X-linked Charcot–Marie–Tooth Disease

(1)

63.1 Clinical Features

and Laboratory Investigations Charcot–Marie–Tooth disease (CMT) is a clinically and genetically heterogeneous group of peripheral nerve disorders characterized by distal weakness, atrophy, sensory loss, and decreased tendon reflexes.

CMT has been classified according to the pattern of inheritance and whether the abnormalities primarily affect myelin (CMT1) or axons (CMT2). The X-linked dominant form of CMT (CMTX) shows both demyeli- nating and axonal aspects, causing problems in cate- gorizing CMTX as a subtype of CMT1 or CMT2.

CMTX affects both males and females, but males are affected more severely than females, with onset of symptoms at an earlier age. Asymptomatic female carriers have been reported. The clinical manifesta- tions of CMTX vary. Onset may be congenital or de- layed until the third decade. Symptoms develop in a length-dependent distribution, meaning that the longest nerves are involved earliest. Thus, the weak- ness always starts in the lower leg muscles with stum- bling and steppage gait. With progression of the dis- ease, the weakness spreads to the hands. The weak- ness varies widely, from mild, causing no functional impairment, to severe, necessitating the use of a wheelchair. Foot deformities, including pes cavus and hammer toes, are common. Muscle atrophy and loss of tendon reflexes occur. Distal sensory loss with glove and stocking distribution occurs, involving touch, pin prick, temperature, vibration, and position sense. Many patients have balance difficulties with a positive Romberg sign. Scoliosis may occur. Breathing difficulties due to phrenic nerve involvement occur in some patients.

Most CMTX patients do not have overt clinical CNS manifestations, but subclinical evidence of CNS dysfunction is common. Hyperreflexia, extensor plantar reflexes, some spasticity, and cerebellar dys- function have been observed in addition to the pe- ripheral neuropathy. Some patients have sensorineur- al hearing loss. Patients may experience episodes of transient neurological problems of central origin, lasting hours to weeks. The problems may fluctuate in severity during that time. Signs reported include dysarthria, cerebellar ataxia, gait ataxia, pyramidal weakness of the extremities (hemiparesis, monopare- sis, paraparesis, or tetraparesis), and cranial nerve palsies including third cranial nerve palsy, facial

weakness, bulbar dysarthria, dysphagia, and loss of the gag reflex. Nausea and vertigo may be present. The patients are usually alert during the episode, but som- nolence, behavior abnormalities, and disorientation may also occur. They may complain of headache.

After the episode, patients recover fully to their previ- ous condition. The episodes seem to be provoked by minor infections, surgery, sports, or staying at high altitudes.

Nerve conduction velocities are reduced in CMTX, but the reductions are less severe than in the other forms of demyelinating CMT, consistent with moder- ate demyelination of the investigated nerves. The re- ductions in conduction velocities may be variable from one nerve segment to the other. Distal latencies are prolonged. Compound muscle action potentials and sensory nerve action potentials have reduced amplitudes. The electromyogram is usually normal, but sometimes fibrillation potentials are found, sug- gesting axonal involvement. Nerve conduction veloc- ities are typically slower in affected males than in their affected female relatives. Abnormalities in brain stem auditory evoked responses have been reported repeatedly with slowed central conduction. Sensory evoked responses may also show a slowing of central conduction.

63.2 Pathology

Findings in sural nerve biopsy specimens are variably described as primary axonal degeneration and pri- mary demyelinating. Findings include loss of myeli- nated fibers and the presence of groups of small, thin- ly myelinated and unmyelinated regenerating fibers.

Axons with disproportionately thin myelin sheaths in relation to the axon caliber and small onion bulb for- mations, indicative of demyelination and consecutive remyelination, may be present.

No brain autopsy studies are available

63.3 Pathogenetic Considerations

CMTX is caused by mutations in the gene, called

CX32 or GJB1, coding for connexin 32, also called gap

junction protein b1. The gene is located on chromo- some Xq13.1. Connexin 32 is a gap junction protein that is found in both the PNS and the CNS. It is incor-

X-linked Charcot–Marie–Tooth Disease

Chapter 63

063_Valk_X_linked_Char 08.04.2005 16:21 Uhr Seite 476

(2)

porated into cell membranes as a subunit of a hemichannel called the connexon. One connexon comprises six subunits and two connexons form a gap junction between two cells. Gap junctions are inter- cellular channels that span the space between two neighboring cells and result from the association of two half-channels, connexons, contributed separately by each of the participating cells. These gap junctions allow rapid exchange of ions, small metabolites, and second messengers between cells or parts of cells. In the PNS, connexin 32 is expressed in Schwann cells at the Schmidt–Lantermann incisures and the paran- odal regions, the noncompacted parts of myelin. In the CNS it is expressed in oligodendrocytes and neu- rons. Connexin is also expressed in nonnervous tis- sues including liver, pancreas, and secretory epitheli- um.

Mutations either lead to loss of function or to al- tered gating properties of the gap junction channels.

There is not yet a hot spot for connexin 32 mutations associated with CNS symptoms. The mutations asso- ciated with CNS disease have been found in the extra-

cellular, transmembrane, and intracellular domains of the protein. By analogy to channelopathies, altered gating properties of connexons due to mutated con- nexin 32 could give rise to transient CNS symptoms.

Situations of metabolic stress may further alter the function of gap junctions and cause transient symp- toms.

63.4 Therapy

At present, no specific therapy exists for patients with CMTX.

63.5 Magnetic Resonance Imaging

Outside the episodes of CNS dysfunction, MRI of the brain is most often described as normal. During the episodes of CNS symptoms, transient white matter abnormalities occur (Fig. 63.1). They are located in the central or posterior part of the centrum semio-

63.5 Magnetic Resonance Imaging 477

Fig. 63.1. MRI of a 14-year-old male patient with CMTX during an episode of CNS symptoms shows mild signal changes in the parieto-occipital white matter, sparing the U fibers.The spleni-

um of the corpus callosum is affected. There is no evident involvement of the brain stem and cerebellar peduncles. From Schelhaas et al. (2002), with permission

(3)

vale, the splenium of the corpus callosum, posterior limb of the internal capsule, and middle cerebellar peduncles. The U fibers are spared. The signal changes are milder than those seen in demyelination or white matter inflammatory disease. They are sym- metrical and confluent. After contrast administra- tion, no enhancement is seen. Diffusion-weighted imaging shows restricted diffusion. As the white mat-

ter abnormalities are reversible within a few months, the restricted diffusion cannot be caused by cytotox- ic edema. Myelin splitting and intramyelinic edema, with compression of the extracellular space, is a more likely explanation.

No systematic study of CMTX patients has been performed to document the MRI findings of the brain outside the episodes of CNS dysfunction.

Chapter 63 X-linked Charcot–Marie–Tooth Disease 478