The blue coloured plasma protein ceruloplasmin binds up to 95% of circulating copper, and has several possible functions. It has been proposed to function in copper transport, oxidation of organic amines, iron(II) oxidation and the regulation of cellular iron levels, and catechols, radical scavenging and other antioxidant processes. This account will consider the relative importance of these multiple functions in terms of the physiological roles of ceruloplasmin.

Ceruloplasmin and what it might do

Will Pickles of Wensleydale. The Life of a Country Doctor. by JOHN PEMBERTON, London, Geoffrey Bles, 1970, pp. 224, illus., £2-50. Will Pickles (1885-1969) was a country general practitioner of Wensleydale, who made a positive contribution to epidemiology, defining the incubation periods of infectious fevers by a method which he described as 'the short and only possible contact'. He applied a simple practical method to find this elusive information and used his general practice as the medium for research. One wonders why it was not done before, but therein lies the greatness of the man. The essence of a general practitioner is his detective urge to gather all the clues, as he does in making a diagnosis. Dr. Pickles applied this to the epidemic ofjaundice which was to start his researches. He thought 'it great fun when we could exercise Sherlock Holmes tactics and nail the culprits'. To follow personally from a clinical history and examination to a family history, village history and dale history was a special opportunity of his general practice. And this is what he did. Family by family, and village by village he was able to look out for personal information at weddings, christenings, parties and funerals, indeed wherever village people met. In the epidemic of 1928, out of a total estimated population in Wensleydale of 5,700 there were some 250 known cases ofjaundice, of whom Dr. Pickles and his partner attended 118. The story of the research, which established the incubation period as 26 to 35 days, includes the uncovering of a secret romance and reveals the broad human interest that motivates the best medical practitioners. By meticulous and accurate note-taking, in which he was fortunate in having his wife Gerty to transpose his diary records to charts, he extended his work to other infectious diseases that beset his patients. Ten years later, he published his Epidemiology in a Country Practice (1939), a work which was to make his name world famous. Will Pickles was the son of a general practitioner of Camp Road, Leeds, and himself practised medicine in Aysgarth for over fifty years. His thinking was in the tradition of those great G.P.s Edward Jenner, William Budd and James Mackenzie. His valley did not limit his horizons and his influence was more than parochial. He was one of the minority of doctors to welcome the National Health Service Act of 1948 and the possibilities that it brought to medical practice. These he used to the full in the service of his patients and of medicine. It was fitting that he should have become the first President of the College of General Practitioners. Professor John Pemberton's account of his life in the closed society of the dales, portrays a community and its doctor which has already gone for ever. The biography grew out of a series of locums which the author did for Dr. Pickles in the ten years after 1949. The picture of this remarkable G.P.'s daily life, the personal reminiscences, the countryside in all its moods and the anecdotes of the villagers make most agreeable reading. JOHN CULE

The Founders of Neurology.

Background Low serum copper is often indicative of copper deficiency. Acquired copper deficiency can cause hematological/neurological manifestations. Wilson disease (copper toxicity) is associated with neurological manifestations and low serum copper, with copper deposited in tissues responsible for the toxicity. Low serum copper can also be observed in some carriers of the Wilson disease gene and aceruloplasminemia. This study was undertaken to determine the clinical significance of low serum copper. Methods The Mayo Medical Laboratories', Metals Laboratory database was reviewed over a 9-month period to identify patients who received their care at the Mayo Clinic and had low serum copper. The medical records were analyzed to determine the significance of the low copper. Results In six of the 57 patients with low serum copper, the low copper was due to Wilson disease. In the remaining 51 patients, copper deficiency due to an underlying cause was identified in 38 as a reason for the low serum copper. The most commonly identified neurological manifestation of copper deficiency was myeloneuropathy. Coexisting nutrient deficiencies and hematological manifestations of copper deficiency were often but not invariably present. Conclusions Copper deficiency, Wilson disease (or a carrier state), and aceruloplasminemia are all associated with low serum copper. The presence of coexisting neurological or hematological manifestations that are recognized sequelae of copper deficiency should be considered prior to making a diagnosis of copper deficiency. Gastrointestinal disease or surgery is a common cause of acquired copper deficiency. Even in patients in whom low serum copper is indicative of copper deficiency, the cause of the copper-deficient state may not be evident.

Clinical significance of the laboratory determination of low serum copper in adults

Dystonias can be classified as primary or secondary, as dystonia-plus syndromes, and as heredodegenerative dystonias. Their prevalence is difficult to determine. In our experience 80–90% of all dystonias are primary. About 20–30% of those have a genetic background; 10–20% are secondary, with tardive dystonia and dystonia in cerebral palsy being the most common forms. If dystonia in spastic conditions is accepted as secondary dystonia, this is the most common form of all dystonia.

In primary dystonias, the dystonic movements are the only symptoms. In secondary dystonias, dystonic movements result from exogenous processes directly or indirectly affecting brain parenchyma. They may be caused by focal and diffuse brain damage, drugs, chemical agents, physical interactions with the central nervous system, and indirect central nervous system effects. Dystonia-plus syndromes describe brain parenchyma processes producing predominantly dystonia together with other movement disorders. They include dopa-responsive dystonia and myoclonus-dystonia. Heredodegenerative dystonias are dystonic movements occurring in the context of other heredodegenerative disorders. They may be caused by impaired energy metabolism, impaired systemic metabolism, storage of noxious substances, oligonucleotid repeats and other processes. Pseudodystonias mimic dystonia and include psychogenic dystonia and various orthopedic, ophthalmologic, vestibular, and traumatic conditions.

Unusual manifestations, unusual age of onset, suspect family history, suspect medical history, and additional signs may indicate nonprimary dystonia. If they are suspected, etiological clarification becomes necessary. Unfortunately, potential etiologies are legion. Diagnostic algorithms can be helpful.

Treatment of nonprimary dystonias, with few exceptions, does not differ from treatment of primary dystonias. The most effective treatment for focal and segmental dystonias is local botulinum toxin injections. Deep brain stimulation of the globus pallidus internus is effective for generalized dystonia. Antidystonic drugs, including anticholinergics, tetrabenazine, clozapine, and gamma-aminobutyric acid receptor agonists, are less effective and often produce adverse effects. Dopamine is extremely effective in dopa-responsive dystonia. The Bertrand procedure can be effective in cervical dystonia. Other peripheral surgery, including myotomy, myectomy, neurotomy, rhizotomy, ramizectomy, and accessory nerve neurolysis, has largely been abandoned. Central surgery other than deep brain stimulation is obsolete. Adjuvant therapies, including orthoses, physiotherapy, ergotherapy, behavioral therapy, social support, and support groups, may be helpful. Analgesics should also be considered where appropriate.

Chapter 38 - Nonprimary dystonias

Tourette's syndrome is a neurodevelopmental disorder clinically characterized by multiple motor and phonic tics. It is likely that a neurobiological susceptibility to the disorder is established during development by the interaction of genetic, biochemical, immunological, and environmental factors. This study sought to investigate the possible correlation of several immunological and biochemical markers with Tourette's syndrome. Children with Tourette's syndrome attending a tertiary pediatric medical center from May 2008 to April 2010, and healthy age-matched control subjects underwent a comprehensive biochemical and immunological work-up. Demographic data were abstracted from the medical records. Findings were compared between the groups and analyzed statistically. Sixty-eight children with Tourette's syndrome (58 males, 85.3%) and 36 healthy children (25 males, 69.4%) were recruited. Compared with the control group, the Tourette's syndrome group had significantly higher levels of ferritin (p = 0.01) and hemoglobin (p = 0.02), a lower level of zinc (p = 0.05), and a lower percentage of non-ceruloplasmin copper (p = 0.01). Analysis of the immunological markers revealed no significant between-group differences in IgA, IgM or IgG; however, IgE and IgG-4 levels were significantly higher in the Tourette's syndrome group (p = 0.04 and p = 0.02, respectively). Children with Tourette's syndrome have high levels of biochemical indices of oxidative stress and the quantitative immunoglobulins. These findings add to the still-limited knowledge on the pathogenesis of Tourette's syndrome and may have implications for the development of novel therapeutic modalities.

Involvement of immunologic and biochemical mechanisms in the pathogenesis of Tourette’s syndrome

A few patients with an affected CNS involving abnormalities in copper metabolism have been described that do not fit any known nosological entities such as Wilson's disease or Menkes' disease. Three sporadic patients (two men and one woman) were examined with involuntary movements and dysarthria associated with abnormal concentrations of serum copper, serum ceruloplasmin, and urinary copper excretion. The onset of neurological symptoms occurred at the age of 15 to 17 years. The common clinical symptoms were involuntary movements and dysarthria. The involuntary movements included dystonia in the neck, myoclonus in the shoulder, athetosis in the neck, and rapid orobuccal movements. The dysarthria consisted of unclear, slow, and stuttering speech. Two of the three patients did not have dementia. A cousin of the female patient had been diagnosed as having Wilson's disease and had died of liver cirrhosis. Laboratory findings showed a mild reduction in serum copper and ceruloplasmin concentrations, whereas urinary copper excretion was significantly reduced in all three patients. Two of the three patients showed a high signal intensity in the basal ganglia on T2 weighted brain MRI. In conclusion, the unique findings of involuntary movements, dysarthria, and abnormal serum copper and urinary copper concentrations suggest that the three patients may constitute a new clinical entity that is distinct from either Wilson's or Menkes disease.

https://jnnp.bmj.com/content/jnnp/71/6/780.full.pdf

N Shimizu

Papers

A new neurological entity manifesting as involuntary movements and dysarthria with possible abnormal copper metabolism.