Neuropathy, Congenital Hypomyelinating, 2

A number sign (#) is used with this entry because of evidence that congenital hypomyelinating neuropathy-2 (CHN2) is caused by heterozygous mutation in the MPZ gene (159440) on chromosome 1q23.

Congenital hypomyelinating neuropathy-2 is an autosomal dominant neurologic disorder characterized by early-onset hypotonia, severely delayed motor development, muscle weakness with areflexia, and severely decreased nerve conduction velocities (NCV) resulting from improper myelination of axons. The severity is variable: some patients may present at birth with contractures and respiratory insufficiency, whereas others may achieve walking (summary by Warner et al., 1996).

CHN shows significant phenotypic overlap with Dejerine-Sottas syndrome (DSS; 145900), which is also a neuropathy with early onset. Some classify the disorders differently, noting that CHN is characterized by hypo- or amyelination resulting from a congenital defect in myelin formation, whereas DSS has features of continuous myelin breakdown, with demyelination and remyelination (summary by Smit et al., 2008).

For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).

Warner et al. (1996) reported a patient (patient 987) who was first examined at age 10 months due to delayed motor milestones. She could not lift her head while prone, but could sit if placed, and had mild hypotonia of the limbs and trunk with absent reflexes. Nerve conduction studies revealed a generalized severe demyelinating neuropathy (4-9 m/s) and absent sensory action potentials. She walked with a few steps at 3.5 years and had scoliosis. Sural nerve biopsy showed abnormally thin myelin sheaths with mild reduction in the number of myelinated fibers, occasional large axons with no myelin, and rare rudimentary atypical onion bulbs. The findings were attributed mainly to a lack of development of proper myelin rather than the result of demyelination and failure of remyelination.

Mandich et al. (1999) reported a patient with CHN2 who presented in the first year of life with delayed motor milestones, diffuse muscle weakness and hypotonia, reduced reflexes, scoliosis, and pes planus. At age 7 years, she had distal muscle wasting of the lower limbs and sensory ataxia. Motor NCVs were severely decreased (3-4 m/s), and sural nerve biopsy showed a diffuse loss of myelinated fibers with abnormally thin myelin sheaths and atypical onion bulbs mainly composed of basal laminae and thin layers of Schwann cell cytoplasm. Sensory nerve action potentials were not recordable.

Szigeti et al. (2003) reported a patient with CHN2 who presented at birth with hypotonia, arthrogryposis of the left hand, and respiratory failure requiring ventilatory support. She later showed facial diplegia, other cranial nerve involvement, areflexia, and severely delayed motor development. At 31 months of age, she had head lag and was able to crawl and kneel, but not pull to a stand. Cognitive development was normal. Motor NCV was 11 m/s, and sural nerve biopsy showed little or no compact myelin and few basal lamina onion bulbs, consistent with CHN. A muscle biopsy showed poor fiber type differentiation and disruption of sarcomeres, presumably caused by abnormal innervation.

Kochanski et al. (2004) reported a Polish boy with CHN2. He was a floppy infant at birth and showed delayed motor development. At age 7 years, he had distal weakness and muscle atrophy that was more pronounced in the lower limbs. He also had scoliosis, chest deformities, and pes equinovarus. Median motor NCV was 3.0 m/s; sensory conduction velocity in the right sural nerve was unrecordable. Sural nerve biopsy showed a profound loss of myelinated fibers and complete absence of large myelinated fibers. Some small onion bulb formations were present. The patient was wheelchair-bound by age 12 years.

Smit et al. (2008) reported a father and daughter with CHN2. The proband was a 1-day old girl born at 34 weeks' gestation with hypokinesia, hypotonia, areflexia, arthrogryposis, and respiratory insufficiency necessitating support. NCV studies showed a severe demyelinating polyneuropathy (2-4 m/s). Her father had a similar neonatal period, with swallowing difficulties, pneumonia, hypotonia, and delayed motor milestones. He was able to walk with aid at age 4 years, and was partially wheelchair-bound as an adult. He had contractures of the distal lower limbs and scoliosis; there were no signs of central nervous system involvement. Sural nerve biopsy of the father showed absence of myelin sheaths and no classic onion bulb formations.

The transmission pattern of CHN2 in the family reported by Smit et al. (2008) was consistent with autosomal dominant inheritance. Smit et al. (2008) noted that transmission of CHN in a family is a rare occurrence.

In a patient (patient 987) with CHN2, Warner et al. (1996) identified a de novo heterozygous nonsense mutation in the MPZ gene (Q186X; 159440.0013). Mandich et al. (1999) identified the same de novo heterozygous mutation, referred to as Q215X, in a different patient with CHN2. The mutation affected the intracellular domain of the protein, which participates in electrostatic interactions.

In a patient with CHN2, Szigeti et al. (2003) identified a de novo heterozygous mutation in the MPZ gene (159440.0027). Functional studies of the variant were not performed.

In a Polish boy with CHN2, Kochanski et al. (2004) identified a de novo heterozygous mutation in the MPZ gene (T124K; 159440.0031).

In a father and daughter with CHN2, Smit et al. (2008) identified a heterozygous frameshift mutation in the MPZ gene (159440.0037). Functional studies of the variant were not performed, but it was predicted to interfere with adhesion properties of the protein.