Contactin-Associated Protein 1 (CNTNAP1) Mutations Induce Characteristic Lesions of the Paranodal Region.
Congenital hypomyelinating neuropathy is a rare neonatal syndrome responsible for hypotonia and weakness. Nerve microscopic examination shows amyelination or hypomyelination. Recently, mutations in CNTNAP1 have been described in a few patients. CNTNAP1 encodes contactin-associated protein 1 (caspr-1), which is an essential component of the paranodal junctions of the peripheral and central nervous systems, and is necessary for the establishment of transverse bands that stabilize paranodal axo-glial junctions. We present the results of nerve biopsy studies of three patients from two unrelated, non-consanguineous families with compound heterozygous CNTNAP1 mutations. The lesions were identical, characterized by a hypomyelinating process; on electron microscopy, we detected, in all nodes of Ranvier, subtle lesions that have never been previously described in human nerves. Transverse bands of the myelin loops were absent, with a loss of attachment between myelin and the axolemma; elongated Schwann cell processes sometimes dissociated the Schwann cell and axon membranes that bound the space between them. These lesions were observed in the area where caspr-1 is located and are reminiscent of the lesions reported in sciatic nerves of caspr-1 null mice. CNTNAP1 mutations appear to induce characteristic ultrastructural lesions of the paranodal region.
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Jean-Michel
JM
Vallat
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Mathilde
M
Nizon
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Alex
A
Magee
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Bertrand
B
Isidor
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Laurent
L
Magy
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Yann
Y
Péréon
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Laurence
L
Richard
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Robert
R
Ouvrier
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Benjamin
B
Cogné
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Jérôme
J
Devaux
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Stephan
S
Zuchner
From the Department of Neurology and 'Centre de Référence des neuropathies rares', University Hospital (CHU) Limoges, Limoges, France (JMV, LM and LR); Department of Medical Genetics, University Hospital (CHU) Nantes, Nantes, France (MN, BI and BC); Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Northern Ireland (AM); Centre de Référence des Maladies Neuromusculaires, Hôtel Dieu Hospital, Nantes, France (YP); The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia (RO); CNRS, CRN2M-UMR 7286, Aix-Marseille University, Marseille, France (JD); Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida (SZ); Department of Neurology, Nerve-Muscle Unit, University Hospital (CHU) Pellegrin, Bordeaux, France (SM).
Stéphane
S
Mathis
D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D013497:Sural Nerve / Q000473:pathology* / Q000502:physiology* / Q000648:ultrastructure
C491323:CNTNAP1 protein, human; D015816:Cell Adhesion Molecules, Neuronal
CNTNAP1; Contactin; Nerve biopsy; Node of Ranvier.