Progressive muscular dystrophy in childhood

The words of Gowers are as true today as they were nearly a century ago. My interest in muscular dystrophy started in 1957 when, as Senior House Officer at Queen Mary's Hospital for Children, Carshalton, Surrey, I first observed a large number of children suffering from this tragic disease. The frustration of helplessly, watching its inevitable course stimulated the present study.After obtaining an initial impression or' the collection from my clinical observations and a review of the hospital records between 1920 and 1950, I started a more systematic enquiry. The present investigation compromises my personal observations on 65 cases ranging in age from 3 to 16 years. Of these, 57 were seen and followed up at Queen Mary's Hospital for Children, and 8 at the Southern Hospital, Dartford, Kent

Clinical and genetic studies in autosomal recessive ataxias

167 patients with the recessive repeat expansion disorder Friedreich’s ataxia (FRDA) were recruited as part of the European FRDA Consortium for Translational Studies (EFACTS) and underwent longitudinal clinical assessment including validated and standardized clinical and functional rating scales. The mean age at onset was 13.7±9.6 years (range 1-55) and disease duration 20.5±11.2 years (range 3-55). The smaller repeat expansion (GAA1 size) correlated with age at onset, Activities of Daily Living (ADL), Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxic Symptoms (INAS) count & Spinocerebellar Degeneration Functional Score (SDFS). 125 patients were seen after 1 year, and 116 after 2 years. Disease progression could be measured using these rating scales: SARA increased over 2 years by 1.3±3.1, ADL by 2.0±3.2 and SDFS by 0.3±0.6. There was no statistical difference in INAS count. A majority of patients could not complete the Spinocerebellar Ataxia Functional Index (SCAFI) which was deemed inappropriate in FRDA. Two novel FXN mutations were identified, as well as a probable macrodeletion. No compound heterozygous exonic deletions were found amongst 1768 cases referred with a possible diagnosis of FRDA, indicating that these deletions are extremely rare. Twenty-six patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) were recruited (mean age onset 15.0±17.4, range 0-51); mean disease duration 28.5±12.9, range 8-56). Loss of mobility, dysarthria, dysphagia, ataxia, sensory loss, square wave jerks and saccadic dysmetria were less common in ARSACS compared to FRDA; nystagmus, spasticity and hyperreflexia were more common. Nine novel SACS mutations were identified. Retinal Nerve Fibre Layer (RNFL) thickening on ocular coherence tomography (OCT) was found to be a specific (99.4%) and sensitive (100%) marker of ARSACS with positive predictive value of 94.4%, amongst 191 patients with ataxia, using a cut-off thickness of 119μm

Gastric tetany

Definition,- Tetany is a condition which has been considered by a large number of writers, and various ideas have been propounded as to its nature, and even regarding the essential features of the affect- ion. Osler's definition is characteristically brief and inclusive; he defines tetany as " an affection characterised by peculiar bilateral tonic spasms, either paroxysmal or continued, of the extremities1(1) Risien Russell states the same thing rather more fully and adds "in severe cases the muscles of the trunk, neck, face, eyes and larynx may become involy - ed in the spasm." (2). Dr Russell considers that "there are different gradations - -- from mild carpo- pedal contractions associated with rickets to sever: general spasms, which may even simulate tetanus ". Carpo- pedal spasm in children is not rare, and Pro - fessor Osler thinks it a mistake to call these cases true tetany.(3). Henoch (4) writing on tetany in children stated:- " This affection is classed with tkiany by many, but, in my opinion, it is well to separate the two diseases entirely. I have never been able to detect the symptoms regarded by Trousseau as distinctive -- in idiopathic contractures of children" But in this relation it must be noted that Trousseau'. symptom is sometimes not obtained in undoubted cases of tetany. (5). Probably the affection occurs under various circumstances, and the spasm can be produc- ed by more than one cause.Tetany occurs in adults mainly in thre. ?conditions, First, in pregancy, lactation, menstrual disorders and the like.Secondly, from deprivation of the thyroid gland (or.r para- thyroid.)Thirdly, in association with gastro -intestinal dis- turbances, usually dilatation of the stomach or in- testines.It occurs very rarely in oh L4 other conditions and in epidemics, and in children is usually assoc -, fated with rickets.(1).This thesis deals 'specially with the third adult variety, but in the attempt to elucidate the fundamental etiology and pathology it will be necessary t to refer to other varities

Neuropathy in childhood mitochondrial disease, including riboflavin transporter deficiency: phenotype, neurophysiology and disease-modifying therapy in a recently described treatable disorder

Introduction: Defining the neurophysiological features of the peripheral neuropathy associated with childhood mitochondrial disease, including the neuropathy/neuronopathy associated with Brown-Vialetto-Van Laere syndrome (BVVL), will aid in classifying the mitochondrial syndrome, directing genetic testing and instituting therapy. Methods: Nerve conduction studies and clinical assessments were performed on children with nuclear or mitochondrial genome mutations. The clinical and genetic profile, neurophysiology, histopathology, audiology and response to riboflavin therapy of nine children with BVVL due to RFVT2 deficiency were evaluated. Results: Peripheral neuropathy was more frequent with nuclear gene mutations. SURF1 was associated with a demyelinating neuropathy while PDHc deficiency caused an axonal neuropathy. POLG mutations caused a sensory axonal neuropathy. The neuropathy associated with mitochondrial disease was not length-dependent. Children with RFVT2 deficiency presented with an auditory neuropathy and sensory ataxia, and developed upper limb weakness. Nerve excitability studies showed an increase in myelin permeability. Riboflavin therapy caused partial reversal of these changes and improvement in strength, audiology and respiratory function. Conclusions: Nerve conduction studies should be part of the initial assessment of children with suspected mitochondrial disease. Clinicians need to be familiar with the unique phenotype of RFVT2 deficiency so that affected children are diagnosed early and commenced on appropriate therapy

Peripheral neuropathies of childhood

Includes synopsis.Incldues bibliographical references (p. 195-220).Peripheral nerve disease was described by Galen (AD 130-200) over a thousand years ago.(3) Detailed anatomical illustrations were documented by Andreas Vesalius in his major work 'De humani corporis fabrica' in 1543.(4) Over the last two centuries an explosion in knowledge in the area has occurred, with a further exponential increase in the last 20 years mostly related to understandings in the field of molecular genetics.(5) Although some degree of diagnostic closure was possible for a number of the hereditary peripheral neuropathies, this has not been the end point of knowledge but only the beginning

Facioscapulohumeral disease

The purpose of this study is to discuss several aspects of facioscapulohumeral disease, also called "autosomal dominant facioscapulohumeral muscular dystrophy" or "Landouzy-Dejerine type of muscular dystrophy" or "Landouzy-Dejerine' s disease" . We consider this disorder well defined and recognizable, justifying the term facioscapulohumeral disease, abbreviated FSHD.UBL - phd migration 201

Handbook on clinical neurology and neurosurgery

HANDBOOKNEUROLOGYNEUROSURGERYКЛИНИЧЕСКАЯ НЕВРОЛОГИЯНЕВРОЛОГИЯНЕЙРОХИРУРГИЯThis handbook includes main parts of clinical neurology and neurosurgery

Behaviour of single motor units in human skeletal muscle

In the first part it was shown that the firing frequencies of motor units at particular grades of isometric contraction depend on the total number of units available for recruitment and so are regulated by length and tension receptors in the muscle. Procainisation showed the importance of the gamma- regulated length receptors in voluntary contraction. In hypertonie Parkinsonism, however, increments of voluntary contraction are presumably largely dependent on recruitment of extra units. Certainly the units recorded in the present study showed a very marked tendency to fire at unusually slow rates. They did so with a regular rhythm suggesting strong tonic inhibition. This is in contrast to the evidence reported in Chapter 8 (Paired response) pointing to the presence of motoneurone facilitation. This paradox would be solved if two antagonistic mechanisms were in action - for instance a supraspinal facilitation and a peripheral as well as supraspinal inhibitory one. Hufschmidt's (1959) work has already been discussed. He has shown that inhibitory reflexes from muscle and tendon receptors are overactive in Parkinsonism. It is now submitted that the mechanism described by him is only one of at least two important factors regulating spinal motoneurones in Parkinsonism, and it may well be that the peripheral inhibitory overaction is reactive, a regulatory reflex called into premature activity owing to the absence of the gamma regulation of the length servo (see Chapter 9).Further work immediately suggests itself. My colleague, R. Levy, has shown that supraspinal facilitation may be temporarily reduced by anticonvulsants and other drugs. Injection of procaine into muscle tendons will paralyse the Golgi tendon organs. Repetition of the observations reported here are planned in Parkinsonian patients after each of these procedures. It has not been a purpose of this thesis to discuss the mechanism of tremor in that disease but it may be pointed out that an interplay of two antagonistic tonic activities in spinal inter-neurones might lead to "oscillation of the servo -system ", causing a rhythmical tremor which would not require presence of the same rhythmicity in a descending extra- pyrimidal outflow.For normal physiology this work emphasizes the importance of peripheral regulatory systems in the performance of voluntary movement, and is in complete accord with the suggestions of Granit and his school. The Unexpected findings in Parkinsonism and in Friedreich's ataxia suggest a further parameter of control which could not be detected by workers with animals in which the activity investigated can scarcely be termed "voluntary ". It has been accepted since the work of Adrian and Bronk (1929) that the tension of voluntary contracted muscle is raised by increasing the firing rates of motor units to a certain limiting value (possibly related to tetanus fusion frequency: see Chapter 3) and also by recruitment of new units. The present study shows that these controls are affected differentially by disease. Simpson (personal communication) suggests that supraspinal facilitation may control the recruitment of alpha motoneurones while the gamma loop regulates their firing frequency. This hypothesis should be tested by animal experiment