Professor Wadia’s contributions to neurology and spinocerebellar ataxia type 2

A contribuição do professor Wadia à neurologia e a ataxia espinocerebelar tipo 2

Fernando Spina Tensini José Luiz Pedroso Orlando G.P. Barsottini Hélio A. G. Teive About the authors

ABSTRACT

The authors present a historical review of the seminal contributions of Professor N. H. Wadia (1925-2016) to neurology, in particular, the first description of spinocerebellar ataxia type 2.

spinocerebellar ataxias; saccades

RESUMO

Os autores apresentam uma revisão histórica sobre a contribuição seminal do Professor N.H. Wadia para a Neurologia, em particular, a primeira descrição mundial da ataxia espinocerebelar tipo 2.

ataxias espinocerebelares; movimentos sacádicos

Spinocerebellar ataxia type 2 (SCA 2) is a rare hereditary neurodegenerative disease caused by expansion of an unstable repeat in the ataxin-2 gene on chromosome 12 (12q23-24.1)11. Pulst SM. Degenerative ataxias, from genes to therapies. The 2015 Cotzias Lecture. Neurology. 2016;86(24):2284-90. https://doi.org/10.1212/WNL.0000000000002777
https://doi.org/10.1212/WNL.000000000000...
. Clinically, SCA 2 is characterized by progressive cerebellar ataxia accompanied by slow saccadic eye movements and signs of peripheral neuropathy11. Pulst SM. Degenerative ataxias, from genes to therapies. The 2015 Cotzias Lecture. Neurology. 2016;86(24):2284-90. https://doi.org/10.1212/WNL.0000000000002777
https://doi.org/10.1212/WNL.000000000000...
. However, the phenotype can be pleomorphic and can include parkinsonism (L-dopa responsive), dementia, movement disorders (chorea and dystonia), amyotrophic lateral sclerosis (ALS) and other extracerebellar features11. Pulst SM. Degenerative ataxias, from genes to therapies. The 2015 Cotzias Lecture. Neurology. 2016;86(24):2284-90. https://doi.org/10.1212/WNL.0000000000002777
https://doi.org/10.1212/WNL.000000000000...
,22. Pedroso JL, Braga-Neto P, Escorcio-Bezerra ML, Abrahão A, Albuquerque MV, Rezende Filho FM et al. Non-motor and extracerebellar features in spinocerebellar ataxia type 2. Cerebellum. 2016 Jan 29. [Epub ahead of print]. https://doi.org/10.1007/s12311-016-0761-5
https://doi.org/10.1007/s12311-016-0761-...
. Spinocerebellar ataxia type 2 has a worldwide distribution but is most frequently found in Cuba (in the province of Holguin)11. Pulst SM. Degenerative ataxias, from genes to therapies. The 2015 Cotzias Lecture. Neurology. 2016;86(24):2284-90. https://doi.org/10.1212/WNL.0000000000002777
https://doi.org/10.1212/WNL.000000000000...
,33. Orozco G, Estrada R, Perry TL, Araña J, Fernandez R, Gonzalez-Quevedo A et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba: clinical, neuropathological, and biochemical findings. J Neurol Sci. 1989;93(1):37-50. https://doi.org/10.1016/0022-510X(89)90159-7
https://doi.org/10.1016/0022-510X(89)901...
. In 1989, Orozco et al. published an outstanding paper on SCA 2 in which they described its clinical, neuropathological and biochemical features33. Orozco G, Estrada R, Perry TL, Araña J, Fernandez R, Gonzalez-Quevedo A et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba: clinical, neuropathological, and biochemical findings. J Neurol Sci. 1989;93(1):37-50. https://doi.org/10.1016/0022-510X(89)90159-7
https://doi.org/10.1016/0022-510X(89)901...
. However, this disorder had already been described in detail in India in 1971 by Wadia and Swami, who emphasized the presence of cerebellar ataxia, and slow eye movements in particular44. Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94(2):359-74. https://doi.org/10.1093/brain/94.2.359
https://doi.org/10.1093/brain/94.2.359...
. Here, we review this very important contribution by Prof. Wadia, of the first clinical description of SCA 2.

NOSHIR H. WADIA – A SHORT BIOGRAPHY

Noshir Hormusji Wadia (Figure 1) was born in 1925 in Surat, Gujarat, India. He chose medicine as his vocation and graduated from Grant Medical College, Mumbai, India, in 195055. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. He then went to London, where he trained as a neurologist between 1952 and 1956. In 1957, he returned to India to dedicate his life to neurology, becoming a clinical neurologist of renowned expertise, an eminent professor and a highly-qualified researcher55. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. In recognition of his contributions to medicine, and neurology in particular, he was awarded the Certificate of Appreciation for Services to Neurology by the World Federation of Neurology in 1993, the Padma Brushan by the Indian government in 2012, honorary membership of the American Neurological Association, fellowship of the Indian National Science Academy, the SS Bhatnagar Indian National Science Academy medal for Excellence in General Science, as well as various other honors55. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. Wadia was also involved with the Sree Chitra Tirunal Institute of Medical Sciences and Technology, of which he was president. He was president of the Neurological Society of India (1963-1964) and a Fellow of the National Academy of Sciences, India, the Indian Academy of Sciences and the Indian National Science Academy55. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. He undertook many activities with the World Federation of Neurology and was awarded the their medal for Services to International Neurology in 2009. Prof. Wadia died on April 10th, 2016, at the age of 9155. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
.

Figure 1
Noshir Hormusji Wadia (1925-2016).

WADIA’S CONTRIBUTIONS TO NEUROLOGY

Wadia made countless contributions to neurology, some of the most notable being studies on manganese poisoning, tuberculous spinal meningitis, congenital atlanto-axial dislocation with myelopathy, and Wilson’s disease in the Parsi community55. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. He published over 130 papers, several chapters in important books and a famous book Neurological Practice: an Indian Perspective55. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. One of Wadia’s best-known contributions was the identification of an adult polio-like disease associated with a hemorrhagic conjunctivitis later known as enterovirus 70 disease55. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. Among his many contributions to neurology and, in particular, to the development of a neurology focusing on the needs of India, we concentrate here on his invaluable work in the field of spinocerebellar ataxias55. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...
. This work was carried out at a time when not only had the advanced genetics techniques available to us today not been developed, but also there was not even an adequate system for classifying the various entities that were being discovered. The most important contribution by Prof. Wadia was the identification, for the first time, of spinocerebellar ataxia with slow eye movements, nowadays defined as SCA 244. Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94(2):359-74. https://doi.org/10.1093/brain/94.2.359
https://doi.org/10.1093/brain/94.2.359...

5. Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
https://doi.org/10.1212/WNL.000000000000...

6. Wadia NH. Heredo: familial spinocerebellar degeneration with slow eye movements: another variety of olivopontocerebellar degeneration. Neurol India. 1977;25(3):147-60.
-77. Wadia N, Pang J, Desai J, Mankodi A, Desai M, Chamberlain S. A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain. 1998;121(12):2341-55. https://doi.org/10.1093/brain/121.12.2341
https://doi.org/10.1093/brain/121.12.234...
.

SPINOCEREBELLAR ATAXIA TYPE 2 – WADIA’S SEMINAL STUDY

In 1971, Wadia published the article A new form of heredo-familial spinocerebellar degeneration with slow eye movements (Figure 2), in which he describes his findings in sixteen patients from nine Indian families44. Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94(2):359-74. https://doi.org/10.1093/brain/94.2.359
https://doi.org/10.1093/brain/94.2.359...
. These patients presented with a form of cerebellar ataxia with slow saccadic eye movements44. Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94(2):359-74. https://doi.org/10.1093/brain/94.2.359
https://doi.org/10.1093/brain/94.2.359...
. Wadia noted that the disease had a clear autosomal dominant pattern in the affected families, with anticipation of age at onset between generations, and that the patients presented with hyporeflexia and features suggestive of peripheral neuropathy. The presence of cerebellar atrophy was suggested but not confirmed because a pathological study was not carried out and the only imaging examination available at the time was pneumoencephalography44. Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94(2):359-74. https://doi.org/10.1093/brain/94.2.359
https://doi.org/10.1093/brain/94.2.359...
. His interest in the disease, which was later called SCA 2, led to the publication, in 1975, of a model of an ocular subsystem based on his findings in these same patients66. Wadia NH. Heredo: familial spinocerebellar degeneration with slow eye movements: another variety of olivopontocerebellar degeneration. Neurol India. 1977;25(3):147-60.,77. Wadia N, Pang J, Desai J, Mankodi A, Desai M, Chamberlain S. A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain. 1998;121(12):2341-55. https://doi.org/10.1093/brain/121.12.2341
https://doi.org/10.1093/brain/121.12.234...
. In the following years he was able to establish a correlation between clinical findings up to that time and olivopontocerebellar atrophy77. Wadia N, Pang J, Desai J, Mankodi A, Desai M, Chamberlain S. A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain. 1998;121(12):2341-55. https://doi.org/10.1093/brain/121.12.2341
https://doi.org/10.1093/brain/121.12.234...
. In the subsequent decade he made two important contributions to our understanding of SCA 2: he showed the importance of correct characterization of patterns of eye movement abnormalities when there is a suspected clinical diagnosis of SCA 288. Pang J, Allotey R, Wadia N, Sasaki H, Bindoff L, Chamberlain S. A common disease haplotype segregating in spinocerebellar ataxia 2 (SCA2) pedigrees of diverse ethnic origin. Eur J Hum Genet. 1999;7(7):841-5. https://doi.org/10.1038/sj.ejhg.5200372
https://doi.org/10.1038/sj.ejhg.5200372...
, and he made progress in the field of genetics by suggesting that the populations affected by SCA 2 in Cuba, England, Japan and India had a common ancestor99. Geiner S, Horn AK, Wadia NH, Sakai H, Büttner-Ennever JA. The neuroanatomical basis of slow saccades in spinocerebellar ataxia type 2 (Wadia-subtype). Prog Brain Res. 2008;171:571-81. https://doi.org/10.1016/S0079-6123(08)00683-3
https://doi.org/10.1016/S0079-6123(08)00...
. In 2008, his last publications on the subject paved the way for further research into the control of eye movements99. Geiner S, Horn AK, Wadia NH, Sakai H, Büttner-Ennever JA. The neuroanatomical basis of slow saccades in spinocerebellar ataxia type 2 (Wadia-subtype). Prog Brain Res. 2008;171:571-81. https://doi.org/10.1016/S0079-6123(08)00683-3
https://doi.org/10.1016/S0079-6123(08)00...
,1010. Ying, SH, Horn AKE, Geiner S, Wadia NH, Büttner-Ennever JA. Selective, circuit-wide sparing of floccular connections in hereditary olivopontine cerebellar atrophy with slow saccades. Prog Brain Res. 2008;171:583-6. https://doi.org/10.1016/S0079-6123(08)00684-5
https://doi.org/10.1016/S0079-6123(08)00...
. Based on histopathological assessment, he suggested that reduced saccade velocity in SCA 2 patients is a result of neuronal loss and reduced synaptic density of excitatory burst neurons in the caudal pons1010. Ying, SH, Horn AKE, Geiner S, Wadia NH, Büttner-Ennever JA. Selective, circuit-wide sparing of floccular connections in hereditary olivopontine cerebellar atrophy with slow saccades. Prog Brain Res. 2008;171:583-6. https://doi.org/10.1016/S0079-6123(08)00684-5
https://doi.org/10.1016/S0079-6123(08)00...
. Pathological findings also enabled him to establish that the floccular and nodular pathways, which control smooth pursuit and vestibular reflexes, are relatively spared whereas elements of the dorsal vermis pathway controlling saccade adaptation are more involved1010. Ying, SH, Horn AKE, Geiner S, Wadia NH, Büttner-Ennever JA. Selective, circuit-wide sparing of floccular connections in hereditary olivopontine cerebellar atrophy with slow saccades. Prog Brain Res. 2008;171:583-6. https://doi.org/10.1016/S0079-6123(08)00684-5
https://doi.org/10.1016/S0079-6123(08)00...
.

Figure 2
Front page of Wadia and Swami11.

In conclusion, Prof. Wadia published several important studies in neurology, most notably the first description of SCA 2, which included a complete clinical evaluation and neuropathological study of the condition.

References

  • 1
    Pulst SM. Degenerative ataxias, from genes to therapies. The 2015 Cotzias Lecture. Neurology. 2016;86(24):2284-90. https://doi.org/10.1212/WNL.0000000000002777
    » https://doi.org/10.1212/WNL.0000000000002777
  • 2
    Pedroso JL, Braga-Neto P, Escorcio-Bezerra ML, Abrahão A, Albuquerque MV, Rezende Filho FM et al. Non-motor and extracerebellar features in spinocerebellar ataxia type 2. Cerebellum. 2016 Jan 29. [Epub ahead of print]. https://doi.org/10.1007/s12311-016-0761-5
    » https://doi.org/10.1007/s12311-016-0761-5
  • 3
    Orozco G, Estrada R, Perry TL, Araña J, Fernandez R, Gonzalez-Quevedo A et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba: clinical, neuropathological, and biochemical findings. J Neurol Sci. 1989;93(1):37-50. https://doi.org/10.1016/0022-510X(89)90159-7
    » https://doi.org/10.1016/0022-510X(89)90159-7
  • 4
    Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94(2):359-74. https://doi.org/10.1093/brain/94.2.359
    » https://doi.org/10.1093/brain/94.2.359
  • 5
    Katrak SM, Singhal BS. Noshir Hormusji Wadia, MD, FRCP, FNA, FANA (1925-2016). Neurology. 2016;87(7):654-5. https://doi.org/10.1212/WNL.0000000000002995
    » https://doi.org/10.1212/WNL.0000000000002995
  • 6
    Wadia NH. Heredo: familial spinocerebellar degeneration with slow eye movements: another variety of olivopontocerebellar degeneration. Neurol India. 1977;25(3):147-60.
  • 7
    Wadia N, Pang J, Desai J, Mankodi A, Desai M, Chamberlain S. A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain. 1998;121(12):2341-55. https://doi.org/10.1093/brain/121.12.2341
    » https://doi.org/10.1093/brain/121.12.2341
  • 8
    Pang J, Allotey R, Wadia N, Sasaki H, Bindoff L, Chamberlain S. A common disease haplotype segregating in spinocerebellar ataxia 2 (SCA2) pedigrees of diverse ethnic origin. Eur J Hum Genet. 1999;7(7):841-5. https://doi.org/10.1038/sj.ejhg.5200372
    » https://doi.org/10.1038/sj.ejhg.5200372
  • 9
    Geiner S, Horn AK, Wadia NH, Sakai H, Büttner-Ennever JA. The neuroanatomical basis of slow saccades in spinocerebellar ataxia type 2 (Wadia-subtype). Prog Brain Res. 2008;171:571-81. https://doi.org/10.1016/S0079-6123(08)00683-3
    » https://doi.org/10.1016/S0079-6123(08)00683-3
  • 10
    Ying, SH, Horn AKE, Geiner S, Wadia NH, Büttner-Ennever JA. Selective, circuit-wide sparing of floccular connections in hereditary olivopontine cerebellar atrophy with slow saccades. Prog Brain Res. 2008;171:583-6. https://doi.org/10.1016/S0079-6123(08)00684-5
    » https://doi.org/10.1016/S0079-6123(08)00684-5
  • 11
    Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94:359-74. https://doi.org/10.1093/brain/94.2.359
    » https://doi.org/10.1093/brain/94.2.359

Publication Dates

  • Publication in this collection
    Apr 2017

History

  • Received
    13 Nov 2016
  • Accepted
    06 Dec 2016
Academia Brasileira de Neurologia - ABNEURO R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices Torre Norte, 04101-000 São Paulo SP Brazil, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revista.arquivos@abneuro.org