Interpreting genetic risks.

Prof. Peter Beighton has given a professional lifetime to helping patients and their families who have been afflicted by inherited disease. His clinical skills have brought certainty, confidence and support to those confronted with some of the most difficult decisions in life's progress. Prof. Beighton's research has led to the discovery of new syndromes and the elucidation of accurate genetic risks in many diseases. This in turn has empowered patients and their families to make informed decisions and has provided doctors with the scientific knowledge to help patients. On the occasion of this festschrift, I join with so many members of Peter's international professional family to pay tribute to his leadership and service - not only in medical genetics - but also in the broadest domains of healthcare.

Jules Cotard (1840-1889): his life and the unique syndrome which bears his name.

Dr. Jules Cotard (1840-1889) was a Parisian neurologist who first described the délire des négations. Cotard's syndrome or Cotard's delusion comprises any one of a series of delusions ranging from the fixed and unshakable belief that one has lost organs, blood, or body parts to believing that one has lost one's soul or is dead. In its most profound form, the delusion takes the form of a professed belief that one does not exist. Encountered primarily in psychoses such as schizophrenia and bipolar disorder, Cotard's syndrome has also been described in organic lesions of the nondominant temporoparietal cortex as well as in migraine. Cotard's delusion is the only self-certifiable syndrome of delusional psychosis. Jules Cotard, a Parisian neurologist and psychiatrist and former military surgeon, was one of the first to induce cerebral atrophy by the experimental embolization of cerebral arteries in animals and a pioneer in studies of the clinicopathologic correlates of cerebral atrophy secondary to perinatal and postnatal pathologic changes. He was the first to record that unilateral cerebral atrophy in infancy does not necessarily lead to aphasia and was also the pioneer of studies of altered conscious states in diabetic hyperglycemia.

Bathtub drownings: report of seven cases.

The domestic bathtub is an important site for infant drownings. A total population study of drowning and near-drowning accidents involving Honolulu infants has enabled the risks to be specified with greater detail. A series of seven consecutive bathtub immersion accidents is presented. The "at risk" profile comprises highly mobile families of lower socioeconomic status; usually younger siblings in larger families are involved and often the father had immediate care of the infant at the time of the accident. Another case of bathtub immersion as a form of nonaccidental injury is described. In five of the other six cases reported, the drowned child was left attended by an older sibling. Preventive strategies are discussed.

The discovery of neuronopathy and neuropathy as a cause of progressive paralysis in childhood. The historical origins of modern differential diagnosis in neuromuscular disease.

The concept of the differential diagnosis has a central place in all clinical medicine. In neurology and paediatrics, evolution of thought concerning the differential diagnosis of the child presenting with symptoms of neuromuscular disease was far in advance of similar diagnostic approaches to problems of infectious, infective and neoplastic disease; and as such forms a significant historical model for the development of modern clinical approaches to the sick or disabled child. The account presented in this paper provides a detailed historical review of the development of thought relating to the causes of neuromuscular disease. Nosological developments concerning diseases of the motor unit can be conveniently classified into three periods: (a) a "state of the art" period to 1850; (b) 1850-1890 - a period of parallel and interdependent advances in both normal neuro-anatomy and neurophysiology, and diseases recognized as variations from such norms. In this era Duchenne was the first to write about the differential diagnosis of the progressive muscular paralysis in childhood; and Gowers was the first to write specifically on the hereditary transmission of this group of diseases; (c) in 1891 was described the first case of childhood neuronopathy recognized as such, and with this development was ushered in the modern era of clinical differential diagnosis of childhood neuromuscular disease. The "splitters" have won the great debate concerning the clinical approach to neurological diseases. The continual further refining of an exact diagnosis is the only way in which a realistic prognosis can be forecast, correct genetic counseling can be offered, and (if the condition is treatable) optimal therapy can be introduced.

Two early dynamometers. An historical account of the earliest measurements to study human muscular strength.

An account of two of the earliest dynamometers is presented, together with results of the first experiments attained with them. The Graham--Desaguliers dynamometer was developed in London in 1763 to measure human muscular force, in such a way that synergistic muscles could not impart a false mechanical advantage to the test. The Regnier dynamometer was invented in Paris in 1798 to measure the traction properties of artillery-horses, but was desinged as an all-purpose instrument to measure specific human muscle groups as well. Dynamometers were developed to record human strength along a continuum, to remove the need for a dead-weight or biological standard, and to measure many different groups of muscles, not just those of lifting or pushing. The foundations of modern clinical dynamometry are described.

Autosomal dominant spinal muscular atrophy: a clinical and genetic study.

A clinical and genetic study of 6 kindreds (13 patients) with autosomal dominant spinal muscular atrophy is presented. Evidence is presented to indicate that two separate autosomal dominant genes are involved. One of these causes clinical disease with onset in early childhood (birth--8 years), which is relatively benign and in which proximal selectively of muscle involvement is not marked. A separate autosomal dominant gene causes a disease with onset in adult life (median age 37 years), showing marked initial proximal selectively; this disease may be more rapid in its clinical progression. Penetrance of both genes approaches 100%. Incidence figures are presented; less than 2% of all cases of childhood onset spinal muscular atrophy, but 30% of adult onset cases, are due to an autosomal dominant gene transmitted from an affected parent. Implications for prognosis, diagnosis and genetic counselling are discussed. A review of 11 kindreds of dominant spinal muscular atrophy in the literature is presented.

A study of environmental factors in relation to fatal infantile spinal muscular atrophy (SMA type I). An analysis of birth order and parental age effects, social class, seasonal influence, and clustering in time and place.

Major studies of the childhood spinal muscular atrophies have suggested that environmentally-produced phenocopies might occur, and that environmental factors might be important in some clinical features of these diseases. A formal analysis of some possible intra-uterine and post-natal influences has been undertaken in 78 index cases (72 families) of acute infantile SMA (acute Werdnig-Hoffmann disease; SMA Type I). There is no evidence to suggest that social class, parental age, birth order, or season of birth influences this disease or that clustering in time and place occurs.

Neuromuscular paralysis caused by tick envenomation.

The Australian scrub-tick Ixodes holocyclus causes a series of significant toxic effects in its victims. The most important feature of tick envenomation is neuromuscular paralysis. Children poisoned by ticks may manifest only local motoneural effects, usually facial paralysis. Progressive ascending flaccid paralysis occurs if the removal of an embedded tick is delayed. The specific neurological features of tick-bite are discussed in the light of a series of 6 children who all showed signs of tick paralysis. Tick venom is known to slow nerve conduction, and may have a botulinum-like effect at the neuromuscular junction. The literature on the neurological effects of tick-envenomation is reviewed.

Distal spinal muscular atrophy. A clinical and genetic study of 8 kindreds.

Twelve patients (8 kindreds) with distal SMA are described, and an analysis presented of their clinical and genetic features. Distal SMA accounted for 10% of all patients with SMA in a total population survey of this disease in North-East England. The parental consanguinity rate is high, occurring in 3 of the 8 kindreds reported; the sex ratio was 1.0; the segregation ratio of sibs did not differ from 0.25. Intrafamilial concordance for clinical features of the disease is high. This current data is consistent with a suggested aetiology of two separate autosomal recessive genes. Clinical features are discussed and a review of the literature presented. The disease is only slowly progressive, but one of the genetic types may present with infantile or early juvenile onset; there is no evidence that it shortens life. 50% of cases did not have a normal gait after 4 years of age; 50% could not run after 17 years of age; and 50% could not walk unaided after 28 years of age. Details of prognosis, and principles of genetic counselling in this disease are discussed.

Blood selenium in chronic spinal muscular atrophy.

The spinal muscular atrophies (SMA) of childhood comprise the second most common fatal recessive disease after cystic fibrosis, yet the nature of the biochemical defect causing the anterior horn cell degeneration is totally unknown. Recent reports of a cluster of adult motor neurone disease cases from a high seleniferous area in South Dakota have prompted the study of blood selenium in children with SMA in Australia. Eight children with chronic SMA were tested, in addition to 9 obligate heterozygote carriers of the gene. Blood selenium levels of patients and carriers did not differ significantly from that observed in controls. The mammalian effects of selenium toxicity are discussed.

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.

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.

The envenomation syndrome caused by the Australian Red-bellied Black Snake Pseudechis porphyriacus.

The Australian elapids inject venom which is characteristic of each species; and which cause characteristic and specific envenomation syndromes in human victims of snakebite. Because many of the medically significant Australian elapids look similar, when glimpsed in the field by snakebite victims, defining human envenomation syndromes with secure species identification has been a slow process. Correlations between securely identified species and the human envenomation syndromes which they produce are still evolving. The genus Pseudechis is the most widespread in Australia of the dangerous Australian elapid genera; and P. porphyriacus, the Red-bellied Black Snake, was the first terrestrial Australian elapid to be described and illustrated and the first to be the subject of experimental study. We present here five previously unreported cases of human envenomation in which the species diagnosis is secure. From these and with the perspective of a selected literature review, we describe the full envenomation syndrome of this species. Until the development of the Commonwealth Serum Laboratories' Venom Detection Kit in 1979 and the occasional case report of victims of securely identified species, envenomation syndromes for most Australian snake species have remained indeterminate, because of the lack of professional expertise in the identification of the species involved. Symptoms of the P. porphyriacus envenomation syndrome include those of bite-site pain, nausea and vomiting, generalised pruritus, chest pain, prostration and abnormalities of taste and smell. Signs include local necrosis and scarring of tissue at the bite-site, gross inflammation of surrounding tissues and, at least in one case, epilepsy. Although envenomation by the Red-bellied Black Snake is not lethal in adults, the correct therapy is Tiger Snake antivenom, administered with judgement, taking into account knowledge of the specific envenomation syndrome of this species and the clinical status of the victim.

The mass of venom injected by two elapidae: the taipan (Oxyuranus scutellatus) and the Australian tiger snake (Notechis scutatus).

Using an enzyme immunoassay technique, a new method for measuring, in vivo, the mass of venom injected during snake bite, is presented. The venom injected into mice (as prey) and the venom left on the skin surface during bites by the two Australian Elapidae, the Taipan (Oxyuranus scutellatus) and the Tiger Snake (Notechus scutatus) has been measured. Venom delivery patterns vary significantly between these two species. In the case of the Tiger Snake (a total of 45 bites studied) the mean mass of venom injected in a first bite was 12.7 mg (S.E. 3.4 mg, median 8.1 mg); an average mass of 0.8 mg (S.E. 0.4 mg, median 0.17 mg) was left on the skin surface. A second bite delivered by the same snake yielded a mean venom mass only 27% of the first. In the case of the Taipan (a total of 24 bites) the mean venom mass injected in the first bite was 20.8 mg (S.E. 6.4 mg); with an average of 0.9 mg (S.E. 0.5 mg) left on the skin surface. In contrast to the situation observed with Tiger Snakes, second and third bites delivered in a rapid sequence yielded increasing masses of venom. The mean delivered in the third of a sequence of three bites was 48.8 mg (S.E. 23.8 mg). The ranges of venom mass, by species and by the sequence number of the bite, are also presented. In 66 of the 69 experimental bites studied in this report, venom could be easily detected, the species identified, and the absolute mass of venom measured.

Further studies on the mass of venom injected by Elapid snakes.

Further experimental studies to determine the mass of venom injected by medically-significant Australian elapids are reported. The use of a modified enzyme immunoassay technique to measure venom injected during snake bite is presented. The feeding biting pattern of the Australian eastern brown snake (Pseudonaja textilis) is described. Using data from ten different snakes of this species, it is established that the mass of venom delivered in a first-bite is 4.69 +/- 0.85 mg (mean +/- S.E.) and a mean of 91% of the delivered venom is injected s.c. or into deeper tissues in a first-bite. For this species, the mass of venom delivered sequentially in a bite sequence falls to 1.32 +/- 0.94 mg in the third bite in such a sequence. For the Australian rough-scaled snake (Tropidechis carinatus), the mass of venom delivered in a first feeding bite is 6.15 +/- 2.23 mg, falling to a minimum of 1.92 +/- 0.61 mg in the third bite of a sequence. for the Australian death adder (Acanthophis antarcticus) the mass of venom delivered in a feeding bite is 41.95 +/- 16.13 mg for a first bite. Biting data is also presented for three species of the genus Pseudechis (the Australian mulga (king brown) and black snakes.

Venom of the Australian rough-scaled snake, Tropidechis carinatus: lethal potency and electrophysiological actions.

A series of experiments to define the lethal potency (LD50) and electrophysiological properties of the venom of the Australian Rough-scaled Snake (Tropidechis carinatus) are described. Crude pooled venom contains at least five fractions which were separated using liquid chromatography and high pressure liquid chromatography techniques (Fractions I-V). LD50 studies are reported using each of these fractions, with data for both adult and neonatal mice. Fraction I (mol. wt greater than 100,000) was essentially non-toxic. Fraction IV (mol. wt less than or equal to 10,000) and Fraction V (mol. wt less than 1,000) were potent toxic components with LD50'S (s.c. injection; fraction in 0.1% bovine serum albumin and 0.85% saline; neonatal mice) of 0.04 mg/kg and 0.06 mg/kg respectively. LD50'S for the whole crude venom were similar in both adult and neonatal mice. Electrophysiological studies using a Bulbring preparation (rat isolated phrenic nerve-hemidiaphragm) indicated that Fractions I, IIa and IIb were inactive. Fraction IV (mol. wt less than or equal to 10,000) caused rapid neuromuscular blockade which appeared to be irreversible. Neurophysiological experiments with a rat isolated extensor digitorum longus muscle preparation suggested that the major toxic activity of the whole venom resides in Fractions III and IV, and that both of these fractions have presynaptic and postsynaptic action.

A corneal abnormality associated with trisomy 8 mosaicism syndrome.

Eye abnormalities are a significant feature of trisomy 8 mosaicism syndrome. This paper gives the first account of the specific histopathology of a corneal opacity which is characteristic of this syndrome. The importance of early recognition is stressed because of potential therapeutic visual improvement. The necessity of including mosaic trisomy 8 in the differential diagnosis of such corneal opacities is illustrated by this case.

Survival rates after serious immersion accidents in childhood.

A study of childhood survival rates, after loss of consciousness in fresh water, has been undertaken. Age-specific, sex-specific and site-specific survival rates for childhood fresh water immersion accidents are reported for the first time. The overall survival rate, after loss of consciousness in the water was 0.49; swimming pool and domestic bath tub serious immersion accidents have a survival rate of 0.60 compared with a rate of 0.05 for similar immersion accidents in creeks and rivers. Young male schoolboys have the lowest potential survival (0.20 or less) of any group. Survival rates were significantly higher during the winter (0.86) than during the warmer months (survival rate of 0.49). This gives a quantitative expression to the protection from cerebral anoxia afforded by body chilling which is not extreme. Survival rates have increased significantly over the 5 year period 1971--1975; it is considered that this is due to public education campaigns of the potential danger of water to children. The use of survival rates to measure factors which modify the pathophysiology of human drowning and near-drowning is discussed.

Successful cardiopulmonary resuscitation outcome reviews.

An implicit question in every pre-hospital cardiopulmonary resuscitation (CPR) scenario is 'what will be the quality of life if a save is achieved?' This issue has implications for doctrine, policy, training and post-CPR counselling of both resuscitator and victim. Post-salvage neurological syndromes in surviving victims include amnesia, personality change, cognitive loss, depression, Parkinsonian syndromes, decorticate and decerebrate states and permanent brain damage with vegetative existence. Children who are salvaged by CPR rarely have pre-existing co-morbidities; but 75% of adults have pre-existing cardiac disease, cancer or diabetes. Such, of course, continue after a successful resuscitation. In the case of children who are resuscitated from acute hypoxic insults, the quality of life is generally good and, in the specific instance of survivors from near-drowning, some 95% will lead lives relatively unmodified. Although successful CPR resuscitation rates remain low in adults, the quality of life of those who leave hospital remains generally high. CPR involves two feature subjects, the resuscitator and the victim. Just as for the victim, so too the resuscitator's life is modified by CPR and its aftermath, whether immediate salvage has been achieved or not. This review addresses these issues, as a successful CPR (dramatic as it is) is not a conclusion but the beginning of a new phase of life for both resuscitator and victim.

Erythroblastosis fetalis--the discovery and partial elimination of rhesus incompatibility--the origins of exchange transfusion in Australia.

The first 2 exchange transfusions in Australia for Rhesus-induced erythroblastosis (hemolytic disease of the newborn) were conducted in the 9 mth period from December 1945 to August 1946. These pioneering endeavours in medical research were undertaken by 3 transfusionists who were, or had been, directors of the Red Cross Blood Transfusion Service in Australia. Called "substitution transfusion" or "exsanguination transfusion" they were conducted prior to the international publication of the first case series of exchange transfusions for "Rhesus Disease". The first successful exchange transfusion in Australia, and one of the first in the world, was performed by Dr George Kelsall at the King Edward Memorial Hospital for Women, in Perth. Dr Kelsall had monitored pregnancies with serum raised himself from blood from a Rhesus monkey in the Perth Zoo. The second exchange transfusion, and the first with volume-monitoring, was successfully undertaken in Brisbane by Dr Eric Shaw, pathologist and Director of the Queensland Red Cross Blood Transfusion Service, and Dr Noel Gutteridge, a former Director and senior pathologist of Brisbane. Dr Kelsall's pioneering transfusion in Perth was a direct non-anticoagulated transfusion which was undertaken within minutes of birth and was completed within 5 min. The first volume-controlled exchange transfusion, in which the input-discard volumes were matched, used a plastic tube obtained from the Telephone Branch of the Postmaster General's Department, and employed citrated blood. These heroic exchanges (heroic for the infants and families concerned as well as for the operators) form a significant milestone in the history of blood transfusion, serology and preventive medicine in Australia.