Phenotypic characterization of hypomyelination and congenital cataract
Corresponding Author
Roberta Biancheri MD, PhD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Largo Gaslini 5, 16147 Genova, ItalySearch for more papers by this authorFederico Zara PhD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorClaudio Bruno MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorAndrea Rossi MD
Department of Pediatric Neuroradiology, G. Gaslini Institute, Genova, Italy
Search for more papers by this authorLaura Bordo BSc
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorElisabetta Gazzerro MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorFederica Sotgia PhD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Departments of Cancer Biology and Biochemistry and Molecular Biology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA
Search for more papers by this authorMarina Pedemonte MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorSara Scapolan MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorMassimo Bado MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorGraziella Uziel MD
Division of Child Neuropsychiatry, C. Besta Institute, Milan, Milan, Italy
Search for more papers by this authorMarianna Bugiani MD
Division of Child Neuropsychiatry, C. Besta Institute, Milan, Milan, Italy
Search for more papers by this authorLaura Doria Lamba MD
Child Neuropsychiatry Unit, G. Gaslini Institute, Genova, Genova, Italy
Search for more papers by this authorValeria Costa MD
Child Neuropsychiatry Unit, Azienda Sanitaria Locale (ASL) 6, Palermo, Palermo, Italy
Search for more papers by this authorAngelo Schenone MD
Department of Neurosciences, Ophthalmology and Genetics, University of Genova, Genova, Italy
Search for more papers by this authorAnnemieke J. M. Rozemuller MD
Department of Neuropathology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorPaolo Tortori-Donati MD
Department of Pediatric Neuroradiology, G. Gaslini Institute, Genova, Italy
Search for more papers by this authorMichael P. Lisanti MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Departments of Cancer Biology and Biochemistry and Molecular Biology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA
Search for more papers by this authorMarjo S. van der Knaap MD, PhD
Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorCarlo Minetti MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorCorresponding Author
Roberta Biancheri MD, PhD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Largo Gaslini 5, 16147 Genova, ItalySearch for more papers by this authorFederico Zara PhD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorClaudio Bruno MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorAndrea Rossi MD
Department of Pediatric Neuroradiology, G. Gaslini Institute, Genova, Italy
Search for more papers by this authorLaura Bordo BSc
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorElisabetta Gazzerro MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorFederica Sotgia PhD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Departments of Cancer Biology and Biochemistry and Molecular Biology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA
Search for more papers by this authorMarina Pedemonte MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorSara Scapolan MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorMassimo Bado MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorGraziella Uziel MD
Division of Child Neuropsychiatry, C. Besta Institute, Milan, Milan, Italy
Search for more papers by this authorMarianna Bugiani MD
Division of Child Neuropsychiatry, C. Besta Institute, Milan, Milan, Italy
Search for more papers by this authorLaura Doria Lamba MD
Child Neuropsychiatry Unit, G. Gaslini Institute, Genova, Genova, Italy
Search for more papers by this authorValeria Costa MD
Child Neuropsychiatry Unit, Azienda Sanitaria Locale (ASL) 6, Palermo, Palermo, Italy
Search for more papers by this authorAngelo Schenone MD
Department of Neurosciences, Ophthalmology and Genetics, University of Genova, Genova, Italy
Search for more papers by this authorAnnemieke J. M. Rozemuller MD
Department of Neuropathology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorPaolo Tortori-Donati MD
Department of Pediatric Neuroradiology, G. Gaslini Institute, Genova, Italy
Search for more papers by this authorMichael P. Lisanti MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Departments of Cancer Biology and Biochemistry and Molecular Biology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA
Search for more papers by this authorMarjo S. van der Knaap MD, PhD
Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorCarlo Minetti MD
Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute and University of Genova, Genova, Italy
Search for more papers by this authorAbstract
Objective
To define the clinical and laboratory findings in a novel autosomal recessive white matter disorder called hypomyelination and congenital cataract, recently found to be caused by a deficiency of a membrane protein, hyccin, encoded by the DRCTNNB1A gene located on chromosome 7p21.3-p15.3.
Methods
We performed neurological examination, neurophysiological, neuroimaging, and neuropathological studies on sural nerve biopsy in 10 hypomyelination and congenital cataract patients from 5 unrelated families.
Results
The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation. Neurophysiological studies showed a slightly to markedly slowed motor nerve conduction velocity in 9 of 10 patients, and multimodal evoked potentials indicated increased central conduction times. Neuroimaging studies demonstrated a diffuse supratentorial hypomyelination, with in some patients, additional areas of more prominent signal change in the frontal region. Sural nerve biopsy showed a slight-to-severe reduction in myelinated fiber density, with several axons surrounded by a thin myelin sheath or devoid of myelin.
Interpretation
Hypomyelination and congenital cataract is a novel autosomal recessive white matter disorder characterized by the unique association of congenital cataract and hypomyelination of the central and peripheral nervous system. Ann Neurol 2007
References
- 1 Schiffmann R, van der Knaap MS. The latest on leukodystrophies. Curr Opin Neurol 2004; 17: 187–192.
- 2 van der Knaap MS, Breiter SN, Naidu S, et al. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999; 213: 121–133.
- 3 van der Knaap MS. Magnetic resonance in childhood white matter disorders. Dev Med Child Neurol 2001; 43: 705–712.
- 4 Zara F, Biancheri R, Bruno C, et al. Deficiency of Hyccin, a novel membrane protein, causes hypomyelination and congenital cataract. Nat Genet 2006; 38: 1111–1113.
- 5 van der Knaap MS, Valk J, de Neeling N, Nauta JJ. Pattern recognition in magnetic resonance imaging of white matter disorders in children and young adults. Neuroradiology 1991; 33: 478–493.
- 6 Dubowitz V, Sewry CA. Muscle biopsy: a practical approach. 3rd ed. St. Louis, MO: Elsevier Limited, 2007.
- 7 Dyck PJ, Thomas PK. Peripheral neuropathy. 3rd ed. Philadelphia: WB Saunders, 1993.
- 8 van der Knaap MS, Naidu S, Pouwels PJ, et al. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. AJNR Am J Neuroradiol 2002; 23: 1466–1474.
- 9 Folkerth RD. Abnormalities of developing white matter in lysosomal storage diseases. J Neuropathol Exp Neurol 1999; 58: 887–902.
- 10 van der Voorn JP, Kamphorst W, van der Knaap MS, Powers JM. The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss and axonal dysfunction. Acta Neuropathol (Berl) 2004; 107: 539–545.
- 11 Di Rocco M, Rossi A, Parenti G, et al. Different molecular mechanisms leading to white matter hypomyelination in infantile onset lysosomal disorders. Neuropediatrics 2005; 36: 265–269.
- 12
van der Knaap MS,
Valk J.
Magnetic resonance of myelination and myelin disorders.
3rd ed.
Berlin:
Springer-Verlag,
2005.
10.1007/3-540-27660-2 Google Scholar
- 13 Uhlenberg B, Schuelke M, Ruschendorf F, et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 2004; 75: 251–260.
- 14 Bugiani M, Al Shahwan S, Lamantea E, et al. GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 2006; 67: 273–279.
- 15 Mercimek-Mahmutoglu S, van der Knaap MS, Baric I, et al. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Report of a new case. Neuropediatrics 2005; 36: 223–226.
- 16 Wolf NI, Harting I, Boltshauser E, et al. Leukoencephalopathy with ataxia, hypodontia, and hypomyelination. Neurology 2005; 64: 1461–1464.
- 17 Timmons M, Tsokos M, Asab MA, et al. Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia. Neurology 2006; 67: 2066–2069.
- 18 Garbern JY, Cambi F, Lewis R, et al. Peripheral neuropathy caused by proteolipid protein gene mutations. Ann NY Acad Sci 1999; 883: 351–365.
- 19 Shy ME, Hobson G, Jain M, et al. Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy. Ann Neurol 2003; 53: 354–365.
- 20 Varho T, Jääskeläinen S, Tolonen U, et al. Central and peripheral nervous system dysfunction in the clinical variation of Salla disease. Neurology 2000; 55: 99–103.
- 21 Graw J. Congenital hereditary cataracts. Int J Dev Biol 2004; 48: 1031–1044.
- 22 van der Knaap MS, van Berkel cG, Herms J, et al. eIF2B-related disorders: antenatal onset and involvement of multiple organs. Am J Hum Genet 2003; 73: 1199–1207.
- 23 He W, Li S. Congenital cataracts: gene mapping. Hum Genet 2000; 106: 1–13.
- 24 Shimizu T, Kagawa T, Wada T, et al. Wnt signaling controls the timing of oligodendrocyte development in the spinal cord. Dev Biol 2005; 282: 397–410.
- 25 Kasai M, Satoh K, Akiyama T. Wnt signaling regulates the sequential onset of neurogenesis and gliogenesis via induction of BMPs. Genes Cells 2005; 10: 777–783.
- 26 Stump RJ, Ang S, Chen Y, et al. A role for Wnt/beta-catenin signaling in lens epithelial differentiation. Dev Biol 2003; 259: 48–61.
- 27 Lyu J, Joo CK. Wnt signaling enhances FGF2-triggered lens fiber cell differentiation. Development 2004; 131: 1813–1824.
- 28 Kawasoe T, Furukawa Y, Daigo Y, et al. Isolation and characterization of a novel human gene, DRCTNNB1A, the expression of which is down-regulated by beta-catenin. Cancer Res 2000; 60: 3354–3358.
Citing Literature
