John Walton

ON THE INHERITANCE OF MUSCULAR DYSTROPHY

The results are reported of a survey of the mode of inheritance of muscular dystrophy, as determined from a series of 102 cases, of which 84 were examined personally. It is believed that this series approaches complete ascertainment of all cases at present recognized in the two counties of Northumberland and Durham. Available sibs and parents of affected individuals were examined whenever possible. It is agreed that rare ocular and distal forms of muscular dystrophy may be distinguished, but evidence is presented for suggesting that the commonly occurring cases can be classified into three types which are separate entities, both clinically and genetically. These maybe referred to as the Duchenne, facioscapulohumeral and limb‐girdle forms.

Some muscular manifestations of hypothyroidism.

Although it has been recognized for many years that symptoms and signs indicating disordered function of the voluntary musculature may be prominent in patients with myxoedema, the muscular manifestations of hypothyroidism have received comparatively little attention in the British literature. Recent reviews have, however, been given by Thomasen (1948), Piaggio Blancho and Malosetti (1950), Millikan and Haines (1953), Herbeuval, Cuny, and Larcan (1956), Dubansky, Svoboda, and Wiedermann (1957), and Perugini and Prati (1957). Kocher (1892) reported that patients with sporadic cretinism or myxoedema often showed bulky musculature, diminished muscular power, and sluggish movement with or without tetany. Hoffmann (1897) later described features suggestive of myotonia in a patient who had undergone thyroidectomy several times; he pointed out that in this case there was a striking delay in muscular relaxation, reminiscent of that which occurs in myotonia congenita (Thomsens disease). Since these early descriptions the syndrome of generalized muscular hypertrophy with sluggishness of muscular contraction and relaxation, which occurs in myxoedematous adults, has been referred to as Hoffmanns syndrome. A similar disorder seen in cretinous infants is generally called the DebreSemelaigne syndrome. Probably this disorder accounts for many cases of so-called acquired myotonia or myotonia acquisita (Talma, 1892). In fact, however, the abnormality of muscle function which results from hypothyroidism must be distinguished from true myotonia, as the overall slowness of muscular activity affects muscular contraction as well as relaxation and the typical electrical after-discharge of myotonia is not seen. Hence the term pseudomyotonia is a more appropriate description for the myxoedematous phenomenon. Whereas it is not difficult in patients with florid myxoedema to appreciate that slowness of movement and stiffness of the voluntary muscles may be attributable to the thyroid disease, particularly when there is also marked muscular hypertrophy, we have been impressed by the fact that the muscular symptoms may not always follow the accepted form and may be the presenting feature in patients in whom hypothyroidism is otherwise clinically unobtrusive. We report below three cases in which diagnosis presented considerable difficulty but nevertheless the response to treatment was rapid and sustained.

THE LIMP CHILD

The clinical syndrome of congenital hypotonia of the skeletal musculature which Oppenheim (1900) entitled myotonia congenita , and was subsequently called amyotonia congenita by Collier and Wilson (1908), may be produced by a variety of pathological entities. Most such cases show a progressive downhill course similar to that seen in classical cases of infantile spinal muscularatrophy of later onset (Werdnig, 1891; Hoffmann, 1893) and are found to have degenerative changes in the anterior horn cells (Beevor, 1902; Rothmann, 1909; Bibergeil, 1914; Greenfield and Stern, 1927; Grinker, 1927; Sheldon, 1929), although it has been suggested that they may also show an error in development of the upper motor neurone (Burdick, Whipple, and Freeman, 1945). Certain cases also resemble the condition referred to as arthrogryphosis multiplex congenita (Stern, 1923) or amyoplasia congenita (Sheldon, 1932), which often appears to be due to a similar spinal muscular atrophy beginning in intra-uterine life (Brandt, 1947). That the disease in some infants with severe congenital hypotonia runs a benign course was first suggested by Oppenheim, and Batten (1910, 1911) believed that these children were suffering from a congenital non-progressive myopathy, a view which received support from Turners (1940, 1949) follow-up of some of Battens cases. Furthermore it has become apparent that infantile hypotonia may sometimes be symptomatic of a variety of neurological, skeletal, and metabolic disorders; the many causes ofsymptomatic hypotonia and their differential diagnosis have been reviewed by Brandt (1950), Tizard (1955), Sandifer (1955), and Walton (1956). Brandt (1950), as a result of an extensive follow-up study of 131 cases previously diagnosed as amyotonia congenita or infantile spinal muscular atrophy, concluded that amyotonia congenita was a syndrome which could result from a variety of diseases-some grave, some benign. After excluding all cases of spinal muscular atrophy and of symptomatic hypotonia he was left with 13 cases, of which six had recovered completely, three had shown striking improvement, three had improved but remained disabled while one had improved but died from pneumonia. Seventeen similar cases are described and discussed below.

Neurological manifestations of xeroderma pigmentosum in two siblings

Abstract Two sibs with xeroderma pigmentosum and neurological complications are described. These included progressive dementia, chorea, perceptive deafness, cortico-spinal tract degeneration, peripheral neuropathy and skeletal abnormalities. Electromyographic studies showed evidence of chronic denervation and the motor and sensory nerve conduction studies indicated the presence of a mixed axonal peripheral neuropathy in both cases. A sural nerve biopsy in 1 case demonstrated a global fall out of both myelinated and unmyelinated nerve fibres and a muscle biopsy in this patient confirmed the presence of chronic denervation atrophy with widespread reinnervation. The significance of these findings is discussed and the basic defect in xeroderma pigmentosum is reviewed.

An investigation of the carrier state in the Duchenne type muscular dystrophy.

In an attempt to discover a laboratory test by means of which female carriers of the gene For the Duchenne type muscular dystrophy could be identified, creatine and creatinine excretion has been studied in forty‐eight female relatives of patients suffering from this variety of muscular iystrophy. The activity in the serum of aldolase, of serum glutamic oxalacetic transaminase (SGOT) and of serum glutamic pyruvic transaminase (SGPT) has also been determined in thirty‐six female relatives. The females tested were divided into three groups: (a) known carriers, (b) possible carriers, and (c) probable non‐carriers. No significant differences were discovered between the results obtained in each of these three groups. No method of identifying female carriers has yet been discovered.

TWO CASES OF MYOPATHY LIMITED TO THE QUADRICEPS

Bramwell, in 1922, demonstrated before the Royal Society of Medicine two cases suffering from a form of myopathy which appeared to be limited to the quadriceps. A third similar case was reported by Denny-Brown in 1939, but no subsequent descriptions of this condition have appeared in the literature. All of the three patients previously reported were over 40 years of age; this paper describes two further cases of this type, one in a young man.

The electroencephalographic sequelae of spontaneous subarachnoid haemorrhage.

Abstract Of 120 patients who have survived an attack of subarachnoid haemorrhage, 15 (12.5 per cent) have shown epileptic manifestations since the illness. EEGs were taken from 8 of these patients 2 to 9 years after the illness; in 6 cases focal abnormalities, usually consisting of slow activity with spikes or sharp waves, were demonstrated. Another 6 patients were examined who gave no history of epilepsy but in whom there was a clinical evidence of cerebral damage at the time of the original illness; in 4 cases the EEG was normal, but in the 2 cases in which residual paralysis was most severe, focal changes were seen 4 and 12 years after the original illness respectively. The findings in these cases are comparable with the reported EEG sequelae of severe head injury.

Benign congenital myopathy with myasthenic features.

It has been increasingly apparent in recent years that in addition to cases which fall into recognizable categories of muscle disease, a number of less common disorders occur from time to time which do not correspond to the accepted descriptions. Some of these appear to be metabolic in origin and can be elucidated, at least in part, by modern methods of investigation (McArdle, 1951) while others seem to fall into a borderland of either myopathy or myasthenia gravis. A case of the latter type is described and discussed below.

The ‘Floppy’ Infant

The traditional concepts of hypotonic disorders in infancy need to be revised. These disorders are well grouped under: (1) infantile spinal muscular atrophy; (2) symptomatic hypotonia; and (3) benign congenital hypotonia. The clinical picture of the first (Werdnig‐Hoffmann disease) as it actually occurs is described, the symptomatic hypotonias are reviewed, and the picture of benign congenital hypotonia made clear.

Progressive Muscular Dystrophy

There is at present no effective treatment for progressive muscuar dystrophy. The main hope for the future lies in the research now being conducted. The three common varieties are the Duchenne, limb-girdle and facioscapulohumeral types. Accurate classification is essential since they differ considerably in age of onset, rate of progress, and mode of inheritance. The most useful diagnostic procedures are electromyography, serum enzyme estimations, and muscle biopsy.