Immunohistochemical evidence of indolamine neurons in monkey spinal cord.

In this study, we have identified over 150 cells in the adult macaque spinal cord that are immunoreactive when stained with an antibody to 5-HT by means of the PAP method. The staining was blocked by preabsorption of the primary antibody by the 5-HT-BSA conjugate (used to generate the antibody) and by 5-HT, while BSA, dopamine, norepinephrine, 5-methoxytryptamine and tryptamine preabsorption did not block staining. In addition, the Falck-Hillarp histofluorescence technique was applied to the lumbosacral cord from one of the three monkeys studied; results confirm the presence of cells with yellow fluorescence and rapid fading to brown characteristic for serotoninergic cells. The neuronal identity of these immunoreactive cells is based on light and electron microscopic morphology and the presence of synaptic terminals in contact with labeled somata and dendrites. Most of these neurons were small (10-25 micrometers) and located ventral to the central canal in lamina X. Some processes of the cells extended into the intermediate gray and the ventromedial area of the ventral horn; other processes wrapped around large blood vessels in lamina X or around the wall of the central canal. Cells were most frequent in the cervical cord (approximately 6-7/mm length of cord) and less frequent in the thoracic (1.5/mm), lumbar (3/mm), and sacral (2/mm) cord. A few cells were also found in the marginal and gelatinosa regions of the dorsal horn of the sacral cord. Examination of sections from the medulla-spinal cord junction (obex level) indicates that the spinal cells may be an extension of cell groups located near the raphe obscurus in the gray region around the IVth ventricle. The indolamine spinal cells may act as interneurons in spinal circuits, control spinal blood flow through vessel innervation, or play a role in CSF composition through central canal innervation.

Benign sexual headache within a family.

The occurrence of the vascular type of benign sexual headache (BSH) is described within members of a family. The most severely affected of the four sisters was successfully treated with propranolol hydrochloride prophylaxis. The literature on headache related to sexual activity is reviewed and the clinical features of BSH are formulated. The familial occurrence is put forth as further evidence to consider the vascular type of BSH as a migraine variant.

Pure motor hemiplegia due to meningovascular neurosyphilis.

Two young male homosexuals developed prodromal syndrome followed by penicillin-responsive meningitis and the acute onset of pure motor hemiplegia. The clinical and laboratory features are consistent with meningovascular neurosyphilis. Basis pontis infarctions were subsequently demonstrated on magnetic resonance imaging scans. To our knowledge, this is the first description of syphilitic arteritis as a pathophysiologic basis for pure motor hemiplegia.

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.

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.

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.

Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease.

OBJECTIVE: To identify mitochondrial DNA (mtDNA) mutations that predispose to PD. BACKGROUND: Mitochondrial complex I activity is deficient in PD. mtDNA mutations may account for the defect, but the specific mutations have not been identified. METHODS: Complete sequencing was performed of all mtDNA-encoded complex I and transfer RNA (tRNA) genes in 28 PD patients and 8 control subjects, as well as screening of up to 243 additional PD patients and up to 209 control subjects by restriction digests for selected mutations. RESULTS: In the PD patients, 15 complex I missense mutations and 9 tRNA mutations were identified. After screening additional subjects, rare PD patients were found to carry complex I mutations that altered highly conserved amino acids. However, no significant differences were found in the frequencies of any mutations in PD versus control groups. The authors were unable to confirm previously reported associations of mutations at nucleotide positions (np) 4336, 5460, and 15927/8 with PD. Complex I mutations previously linked to Leber's hereditary optic neuropathy, one of which has been linked to atypical parkinsonism, were not associated with PD. CONCLUSIONS: mtDNA mutations with a high mutational burden (present in a high percentage of mtDNA molecules in an individual) in complex I or tRNA genes do not play a major role in the risk of PD in most PD patients. Further investigations are necessary to determine if any of the rare mtDNA mutations identified in PD patients play a role in the pathogenesis of PD in those few cases.

Sensory ataxic neuropathy as the presenting feature of a novel mitochondrial disease.

Four unrelated patients presented with a severe sensory ataxic neuropathy in association with dysarthria and chronic progressive external ophthalmoplegia. Electrophysiologic and pathologic studies showed severe axonal loss disproportionately affecting sensory nerves. Molecular genetic analysis revealed multiple mitochondrial DNA deletions in muscle and peripheral nerve. Sensory ataxic neuropathy may be the predominant and presenting manifestation of a mitochondrial disorder, and a mitochondrial etiology should be included in its differential diagnosis. The triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) may represent a novel mitochondrial disease associated with multiple mitochondrial DNA deletions.

Expanding the phenotype of the 8344 transfer RNAlysine mitochondrial DNA mutation.

The A-to-G mutation at position 8344 in the transfer RNAlysine mitochondrial DNA gene is associated mostly with the myoclonic epilepsy and ragged red fibers syndrome. We describe a five-generation family with this mutation and 19 affected members with a variant neurologic syndrome of ataxia, myopathy, hearing loss, and neuropathy. Along with axial lipomas and diabetes mellitus, hypertension is a frequent somatic feature, suggesting that mitochondrial mutations may contribute to hypertension in these patients.

Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation.

OBJECTIVE: To investigate a family with maternally inherited, adult-onset multisystem degeneration including prominent parkinsonism to determine whether clinical features can result from a mitochondrial DNA (mtDNA) mutation. The parkinsonism was levodopa responsive and was associated with the loss of pigmented neurons in the substantia nigra in at least one patient. BACKGROUND: Mitochondrial dysfunction is hypothesized to play a role in late-onset neurodegenerative diseases including PD and AD. Mitochondrial genetic mutations are hypothesized to account for these defects, but attempts to identify specific mtDNA mutations have been inconclusive. METHODS: Clinical examinations, DNA sequencing, and restriction digestion and biochemical analyses were performed. RESULTS: Maternal relatives harbor a G-to-A missense mutation, heteroplasmic in some patients, at nucleotide position 11778 of the mitochondrial ND4 gene of complex I that converts a highly conserved arginine to a histidine. Sequencing of the entire mitochondrial genome in an affected family member reveals no other mutations likely to be pathogenic. This mutation has been identified previously only in families with Leber's hereditary optic neuropathy-a disorder also linked to complex I dysfunction but usually limited clinically to optic atrophy. CONCLUSIONS: These data reveal previously unsuspected clinical heterogeneity of the G11778A mutation, and suggest that an inherited mtDNA mutation can contribute to the development of adult-onset parkinsonism and multisystem degeneration.

Rapid response to acyclovir in herpes zoster-associated encephalitis.

A previously healthy patient became acutely encephalopathic, with complete disorientation and amnesia, several days after the onset of thoracic herpes zoster. She had transiently abnormal electroencephalographic results, abnormalities on radionuclide brain scanning, and cerebrospinal fluid pleocytosis. There was no evidence of a toxic/metabolic encephalopathy except for a mildly elevated ammonia level. Intravenously administered acyclovir (30 mg/kg per day) induced a dramatic response, with complete resolution of the encephalopathy within 72 hours and normalization of the electroencephalographic results. The scant clinical experience with the successful use of acyclovir in the treatment of herpes zoster-associated encephalitis is reviewed.

Mitochondrial neurogastrointestinal encephalomyopathy: diagnosis by rectal biopsy.

A 14-year-old girl with the mitochondrial neurogastrointestinal encephalopathy syndrome had an 8-year history of intestinal pseudoobstruction with abdominal pain, persistent vomiting, gastric and duodenal dilatation, and duodenal diverticulosis. The child appeared chronically malnourished and had severe growth failure. Multisystem involvement was evident with the presence of ptosis, external ophthalmoplegia, muscle wasting, peripheral neuropathy, and diffuse white matter disease seen on magnetic resonance imaging. Lactic acidosis and increased cerebrospinal fluid protein were observed. Mitochondrial enzyme analysis of fresh-frozen skeletal muscle revealed a respiratory chain defect. Molecular genetic studies showed multiple mitochondrial DNA deletions. Pathologic findings in the intestine included atrophy of the external layer of the muscularis propria and an increased number of abnormal-appearing mitochondria in ganglion and smooth-muscle cells. Microvesicular steatosis was observed in liver, skeletal, and gastrointestinal smooth muscle, and Schwann cells of peripheral nerve. Brightly eosinophilic inclusions in the cytoplasm of gastrointestinal ganglion cells were visible by light microscopy, which were confirmed to be megamitochondria by ultrastructural studies. This is the first report of abnormal mitochondria observed in intestinal ganglion and smooth-muscle cells in this syndrome.

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.

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.

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.

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.

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.

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.

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).