro-ophthalmologic examination and were found to have a characteristic optic neuropathy, Cuban epidemic optic neuropathy (CEON). At the same time, one patient was diagnosed with typical LHON that occurred during the epidemic. Blood samples were taken from these patients as well as from 3 controls with normal neuro-ophthalmologic examinations. These samples were blindly analyzed for 9 LHON-associated mtDNA mutations by molecular genetic methods. RESULTS: CEON bore clinical and epidemiological similarity to LHON, however, family histories, systemic symptoms (especially weight loss and polyuria), and symptoms of peripheral neuropathy permitted a clinical distinction. None of the 12 patients with CEON or 3 controls had any of the LHON-associated mtDNA mutations. Only the patient with clinical LHON, who did not meet the case definition for CEON, harbored the 11778 mtDNA mutation. CONCLUSIONS: Known mtDNA mutations are not found frequently in CEON patients but they may contribute to some cases of Cuban optic neuropathy. CEON may represent an acquired variety of mitochondrial dysfunction induced by nutritional deficiencies, toxins, or both. Alternatively, CEON patients may also harbor as yet undiscovered mtDNA mutations that contribute to their genetic susceptibility.

Cuba↗
PubMed1994

Mitochondrial DNA mutations in Cuban optic and peripheral neuropathy.

OBJECTIVE: To investigate the potential role of mitochondrial DNA (mtDNA) mutations in the recent outbreak in Cuba of optic neuropathy and peripheral neuropathy (COPN). DESIGN AND METHODS: Historical features were reviewed and neuro-ophthalmologic examinations were performed on a sample of COPN patients (n = 9) and Cuban patients with other forms of optic neuropathy (n = 2). Molecular genetic methods were then used to test for the presence of 9 mtDNA mutations that were previously associated with Leber's hereditary optic neuropathy (LHON). RESULTS: Two (22%) of 9 COPN patients harbored an LHON-associated mtDNA mutation at nucleotide position 9438 and a novel mutation at nucleotide position 9738 in the cytochrome c oxidase subunit III gene. None of the Cuban patients harbored any of the 8 other LHON-associated mtDNA mutations. Detailed sequence analysis revealed that the Cuban patients could be divided into 7 distinct mtDNA haplotypes and that the 2 COPN patients with mtDNA mutations in the cytochrome c oxidase subunit III gene were not members of the same maternal lineage. CONCLUSIONS: The pathogenesis of epidemic COPN is likely complex and multifactorial. Our preliminary results in a small sample of Cuban patients suggest that mtDNA mutations may play a role in some cases. mtDNA mutations may render an individual genetically susceptible to a variety of factors that impair oxidative phosphorylation, including nutritional deficiency, tobacco, alcohol, and other toxins.

Adult↗
PubMed1993

Cytochrome c oxidase mutations in Leber hereditary optic neuropathy.

New mitochondrial DNA mutations were discovered in the cytochrome c oxidase subunit III gene in 8 independent Leber hereditary optic neuropathy probands. A mutation at nucleotide position 9438 was found in 5 probands, changed highly conserved glycine-78 to serine (G78S), and was not found in controls. A mutation at nucleotide position 9804 was found in 3 probands, changed highly conserved alanine-200 to threonine (A200T), and also was not found in controls. The 9438 mutation is readily detected by the loss of a Stu 1 restriction site and the 9804 mutation is detected by the gain of an Mae III restriction site. These mtDNA mutations may represent the first convincing examples of cytochrome c oxidase (Complex IV) mutations associated with a human disease.

Amino Acid Sequence↗
PubMed1993

Atypical Leber's hereditary optic neuropathy with molecular confirmation.

OBJECTIVE: Leber's hereditary optic neuropathy (LHON) is typically a familial disease of primarily young, male adults. Analysis of mitochondrial DNA has identified point mutations associated with LHON and allowed us to identify cases of LHON not consistent with traditional descriptions of the disease. DATA SOURCES: The collective experience of three tertiary referral centers contributed to this report. STUDY SELECTION: Patients with bilateral optic neuropathies who were positive for the 11778 LHON mutation were included in this study if they were female and there was no family history of visual loss. DATA EXTRACTION: Six case histories are presented. DATA SYNTHESIS: The diagnosis of LHON remained unknown in six female patients with bilateral optic neuropathies until molecular analysis revealed the 11778 mitochondrial DNA mutation. None of the patients had a family history of visual loss, and five were initially diagnosed as having factitious visual loss. Other individual features atypical for LHON included lack of the characteristic LHON funduscopic appearance, bitemporal hemianopia, optic disc cupping, and premonitory episodes of transient visual loss. In one patient the correct diagnosis was delayed 17 years. CONCLUSIONS: The diagnosis of LHON should be considered in all cases of unexplained optic neuropathy, including those with negative family history, late or early age at onset, female gender, or normal funduscopic appearance.

Adult↗
PubMed1993

Leber's hereditary optic neuropathy. Clinical manifestations of the 14484 mutation.

OBJECTIVE: To define the clinical features of Leber's hereditary optic neuropathy associated with the 14484 mitochondrial DNA mutation and to compare these features with those associated with three other pathogenetic mutations. DESIGN AND PATIENTS: Clinical and historical data were collected from 19 visually symptomatic patients from 17 independent pedigrees with the molecularly confirmed 14484 mutation. MAIN OUTCOME MEASURES: Demographic features, age of onset of visual loss, nadir of visual acuity, occurrence and timing of visual recovery, family history of visual loss, and associated medical and environmental conditions. RESULTS: Clinical characteristics associated with the 14484 mutation are similar overall to those of the three other primary mutations. One notable distinguishing feature is the higher incidence of visual recovery among patients with the 14484 mutation. Thirty-seven percent of our patients experienced visual recovery compared with 5% with the 11778 mutation (P < .001), 22% with the 3460 mutation, and 29% with the 15257 mutation. The average age of onset of visual symptoms for the patients with the 14484 mutation who had visual recovery was younger than for those without recovery (19.6 vs 30.6 years). Thirteen of the 19 patients had a history of metabolic disturbance, trauma, or substance abuse. CONCLUSIONS: Leber's hereditary optic neuropathy associated with the 14484 mitochondrial DNA mutation may have a better prognosis for visual recovery. The phenotypic expression of the 14484 mutation may be influenced by concurrent medical and environmental factors. Molecular genetic testing in suspected Leber's hereditary optic neuropathy is useful to confirm the diagnosis and to assess visual prognosis.

Adolescent↗
PubMed1993

Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes.

Recent advances in molecular genetics have led to a better understanding of mitochondrially inherited diseases. Mitochondrial encephalomyopathy overlap syndrome is one such group of diseases in which ocular abnormalities are frequently manifest. The authors describe the clinical, molecular genetic, and pathologic findings of two patients with the mitochondrial encephalomyopathy overlap syndrome. The patients shared a similar clinical course with features overlapping the three traditionally distinct clinical phenotypes (the Kearns-Sayre syndrome; the syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke [MELAS], and the syndrome of myoclonus, epilepsy, and ragged red fibers [MERRF]). The patients had identical mitochondrial DNA mutations (at nucleotide position 3243) and had similar ultrastructural abnormalities, including abundant enlarged mitochondria with "whorled" and "tubular" cristae. These abnormal mitochondria appeared to be preferentially distributed in cells with high metabolic activity (retinal pigment epithelium, corneal endothelium, and extraocular muscles).

Abnormalities, Multiple↗
PubMed1993

Leber's hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia.

OBJECTIVE: To determine the frequency of known primary mitochondrial DNA (mtDNA) mutations for Leber's hereditary optic neuropathy (LHON) in patients previously diagnosed as having tobacco-alcohol amblyopia. DESIGN: A case series of 12 patients with tobacco-alcohol amblyopia. Follow-up ranged from 2 months to 15 years. SETTING: Tertiary care. PATIENTS: Twelve patients diagnosed as having tobacco-alcohol amblyopia, based on the classic clinical presentation, were tested for all the known primary mtDNA mutations associated with LHON. All patients had a history of heavy alcohol or tobacco use or both. Twelve other patients who fit inclusion criteria were unable to be contacted or refused to participate in the study. MAIN OUTCOME MEASURES: Presence of a known primary mutation for LHON at nucleotide positions 11778, 3460, 15257, or 14484 of mtDNA. RESULTS: Two (17%) of 12 patients previously diagnosed as having tobacco-alcohol amblyopia tested positive for known LHON genetic mutations, one for the 11778 mutation and one for the 3460 mutation. CONCLUSIONS: The diagnosis of LHON should be considered in all patients diagnosed as having tobacco-alcohol amblyopia, particularly those with visual acuities of 20/200 or less. The availability of molecular genetic testing for LHON now allows confirmation of the diagnosis of LHON in patients who otherwise may be misdiagnosed.

Adult↗
PubMed1993

Heteroplasmy in Leber's hereditary optic neuropathy.

OBJECTIVES: To determine the incidence and clinical significance of peripheral blood heteroplasmy and the presence of normal and mutant mitochondrial DNA in Leber's hereditary optic neuropathy through evaluation of a large series of families with the 11778 mutation and to evaluate the pattern of transmission of heteroplasmy. DESIGN: We studied heteroplasmy in 75 visually symptomatic patients with the 11778 mutation and in 101 asymptomatic family members. We compared the incidence of heteroplasmy in these two groups, collected clinical information for each symptomatic patient, and calculated the incidence of heteroplasmy within each generation of the pedigrees. RESULTS: We detected heteroplasmy in 24 (14%) of the 176 persons tested. Kaplan-Meier life-table analysis suggests that heteroplasmic persons are more likely to remain asymptomatic than those who are homoplasmic mutant (males, P = .17; females, P = .14). However, heteroplasmic persons who become symptomatic do not seem to differ clinically from symptomatic patients who are homoplasmic mutant. Pedigree analysis reveals a strong tendency for progression from heteroplasmy toward homoplasmy in subsequent generations (P = .001). CONCLUSION: Heteroplasmy for the 11778 mutation seems to play a role in the clinical expression of Leber's hereditary optic neuropathy and tends to progress toward homoplasmy in successive generations.

Adolescent↗
PubMed1993

Identical twins who are discordant for Leber's hereditary optic neuropathy.

OBJECTIVE: Leber's hereditary optic neuropathy is a maternally inherited form of visual loss that is associated with several mitochondrial DNA mutations. These mitochondrial DNA mutations are not the sole determinants of visual loss, as epigenetic factors may play a pathogenetic role. To clarify the role of these factors, we studied two visually discordant twins and determined their zygosity and mitochondrial genotype. DESIGN: Case series. SETTING: Referral center. PATIENTS: Identical twin brothers from a family with the 11778 mitochondrial DNA mutation. MAIN OUTCOME MEASURES: Visual acuity, results of testing for visual fields (measured with static and dynamic perimetry) and color vision, and results of funduscopic examination; alcohol and tobacco use, head trauma, co-existent medical illness, and occupational exposure; and results of mitochondrial DNA analysis and determination of zygosity. RESULTS: The monozygous twin brothers have remained discordant for the development of optic neuropathy for 6 1/2 years despite harboring the identical homoplasmic 4216, 13708, and 11778 mitochondrial DNA mutations. CONCLUSIONS: The patients are visually discordant despite being genetically identical at the nuclear and mitochondrial levels. Epigenetic factors are important determinants of visual loss in Leber's hereditary optic neuropathy in these brothers. Among those factors studied in these patients, a substantial difference was noted in regard to occupational exposure to toxic substances. Epigenetic factors that may influence the clinical expression of the mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy should be systematically studied. Risk-factor intervention strategies should be formulated and implemented.

Adult↗
PubMed1993

A maculopathy associated with the 15257 mitochondrial DNA mutation.

OBJECTIVE: To report a new retinal finding associated with the mitochondrial DNA mutation at nucleotide position 15257, a primary mutation associated with Leber's hereditary optic neuropathy. DESIGN AND PATIENTS: Clinical and historical data were collected for 24 visually symptomatic patients from 20 independent pedigrees with the 15257 mutation. RESULTS: Fundoscopic examination in three patients who presented with acute, bilateral visual loss revealed retinal pigment epithelial changes in the maculae accompanied by normal-appearing optic discs. The conditions of two of these patients were initially diagnosed as Stargardt's disease, and subsequent molecular genetic analysis revealed the presence of the 15257 mutation. The third patient underwent molecular genetic analysis several months after presenting with a presumed maculopathy. Two of the patients also demonstrated evidence of a concurrent optic neuropathy. CONCLUSIONS: The association of macular changes with Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation has not been previously reported. The mitochondrial DNA mutation at nucleotide position 15257 may cause a maculopathy as well as the typical optic neuropathy usually seen in Leber's hereditary optic neuropathy. A subset of patients whose conditions were diagnosed as Stargardt's disease may harbor a mitochondrial DNA mutation. These three cases illustrate the importance of molecular genetic testing in some atypical cases of optic neuropathies and maculopathies.

Adolescent↗