Home日本語

Congenital cerebral hypomyelination; network for Pelizaeus-Merzbacher disease and related disorders

  • Inherited white matter disorders
  • Congenital cerebral hypomyelination

MENU

Guidelines on Hereditary Leukodystrophies

Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH; OMIM #609136)

Disease description: Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease is caused by a mutation in the SOX10 gene. It exhibits autosomal dominant inheritance, but since most cases are de novo mutations, it is typically clinically sporadic. Its severity varies widely, ranging from respiratory dysfunction immediately after birth in the most severe cases to comparatively mild. Sensorineural hearing loss is treated with cochlear implants, Hirschsprung disease is treated surgically, and peripheral neuropathy and central dysmyelinating leukodystrophy are treated symptomatically.

1. Concept

Definition

Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) is a rare disease characterized by the abnormal development of oligodendrocytes as well as developmental anomalies in Schwann cells, melanocytes, gastrointestinal ganglion cells, and other neural crest–derived cells. Its clinical presentation includes not only central dysmyelinating leukodystrophy but also demyelinating neuropathy of the peripheral nervous system with the addition of Waardenburg syndrome and Hirschsprung disease for a total of four syndromes. Individual patients may not experience all four. The causative gene is SOX10 and the disease exhibits autosomal dominant inheritance, with most cases constituting sporadic de novo mutations. It is distinguished from Waardenburg syndrome type 4 (WS4, the combination of Waardenburg syndrome and Hirschsprung disease), which is also caused by a mutation in SOX10, by the presence of peripheral neuropathy and central nervous system symptoms.

Epidemiology

No epidemiological information such as the incidence of this disease has been reported. It is extremely rare, and fewer than 10 cases have been reported in Japan to date.

Etiology and pathophysiology

SOX10, the causative gene for this condition, encodes a transcription factor expressed in the initial stages of development and differentiation of neural crest–derived cells in the process of neuronal development (1). Its expression in neural crest–derived melanocytes, Schwann cells, and intestinal ganglion cells is associated with the pathophysiology of Waardenburg syndrome, demyelinating neuropathy, and Hirschsprung disease. It is also expressed in oligodendrocyte-lineage cells, which are not derived from the neural crest, which causes the central dysmyelinating leukodystrophy (2). The molecular pathology of PCWH is believed to consist of the impairment of the development, differentiation, and maintenance of these cells to varying degrees according to SOX10 mutation type (2-4). SOX10 mutations have also been reported in various diseases other than PCWH, including WS4 (5) and Kallmann syndrome with deafness (6), but PCWH is the most severe phenotype. It is a historically new disease: the first case was reported by Inoue et al. in 1999, and the disease concept was established in 2004.

Clinical symptoms

Most patients require surgical treatment for Hirschsprung disease immediately after birth. In terms of neurological symptoms, in severe cases there is almost no myelination of either the peripheral or the central nervous system immediately after birth; these patients soon die. Moderate cases exhibit delayed psychomotor development and hypotonia, with spastic limb paralysis present in around half of all patients as well as demyelinating neuropathy. In mild cases, mildly delayed motor development and demyelinating neuropathy are present. Waardenburg syndrome produces partial hypopigmentation of the irises, hair, skin, and other areas with sensorineural hearing loss.

Imaging and other investigations

Cranial magnetic resonance imaging (MRI) shows diffuse hyperintensity of the cerebral white matter of varying severity on T2-weighted imaging. In severe cases, white matter hypoplasia results in atrophy of the brainstem and the cerebellar and cerebral white matter. In mild cases, however, only slight hyperintensity of the periventricular white matter is present. Decreased peripheral nerve conduction velocity of varying severity is also present.

Genetic diagnosis

Almost all cases are caused by a point mutation in the gene encoding the SOX10 protein, which can be detected by DNA sequencing (7). Most occur as de novo mutations in children. Deletions of the region of the genome that includes SOX10 have also been reported (8).

Most of the mutations that cause PCWH are frame-shift or nonsense mutations in exon 5, the final exon (3). Mutations in upstream exons often cause WS4. Because mutant mRNA including a stop codon generated in an upstream exon is broken down by nonsense-mediated mRNA decay (NMD), aberrant proteins do not exist; thus, haploinsufficiency is responsible for the pathophysiology of PCWH. Mutations in the stop codon of the final exon are not broken down by NMD; therefore, truncated proteins are translated from mutant mRNA (3, 9). Because the SOX10 DNA binding site is upstream, these truncated proteins are able to bind to the target binding sequence more strongly than wild-type proteins can. However, because the C-terminal activation site is missing, they lack transcriptional activity and competitively inhibit the binding of wild-type SOX10 expressed by the normal allele, exerting a dominant-negative effect. A few nonsense mutations also exist in which the normal stop codon is destroyed and translation continues to the 3' untranslated region, generating mutant proteins that are longer than wild-type proteins (2). Those mutations cause a more severe PCWH phenotype despite the amino acid sequence of wild-type SOX10 protein being mostly preserved. This is because the non-specific sequences translated from the 3' untranslated region include a human-specific 11-residue sequence (known as the WR domain because of its high tryptophan and arginine content) that possesses functional toxicity, meaning that these are probably gain-of-function mutations (10, 11). Thus, WS4 is caused by haploinsufficiency, whereas two different molecular pathologies, dominant inhibition and gain-of-function, are involved in PCWH.

Treatment and care

At this point there is no cure for congenital cerebral leukodystrophy; thus, symptomatic therapy is provided.

Diet and nutrition

Diet is based on the management of Hirschsprung disease. PCWH affects a wide area, and long-segment disease is common, meaning that treatment may be difficult.

Prognosis

In severe cases, the prognosis is poor, with some patients dying within 2 months after birth (4, 12). However, some mild familial cases are also known. There has been no study of the natural history of PCWH; therefore, the details are unknown.

2. Diagnosis

I. Main clinical symptoms
  1. Spastic limb paralysis or paralysis of the legs
  2. Nystagmus
  3. Delayed psychomotor development
  4. Cerebellar impairment: trunk and limb ataxia, intention tremors, dysmetria, conversion disorder, and slow language acquisition in childhood
  5. Demyelinating peripheral neuropathy
  6. Waardenburg syndrome: sensorineural hearing loss and hypopigmentation of the irises, hair, skin, and elsewhere
  7. Hirschsprung disease
II. Important test results
  1. MRI: Diffuse hyperintensity of the white matter on T2-weighted imaging
    (excluding patients with signs of demyelinating disorders )
  2. Low peripheral nerve conduction velocity
  3. Genetic screening: SOX10 mutation

PCWH is diagnosed if at least four of the symptoms in list I are present, including at least three of symptoms 1, 5, 6, and 7, together with either 1, 2, or 3 from list II.

3. Treatment guidelines

Peripheral neuropathy is treated with symptomatic therapy according to its severity. In severe cases, respiratory management for respiratory muscle paralysis may be required. Central dysmyelination frequently causes both intellectual and motor disabilities; in practice, children usually receive the same special needs care as that provided for children with cerebral palsy. Sensorineural hearing loss associated with Waardenburg syndrome is treated with cochlear implants (13). Surgery is often required immediately after birth to treat Hirschsprung disease, but some patients suffer no worse than chronic constipation; surgical or medical treatment may be used to manage the symptoms of individual patients.

4. Differential diagnosis

If neurological signs are minor and difficult to discern, other types of WS4 must be included in the differential diagnosis. Waardenburg syndrome type 4 is classified into types A–C depending on the causative gene: type A is caused by the EDNRB gene encodingendothelin receptor type B, type B by the EDN3 gene encoding endothelin 3, and type C by SOX10. PCWH must also be distinguished from other congenital cerebral leukodystrophies.

5. Recent topics

  • A case of PCWH with abnormal sex differentiation caused by duplication of the region of the genome containing SOX10 was reported (14).
  • Model mice with additive mutations of SOX10, the causative gene of PCWH, have been produced, clarifying the cellular pathology of gain-of-function mutations (11).
  • Concerning their molecular pathology, mutant proteins translated from missense mutations of SOX10, the causative gene of PCWH, co-localize with p54NRB and other intranuclear proteins in the nucleus and induce abnormal agglutination, exerting a dominant negative effect because wild-type SOX10 is also simultaneously incorporated into these agglutinations (15).
References
(Unless otherwise noted at the end, all are evidence level 6.)
  1. Kuhlbrodt K, Herbarth B, Sock E, Hermans-Borgmeyer I, Wegner M. Sox10, a novel transcriptional modulator in glial cells. J Neurosci. 1998;18(1):237-50.
  2. Inoue K, Tanabe Y, Lupski JR. Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation. Ann Neurol. 1999;46(3):313-8.　 Evidence level 5
  3. Inoue K, Khajavi M, Ohyama T, Hirabayashi S, Wilson J, Reggin JD, et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet. 2004;36(4):361-9.　 Evidence level 5
  4. Inoue K, Shilo K, Boerkoel CF, Crowe C, Sawady J, Lupski JR, et al. Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: Phenotypes linked by SOX10 mutation. Ann Neurol. 2002;52(6):836-42.　Evidence level 5
  5. Herbarth B, Pingault V, Bondurand N, Kuhlbrodt K, Hermans-Borgmeyer I, Puliti A, et al. Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. Proc Natl Acad Sci U S A. 1998;95(9):5161-5.
  6. Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A, et al. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet. 2013;92(5):707-24.　Evidence level 5
  7. Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010;31(4):391-406.
  8. Bondurand N, Dastot-Le Moal F, Stanchina L, Collot N, Baral V, Marlin S, et al. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4. Am J Hum Genet. 2007;81(6):1169-85.　Evidence level 5
  9. Khajavi M, Inoue K, Lupski JR. Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. European journal of human genetics : EJHG. 2006;14(10):1074-81.
  10. Inoue K, Ohyama T, Sakuragi Y, Yamamoto R, Inoue NA, Yu LH, et al. Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain. Hum Mol Genet. 2007;16(24):3037-46.
  11. Ito Y, Inoue N, Inoue YU, Nakamura S, Matsuda Y, Inagaki M, et al. Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH. Neurobiol Dis. 2015;80:1-14.
  12. Touraine RL, Attie-Bitach T, Manceau E, Korsch E, Sarda P, Pingault V, et al. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Am J Hum Genet. 2000;66(5):1496-503.　Evidence level 5
  13. Bayrak F, Catli T, Atsal G, Tokat T, Olgun L. Waardenburg Syndrome: An Unusual Indication of Cochlear Implantation Experienced in 11 Patients. J Int Adv Otol. 2017;13(2):230-2.　Evidence level４b
  14. Falah N, Posey JE, Thorson W, Benke P, Tekin M, Tarshish B, et al. 22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease. American journal of medical genetics Part A. 2017;173(4):1066-70.　Evidence level 5
  15. Chaoui A, Kavo A, Baral V, Watanabe Y, Lecerf L, Colley A, et al. Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations. Hum Mol Genet. 2015;24(17):4933-47
Literature search
  • Peripheral[All Fields] AND demyelinating[All Fields] AND neuropathy[All Fields] AND central[All Fields] AND dysmyelinating[All Fields] AND leukodystrophy[All Fields] AND ("waardenburg syndrome"[MeSH Terms] OR ("waardenburg"[All Fields] AND "syndrome"[All Fields]) OR "waardenburg syndrome"[All Fields]) AND ("hirschsprung disease"[MeSH Terms] OR ("hirschsprung"[All Fields] AND "disease"[All Fields]) OR "hirschsprung disease"[All Fields])　10 results　Search performed 2017/12/18
  • (("soxe transcription factors"[MeSH Terms] OR ("soxe"[All Fields] AND "transcription"[All Fields] AND "factors"[All Fields]) OR "soxe transcription factors"[All Fields] OR "sox10"[All Fields]) AND ("mutation"[MeSH Terms] OR "mutation"[All Fields])) AND (hypomyelinated[All Fields] OR hypomyelinatiing[All Fields] OR hypomyelinating[All Fields] OR hypomyelinatingjimpy[All Fields] OR hypomyelination[All Fields] OR hypomyelinative[All Fields])　12 results　Search performed 2017/12/18
  • ("soxe transcription factors"[MeSH Terms] OR ("soxe"[All Fields] AND "transcription"[All Fields] AND "factors"[All Fields]) OR "soxe transcription factors"[All Fields] OR "sox10"[All Fields]) AND pcwh[All Fields]　14 results　 Search performed 2017/12/18
  • PCWH[All Fields] 19 results　 Search date 2017/12/18