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Clinical and Molecular Studies in a Family With Probable X-linked Dominant Charcot-Marie-Tooth Disease Involving the Central Nervous System
Fuki M. Hisama, MD;
Helen H. Lee, BS;
Amy Vashlishan;
Poornima Tekumalla, PhD;
David S. Russell, MD, PhD;
Elizabeth Auld, PA;
Jonathan M. Goldstein, MD
Arch Neurol. 2001;58:1891-1896.
Objective To investigate the clinical and molecular
characteristics of an apparently X-linked dominant form of
Charcot-Marie-Tooth (CMT) disease in a family with central nervous
system involvement and additional features.
Background Charcot-Marie-Tooth disease may be inherited as an
autosomal dominant, autosomal recessive, or X-linked trait. In the
X-linked dominant form of CMT, females demonstrate milder clinical and
electrophysiological features compared with their male relatives.
Methods Clinical and related examinations were performed in 4
affected individuals from a family with a novel form of CMT affecting
males more severely than females. DNA analysis of the connexin 32
(Cx32) gene and proteolipid protein (PLP) gene was
performed. We genotyped 3 members of the family to determine which
regions of the X chromosome were inherited discordantly in the affected
and unaffected brothers.
Results Clinical studies revealed significant
spasticity, hyperreflexia, and delayed central conduction, in addition
to peripheral neuropathy. Nerve conduction velocities were slower in
the affected males than in the affected females. Direct DNA sequencing
of the Cx32 coding region and neural-specific promoter were
normal. A PLP null mutation was excluded. Levels of very long
chain fatty acids were normal. Genotyping studies of the X chromosome
supported X-linked inheritance of the neuropathy.
Conclusions This family differs from others with hereditary
motor and sensory neuropathic diseases by the presence of upper motor
neuron signs and additional features. The clinical features and
inheritance pattern are consistent with X-linked dominant inheritance
or autosomal dominant inheritance.
From the Departments of Neurology (Drs Hisama, Tekumalla, Russell, and
Goldstein) and Psychiatry
(Dr Russell), and the Neurogenetics
Program
(Drs Hisama and Tekumalla and Mss Lee and Vashlishan), Yale
University School of Medicine, New Haven, Conn; and the Division of
Ambulatory Care, Department of Medicine, Veterans Administration
Medical Center, West Haven, Conn (Ms Auld).
Corresponding author and reprints: Fuki M. Hisama, MD, Neurogenetics
Program, Department of Neurology, Yale University School of Medicine,
LCI 1000, PO Box 208018, New Haven, CT 06520-8018 (e-mail: fuki.hisama{at}yale.edu).
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Sanahuja et al.
Arch Neurol 2005;62:1911-1914.
ABSTRACT
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