Sixty years of the first studies by Horácio Martins Canelas on Wilson's disease

Abstract

Research into Wilson's disease (WD) in Brazil had the effective participation of Professor Horácio Martins Canelas, from the Neurologic Clinic of the Teaching Hospital of the School of Medicine of Universidade de São Paulo (USP). His exponential contributions to the study of WD placed Brazil on the international stage, making USP's Neurologic Clinic one of the world's leading research centers in the area of neurodegenerative diseases with metal accumulation.

Keywords

Hepatolenticular Degeneration - Kayser-Fleischer Rings - Fibrosis - History

INTRODUCTION

Wilson's disease (WD) is an autosomal recessive disorder of the copper metabolism, leading to its accumulation in different organs and tissues. Hepatic and neurological symptoms are its main clinical features.[1] [2]

Prior to Kinnier Wilson's classic description, WD was described by various authors in the form of case reports, such as Frerichs in 1861, Westphal in 1883 (“Pseudosclerosis”), Gowers in 1888 (“Tetanoid chorea”) and in 1906 (“On tetanoid chorea and its association with cirrhosis of the liver”), Strümpell in 1898 and 1899, Omerod in 1890, and Homén in 1890.[1] [2] [3]

In 1902, Kayser[4] reported the presence of a greenish-brown ring around the cornea of a 23-year-old man, thought to have multiple sclerosis. The following year, Fleischer[5] described the same pigmented ring in a case of “pseudosclerosis” and in another case of alleged multiple sclerosis.

In 1902 and 1903, Kayser[4] [5] reported the presence of a greenish-brown ring around the cornea of two patients, who were thought to have multiple sclerosis, with one of them also being reported with “pseudosclerosis.”

In 1911, Wilson presented his monograph describing the “progressive lenticular degeneration”, which resulted in the publication of a historical paper in Brain Journal, with the title “Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver”, the following year.[1] In these seminal reports, Wilson described four personal cases (three of them with neuropathological study), two referred by Gowers and Ormerod, and six other cases from the literature. He emphasized the familial character of some cases, as well as the presence of cirrhosis of the liver, mostly asymptomatic. However, Wilson believed the liver did not contribute to the disease's clinical progression.[1]

Wilson did not note, in his first papers, a relationship between his cases and the pseudosclerosis of Westphal-Strümpell. However, 2 years later, while writing on “progressive lenticular degeneration,” the author mentioned similarities between the entities.[6]

After Wilson's seminal publication, research into the disease took a major step forward, with evidence of an increase in the amount of copper in the liver, as well as evidence of an elevation in copper concentration in the urine of the patients with WD.[6] In 1948, Cumings[7] proved the accumulation of copper in the liver and brain of this cohort.

Treatment plans with copper chelating agents were unsuccessful until the introduction of the penicillamine by Walshe,[8] in 1956, which made long-term treatment of the disease possible. Until then, the disease had been invariably fatal.

CANELAS' CONTRIBUTION TO THE STUDY OF WILSON'S DISEASE IN BRAZIL

The Brazilian neurological literature registers one WD case report made by Austregésilo Filho,[9] in 1944. The second case registered was a 20-year-old patient studied in Division of Neurology of the Teaching Hospital of the School of Medicine of Universidade de São Paulo (USP), under the supervision of Drs. Ibrahim Mathias and Oswaldo Lange, with the typical “wing beat tremor” and Kayser-Fleischer's rings.[10]

At the beginning of the 1960s, penicillamine had already been used in several countries in Europe and the USA and its efficacy was definitively proven. Thus, WD left a long list of untreatable, inherited, metabolic neurological diseases and begun to attract the interest of a growing number of researchers worldwide, focused on precise diagnosis and correct treatments.[6] [8] At that time, in Brazil, Horácio Martins Canelas ([Figure 1]) developed a project to investigate WD at USP's Neurologic Clinic, which would become one of the most fruitful lines of research in the following decades. Horacio Martins Canelas was a full professor of Clinical Neurology at USP's School of Medicine. He was a disciple of Professor Aderbal Tolosa, who replaced Professor Enjolras Vampre, a pioneer of neurology in the state of São Paulo who died prematurely as a full professor at USP's School of Medicine.

Figure 1 Professor Horácio Martins Canelas (1919–1995) at the Brazilian Neurology Congress, Belo Horizonte, 1986.

To develop this research project, Canelas collaborated with Francisco Bastos de Jorge, who cooperated with laboratorial support. As such, in 1962, Canelas published, along with de Jorge and Costa-Silva, a paper focusing on the copper determination methodology in biological materials.[11] In the following year, Canelas published, with de Jorge and Spina-França's participation, a study concerning the average values of copper in the blood, cerebrospinal fluid, and urine.[12] In 1964, again with de Jorge, a study of ceruloplasmin levels in normal individuals was published.[13] In the same year, Canelas and his collaborators achieved an international publication in Clinica Chimica Acta (Amsterdam, Netherlands) concerning copper concentration in the saliva, salivary glands, and pancreas.[14] With these pioneering studies, Canelas and his team achieved the know-how of laboratorial tools to evaluate copper metabolism.

Besides the laboratorial investigations, Canelas and his team reported important clinical studies.[15] [16] Thus, in 1963, Canelas and his collaborators published a detailed study of 3 cases of WD, two of which included neuropathological examination.[15]

In 1967, Canelas, de Jorge, and Tognola published a fascinating comparative study of copper metabolism in patients with WD undergoing a vegetarian and mixed diet in the Journal of Neurology, Neurosurgery, and Psychiatry.[17]

Canelas' main publications on WD are summarized in [Table 1].

Table 1 Canelas' main publications on Wilson's disease

Year	Journal	Topic
1963	Arq Neuropsiquiatr	Ceruloplamin levels in the blood
1963	Rev Paul Med	Copper metabolism – blood, CSF, and urine
1963	Arq Neuropsiquiatr	WD – Clinical and biochemical study
1964	Clin Chim Acta	Copper metabolism – saliva, salivary glands, and pancreas
1966	Rev Paul Med	Case series of WD
1966	Rev Bras Oftalmol	Copper levels in ocular tissues
1967	J Neurol Neurosurg Psychiatr	Metabolic balances of copper and diets
1976	Rev Hosp Clin Fac Med São Paulo	WD and pregnancy
1976	Arq Neuropsiquiatr	Copper and ceruloplasmin blood serum of peripheral veins and pre-hepatic veins
1978	Acta Neurol Scand	WD and osteoarhtopathy
1978	Acta Neurol Scand	WD and heart involvement
1985	Arq Neuropsiquiatr	WD – study of 95 cases
1987	Arq Neuropsiquiatr	WD abdominal ultrasonography – 33 patients
1987	Arq Neuropsiquiatr	WD – 102 cases
1990	Arq Neuropsiquiatr	WD and non-Wilsonian extrapyramidal syndrome – case report
1991	Arq Neuropsiquiatr	Case series – 76 WD treated patients
1992	Arq Neuropsiquiatr	WD and Zinc treatment – report of 3 cases
1993	Rev Paul Med	WD – Brain MRI and clinical correlation in 16 patients

Abbreviations: Acta Neurol Scand, Acta Neurologica Scandinavica; Arq Neuropsiquiatr, Arquivos de Neuro-Psiquiatria; Clin Chim Acta, Clinical Chimica Acta; CSF, cerebrospinal fluid; J Neurol Neurosurg Psychiatry, Journal of Neurology, Neurosurgery and Psychiatry; MRI, magnetic resonance inaging; Rev Bras Oftalm, Revista Brasileira de Oftalmologia; Rev Hosp Clin Fac Med São Paulo, Revista do Hospital de Clínicas da Faculdade de Medicina da Universidade de São Paulo; Rev Paul Med, Revista Paulista de Medicina; WD, Wilson's disease.

With these publications, Canelas raises USP's Neurologic Clinicas a national and international reference center for WD research. This line of investigation remains one of the most traditional of USP's Neurologic Clinic and, for the past 36 years, has counted with an effective participation of researchers from the Gastroenterology Department.[18] [19]

Professor Canelas was my advisor (ERB) in my master's and doctorate theses, both of which had WD as their theme. In the preparation of these academic works, through his constant and dedicated collaboration, I was able to observe his talent as a university professor, capable of transmitting the complex guidelines for the elaboration of a scientific text in a didactic manner, with the strictest standards. Professor Canelas was deeply knowledgeable about Brazilian Portuguese, and everyone who had the privilege of writing academic texts under his guidance improved the quality of their scientific writing.

Conflict of Interest

The authors have no conflict of interest to declare.

Authors' Contributions

ERB, HAGT, ELRC: conception and design of the present manuscript; JBP, RC, PAAMB: organized and analyzed the historical data, performed the literature review, organized the figures and wrote the manuscript. All authors contributed to reviewing the manuscript and approved the submitted version.

Editor-in-Chief: Ayrton Roberto Massaro.

Associate Editor: Ylmar Correa Neto.

• References

• 1 Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 1912; 34: 295-509
• 2 Scheinberg H. Sternlieb. Wilson's disease. Philadelphia Saunders;; 1984: 4-8
• 3 Tyler KL. Classics in neurology. Fragments of neurologic history: “Tetanoid Chorea” and progressive lenticular degeneration. Neurology 1983; 33 (04) 461-462
• 4 Kayser B. Über einen Fall von angeborener grünlicher Verfärbung der Cornea. Klin Monbl Augenheilkd 1902; 40: 22-25
• 5 Fleischer B. Zwei weitere Fälle von grünlicher Verfärbung der Kornea. Klin Monbl Augenheilkd 1903; 41: 489-491
• 6 Walshe JM. History of Wilson's disease: 1912 to 2000. Mov Disord 2006; 21 (02) 142-147
• 7 Cumings JN. The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration. Brain 1948; 71 (Pt. 4): 410-415
• 8 Walshe JM. Wilson's disease; new oral therapy. Lancet 1956; 270 (6906) 25-26
• 9 Autregesilo-Filho A. Degeneração mucóide da oligodendroglia em um caso de enfermidade do tipo Wilson. Arq Neuropsiquiatr 1944; 2: 1706
• 10 Barbosa ER, Machado AA, Cançado EL, Deguti MM, Scaff M. Wilson's disease: a case report and a historical review. Arq Neuropsiquiatr 2009; 67 (2B): 539-543
• 11 de JORGE F, Canelas HM, Spina-França A. [Contribution to the study of copper metabolism. II. Normal blood, cerebrospinal fluid and urine levels]. Rev Paul Med 1963; 62: 125-128 Portuguese. PMID: 13964904
• 12 de JORGE F, Canelas HM. de COSTA-SILVA. [Contribution to the study of copper metabolism. I. Methodology of determination of copper in biological materials]. Rev Paul Med 1962; 61: 350-355 Portuguese. PMID: 13964903
• 13 Canelas HM, De Jorge FB. Studies on ceruloplasmin: I - Normal concentrations in blood serum. . Arq Neuropsiquiatr 1964; 22: 271-276 Portuguese.
• 14 Canelas HM, De Jorge FB, Dias JC, Cury L. Studies on copper metabolism. III: Cooper contents of saliva, pancreas, and salivary glands. Clin Chim Acta 1964; 9: 148-150
• 15 Canelas HM, Escalante OD, de Jorge FB, Rocha-Quintão EC. Hepatolenticular degeneration; Clinical and biochemical study of three cases. Arq Neuropsiquiatr 1963; 21: 229-250
• 16 Cançado EL, Rocha MdeS, Barbosa ER. et al. Abdominal ultrasonography in hepatolenticular degeneration. A study of 33 patients. Arq Neuropsiquiatr 1987; 45 (02) 131-136
• 17 Canelas HM, de Jorge FB, Tognola WA. Metabolic balances of copper in patients with hepatolenticular degeneration submitted to vegetarian and mixed diets. J Neurol Neurosurg Psychiatry 1967; 30 (04) 371-373
• 18 Deguti MM, Genschel J, Cancado EL. et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat 2004; 23 (04) 398
• 19 Machado A, Chien HF, Deguti MM. et al. Neurological manifestations in Wilson's disease: Report of 119 cases. Mov Disord 2006; 21 (12) 2192-2196

Publication History

Received: 28 December 2023

Accepted: 29 September 2024

Article published online:
24 February 2025