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CACH syndrome

Orpha number ORPHA135
Synonym(s) Childhood ataxia with diffuse central nervous system hypomyelination
Leukoencephalopathy with vanishing white matter
Myelinosis centralis diffusa
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Childhood
ICD-10
  • E75.2
ICD-O -
OMIM
UMLS
  • C1858991
  • C2931489
MeSH
  • C537420
MedDRA -
SNOMED CT -

Summary

A new leukoencephalopathy, the CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) or VWM (Vanishing White Matter) was identified on clinical and MRI criteria. Classically, this disease is characterized by (1) an onset between 2 and 5 years of age, with a cerebello-spastic syndrome exacerbated by episodes of fever or head trauma leading to death after 5 to 10 years of disease evolution, (2) a diffuse involvement of the white matter on cerebral MRI with a CSF-like signal intensity (cavitation), (3) a recessive autosomal mode of inheritance, (4) neuropathologic findings consistent with a cavitating orthochromatic leukodystrophy with increased number of oligodendrocytes with sometimes ``foamy'' aspect. A total of 148 cases have been reported so far. This disease is linked to mutations in the five EIF2B genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B), involved in the protein synthesis and its regulation under cellular stress. Clinical symptoms are variable, from fatal infantile forms (Cree leukoencephalopathy) and congenital forms associated with extra-neurological affections, to juvenile and adult forms (ovarioleukodystrophy) characterized by cognitive and behavioural dysfunctions and by a slow progression of the disease, leading to the term of eIF2B-related leukoencephalopathies. Prevalence of this disease remains unknown. Diagnosis relies on the detection of eIF2B mutations, predominantly affecting the EIF2B5 gene. A decrease in the intrinsic activity of the eIF2B factor (the guanine exchange activity, GEF) in lymphoblasts from patients seems to have a diagnostic value. The patho-physiology of the disease would involve a deficiency in astrocytes maturation leading to an increased susceptibility of the white matter to cellular stress. No specific treatment exists besides the ``prevention'' of cellular stress. Corticosteroids sometimes proved to be useful in acute phases. Prognosis seems to be correlated with the age of onset, the earliest forms being more severe.

Expert reviewer(s)

  • Pr Odile BOESPFLUG-TANGUY
  • Dr Anne FOGLI
  • Pr Pierre LABAUGE
  • Dr Florence NIEL
  • Pr Diana RODRIGUEZ

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Detailed information

Review article
  • EN (2011)
  • FR (2007,pdf)
Clinical practice guidelines
  • DE (2012)
Clinical genetics review
  • EN (2012)
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