A number sign (#) is used with this entry because of evidence that demyelinating Charcot-Marie-Tooth disease-1H (CMT1H) is caused by heterozygous mutation in the gene encoding fibulin-5 (FBLN5; 604580) on chromosome 14q32.

Heterozygous mutation in the FBLN5 gene can also cause autosomal dominant cutis laxa-2 (ADCL2; 614434) and isolated age-related macular degeneration-3 (ARMD3; 608895). Skin laxity and ARMD may rarely occur in patients with CMT1H.

Demyelinating Charcot-Marie-Tooth disease-1H (CMT1H) is an autosomal dominant peripheral sensorimotor neuropathy with onset usually in adulthood (third to fifth decades). Affected individuals present with foot deformities, upper or lower limb sensory disturbances, and motor deficits, mainly impaired gait. Of note, many patients complain of unpleasant sensory sensations in the upper extremities and hands. The disorder is slowly progressive and becomes more apparent with age, although patients usually remain ambulatory. Other features include hypo- or areflexia, limb muscle weakness, and impaired gait. Electrophysiologic studies are consistent with a demyelinating polyneuropathy. Rare patients may have hyperelastic skin or develop age-related macular degeneration (summary by Auer-Grumbach et al., 2011 and Safka Brozkova et al., 2020)

For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

Auer-Grumbach et al. (2011) reported a large Austrian kindred (families A and B) in which multiple individuals spanning several generations had demyelinating CMT. Eight patients were studied in detail. The severity of the phenotype was variable, but common features included distal muscle weakness and atrophy variably affecting the lower and upper limbs and distal sensory impairment. The age at onset ranged from 25 to 50 years. Most patients had hypo- or areflexia, and several had symptoms consistent with carpal tunnel syndrome. None had hyperelastic skin, and only the oldest patient had age-related macular degeneration at age 81 years. Electrophysiologic studies performed in some patients showed decreased nerve conduction velocities, consistent with a demyelinating peripheral neuropathy.

Another family (family C) with 5 members reported by Auer-Grumbach et al. (2011) had more variable manifestation of a peripheral neuropathy. Two brothers had early onset of spinal CMT at age 4. They had severe distal muscle weakness and wasting predominantly of the lower limbs without sensory impairment. In addition, they both had hyperelastic skin, joint hypermobility, high palate, and mild skeletal abnormalities; neither had macular degeneration at 19 and 21 years of age. Nerve conduction velocities suggested an axonal neuropathy, and EMG showed chronic neurogenic disturbances, but sural nerve biopsy was normal. Family studies identified a parent, grand-aunt, and grandparent who had mild peripheral neuropathy and hyporeflexia. The parent also had hyperelastic skin, whereas the grand-aunt had ARMD at age 71 years. In a third family (family D), a 46-year-old proband had spinal CMT with onset at age 20 and hyperelastic skin. The father was asymptomatic but had evidence of a mild peripheral neuropathy of the lower limbs; he also had ARMD at age 82 years. Six additional patients with sporadic occurrence of ARMD who were over the age of 79 years were subsequently found to have variable features of peripheral neuropathy, and 2 patients in their eighties had sporadic peripheral neuropathy without ARMD. Auer-Grumbach et al. (2011) concluded that the overall phenotype in these patients represented a novel syndrome associated with FBLN5 gene mutations, including presence of peripheral neuropathy with or without ARMD and occasionally hyperelastic skin, with intrafamilial variability.

Safka Brozkova et al. (2013) reported a large family of Czech descent with CMT1H. Affected individuals had onset in their twenties of distal muscle atrophy and weakness affecting mainly the lower limbs, with some patients having weakness of the upper limbs. Two older patients reported distal sensory impairment. Some younger patients were clinically asymptomatic, but electrophysiologic studies indicated a demyelinating peripheral neuropathy. Patellar reflexes were decreased or absent in all patients. None had hyperelastic skin or ARMD.

Cheng et al. (2017) reported a Chinese family with CMT1H. The 46-year-old proband developed distal numbness and muscle weakness at age 34 years when he was also diagnosed with diabetes mellitus. The neurologic disorder was slowly progressive, and he developed gait difficulties and distal sensory impairment of several modalities in both the lower and upper limbs. Other features included hypo- or areflexia, steppage gait, and atrophy of the distal muscles of the upper and lower limbs. The disorder remained essentially static over about 10 years. The patient's 81-year-old mother had a mild peripheral neuropathy with distal sensory impairment, areflexia, and pes cavus; she developed age-related macular degeneration and cataract of the right eye. The proband's 16-year-old daughter had no clinical symptoms, although deep tendon reflexes were absent. Electrophysiologic studies in all 3 patients were indicative of a demyelinating sensorimotor neuropathy with more prominent findings in the proband, who was the most severely affected. Ultrasound detected abnormally enlarged nerves, and sural nerve biopsy of the proband showed a decrease in myelinated fibers as well as the presence of onion bulb formations and poorly myelinated axons.

Safka Brozkova et al. (2020) reported 38 affected individuals from 19 families with CMT1H confirmed by genetic analysis. The families were of Austrian, Czech, French, and German origin; 3 of the families had previously been reported. Most patients were diagnosed between the third and fifth decades (median 39 years of age), and the presenting features included foot deformities, upper or lower limb sensory disturbances, and motor deficits, mainly impaired gait. Of note, many patients complained of unpleasant sensory sensations in the upper extremities and hands. In retrospect, many patients had foot deformities since childhood, but had no physical limitations at that time. The disorder was slowly progressive and became more apparent with age, although all remained ambulatory and had purposeful hand use. Several younger individuals carrying the mutation were clinically asymptomatic, although decreased reflexes and foot deformities were noted. None had hyperelastic skin; 1 patient had age-related macular degeneration at age 81. Electrophysiologic studies were consistent with a demyelinating polyneuropathy.

The transmission pattern of CMT1H in the families reported by Auer-Grumbach et al. (2011) and Safka Brozkova et al. (2013) was consistent with autosomal dominant inheritance with variable expressivity and age-dependent penetrance.

In affected members of 3 families with CMT1H, Auer-Grumbach et al. (2011) identified 3 different heterozygous missense mutations in the FBLN5 gene (604580.0012-604580.0014). Functional studies of the variants were not performed.

Safka Brozkova et al. (2013) identified a heterozygous missense mutation in the FBLN5 gene (R373C; 604580.0012) in affected members of a Czech family with CMT1H. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

In 3 affected members spanning 3 generations of a Chinese family with CMT1H, Cheng et al. (2017) identified a heterozygous R373C mutation in the FBLN5 gene (604580.0012).

In affected members of 19 families with CMT1H, some of whom had previously been reported, Safka Brozkova et al. (2020) identified 3 different heterozygous missense mutations in the FBLN5 gene. R373C (604580.0012) was the most common mutation, occurring in 15 families of Austrian, Czech, and French origin. Three families of Czech or German origin carried a heterozygous R331H mutation (604580.0015), and 1 French family carried a D329V mutation (604580.0016). The mutations, which were detected by Sanger sequencing, multigene panel sequencing, or whole-exome sequencing, segregated with the disorder in families from whom DNA was available for the affected members. Functional studies of the variants were not performed, but they were either absent from or found only once in the gnomAD database.