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Shy–Drager Syndrome
Shy–Drager Syndrome
peripheral changes occurring in both blood platelets and gut enterochromaffin cell compartments.
Diagnosis and Treatment Serotonin syndrome has been reported in patients of all ages, including infants due to in utero exposure. The diagnosis of serotonin syndrome is guided by the criteria defined in 1991 by Harvey Sternbach, Professor of Psychiatry at UCLA. More recently, Australian researchers have developed the ‘Hunter Serotonin Toxicity Criteria,’ which have better sensitivity. There is no laboratory test for serotonin syndrome even if an elevation of the total creatine kinase and leukocyte count, elevated transaminase levels, or lower bicarbonate blood levels have been reported. The most important clinical symptoms to be considered in serotonin syndrome are tremor, akathisia, or myoclonus. The physical examination of the patient should include assessment of deep tendon reflexes and muscle rigidity, the dryness of oral mucosa, the size and reactivity of the pupils, the intensity of bowel sounds, the skin color, and the quality of sweating. The physical examination must be complemented by a detailed history of any prescribed or illicit drug use. Serotonin toxicity usually gives a specific clinical picture, but at times may be mistaken for viral illness, an anxiety attack, neurological disorders, anticholinergic poisoning, sympathomimetic toxicity, or neuroleptic malignant syndrome (NMS). Serotonin syndrome and NMS can be distinguished by the fact that 5-HT toxicity has a rapid onset and responds to pharmacological blockade with drugs such as chlorpromazine and cyproheptadine. Dopamine blockade in NMS has a slow onset following the administration of a
neuroleptic drug and responds to dopamine agonists such as bromocryptine. The management of serotonin syndrome involves the removal of serotonergic agents. Supporting care includes the administration of intravenous electrolyte solution in order to maintain a physiological diuresis. Benzodiazepines may be used to control agitation and reduce anxiety. Upon initiation of therapy and discontinuation of serotonergic drugs, most cases of serotonin syndrome resolve within 24 hours. In some cases, muscle pain and weakness can persist for several months. Nevertheless, an appropriate medical management of serotonin syndrome is generally associated with a favorable prognosis. See also: Antidepressants and Movement Disorders; Serotonin and Tryptophan.
Further Reading Birmes P, Coppin D, Schmitt L, and Lauque D (2003) Serotonin syndrome: A brief review. Canadian Medical Association Journal 168(11): 1439–1443. Gillman PK (1997) Serotonin syndrome treated with chlorpromazine. Journal of Clinical Psychopharmacology 17: 128–129. Gillman PK (1999) The serotonin syndrome and its treatment. Journal of Psychopharmacology 13: 100–109. Lane R and Baldwin D (1997) Selective serotonin reuptake inhibitorinduced serotonin syndrome: Review. Journal of Clinical Psychopharmacology 17: 208–221. LoCurto MJ (1997) The serotonin syndrome. Emergency Medicine Clinics of North America 15: 665–675. Mills KC (1997) Serotonin syndrome. A clinical update. Critical Care Clinics 13: 763–783. Sternbach H (1991) The serotonin syndrome. American Journal of Psychiatry 148: 705–713. Trindade E, Menon D, Topfer LA, and Coloma C (1998) Adverse effects associated with selective serotonin reuptake inhibitors and antidepressants: A meta-analysis. Canadian Medical Association Journal 159: 1245–1252.
Shy–Drager Syndrome C Colosimo, Sapienza University of Rome, Rome, Italy D Tiple, Sapienza University of Rome, Rome, Italy ã 2010 Elsevier Ltd. All rights reserved.
Glossary Multiple system atrophy (MSA) – A term coined to describe the clinical and pathological overlap among three major neurodegenerative diseases which were previously described separately: (1) Shy–Drager syndrome, (2) striatonigral degeneration, and (3) sporadic olivopontocerebellar atrophy.
111
Olivopontocerebellar atrophy – Indicates primarily cerebellar defects due to degeneration of neurons in specific areas of the brainstem (pons and inferior olives) and the cerebellum, with minor degrees of parkinsonism. It may be sporadic or genetically determined. Orthostatic hypotension – Sudden fall in blood pressure that occurs when a person assumes a
112
Shy–Drager Syndrome
standing position manifested by dizziness, lightheadedness, blurred vision, and syncope. Shy–Drager syndrome – Neurological syndrome characterized by severe autonomic failure (orthostatic hypotension, urinary retention or incontinence, and male erectile failure) combined with parkinsonism, cerebellar and pyramidal signs. Striatonigral degeneration – A disease caused by the degeneration of the striatum and substantia nigra, clinically presenting as parkinsonism with or without some degree of autonomic and cerebellar dysfunction.
Definition and History In May 1960, Milton Shy from the National Institutes of Health and Glenn Drager from Baylor College of Medicine described a neurological syndrome associated with orthostatic hypotension, termed later as the Shy–Drager syndrome (Figure 1). In their original article, they described the clinical features of two male patients who developed autonomic failure followed by other neurological symptoms. Their description of the new syndrome comprised of a complex series of symptoms and signs, including autonomic failure (orthostatic hypotension, urinary and rectal incontinence, impotence, loss of sweating, and iris atrophy), parkinsonism (rigidity, tremor, loss of associated movements), involvement of the anterior horn cells (fasciculations, wasting of distal muscles, evidence of a neuropathic lesions in the electromyogram, and in the muscle biopsy), and external ocular palsy. They were also able to carefully study the neuropathologic changes in one of these patients, in whom neuronal degeneration at many sites was found, including the intermediolateral columns of the spinal cord. Numerous clinical details were cited in the text, though other parts of the article were discordant (description of the rectal incontinence and ocular muscle paresis in both patients, presence of fasciculations in patient 2 instead of patient 1, and presence of distal wasting in patient 2, whereas the text stated there was none). Although meticulously delineated in the article text, the ‘full syndrome’ description also failed to mention cerebellar and pyramidal signs. Shy and Drager recognized that there was a link between low blood pressure during erect posture (orthostatic hypotension) and disturbance in the central autonomic nervous system. Since their seminal report, growing interest in autonomic disorders has spawned studies outlining the clinical and neuropathologic findings in such patients.
Figure 1 (a) Milton Shy (b) Glenn Drager.
The eponym Shy–Drager syndrome became popular, but then it has been progressively replaced by the use of a new term, multiple system atrophy (MSA). This was first coined in 1969 by two British authors, Graham and Oppenheimer. The term MSA recognized the significant clinical and pathological overlap among three major neurodegenerative diseases which were previously described separately: (1) Shy–Drager syndrome, (2) striatonigral degeneration, and (3) sporadic olivopontocerebellar atrophy.
Shy–Drager Syndrome
Clinical Features and Diagnostic Criteria For various reasons, some uncertainty in the terminology generated over the following years. For instance, Wenning et al. described a series of 100 patients with clinically probable MSA (15 of them pathologically confirmed); in none of them, the ‘full Shy–Drager syndrome’ was found. These authors described fecal incontinence in only two patients, but neither of them had suffered painful muscle cramps or iris atrophy, and only one had fasciculations, weakness, and focal muscle atrophy. Although they admitted that rectal incontinence, iris atrophy, external ocular palsies, and signs suggestive of anterior horn cell involvement can occur occasionally in MSA, these features should not be considered typical of the disease. In addition, they suggested that the term Shy–Drager should be restricted to the situation in which severe autonomic failure (male erectile failure, orthostatic hypotension, urinary retention, or incontinence) is combined with parkinsonism, cerebellar and pyramidal signs. Respiratory stridor (high-pitched breathing sounds due to airway obstruction) and stimulussensitive finger myoclonus, developing each in one-third of cases, were included as optional diagnostic criteria. Unlike the original description (which antedated the introduction of levodopa), information on the response to levodopa treatment (which is often poor or absent in MSA, except for 20–30% of the cases in whom it may be transiently good) was also included. In a subsequent commentary, Quinn et al. substantiated that the Shy–Drager syndrome signifies autonomic failure plus central nervous system dysfunction attributable to MSA, and that it is inappropriate to use the term simply as a shorthand for parkinsonism with autonomic failure. However, it later became clear that the new complex classification was not well served by the term ‘Shy–Drager syndrome.’ Thus, a new terminology was needed. The American Autonomic Society and the American Academy of Neurology eventually disapproved the Shy–Drager syndrome as a disease entity in 1996, and existing cases were redefined as MSA with autonomic involvement. However, the term ‘Shy–Drager syndrome’ is still used occasionally for MSA when the primary symptom is autonomic failure. At the very least, this nomenclature implies that several areas in the central nervous system are involved in the neurodegenerative process. MSA is defined as a sporadic, progressive, adult-onset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. Onset usually takes place in the sixth or seventh decade, and most patients are severely disabled within 5–7 years. More males are affected than females, and prevalence is less than one in 10 000 persons. The etiology is unknown. Depending upon which part of the central nervous system is affected first, MSA may present in different ways. According to the current diagnostic criteria, MSA is divided into two main
113
clinical categories: (1) MSA–parkinsonism type (MSA–P), which implies parkinsonism with or without some degree of cerebellar dysfunction (striatonigral degeneration), and (2) MSA–cerebellar type (MSA–C), which indicates primarily cerebellar defects with minor degrees of parkinsonism (olivopontocerebellar atrophy). In both conditions, autonomic failure could be a predominant or an associated manifestation of the clinical spectrum of the disease. The most prominent symptom of autonomic failure in MSA is what is known as ‘postural hypotension.’ In cases of severe autonomic insufficiency, wide swings in blood pressure without modification in pulse rate are observed. Upon standing or sitting, patient’s blood pressure drops to such a low level that they get dizzy, lightheaded, or momentarily blackout. Urinary and erectile (in males) dysfunction symptoms are also prominent early features in MSA patients. Urogenital symptoms in MSA are usually due to a complex mixture of central and peripheral nervous abnormalities, sometimes superimposed on previous local pathological conditions such as benign prostatic hyperplasia and perineal laxity. Unfortunately, although orthostatic hypotension and bladder disorders can be managed successfully, no effective treatment is available for the other manifestations of autonomic dysfunction or for the cerebellar and pyramidal symptoms. MSA usually concludes by the patient’s death within 7–10 years after diagnosis. Breathing problems such as aspiration, stridor, or cardiopulmonary arrest are common causes of death. See also: Multiple System Atrophy; Olivopontocerebellar Atrophy; Striatonigral Degeneration.
Further Reading Colosimo C, Geser F, Benarroch EE, and Wenning GK (2006) Multiple System Atrophy. In: Gilman S (ed.) Neurobiology of Disease, pp. 83–94. Academic Press. Gilman S, Wenning GK, Low PA, et al. (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71: 670–676. Graham JG and Oppenheimer DR (1969) Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. Journal of Neurology Neurosurgery and Psychiatry 32: 28–34. Mathias CJ and Williams AC (1994) The Shy Drager syndrome and multiple system atrophy. In: Calne DB (ed.) Neurodegenerative Diseases, pp. 743–767. Philadelphia: WB Saunders. Papatsoris AG, Papapetropoulos S, Singer C, and Deliveliotis C (2008) Urinary and erectile dysfunctions in multiple system atrophy (MSA). Neurourology Urodin 27: 22–27. Quinn NP, Wenning G, and Marsden CD (1995) The Shy–Drager syndrome: What did Shy and Drager really describe? Archives of Neurology 52: 656–657. Sandroni P, Ahlskog E, Fealey RD, and Low PA (1991) Autonomic involvement in extrapyramidal and cerebellar disorders. Clinical Autonomic Research Society 1: 147–155. Schatz IJ (1996) Farewell to the ‘Shy–Drager syndrome’. Annals of International Medicine 125: 74–75.
114
Sialidosis
Schmidt C, Herting B, Prieur S, et al. (2008) Autonomic dysfunction in different subtypes of multiple system atrophy. Movement Disorders 23: 1766–1772. Shy M and Drager GA (1960) A neurological syndrome associated with orthostatic hypotension. Archives of Neurology 3: 511–527. Testa D, Filippini G, Farinotti M, Palazzini E, and Caraceni T (1996) Survival in multiple system atrophy: A study of prognostic factors in 59 cases. Journal of Neurology 243: 401–404.
The Consensus Committee of the American Autonomic Society and the American Academy of Neurology (1996) Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 46: 1470. Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, and Quinn NP (1994) Clinical features and natural history of multiple system atrophy: An analysis of 100 cases. Brain 117: 835–845.
Sialidosis S Igdoura, Departments of Biology and Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada ã 2010 Elsevier Ltd. All rights reserved.
Clinical Presentation An inherited, primary deficiency of lysosomal sialidase was first demonstrated in the severe form of Sialidosis (type II). Shortly thereafter, several investigators described a similar deficiency in a clinically milder disorder, ‘cherryred spot-myoclonus syndrome,’ now classified as Sialidosis type I, which becomes apparent during the second decade of life. Associated symptoms include cherry-red spots within the middle layers of the eyes; loss of visual clarity; and sudden, involuntary, ‘shock-like’ contractions (myoclonus) of muscles of the arms and legs. The myoclonus is progressive in nature and may be triggered by voluntary movements (action myoclonus) or certain external stimuli such as sound (reflex myoclonus).
Pathogenesis/Pathophysiology In type I patients, increased excitability and reduced inhibition were found in some cortical motor pathways, but no abnormalities were found in the brain stem and spinal motor pathways tested. These findings suggest that the electrophysiological abnormalities are restricted to a level above the brainstem. While pathological features of lysosomal storage are apparent in the brainstem and spinal cord, circuits within the brainstem or spinal cord do not appear affected. Biochemically, this may be explained by the more profound role for Sialidase on the plasma membrane in the brain cerebellar cortex and the cerebellum. Sialidase deficiency leads to defective lysosomal catabolism of sialoglycoconjugates with their subsequent accumulations in tissues and excessive excretion in the urine. The concentration of urinary oligosaccharides is reported to be correlated with the clinical severity of the affected patients,
that is, over 3 times more in the infantile-type II Sialidosis patients than in the late-type I patients. Sialidosis patients will excrete high sialic acid conjugated molecules in the urine. Sialidosis has traditionally been diagnosed using enzyme assays that measure sialidase activity in blood leukocytes. Enzyme diagnostic tests for Sialidosis use a variety of both natural (sialyllactose, sialylhexasaccharides, and fetuin) and synthetic (3-methoxyphenyl-N-acetylneuraminic acid and 4-methylumbelliferyl-a-D-N-acetyl-neuraminic acid, muNANA) substrates. Only in recent times has it become possible to probe the disease at the level of the DNA lesion. Human lysosomal sialidase (44 kDa) exists in a multienzyme complex consisting of b-galactosidase, cathepsin A, and sialidase (GCS complex). Cathepsin A is required to promote the formation of the enzyme complex. Mechanistically, the sialidase associates with cathepsin A in the endoplasmic reticulum and is then transported to the lysosomes. In fact, transport impaired cathepsin A prevents sialidase from reaching the lysosomes. The sialidase complex is also present on the cell membrane where it is involved in cellular signaling, particularly, in T-lymphocytes, where it activates the macrophage activating factor. Genetically, Sialidosis is inherited as an autosomal recessive trait. The human sialidase gene was mapped to chromosome 6p2l within the human major histocompatibility complex (MHC). The human and mouse sialidase genes are structurally similar (both about 4.5 kb). The two genes contain five introns which range in size from 96 bp to 1.2 kb. The levels of sialidase expression in different mouse tissues, evaluated by Northern blot analysis, were found to be high in kidney, epididymis, brain and spinal cord, and moderate to low in adrenal, liver, lung, spleen, and heart. The isolation and cloning of the human lysosomal sialidase gene has allowed for the characterization of many disease-causing mutations. Thus far, more than
peripheral changes occurring in both blood platelets and gut enterochromaffin cell compartments.
Diagnosis and Treatment Serotonin syndrome has been reported in patients of all ages, including infants due to in utero exposure. The diagnosis of serotonin syndrome is guided by the criteria defined in 1991 by Harvey Sternbach, Professor of Psychiatry at UCLA. More recently, Australian researchers have developed the ‘Hunter Serotonin Toxicity Criteria,’ which have better sensitivity. There is no laboratory test for serotonin syndrome even if an elevation of the total creatine kinase and leukocyte count, elevated transaminase levels, or lower bicarbonate blood levels have been reported. The most important clinical symptoms to be considered in serotonin syndrome are tremor, akathisia, or myoclonus. The physical examination of the patient should include assessment of deep tendon reflexes and muscle rigidity, the dryness of oral mucosa, the size and reactivity of the pupils, the intensity of bowel sounds, the skin color, and the quality of sweating. The physical examination must be complemented by a detailed history of any prescribed or illicit drug use. Serotonin toxicity usually gives a specific clinical picture, but at times may be mistaken for viral illness, an anxiety attack, neurological disorders, anticholinergic poisoning, sympathomimetic toxicity, or neuroleptic malignant syndrome (NMS). Serotonin syndrome and NMS can be distinguished by the fact that 5-HT toxicity has a rapid onset and responds to pharmacological blockade with drugs such as chlorpromazine and cyproheptadine. Dopamine blockade in NMS has a slow onset following the administration of a
neuroleptic drug and responds to dopamine agonists such as bromocryptine. The management of serotonin syndrome involves the removal of serotonergic agents. Supporting care includes the administration of intravenous electrolyte solution in order to maintain a physiological diuresis. Benzodiazepines may be used to control agitation and reduce anxiety. Upon initiation of therapy and discontinuation of serotonergic drugs, most cases of serotonin syndrome resolve within 24 hours. In some cases, muscle pain and weakness can persist for several months. Nevertheless, an appropriate medical management of serotonin syndrome is generally associated with a favorable prognosis. See also: Antidepressants and Movement Disorders; Serotonin and Tryptophan.
Further Reading Birmes P, Coppin D, Schmitt L, and Lauque D (2003) Serotonin syndrome: A brief review. Canadian Medical Association Journal 168(11): 1439–1443. Gillman PK (1997) Serotonin syndrome treated with chlorpromazine. Journal of Clinical Psychopharmacology 17: 128–129. Gillman PK (1999) The serotonin syndrome and its treatment. Journal of Psychopharmacology 13: 100–109. Lane R and Baldwin D (1997) Selective serotonin reuptake inhibitorinduced serotonin syndrome: Review. Journal of Clinical Psychopharmacology 17: 208–221. LoCurto MJ (1997) The serotonin syndrome. Emergency Medicine Clinics of North America 15: 665–675. Mills KC (1997) Serotonin syndrome. A clinical update. Critical Care Clinics 13: 763–783. Sternbach H (1991) The serotonin syndrome. American Journal of Psychiatry 148: 705–713. Trindade E, Menon D, Topfer LA, and Coloma C (1998) Adverse effects associated with selective serotonin reuptake inhibitors and antidepressants: A meta-analysis. Canadian Medical Association Journal 159: 1245–1252.
Shy–Drager Syndrome C Colosimo, Sapienza University of Rome, Rome, Italy D Tiple, Sapienza University of Rome, Rome, Italy ã 2010 Elsevier Ltd. All rights reserved.
Glossary Multiple system atrophy (MSA) – A term coined to describe the clinical and pathological overlap among three major neurodegenerative diseases which were previously described separately: (1) Shy–Drager syndrome, (2) striatonigral degeneration, and (3) sporadic olivopontocerebellar atrophy.
111
Olivopontocerebellar atrophy – Indicates primarily cerebellar defects due to degeneration of neurons in specific areas of the brainstem (pons and inferior olives) and the cerebellum, with minor degrees of parkinsonism. It may be sporadic or genetically determined. Orthostatic hypotension – Sudden fall in blood pressure that occurs when a person assumes a
112
Shy–Drager Syndrome
standing position manifested by dizziness, lightheadedness, blurred vision, and syncope. Shy–Drager syndrome – Neurological syndrome characterized by severe autonomic failure (orthostatic hypotension, urinary retention or incontinence, and male erectile failure) combined with parkinsonism, cerebellar and pyramidal signs. Striatonigral degeneration – A disease caused by the degeneration of the striatum and substantia nigra, clinically presenting as parkinsonism with or without some degree of autonomic and cerebellar dysfunction.
Definition and History In May 1960, Milton Shy from the National Institutes of Health and Glenn Drager from Baylor College of Medicine described a neurological syndrome associated with orthostatic hypotension, termed later as the Shy–Drager syndrome (Figure 1). In their original article, they described the clinical features of two male patients who developed autonomic failure followed by other neurological symptoms. Their description of the new syndrome comprised of a complex series of symptoms and signs, including autonomic failure (orthostatic hypotension, urinary and rectal incontinence, impotence, loss of sweating, and iris atrophy), parkinsonism (rigidity, tremor, loss of associated movements), involvement of the anterior horn cells (fasciculations, wasting of distal muscles, evidence of a neuropathic lesions in the electromyogram, and in the muscle biopsy), and external ocular palsy. They were also able to carefully study the neuropathologic changes in one of these patients, in whom neuronal degeneration at many sites was found, including the intermediolateral columns of the spinal cord. Numerous clinical details were cited in the text, though other parts of the article were discordant (description of the rectal incontinence and ocular muscle paresis in both patients, presence of fasciculations in patient 2 instead of patient 1, and presence of distal wasting in patient 2, whereas the text stated there was none). Although meticulously delineated in the article text, the ‘full syndrome’ description also failed to mention cerebellar and pyramidal signs. Shy and Drager recognized that there was a link between low blood pressure during erect posture (orthostatic hypotension) and disturbance in the central autonomic nervous system. Since their seminal report, growing interest in autonomic disorders has spawned studies outlining the clinical and neuropathologic findings in such patients.
Figure 1 (a) Milton Shy (b) Glenn Drager.
The eponym Shy–Drager syndrome became popular, but then it has been progressively replaced by the use of a new term, multiple system atrophy (MSA). This was first coined in 1969 by two British authors, Graham and Oppenheimer. The term MSA recognized the significant clinical and pathological overlap among three major neurodegenerative diseases which were previously described separately: (1) Shy–Drager syndrome, (2) striatonigral degeneration, and (3) sporadic olivopontocerebellar atrophy.
Shy–Drager Syndrome
Clinical Features and Diagnostic Criteria For various reasons, some uncertainty in the terminology generated over the following years. For instance, Wenning et al. described a series of 100 patients with clinically probable MSA (15 of them pathologically confirmed); in none of them, the ‘full Shy–Drager syndrome’ was found. These authors described fecal incontinence in only two patients, but neither of them had suffered painful muscle cramps or iris atrophy, and only one had fasciculations, weakness, and focal muscle atrophy. Although they admitted that rectal incontinence, iris atrophy, external ocular palsies, and signs suggestive of anterior horn cell involvement can occur occasionally in MSA, these features should not be considered typical of the disease. In addition, they suggested that the term Shy–Drager should be restricted to the situation in which severe autonomic failure (male erectile failure, orthostatic hypotension, urinary retention, or incontinence) is combined with parkinsonism, cerebellar and pyramidal signs. Respiratory stridor (high-pitched breathing sounds due to airway obstruction) and stimulussensitive finger myoclonus, developing each in one-third of cases, were included as optional diagnostic criteria. Unlike the original description (which antedated the introduction of levodopa), information on the response to levodopa treatment (which is often poor or absent in MSA, except for 20–30% of the cases in whom it may be transiently good) was also included. In a subsequent commentary, Quinn et al. substantiated that the Shy–Drager syndrome signifies autonomic failure plus central nervous system dysfunction attributable to MSA, and that it is inappropriate to use the term simply as a shorthand for parkinsonism with autonomic failure. However, it later became clear that the new complex classification was not well served by the term ‘Shy–Drager syndrome.’ Thus, a new terminology was needed. The American Autonomic Society and the American Academy of Neurology eventually disapproved the Shy–Drager syndrome as a disease entity in 1996, and existing cases were redefined as MSA with autonomic involvement. However, the term ‘Shy–Drager syndrome’ is still used occasionally for MSA when the primary symptom is autonomic failure. At the very least, this nomenclature implies that several areas in the central nervous system are involved in the neurodegenerative process. MSA is defined as a sporadic, progressive, adult-onset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. Onset usually takes place in the sixth or seventh decade, and most patients are severely disabled within 5–7 years. More males are affected than females, and prevalence is less than one in 10 000 persons. The etiology is unknown. Depending upon which part of the central nervous system is affected first, MSA may present in different ways. According to the current diagnostic criteria, MSA is divided into two main
113
clinical categories: (1) MSA–parkinsonism type (MSA–P), which implies parkinsonism with or without some degree of cerebellar dysfunction (striatonigral degeneration), and (2) MSA–cerebellar type (MSA–C), which indicates primarily cerebellar defects with minor degrees of parkinsonism (olivopontocerebellar atrophy). In both conditions, autonomic failure could be a predominant or an associated manifestation of the clinical spectrum of the disease. The most prominent symptom of autonomic failure in MSA is what is known as ‘postural hypotension.’ In cases of severe autonomic insufficiency, wide swings in blood pressure without modification in pulse rate are observed. Upon standing or sitting, patient’s blood pressure drops to such a low level that they get dizzy, lightheaded, or momentarily blackout. Urinary and erectile (in males) dysfunction symptoms are also prominent early features in MSA patients. Urogenital symptoms in MSA are usually due to a complex mixture of central and peripheral nervous abnormalities, sometimes superimposed on previous local pathological conditions such as benign prostatic hyperplasia and perineal laxity. Unfortunately, although orthostatic hypotension and bladder disorders can be managed successfully, no effective treatment is available for the other manifestations of autonomic dysfunction or for the cerebellar and pyramidal symptoms. MSA usually concludes by the patient’s death within 7–10 years after diagnosis. Breathing problems such as aspiration, stridor, or cardiopulmonary arrest are common causes of death. See also: Multiple System Atrophy; Olivopontocerebellar Atrophy; Striatonigral Degeneration.
Further Reading Colosimo C, Geser F, Benarroch EE, and Wenning GK (2006) Multiple System Atrophy. In: Gilman S (ed.) Neurobiology of Disease, pp. 83–94. Academic Press. Gilman S, Wenning GK, Low PA, et al. (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71: 670–676. Graham JG and Oppenheimer DR (1969) Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. Journal of Neurology Neurosurgery and Psychiatry 32: 28–34. Mathias CJ and Williams AC (1994) The Shy Drager syndrome and multiple system atrophy. In: Calne DB (ed.) Neurodegenerative Diseases, pp. 743–767. Philadelphia: WB Saunders. Papatsoris AG, Papapetropoulos S, Singer C, and Deliveliotis C (2008) Urinary and erectile dysfunctions in multiple system atrophy (MSA). Neurourology Urodin 27: 22–27. Quinn NP, Wenning G, and Marsden CD (1995) The Shy–Drager syndrome: What did Shy and Drager really describe? Archives of Neurology 52: 656–657. Sandroni P, Ahlskog E, Fealey RD, and Low PA (1991) Autonomic involvement in extrapyramidal and cerebellar disorders. Clinical Autonomic Research Society 1: 147–155. Schatz IJ (1996) Farewell to the ‘Shy–Drager syndrome’. Annals of International Medicine 125: 74–75.
114
Sialidosis
Schmidt C, Herting B, Prieur S, et al. (2008) Autonomic dysfunction in different subtypes of multiple system atrophy. Movement Disorders 23: 1766–1772. Shy M and Drager GA (1960) A neurological syndrome associated with orthostatic hypotension. Archives of Neurology 3: 511–527. Testa D, Filippini G, Farinotti M, Palazzini E, and Caraceni T (1996) Survival in multiple system atrophy: A study of prognostic factors in 59 cases. Journal of Neurology 243: 401–404.
The Consensus Committee of the American Autonomic Society and the American Academy of Neurology (1996) Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 46: 1470. Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, and Quinn NP (1994) Clinical features and natural history of multiple system atrophy: An analysis of 100 cases. Brain 117: 835–845.
Sialidosis S Igdoura, Departments of Biology and Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada ã 2010 Elsevier Ltd. All rights reserved.
Clinical Presentation An inherited, primary deficiency of lysosomal sialidase was first demonstrated in the severe form of Sialidosis (type II). Shortly thereafter, several investigators described a similar deficiency in a clinically milder disorder, ‘cherryred spot-myoclonus syndrome,’ now classified as Sialidosis type I, which becomes apparent during the second decade of life. Associated symptoms include cherry-red spots within the middle layers of the eyes; loss of visual clarity; and sudden, involuntary, ‘shock-like’ contractions (myoclonus) of muscles of the arms and legs. The myoclonus is progressive in nature and may be triggered by voluntary movements (action myoclonus) or certain external stimuli such as sound (reflex myoclonus).
Pathogenesis/Pathophysiology In type I patients, increased excitability and reduced inhibition were found in some cortical motor pathways, but no abnormalities were found in the brain stem and spinal motor pathways tested. These findings suggest that the electrophysiological abnormalities are restricted to a level above the brainstem. While pathological features of lysosomal storage are apparent in the brainstem and spinal cord, circuits within the brainstem or spinal cord do not appear affected. Biochemically, this may be explained by the more profound role for Sialidase on the plasma membrane in the brain cerebellar cortex and the cerebellum. Sialidase deficiency leads to defective lysosomal catabolism of sialoglycoconjugates with their subsequent accumulations in tissues and excessive excretion in the urine. The concentration of urinary oligosaccharides is reported to be correlated with the clinical severity of the affected patients,
that is, over 3 times more in the infantile-type II Sialidosis patients than in the late-type I patients. Sialidosis patients will excrete high sialic acid conjugated molecules in the urine. Sialidosis has traditionally been diagnosed using enzyme assays that measure sialidase activity in blood leukocytes. Enzyme diagnostic tests for Sialidosis use a variety of both natural (sialyllactose, sialylhexasaccharides, and fetuin) and synthetic (3-methoxyphenyl-N-acetylneuraminic acid and 4-methylumbelliferyl-a-D-N-acetyl-neuraminic acid, muNANA) substrates. Only in recent times has it become possible to probe the disease at the level of the DNA lesion. Human lysosomal sialidase (44 kDa) exists in a multienzyme complex consisting of b-galactosidase, cathepsin A, and sialidase (GCS complex). Cathepsin A is required to promote the formation of the enzyme complex. Mechanistically, the sialidase associates with cathepsin A in the endoplasmic reticulum and is then transported to the lysosomes. In fact, transport impaired cathepsin A prevents sialidase from reaching the lysosomes. The sialidase complex is also present on the cell membrane where it is involved in cellular signaling, particularly, in T-lymphocytes, where it activates the macrophage activating factor. Genetically, Sialidosis is inherited as an autosomal recessive trait. The human sialidase gene was mapped to chromosome 6p2l within the human major histocompatibility complex (MHC). The human and mouse sialidase genes are structurally similar (both about 4.5 kb). The two genes contain five introns which range in size from 96 bp to 1.2 kb. The levels of sialidase expression in different mouse tissues, evaluated by Northern blot analysis, were found to be high in kidney, epididymis, brain and spinal cord, and moderate to low in adrenal, liver, lung, spleen, and heart. The isolation and cloning of the human lysosomal sialidase gene has allowed for the characterization of many disease-causing mutations. Thus far, more than