Neuropathy, Hereditary, With Or Without Age-Related Macular Degeneration

A number sign (#) is used with this entry because of evidence that hereditary neuropathy with or without age-related macular degeneration (HNARMD) 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), which may be a feature in some patients with HNARMD. It may also cause isolated age-related macular degeneration (ARMD3).

Description

Hereditary neuropathy with or without age-related macular degeneration is a complex autosomal dominant syndrome characterized by a variable peripheral neuropathy resembling demyelinating Charcot-Marie-Tooth disease (see, e.g., CMT1A, 118220) and/or axonal CMT (see, e.g., CMT2A1, 118210) with sensorimotor impairment mainly of the distal lower extremities, or spinal CMT, also known as distal hereditary motor neuropathy (see, e.g., HMN1; 182960) with intact sensation. Age-related macular degeneration, if present, shows very late onset in the seventies or eighties. In addition, some patients may show hyperelasticity of the skin or joints. The age at onset of neuropathy and severity of the disorder is highly variable, even within families (summary by Auer-Grumbach et al., 2011).

For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration, see 603075.

Clinical Features

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 HRARMD. 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.

Inheritance

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

Pathogenesis

Mullins et al. (2007) localized the fibulin-5 protein to the Bruch membrane and to the intercapillary pillars of the choriocapillaris in normal human donor eyes. In eyes with age-related macular degeneration, they localized the protein to pathologic basal deposits beneath the retinal pigment epithelium (RPE) as well as in some small drusen. Mullins et al. (2007) suggested that fibulin-5 may promote extracellular deposit formation in macular degeneration.

Molecular Genetics

In affected members of 3 families with HNARMD, 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 (604580.0012) in affected members of a Czech family with HNARMD. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

Stone et al. (2004) studied 402 patients with age-related macular degeneration and identified 7 different mutations in the FBLN5 gene (604580.0003-604580.0009) that were not found in 429 controls (p = 0.006). The 7 patients all had clusters of small, round, uniform drusen in association with variable degrees of detachment of retinal pigment epithelium. All of the patients were examined in a retina clinic. Given that some of the patients reported by Auer-Grumbach et al. (2011) had mild features of neuropathy, it is possible that such may have been missed in the patients reported by Stone et al. (2004).