The prevalence of faecal incontinence in myotonic dystrophy type 1.

Faecal incontinence is recognised as a feature of myotonic dystrophy along with other symptoms of bowel dysfunction, but its prevalence is poorly defined. We have surveyed 152 unselected myotonic dystrophy patients. We identified issues with bowel control in 104 (68% of the study population). Forty-eight (32%) reported faecal incontinence in the 4 weeks prior to completion of the questionnaire. Fifty-six patients (37%) reported having to change their lifestyle because of incontinence issues at some point in the prior 4 weeks. This study shows a high frequency of life-changing symptoms in a large unselected, cohort of patients with myotonic dystrophy type 1, and highlights lower gastrointestinal symptoms as an important issue for further research.

Assessment of sleep studies in myotonic dystrophy.

Myotonic dystrophy (MD) is the commonest adult muscular dystrophy and is associated with respiratory muscle weakness. The role of screening sleep studies is unclear in MD. We prospectively evaluated polysomnography/overnight oximetry in a group of MD patients and related this to the daytime respiratory function in an attempt to evaluate the usefulness of screening sleep studies. Twenty-five patients with type I MD [15 males; mean age (SD) 40.0 (10.9) years] who had at least one symptom suggestive of nocturnal hypoventilation were included in the study. We performed spirometry, maximal inspiratory and expiratory mouth pressures, sniff nasal inspiratory pressure, arterial blood gases and polysomnography or overnight oximetry. Excessive tiredness and sleepiness were the most common presenting symptoms. Prevalence of sleep related breathing disorder (SRBD) was 36%. FVC was found to be normal in 33% of subjects with significant SRBD. Mouth pressures were reduced more than FVC, even in patients with normal overnight oxygen saturation. Of all the daytime measures, FVC correlated best with arterial carbon dioxide tension (r = -0.7). Sleep studies were useful to identify a small group of myotonic dystrophy patients (12%, three out of 25 in our series) with SRBD that would have been missed with routine daytime assessments. Targeted sleep monitoring in patients who are older, with multiple symptoms suggestive of SRBD, especially if they are overweight seems to be the best way to utilize the existing resources. Home unattended oximetry was well tolerated and offers a practical screening tool in this challenging patient group where excess daytime sleepiness is often due to causes other than SRBD.

Catastrophic presentation of mitochondrial disease due to a mutation in the tRNA(His) gene.

The authors describe a patient who presented with headache, seizures, and severe cerebral edema in whom they identified a novel mutation in the mitochondrial (mt-) tRNA(His) gene. This G12147A transition is heteroplasmic, predicted to disrupt a highly conserved base pair, and segregates with the cytochrome c oxidase deficiency in single muscle fibers.

Muscle fibrillin deficiency in Marfan's syndrome myopathy.

OBJECTIVE: To report a family with Marfan's syndrome in whom a myopathy was associated with respiratory failure; muscle biopsies from affected individuals were examined to determine whether there were abnormalities in fibrillin. METHODS: 21 family members underwent detailed clinical examination, including neurological and pulmonary assessment. Muscle biopsies in the most severely affected cases were immunostained using monoclonal antibodies to specific fibrillin components. Genomic DNA from all 21 members was analysed for mutations in the fibrillin gene, FBN1, on 15q21. RESULTS: 13 individuals had a C4621T base change in exon 37 of the FBN1 gene, which in four cases segregated with muscle weakness or evidence of respiratory muscle dysfunction or both. Their muscle biopsies revealed an abnormality in fibrillin immunoreactivity. CONCLUSIONS: Abnormalities in fibrillin can be detected in muscle biopsies from patients with Marfan's syndrome who have myopathy. This pedigree, with a point mutation in FBN1, also draws attention to the potential for respiratory failure associated with myopathy.

The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls.

5- and 6-Hydroxydopamine, which we had earlier identified as naturally occurring amines in human urine, were quantified in Parkinson's patients treated with L-DOPA, Parkinson's patients whose treatment did not include L-DOPA and in age matched controls. Analysis was carried out by GC-MS of the ditrifluoromethylbenzoyl-trimethylsilyl (DTFMB-TMS) derivatives of the compounds. The concentrations of 5- and 6-hydroxydopamine in the urine of DOPA treated Parkinson's patients were significantly higher than the concentrations from patients not treated and from normal controls. Urinary dopamine levels were greatly elevated in DOPA treated Parkinson's patients while p-tyramine levels were suppressed. No marked differences were seen between the three groups in terms of the urinary concentrations of any of the other amines measured.

Brainstem encephalitis and the Miller Fisher syndrome.

A case is described of a man with an acute onset areflexic ataxic syndrome with partial ophthalmoparesis and normal limb muscle power. There was evidence of both a peripheral neuropathy and a brainstem encephalitis. The patient made a full recovery and the interrelationship and nosology of brainstem encephalitis and the Miller Fisher syndrome are discussed.

The neurological features of HIV-positive patients in Glasgow--a retrospective study of 90 cases.

A retrospective study of the neurological problems arising in HIV-I seropositive patients in a single defined geographical area was undertaken. Ninety patients were referred for a neurological opinion from a total known HIV-I seropositive population of 436. Minor problems were frequently encountered early in the course of disease (20 at CDC stage II, 12 at CDC stage III), including seizures related to drug abuse in six. The most frequent neurological problem in those patients in CDC group IV (58 patients) were the AIDS dementia complex (14 patients), an axonal sensorimotor neuropathy (12), toxoplasmosis (nine) and cryptococcal meningitis (three). All patients with a structural lesion had appropriate focal signs on examination. The value and role of CT cranial scanning in the diagnosis of toxoplasmosis is discussed and the importance of recognizing potentially treatable causes of both intellectual impairment and cytomegalovirus-related neuropathies is stressed. This is the first report of an unselected series of patients at all stages of HIV-I related neurological disease from a single UK centre.

A new mitochondrial disease associated with mitochondrial DNA heteroplasmy.

A variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy occurred in four members of a family and was maternally transmitted. There was no histochemical evidence of mitochondrial myopathy. Blood and muscle from the patients contained two populations of mitochondrial DNA, one of which had a previously unreported restriction site for AvaI. Sequence analysis showed that this was due to a point mutation at nucleotide 8993, resulting in an amino acid change from a highly conserved leucine to arginine in subunit 6 of mitochondrial H(+)-ATPase. There was some correlation between clinical severity and the amount of mutant mitochondrial DNA in the patients; this was present in only small quantities in the blood of healthy elderly relatives in the same maternal line.

Cerebellar cortical degeneration in association with small-cell carcinoma of the oesophagus.

We report the association of paraneoplastic cerebellar cortical degeneration with small-cell oesophageal carcinoma in a 60-year-old woman and describe the histopathological findings. We believe this to be the first report of such an occurrence. The cytoplasmic antigen PGP 9.5, which is strongly expressed in cerebellar Purkinje cells, was identified immunohistologically in the primary tumour and immunoglobulin demonstrated on Purkinje cells. These findings support an immunological pathogenesis for this condition and suggest that it is mediated by antibodies directed against tumour antigen which cross-react with Purkinje cells.

The cerebral metabolism of glucose and oxygen measured with positron tomography in patients with mitochondrial diseases.

Cerebral oxygen and glucose metabolism have been studied in 8 patients with biochemically defined mitochondrial myopathies and 7 normal control subjects using positron emission tomography. Four patients had myopathy alone and 4 had predominantly central nervous system (CNS) disease. Cerebral oxygen and glucose metabolism were measured concurrently in the two groups of patients with 15O, 11C and 18F labelled tracers and positron emission tomography (PET). Patients with major CNS disease showed an uncoupling of glucose and oxygen metabolism when compared with patients without cerebral disease and normal subjects. The mean ratio between oxygen and glucose utilization was 3.8 moles of oxygen per mole of glucose in patients with CNS disease, compared with 5.6 for controls and 6.4 for patients with myopathy alone. The altered stoichiometry in CNS cases indicates aerobic glycolysis to lactate and/or other intermediate metabolites. Patients with major CNS disease showed a 50% reduction in cerebral oxygen utilization compared with cerebrally unaffected patients and normal subjects. These findings indicate that in patients with a mitochondrial encephalopathy the defect identified in skeletal muscle is also expressed in the brain.

Mitochondrial myopathy: a genetic study of 71 cases.

Of 71 index cases with histologically defined mitochondrial myopathy, 13 (18%) had relatives who were definitely affected with a similar disorder. Eight familial cases from four families were confined to a single generation. In five families maternal transmission to offspring occurred. There were no instances of paternal transmission, but one patient had an affected cousin in the paternal line. No consistent clinical syndrome or pattern of inheritance emerged for any identified defect of the mitochondrial respiratory chain, localised biochemically in 41 cases. Overall, the recurrence rate was 3% for sibs and 5.5% for offspring of index cases. Review of published reports of familial cases of mitochondrial myopathy suggests that the ratio of maternal to paternal transmission is about 9:1. We conclude that these disorders may be caused by mutations of either nuclear or mitochondrial genes.

Chronic administration of the oral hypoglycaemic agent diphenyleneiodonium to rats. An animal model of impaired oxidative phosphorylation (mitochondrial myopathy).

Daily subcutaneous administration of the oral hypoglycaemic agent, diphenyleneiodonium at a low dose (1.5 mg/kg body weight) over a 4-5 week period resulted in a normoglycaemic stable animal model of impaired oxidative phosphorylation in the rat. Diphenyleneiodonium specifically inhibits NAD-linked mitochondrial oxidation [Bloxham, Biochem. Soc. Trans. 7, 103 (1979)], and in isolated mitochondrial preparations from heart, soleus and gastrocnemius muscle and liver from treated animals NAD-linked respiration was reduced by 40% or more of mean control values. Brain and kidney mitochondria isolated from the treated group had similar rates of NAD-linked respiration to their respective control values. The activity of NADH-ferricyanide reductase was significantly reduced in all tissues tested, even in the isolated brain and kidney mitochondria where the activity in these tissues was 60-75% of control values. This suggests that at least 40% of Complex I activity must be inhibited before there is a decline in NAD-linked mitochondrial respiration. This paper discusses the use of diphenyleneiodonium as a means of establishing an animal model of the human disease state, termed mitochondrial myopathy.

An animal model of mitochondrial myopathy: a biochemical and physiological investigation of rats treated in vivo with the NADH-CoQ reductase inhibitor, diphenyleneiodonium.

Chronic administration of the NADH-CoQ reductase inhibitor, diphenyleneiodonium to rats at two dose levels, 1.0 and 1.5 mg/kg per day, caused a 40% and 60% reduction, respectively, in the in vitro rate of NAD-linked respiration by skeletal muscle mitochondria. At the highest dose, muscle fatigue, lactic acidosis and an over-utilization of phosphocreatine was observed in the gastrocnemius muscle during mild stimulation of 1 Hz frequency. The resynthesis of phosphocreatine following muscle stimulation was about 2 fold slower in the treated animal group. At the low dose, no significant biochemical changes were observed during muscle stimulation at 4 Hz. The results are discussed in terms of skeletal muscle "oxidative reserve", twitch tension maintenance and the relevance to the human diseased state of mitochondrial myopathy.

The clinical features of mitochondrial myopathy.

The clinical features of 66 patients with histologically defined mitochondrial myopathy are described. The age of onset of symptoms ranged from birth to 68 years, but was before 20 years in 61%. Nineteen patients had similarly affected relatives. Three groups of cases could be identified clinically: a combination of progressive external ophthalmoplegia and weakness of the limbs induced or increased by exertion (55%); such limb weakness alone (18%); and those with clinical features, such as ataxia, dementia, deafness, involuntary movements and seizures, predominantly or exclusively arising from the CNS (27%). There was considerable overlap between these groups, and pigmentary retinopathy, present in 36% of patients, occurred in all three. At a mean disease duration of twenty years, 9 patients (all from Group 3) were severely disabled but 42 were still able to work. In vitro studies of mitochondrial metabolism, performed in 33 cases, most commonly showed deficiencies of the mitochondrial respiratory chain localized to complex I (18 patients) or complex III (9). No typical clinical picture emerged for any of the identifiable biochemical defects.

Emery-Dreifuss syndrome.

A young adult male is described with muscular dystrophy of probable X-linked recessive inheritance. An onset of muscle weakness in late adolescence was preceded by contractures of the neck and elbows dating back to childhood. The distribution of muscle weakness was proximal in the upper limbs and both proximal and distal in the lower. The mixed pattern of muscle involvement in the legs favours the view that cases of Emery-Dreifuss muscular dystrophy with proximal weakness in both the upper and lower limbs and X-linked scapuloperoneal muscular dystrophy represent the same disorder. A muscle biopsy in the present case showed unique appearances.

The retinal manifestations of mitochondrial myopathy. A study of 22 cases.

In a series of 61 patients with the morphologic and histochemical features of mitochondrial myopathy, 22 (36%) had pigmentary retinopathy. Three patterns of retinopathy were identified. Eighteen patients had a "salt and pepper" type of retinal appearance, which was usually associated with good visual function. Two had many features of retinitis pigmentosa, and two others showed generalized loss, or atrophy, of the retinal pigment epithelium and choriocapillaris. These last four patients had markedly reduced visual acuities, with optic atrophy and attenuated retinal vessels. Electroretinography and electro-oculography were performed in 11 patients. Both rod and cone mediated electroretinographic functions were subnormal in eight patients, while only cone mediated functions were depressed in the remaining three. The electro-oculographic changes were variable.