Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 37
Neurologic manifestations of inherited disorders of connective tissue STE´PHANIE DEBETTE1,2,3* AND DOMINIQUE P. GERMAIN3,4 Department of Epidemiology and Public Health, Raymond Poincar Hospital, Garches, France
1
2
INSERM Unit U708, Piti-Salptrire Hospital, Paris, France
3
University of Versailles — St Quentin en Yvelines, Versailles, France
4 Division of Medical Genetics, National Referral Center for Fabry Disease and Inherited Disorders of Connective Tissue, CHU Raymond Poincar, Garches, France
INTRODUCTION Inherited disorders of connective tissue are monogenic diseases that affect the structure or function of the connective tissue. While these disorders are transmitted within families according to a Mendelian inheritance pattern, de novo mutations are common and a substantial proportion of patients do not have any family history of the disease. Although neurologic manifestations are often not part of the major diagnostic criteria, they represent classic and potentially severe complications of many inherited connective tissue disorders. For the neurologist, being aware of the main characteristics and diagnostic criteria of these disorders is important for two reasons: (1) in some cases neurologic complications can be the first manifestation of the disease, and (2) special caution may be required for the management of these patients, especially with regards to invasive exams or procedures and antithrombotic therapy. In the first part of this chapter we describe the most common neurologic manifestations of inherited disorders of connective tissue in adults. The second part reviews the main diagnostic and therapeutic implications of these disorders for the practicing neurologist.
NEUROLOGIC MANIFESTATIONS OF THE MOST COMMON INHERITED DISORDERS OF CONNECTIVE TISSUE Inherited disorders of connective tissue leading to neurologic complications are summarized in Table 37.1. The majority of neurologic manifestations are cerebrovascular, mostly due to alterations in the vascular connective tissue. Other neurologic manifestations are mostly secondary to osteoarticular complications.
Vascular Ehlers–Danlos syndrome GENERAL DESCRIPTION Vascular Ehlers–Danlos syndrome (vEDS, OMI 130050) is a rare autosomal dominant disease, due to mutations in the COL3A1 gene on chromosome 2q31. The prevalence is estimated at 0.2–1/100 000 (Germain, 2007), and the median survival at 48 years (Pepin et al., 2000). The diagnosis is suggested clinically by the presence of at least two out of four major clinical criteria (Beighton et al., 1998): easy
*Correspondence to: Ste´phanie Debette, M.D., Ph.D., Department of Epidemiology and Public Health, Raymond Poincare´ Hospital, Paris Iˆle-de-France Ouest University Hospital, Garches, France. Tel: þ33-6-84-07-72-53, Fax: þ33-1-47-10-44-36, E-mail: [email protected]
Table 37.1 Main characteristics of inherited disorders of connective tissue leading to neurologic complications Disease
Prevalence
Inheritance
Gene
Cerebrovascular manifestations
Other neurologic manifestations
Ehlers–Danlos syndrome type I and II (classic)
1–5/100 000
AD
Exceptional arterial rupture
Plexus neuropathies due to ligament laxity Sensorimotor polyneuropathy, myopathy Rarely nerve root or spinal cord compression due to kyphoscoliosis Recurrent headaches Congenital malformations of brain parenchyma and vessels
Carotid-cavernous fistula Cervical artery dissection ischemic stroke Intracranial dissection and aneurysms –>SAH, ICH Arterial rupture – > ICH or SAH Aortic dissection extending to cervical arteries Cardioembolic ischemic stroke Aortic dissection extending to cervical arteries Arterial tortuosities of head and neck vessels Ischemic stroke Rare ischemic stroke
Ehlers–Danlos syndrome type III (hypermobile)
1/10 000
AD
COL5A1, COL5A2 COL5A1, COL5A2 TNXB?
Ehlers–Danlos syndrome type IV (vascular)
0.2–1/100 000
AD
COL3A1
Marfan syndrome
1/5000
AD
Fibrillin 1
Loeys–Dietz syndrome
?
AD
TGFBR1, TGFBR2
Arterial tortuosity syndrome Pseudoxanthoma elasticum Osteogenesis imperfecta
? 1/75 000
Chapter 37
Neurologic manifestations of inherited disorders of connective tissue STE´PHANIE DEBETTE1,2,3* AND DOMINIQUE P. GERMAIN3,4 Department of Epidemiology and Public Health, Raymond Poincar Hospital, Garches, France
1
2
INSERM Unit U708, Piti-Salptrire Hospital, Paris, France
3
University of Versailles — St Quentin en Yvelines, Versailles, France
4 Division of Medical Genetics, National Referral Center for Fabry Disease and Inherited Disorders of Connective Tissue, CHU Raymond Poincar, Garches, France
INTRODUCTION Inherited disorders of connective tissue are monogenic diseases that affect the structure or function of the connective tissue. While these disorders are transmitted within families according to a Mendelian inheritance pattern, de novo mutations are common and a substantial proportion of patients do not have any family history of the disease. Although neurologic manifestations are often not part of the major diagnostic criteria, they represent classic and potentially severe complications of many inherited connective tissue disorders. For the neurologist, being aware of the main characteristics and diagnostic criteria of these disorders is important for two reasons: (1) in some cases neurologic complications can be the first manifestation of the disease, and (2) special caution may be required for the management of these patients, especially with regards to invasive exams or procedures and antithrombotic therapy. In the first part of this chapter we describe the most common neurologic manifestations of inherited disorders of connective tissue in adults. The second part reviews the main diagnostic and therapeutic implications of these disorders for the practicing neurologist.
NEUROLOGIC MANIFESTATIONS OF THE MOST COMMON INHERITED DISORDERS OF CONNECTIVE TISSUE Inherited disorders of connective tissue leading to neurologic complications are summarized in Table 37.1. The majority of neurologic manifestations are cerebrovascular, mostly due to alterations in the vascular connective tissue. Other neurologic manifestations are mostly secondary to osteoarticular complications.
Vascular Ehlers–Danlos syndrome GENERAL DESCRIPTION Vascular Ehlers–Danlos syndrome (vEDS, OMI 130050) is a rare autosomal dominant disease, due to mutations in the COL3A1 gene on chromosome 2q31. The prevalence is estimated at 0.2–1/100 000 (Germain, 2007), and the median survival at 48 years (Pepin et al., 2000). The diagnosis is suggested clinically by the presence of at least two out of four major clinical criteria (Beighton et al., 1998): easy
*Correspondence to: Ste´phanie Debette, M.D., Ph.D., Department of Epidemiology and Public Health, Raymond Poincare´ Hospital, Paris Iˆle-de-France Ouest University Hospital, Garches, France. Tel: þ33-6-84-07-72-53, Fax: þ33-1-47-10-44-36, E-mail: [email protected]
Table 37.1 Main characteristics of inherited disorders of connective tissue leading to neurologic complications Disease
Prevalence
Inheritance
Gene
Cerebrovascular manifestations
Other neurologic manifestations
Ehlers–Danlos syndrome type I and II (classic)
1–5/100 000
AD
Exceptional arterial rupture
Plexus neuropathies due to ligament laxity Sensorimotor polyneuropathy, myopathy Rarely nerve root or spinal cord compression due to kyphoscoliosis Recurrent headaches Congenital malformations of brain parenchyma and vessels
Carotid-cavernous fistula Cervical artery dissection ischemic stroke Intracranial dissection and aneurysms –>SAH, ICH Arterial rupture – > ICH or SAH Aortic dissection extending to cervical arteries Cardioembolic ischemic stroke Aortic dissection extending to cervical arteries Arterial tortuosities of head and neck vessels Ischemic stroke Rare ischemic stroke
Ehlers–Danlos syndrome type III (hypermobile)
1/10 000
AD
COL5A1, COL5A2 COL5A1, COL5A2 TNXB?
Ehlers–Danlos syndrome type IV (vascular)
0.2–1/100 000
AD
COL3A1
Marfan syndrome
1/5000
AD
Fibrillin 1
Loeys–Dietz syndrome
?
AD
TGFBR1, TGFBR2
Arterial tortuosity syndrome Pseudoxanthoma elasticum Osteogenesis imperfecta
? 1/75 000
