Hypertrophic Neuropathy Of Dejerine-Sottas

A number sign (#) is used with this entry because of the demonstration that Dejerine-Sottas syndrome (DSS) can be caused by mutations in the MPZ gene (159440), the PMP22 gene (601097), the PRX gene (605725), and the EGR2 (129010) gene.

There is also evidence that mutations in the GJB1 gene (304040) may contribute to the phenotype.

See also severe congenital hypomyelination (605253), which shows phenotypic overlap with DSS.

Dejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (summary by Baets et al., 2011).

Andermann et al. (1962) described Dejerine-Sottas hypertrophic neuropathy in grandfather, father, and 4-year-old daughter. Features included nystagmus, distal muscular weakness, distal sensory change, pes cavus and exacerbations and remissions. Isaacs (1960) described a family in which paralysis of the extremities was precipitated by cold weather. No sensory changes occurred in the family of Russell and Garland (1930), restudied by Croft and Wadia (1957) with tracing of the disorder through 5 generations. On the other hand Andermann et al. (1962) described sensory changes. They also demonstrated advanced involvement of cranial and spinal nerves. Spinal nerve root enlargement was demonstrable by myelography. Elevated spinal fluid protein is often found in this condition and in Refsum syndrome (266500). Bedford and James (1956) also observed a family with affected members in 5 generations. The onset is usually with weakness and deformity of the feet and lower limbs. 'Onion bulb' formation makes the histologic diagnosis.

In the original cases described by Dejerine and Sottas (1893), 2 sibs of presumably unaffected parents were affected. Onset was in infancy in Fanny Roy and at age 14 in Henri Roy. The patients showed clubfoot, kyphoscoliosis, generalized weakness and muscular atrophy with fasciculations beginning first in the leg muscles, decreased reactivity to electric stimulation, areflexia, marked distal sensory loss in all four extremities, incoordination in the arms, Romberg sign, miosis, decreased pupillary reaction to light, and nystagmus. Fanny died at age 45. Autopsy showed the peripheral nerves to be increased in size, firm and gelatinous. Only rare nerve fibers contained myelin. Dyck et al. (1970) found changes in nerves and liver suggesting a systemic defect in the metabolism of ceramide hexosides and ceramide hexoside sulfates.

Thomas et al. (1972) studied 9 kindreds in which 2 types of the disorder were suggested. In one type, onset was in childhood with leg weakness, foot deformity, and only mild sensory changes. In the other type, sensory loss was severe and often associated with chronic ulceration of the feet.

Joosten (1982) described 8 patients with Dejerine-Sottas disease. Two of the patients were sibs and 2 others had sibs with a similar disorder, suggesting autosomal recessive inheritance. In 6 cases the parents were studied clinically and electroneurographically, and no signs of polyneuropathy were found. In 1 family, the parents were related.

Ionasescu et al. (1996) reported a 55-year-old black male with Dejerine-Sottas neuropathy who belonged to a family with 9 severely affected DSN patients in an autosomal dominant pedigree pattern. Onset had occurred at 2 years of age with steppage gait. He showed pes cavus, hammertoes, progressive severe weakness and atrophy of the legs, and claw hands. He developed Charcot joints at both shoulders. A brother, aged 47, had similar neurologic findings and demonstrated Charcot joints with degeneration of the interphalangeal joints of the fourth and fifth fingers.

Roa et al. (1993) identified mutations in the PMP22 gene, located on chromosome 17p11, in patients with Dejerine-Sottas neuropathy.

Hayasaka et al. (1993) identified mutations in the MPZ gene, located on chromosome 1q22, in patients with Dejerine-Sottas neuropathy.

In family studies, Boerkoel et al. (2001) found linkage of recessive Dejerine-Sottas neuropathy to 19q13.1-q13.2.

Ionasescu et al. (1996) performed family studies showing linkage of DSN to microsatellite markers in the 8q23-q24 region. Positive lod scores were obtained for D8S257, D8S284, D8S256, and D8S274 with values between 1.81 and 2.11. Linkage to both PMP22 and MPZ was excluded and no duplication of PMP22 was demonstrated.

Hayasaka et al. (1993) investigated the MPZ gene as a candidate gene in 2 sporadic cases of Dejerine-Sottas neuropathy. They found 2 different mutations in the patients (159440.0004, 159440.0005). Roa et al. (1993) demonstrated that 2 point mutations in the PMP22 gene on 17p11.2 also caused Dejerine-Sottas neuropathy. Two unrelated patients were heterozygous for different mutations (601097.0006, 601097.0007).

In 3 sibs with Dejerine-Sottas syndrome, Parman et al. (1999) identified a homozygous mutation in the PMP22 gene (601097.0018). The unaffected parents were related as first cousins and both were heterozygous for the mutation. Parman et al. (1999) commented that DSS caused by mutation in the PMP22 gene is usually autosomal dominant, caused by a heterozygous mutation, and that the findings in this family demonstrate autosomal recessive inheritance.

In 3 unrelated patients with Dejerine-Sottas neuropathy, Boerkoel et al. (2001) identified recessive mutations in the PRX gene; see 605725.0001-605725.0004.

Timmerman et al. (1999) screened 170 unrelated neuropathy patients and identified 2 with Dejerine-Sottas neuropathy who had a heterozygous R359W mutation (129010.0004) in the alpha-helix domain of the first zinc finger of EGR2. Sural nerve biopsy showed severe demyelination, classic onion bulbs, and focally folded myelin sheaths. Boerkoel et al. (2001) reported 2 additional DSN patients with the R359W mutation and suggested that it is the most common neuropathy-associated EGR2 mutation and consistently causes DSN. The expressivity ranged from that typical for DSN to a more rapidly progressive neuropathy that can cause death by age 6 years. Furthermore, in contrast to patients with typical DSN, patients with the EGR2 R359W mutation had more respiratory compromise and cranial nerve involvement.

Takashima et al. (2002) reported a patient, born of consanguineous parents, with Dejerine-Sottas neuropathy due to a homozygous deletion in the PRX gene (605725.0007). Neuropathology showed demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon.

Chung et al. (2005) reported an unusual case of a Korean girl with DSS who had mutations in 2 different genes: EGR2 (R359W; 129010.0004) and GJB1 (V136A; 304040.0021). She inherited a heterozygous R359W mutation from her father, who had Charcot-Marie-Tooth disease-1D (607678). The GJB1 mutation was de novo. The father had pes cavus and developed difficulty walking at age 8 years, but had a milder phenotype than the daughter, who had experienced gait difficulties since infancy and facial weakness. She also had bilateral hand muscle weakness and atrophy and had sensory impairment of both upper and lower extremities. Chung et al. (2005) concluded that the more severe phenotype in the daughter was caused by an additive effect of the 2 mutations.

Al-Thihli et al. (2008) reported a 7-year-old boy with autosomal recessive Dejerine-Sottas disease associated with compound heterozygous deletions in the PMP2 gene: the common 1.5-Mb deletion (601097.0004), inherited from the mother, and a deletion encompassing exons 2 and 3 (601097.0020), inherited from the father. The nonconsanguineous parents were each heterozygous for a deletion and showed a phenotype consistent with hereditary neuropathy with liability to pressure palsies (HNPP; 162500). The boy had a severe phenotype with significantly delayed motor development, pes cavus, scoliosis, hyporeflexia, hearing deficits, severe demyelination on sural nerve biopsy, and gastroesophageal reflux. Al-Thihli et al. (2008) commented that the deletions in this patient were the largest compound heterozygous PMP22 deletions reported in the literature.

Low (1976, 1976) suggested that the Trembler mouse may be a mouse model of Dejerine-Sottas syndrome. Suter et al. (1992) identified a mutation in the Pmp22 gene in the Trembler mouse.