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At a glance

A familial syndrome characterized by mental retardation, agenesis of the corpus callosum, and progressive sensorimotor neuropathy.

Synonyms

Charlevoix Disease (named after the Charlevoix region in Quebec, Canada, where the first described families with the disease originated from); Agenesis of the Corpus Callosum with Peripheral Neuropathy; Agenesis of the Corpus Callosum with Neuronopathy.

Incidence

Originally described in French Canadians from the Charlevoix County, Quebec, Canada. The disease can be traced back to a couple married in Quebec City in the 17th century. The incidence in the Charlevoix and Saguenay Lac St.-Jean regions in the province of Quebec has been estimated as 1:2,100 live births. The carrier rate is 1:23 inhabitants. Only a few patients with Andermann Syndrome have been reported from other parts of the world.

Genetic inheritance

Autosomal recessive. The defect is caused by mutations in the Solute Carrier Family 12 member 6 (SLC12A6 or KCC3) gene, which has been mapped to chromosome 15q14. This potassium-chloride (K-Cl) cotransporter (KCC3) protein could be involved in maintaining concentration gradients of potassium and chloride in the axons. Abnormal function of this cotransporter in the axonal membrane may lead to axonal swelling.

Pathophysiology

Electromyography shows absent sensory action potentials, a slight reduction in motor nerve conduction velocity, and signs of denervation and reinnervation in the distal muscles of the lower extremities. Muscle biopsy reveals angular fibers and atrophy. The overall pathologic picture is consistent with a chronic demyelinating neuropathy.

Diagnosis

Based on the clinical findings of the characteristic facial features. The clinical course provides valuable clues to the diagnosis. CT- and/or MRI-scans show total (about 59% of patients) or partial agenesis of the corpus callosum.

Clinical aspects

The neonatal period may be unremarkable and followed by progressive, symmetrical, distal, and proximal limb weakness with muscle atrophy. Muscular hypotonia and delayed motor development start to become evident at the age of 4 to 6 months. Some patients eventually learn to walk (although rarely independently) between the age of 2 and 5 years, but they will typically be wheelchair-bound by the age of 10 to 15 years. Progressive weakness will lead to death in early adulthood (on average at around 25 years of age). The characteristic autopsy findings are extremely swollen axons in cranial nerves and dorsal and ventral nerve roots. Similar, but less striking changes with small oval vacuoles can also be found scattered throughout the white matter. Nerve conduction and EMG studies invariably show absent sensory potentials (sural, median, cubital) already in infancy and variable reductions in motor nerve conduction velocities (median, cubital, tibial). Sural nerve biopsies show absence of large myelinated fibers and signs of axonal loss and Wallerian degeneration. Electron microscopy reveals enlarged axons with a reduced density of neurofilaments. ...

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