Combined enzyme defect of mitochondrial fatty acid oxidation.

A young girl presented with recurrent episodes of muscle weakness culminating in a severe attack of generalized muscle weakness. In the muscle mitochondria from the patient there was an abnormal pattern of intermediates of beta-oxidation with an accumulation of 3-hydroxyacyl- and 2-enoyl-CoA and carnitine esters, and 3-oxoacylcarnitines. There was low activity of long-chain 3-hydroxyacyl-CoA dehydrogenase in mitochondria from all tissues. The activity of long-chain 2-enoyl-CoA hydratase was low in muscle mitochondria and 3-oxoacyl-CoA thiolase activity measured with 3-oxohexadecanoyl-CoA as substrate was low in fibroblast, muscle, and cardiac mitochondria but only partial deficiency was present when the activity was measured with 3-oxooctanoyl-CoA. The activity of the long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-oxoacyl-CoA thiolase in fibroblasts from the patient's parents was intermediate between those of controls and the patient. The patient has a combined defect of the long-chain 3-hydroxyacyl-CoA dehydrogenase, long-chain 3-oxoacyl-CoA thiolase, and long-chain 2-enoyl-CoA hydratase which appears to be inherited in an autosomal recessive manner. This suggests there is a multifunctional enzyme catalyzing these activities in human mitochondria and that this enzyme is deficient in our patient.

Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'.

The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission.

Congenital myotonic dystrophy: fiber type abnormalities in two cases.

Histometric data on muscle fiber types were studied in two cases of congenital myotonic dystrophy (CMD); one underwent biopsy at the age of 5 months and the other at the age of 10 years. A previously unreported severe deficiency of type IIB fibers were found in both cases. In addition, in the first case, there was type I fiber preponderance and hypotrophy as described in cases of congenital fiber type disproportion (CFTD). It is suggested that an abnormality of motor unit maturation may be common to CMD and to CFTD, and that this results from a disorder of neural trophic influences during muscle development.

Patterns of muscle fiber-type disproportion in hypotonic infants.

We studied the histochemical characteristics of muscle in five hypotonic infants. A number of different patterns of disproportion in the sizes and numbers of type 1 and type 2 fibers were found. In three cases, type 1 fibers were smaller than type 2 fibers and type 2b or 2c fibers were largest. In one case, type 2 fibers were smaller than type 1 fibers and were reduced in number, while in a case of Prader-Willi syndrome there was a preponderance of type 2 fibers that were smaller than type 1 fibers. Type 2c fibers were increased in number in all but one case. We postulate that these various patterns of fiber-type disproportion are the result of altered neural influences leading to impaired maturation of type 1 or type 2 motor units.

Electrocardiographic abnormalities in carriers of Duchenne muscular dystrophy.

Electrocardiographic (ECG) abnormalities characteristic of Duchenne muscular dystrophy (tall R waves in the right precordial leads and deep Q waves in the lateral chest leads) are rarely observed in carriers, but Emery (1969) found that the (R-S) amplitude sum in lead V1 was significantly greater in carriers than in age-matched controls. In a prospective single-blind study, we analyzed coded records from 11 carriers and 12 age-matched normal women for (R-S) amplitude sums and R/S ratios in leads V1 and V2. Values in carriers were significantly greater for all these characteristics, discrimination being most marked for R/S in V2 (p less than 0.01). This was confirmed in a further retrospective study, comparing records from 18 carriers with 100 normal ECGs from women of the same age range. Density functions for (R-S) in V1 and the R/S ratio in V2 derived from carrier and normal population can be incorporated into probability calculations to determine risk of carrier status.

CSF antigliadin antibodies and the Ramsay Hunt syndrome.

Although the association between celiac disease and progressive myoclonic ataxia is well recognized, in each of the reported cases the neurologic features began in middle adult life and usually in patients who had clinical or laboratory evidence of malabsorption. We report a case of progressive myoclonic ataxia and epilepsy (Ramsay Hunt syndrome) that began in childhood. In this patient there were no features suggestive of gluten intolerance. The presence of antigliadin antibodies in the serum and CSF suggested celiac disease was the cause of the patient's neurologic syndrome. Duodenal morphologic abnormalities reversed with treatment but no major changes were noted in the patient. Celiac disease should be considered in the differential diagnosis of myoclonic ataxia at any age, even in the absence of clinical evidence of gluten-sensitive enteropathy.

Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy.

We have analysed the results of clinical assessment, X-inactivation status, deletion screening and dystrophin analysis in eight manifesting carriers of Duchenne and Becker muscular dystrophy (DMD and BMD). Only two had a prior family history of X-linked muscle disease, all had normal karyotypes and none were twins. Presentation varied from 2 to 25 yr and progression varied from a DMD-like severity to a very mild BMD-like course. In one girl the initial symptoms were restricted to learning difficulties. Where methods for assessing X-inactivation were informative, three patients showed an abnormal pattern. However, in one patient, the obligate carrier daughter of a BMD patient who had presented at the age of 2 yr, X-inactivation appeared normal in lymphocytes and muscle. While dystrophin analysis seems to be reliable in identifying manifesting carriers of DMD and BMD, the relationship between X-inactivation status, dystrophin analysis and phenotype is not simple.

Multiple chromosome rearrangements in a childhood ependymoma.

Multiple karyotypically abnormal cell lines were observed in long-term cultures of an ependymoma of the fourth ventricle of a child. A previous report of a G-banded ependymoma karyotype described monosomy 8, trisomy 9, t(1;7)(p12;p13), and t(X;10)(q22-23;q24). This case also shows involvement of Xq22 and 10q24.

The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural history.

We have investigated 67 patients with proven Becker muscular dystrophy (BMD) using a standard protocol including a detailed history and a functional and clinical examination. Our aim was to define the natural history of the disease in a large cohort of patients in the light of the diagnostic methods now available. In all patients with or without an X-linked family history, the diagnosis was confirmed by the identification of a deletion or other abnormality in the dystrophin gene, and abnormal dystrophin on immunoblotting and immunocytochemistry of muscle biopsy samples. In graphs of functional and muscle score against age, two groups of patients emerged. In the larger group the disease was milder and patients remained ambulant into their forties or beyond. A smaller group had more severe disease with a slightly earlier onset, much earlier loss of ambulation, more frequent abnormal electrocardiographic findings and much lower reproductive fitness. The relationship of these clinical findings to the genetic and protein abnormalities found in the patients is explored in the accompanying paper.

The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. II. Correlation of phenotype with genetic and protein abnormalities.

We have correlated a detailed clinical assessment of 67 patients with proven Becker muscular dystrophy with the results from genetic and protein analyses. There was an overall deletion frequency of 80%, rising to 92.6% in the large group of patients defined on clinical grounds as being of "typically" mild severity. The deletions in this group were all clustered in the region of the gene between exons 45 and 59; the most common deletion was of exons 45-47 and all but one started at exon 45. No similar deletions were seen in the patients with more severe disease, in whom the diverse genetic defects included a duplication and a very large deletion. Dystrophin patterns in the "typical" group were also very characteristic, and in both groups were as predicted from the genetic defect, the size of deletions being inversely proportional to the size of the protein produced.

Severe muscular dystrophy in girls.

Twelve girls and 2 boys with severe but not congenital muscular dystrophy were found in a national survey. An autosomal recessive gene is likely to account for most if not all of these cases. The condition differs slightly from X-linked Duchenne muscular dystrophy in showing prominent early toe-walking, a milder course, relatively more weakness of the deltoid muscles, normal intelligence, a normal ECG and a more focal pattern of muscle pathology.

Neutrophil function in Duchenne muscular dystrophy.

Spontaneous migration, chemotactic and bactericidal activity and nitroblue-tetrazolium (NBT) reduction by neutrophils from patients with Duchenne muscular dystrophy were evaluated using quantitative techniques. Significant reductions in spontaneous migration and chemotaxis were found in the DMD group when compared with a control group of subjects. No significant differences were found in bactericidal activity or NBT reduction. The findings suggest that there is a defect in the contractile system or cell membrane function of neutrophils in DMD and that the genetic defect is expressed in leucocytes as well as other tissues.

A clinical study of chronic childhood spinal muscular atrophy. A review of 141 cases.

The case histories and clinical details of 141 children (67 males and 74 females) with chronic childhood spinal muscular atrophy (SMA) have been reviewed. Hundred of these children were alive at the time of the study. The cases comprise a consecutive unselected series of all with this disease who presented to two large English neurological centres over a 10-year tracing period. Chronic childhood SMA is defined here as a progressive disease of anterior horn cells with initial proximal selectivity, which does not of itself cause death before 18 months of age. Clinical signs are first manifest between birth and 8 years of age, but in 95% before 3 years. Cumulative frequency tables for motor skills are presented; 46% of children never walked, even with orthopaedic aids; 37.6% were able to walk unaided at some stage. No child was able to run after 12 years of age. Late-presenting sporadic cases retain motor skills longer than do familial cases. A sex influence on the clinical course of the disease has been demonstrated, males being more severely affected. Cumulative frequency curves for age-at-onset and age-at-presentation have been compiled. A sib of an affected index case, still clinically normal at 2 years of age, has passed 90 percent of his risk period; the use of such cumulative frequency curves for studies of carrier-frequency and incidence is discussed. The median age at death for this disease exceeds 10 years. The range encompassed by the clinical spectrum is discussed.

Adrenergic receptor responses of vascular smooth muscle in Becker dystrophy. A muscle blood flow study using the 133Xe clearance method.

The effect of intravenous adrenaline and of alpha and beta blockade on muscle blood flow in the tibialis anterior muscle of 8 normal subjects and 8 patients with the Becker form of X-linked muscular dystrophy has been assessed using the 133Xe clearance method. Whereas beta receptor responses to stimulation by adrenaline and blocking by propranolol did not differ significantly in the Becker patients and normal controls, the degree of alpha receptor blockade produced by phentolamine was significantly less in the Becker patients, suggesting a quantitative or qualitative abnormality of vascular alpha receptors. This pattern of response was not found in patients with spinal muscular atrophy or polymyositis. The possible significance of these findings is considered.

Serum pyruvate kinase in carriers of Duchenne muscular dystrophy.

Five out of 17 carriers of the gene for Duchenne muscular dystrophy had an increased level of serum pyruvate kinase activity, whilst 11, including the same 5, showed an increase in serum creatine kinase.

Familial intermittent ataxia with possible X-linked recessive inheritance. Two patients with abnormal pyruvate metabolism and a response to acetazolamide.

Five males in one kindred suffered from intermittent ataxia and one female may have been more mildly affected. The pattern of inheritance strongly suggests X-linkage. Cerebral pathology in one case had some features of Leigh's disease. A defect in pyruvate metabolism was found in two cases. Acetazolamide gave a temporary clinical and biochemical improvement in two cases.

Carrier testing in families of isolated cases of duchenne muscular dystrophy. Creatine kinase activities in female relatives of mothers with normal CK activity.

A study of the serum creatine kinase (CK) activity in the female relatives of mothers of isolated cases of Duchenne muscular dystrophy (DMD) was undertaken.. It was restricted to the relatives of mothers with normal serum CK values. Ninety-eight females in 19 families were studied; none was found to have a serum CK activity more than 3 SD above the normal mean. This evidence, derived from a study in which the measurement of serum CK activity was used as the sole means of detecting carriers, suggests that very few distant female relatives in such families are carriers of the gene and provides some evidence against the hypothesis that mutation is a rare cause of isolated cases of Duchenne muscular dystrophy.

A genetic study of subacute and chronic spinal muscular atrophy in childhood. A nosological analysis of 124 index patients.

A genetic study of the subacute spinal muscular atrophies (SMA) of late infancy and early childhood has been undertaken. All such patients with chronic disease (with ages at onset up to 14 years, and excluding SMA Type I) known to 2 large Neurological Centres were reassessed clinically and genetically. There were 124 index patients (67 females and 57 males) and 17 secondary cases, which formed two consecutive unselected series. To investigate the genetic composition of this group, 4 nosological approaches were used; cluster analysis of clinical features of the disease, Haldane's sib-sib analysis on familial cases, interpretation of frequency distribution histograms, and a segregation analysis. A single autosomal recessive gene accounts for over 90% of cases, causes a clinical syndrome which manifests its first clinical signs before 5 years of age and in almost all cases before two years of age, but which is compatible with life into the third decade. Moderate intrafamilial discordance for some clinical features may be observed, but no genetic heterogeneity within this group was demonstrated. A small group of cases is caused by (a) new dominant mutation(s), or (b) is composed of phenocopies, or both. This relatively uncommon form may comprise the majority of late-presenting cases, and may account for all cases which manifest the first signs after 5 years of age. The spectrum of age-at-onset of this group cannot be determined at present, but the disease may be manifest before the age of two years; it is clinically indistinguishable from SMA caused by an autosomal recessive gene. The literature has been reviewed in the light of these findings. Empirical risks for use in genetic counselling are presented.

Familial intermittent ataxia due to a defect of the E1 component of pyruvate dehydrogenase complex.

Disturbances of pyruvate metabolism have been implicated in the aetiology of several neurological disorders including Leigh's disease and familial ataxia. We have re-investigated a patient whose initial description documented intermittent ataxia, a presumed disorder of pyruvate metabolism and an X-linked pattern of inheritance. Recent studies showed he had slow oxidation of pyruvate, low pyruvate dehydrogenase complex (PDC) activity and immunochemical evidence of E1 deficiency in skeletal muscle mitochondria. This is consistent with the recent finding that the gene for E1 alpha is on the X chromosome.

An evaluation of some carrier detection techniques in Duchenne muscular dystrophy.

Some recently described abnormalities in the serum and red cell membranes in Duchenne dystrophy have been examined as methods of carrier detection in a single-blind controlled study. Twelve carriers (4 definite, 3 probable and 5 possible carriers previously found to have raised creatine kinase levels) and 12 normal female controls of the same age, were examined on 3 separate occasions at approximately two-weekly intervals. Analysis of age-dependent red cell shape changes, serum haemopexin levels, red cell K+ efflux rate, sensitivity of red cell ghost membrane ATPase to ouabain, membrane protein phosphorylation studies and lactate dehydrogenase isoenzyme profiles on agarose gel electrohoresis all failed to distinquish carriers from controls. The carriers suffered muscle cramps more frequently than the controls and all but one carrier and two control subjects were correctly identified by manual muscle strength testing, certain proximal muscles in paricular being consistently weaker in carriers than in the control group subjects. Scalar electrocardiography revealed higher values for the R/S ratio in Leads V1 and V2 and the sum (R-S) in V2.