An X-linked form of sensory and motor neuropathy characterized by atrophy of the peroneal muscles (but also involving other distal muscles of the legs and arms), deafness, and cognitive impairment.
Cowchock-Fischbeck Syndrome; Charcot-Marie-Tooth Disease with Deafness and Mental Retardation; Charcot-Marie-Tooth Disease Type IV; Hereditary Motor Sensory Neuropathy (HMSN) II.
First described in 1985 by the American physician F. Susan Cowchock and colleagues in seven males of two generations of one family.
Unknown, but the five types of X-linked Charcot-Marie-Tooth Disease account for 7 to 10% of all Charcot-Marie-Tooth (CMT) Disease cases. Only males are affected, whereas female carriers show only minor abnormalities in sensory nerve conduction, electromyography, and hearing.
X-linked recessive. It is caused by mutations in the AIFM1 (Mitochondria-Associated Apoptosis-Inducing Factor 1) gene, which has been mapped to chromosome Xq26.1. AIFM1 gene encodes the mitochondrial, flavoprotein-dependent NADH oxidoreductase apoptosis-inducing factor that is involved in oxidative phosphorylation and in caspase-independent, apoptotic cell death-related actions such as chromatin condensation and DNA breakdown. The mutation in this disorder alters the redox properties of the AIF protein resulting in increased apoptotic cell death, but does not affect the activity of the respiratory chain complexes.
Based on the clinical findings in infants with foot drop, clawing of fingers, and progressive atrophy and weakness of peroneal and other distal foot muscles in combination with a positive family history. Electrophysiology plus microscopy show reduced conduction velocity, demyelination, and axonal degeneration.
Onset is in the perinatal period or in early infancy with slowly progressive and eventually profound generalized muscle weakness and atrophy, which is more severe in the lower limbs and distally. The deep tendon reflexes are diminished or absent. Motor development is delayed. The diaphragm, phrenic nerve, and vocal cords are occasionally involved. Hammertoes and pes cavus deformity are present in most adult patients, who are usually able to walk short distances unassisted and experience moderate disability in adulthood. Other clinical features may include foot dropping (manifesting as frequent tripping), steppage or equine gait, “inverted Champagne bottle” or stork legs, muscle cramping, and clawhand. Pain and temperature sensation are normal. An association with mental retardation and sensorineural hearing loss is frequent. Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging has been performed in two patients and revealed multiple punctate hyperintensities in the supratentorial white matter. Laboratory testing may detect mild elevations in serum transaminases, lactate dehydrogenase, and creatine kinase, while pyruvate and free and total carnitine levels are normal. Electromyography shows signs of widespread denervation with occasional fibrillation. Motor nerve conduction velocities range from normal to moderately delayed, while sensory nerve conduction velocities are markedly abnormal. A sural nerve biopsy may show only a few myelinated fibers ...