Neuropathy, Congenital Hypomyelinating, 1, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that congenital hypomyelinating neuropathy-1 (CHN1) can be caused by homozygous mutation in the EGR2 gene (129010) on chromosome 10q21.

One patient with a heterozygous mutation in the EGR2 gene has been reported.

Description

Congenital hypomyelinating neuropathy (CHN) is characterized clinically by onset of hypotonia at birth, areflexia, distal muscle weakness, and very slow nerve conduction velocities (often less than 10 m/s). Warner et al. (1997, 1998) noted that pathologic findings on sural nerve biopsies show hypomyelination of most or all fibers. Based on these findings, CHN is considered to be a result of congenital impairment in myelin formation.

There has been some controversy and difficulty in differentiating congenital hypomyelination from Dejerine-Sottas syndrome (DSS; 145900) because there is considerable overlap in clinical presentation. Based on pathologic findings of sural nerve biopsies (the absence of active myelin breakdown and the paucity of the onion bulbs in CHN and the presence of demyelination/remyelination and an abundance of well-organized onion bulbs in DSS; see Balestrini et al., 1991), CHN is considered to result from a congenital impairment in myelin formation, whereas DSS is thought to be due to aberrant demyelination and subsequent remyelination of the peripheral nerve.

There is also variation in the prognosis of patients diagnosed with CHN. In patients with CHN, Harati and Butler (1985) showed correlation of morbidity and mortality with the presence/absence of onion bulbs: patients with few onion bulbs died in early infancy, usually because of difficulty in swallowing and respiration after birth. Patients with atypical onion bulbs survived but were affected with severe motor and sensory impairment. These differences in outcome may represent genetic heterogeneity such that mutations in essential early myelin gene(s) cause a severe phenotype, whereas mutations in other, possibly later acting gene(s), such as MPZ, lead to a less severe outcome.

Genetic Heterogeneity of Congenital Hypomyelinating Neuropathy

See also CHN2 (618184), caused by mutation in the MPZ gene (159440) on chromosome 1q23; and CHN3 (618186), caused by mutation in the CNTNAP1 gene (602346) on chromosome 17q21.

Clinical Features

Warner et al. (1998) reported 3 brothers, born of consanguineous parents (family HOU336), with CHN. The patients were floppy at birth, had delayed motor milestones, and walked with crutches. They had steppage gait due to foot drop and muscle wasting, particularly of the distal muscles. Electrophysiologic studies showed absent sensory responses and extremely low or absent compound muscle action potentials with absent or very low nerve conduction velocities (3 m/s). Sural nerve biopsies showed absence of myelin in virtually all fibers. Brain imaging, performed in 2 patients, was normal, with no white matter abnormalities. The parents were unaffected.

Autosomal Dominant/Sporadic Occurrence

Warner et al. (1998) also reported a 7-year-old girl (patient 1085) with sporadic occurrence of CHN. She presented with infantile hypotonia and delayed motor development. She walked after 2 years of age. At age 7 years, she was generally hypotonic and her muscle bulk was diminished, more distally than proximally. Her strength was also more impaired distally. She ambulated with a walker and ankle-foot orthotics for bilateral foot drop. Electrophysiologic studies showed marked abnormalities with absent sural, ulnar and median sensory responses, low compound muscle action potential amplitudes, and markedly delayed distal latencies. Conduction velocities were markedly slowed at less than 8 m/s. Light microscopic and enzyme histochemical analysis of a sural nerve biopsy showed profound absence or loss of myelin in virtually all axons and only 2 or 3 normally myelinated axons within the entire cross-section of the nerve. Axons were relatively preserved. She was initially diagnosed with DSS, but based on the nerve biopsy findings, the diagnosis was changed to CHN.

Inheritance

The transmission pattern of CHN1 in the family reported by Warner et al. (1998) was consistent with autosomal recessive inheritance.

Molecular Genetics

The EGR2 gene attracted the attention of Warner et al. (1997, 1998) as a potential candidate for CHN because of the expression and knockout phenotype of its mouse homolog, Krox20. Krox20, a member of a multigene family of zinc finger proteins, is thought to function as an immediate early protein with basal expression in selected neuronal populations of the central and peripheral nervous systems. Krox20 knockout mice showed disrupted hindbrain segmentation and development and a block of Schwann cells at an early stage of differentiation as evidenced by the fact that the expression of early myelin genes, such as myelin-associated glycoprotein (159460), are barely affected whereas the expression of the late myelin genes, myelin basic protein (159430) and myelin protein zero (159440), are decreased or absent. Warner et al. (1997, 1998) hypothesized that Krox20 may be a transcription factor affecting late myelin genes. Using heteroduplex analysis for a mutational screen on 22 patients diagnosed with a severe peripheral neuropathy, 1 was found to have a mutation in the EGR2 gene. The patient was part of a family in which 3 sibs had CHN and the parents were first cousins. All 3 affected sibs were homozygous for an ile218-to-asn missense mutation (129010.0001). Both parents and an unaffected sib were heterozygous for the same mutation.

In a patient with infantile hypotonia and gross motor developmental delay with ambulation after 2 years of age, Warner et al. (1998) found de novo heterozygous mutations at consecutive nucleotides of the EGR2 gene, a T-to-G transversion and a G-to-T transversion, predicted to cause ser382-to-arg and asp383-to-tyr substitutions within the second zinc finger of the protein (129010.0003). The mutations occurred in cis.

Cytogenetics

Funalot et al. (2012) reported a female infant, born of consanguineous Moroccan parents, with congenital amyelinating neuropathy. The patient was born prematurely and showed significant hypotonia with nearly complete absence of spontaneous limb movements and respiratory distress at birth. Her face was inexpressive and she showed distal limb flexion. Electroneuromyogram showed an absence of peripheral response and fibrillation potentials in muscles, and brainstem auditory evoked potentials were suggestive of an auditory neuropathy. Brain MRI showed no significant abnormality. She died of respiratory complications at 7.5 months of age. Electron microscopy of the patient's peripheral nerves showed a complete absence of myelin, consistent with amyelinating neuropathy. Schwann cells never appeared to initiate the spiralization of outer mesaxons to form myelin sheaths, and Schwann cells did not express MPZ, MBP (159430), or EGR2. However, the transcription factor SOX10 (602229) was expressed. Schwann cells were surrounded by a basal lamina, which frequently formed onion-bulb-like proliferations. Spinal cord nerve roots contained oligodendrocytes and astrocytes, indicating a transgression of the boundary between the central and peripheral nervous systems. The cerebral white matter appeared to be correctly myelinated. Both parents were asymptomatic, but the mother had had 2 previous pregnancies resulting in stillbirths. No mutations were found in the coding sequence of the EGR2 gene. Rather, the patient was found to carry a homozygous 10.7-kb deletion of chromosome 10q21 in the myelinating Schwann cell element (MSE; 614996), a highly conserved sequence located about 40 kb downstream of the EGR2 gene that regulates expression of the EGR2 gene. Analysis of the deletion boundaries suggested that it resulted from either a replication-based mechanism or a nonhomologous end joining at the origin of the deletion. Both parents were heterozygous for the deletion, which was not found in 170 control individuals or in a database of 2,026 subjects. The findings highlighted the important role of the MSE regulatory region in peripheral nerve myelination in humans.

Animal Model

Wrabetz et al. (2000) showed, through studies in transgenic mice, that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero. Transgenic mice containing extra copies of Mpz manifested a dose-dependent, demyelinating neuropathy. Mutations in the MPZ gene (159440) had been observed as the cause of congenital hypomyelination syndrome, as had mutations in the EGR2 gene. Wrabetz et al. (2000) suggested an interrelationship between mutations in EGR2 and MPZ. Mutations in the Krox20 transcription factor, encoded by EGR2, are expected to disinhibit Krox20, and Krox20 may regulate P(0) expression. Thus it is possible that MPZ overexpression contributes to the pathogenesis of the phenotype associated with the EGR2 mutation.