NeurometPlus

Incidence

CACH/VWM is inherited in an autosomal recessive manner. The prevalence is not known, but CACH/VWM is considered one of the most common leukodystrophies. In some countries, its incidence is close to that of metachromatic leukodystrophy.

Clinical Characteristics

CACH/VWM phenotypes range from a subacute infantile form (onset < one year) to an early-childhood-onset form (onset one to five years) to a late-childhood/juvenile-onset form (onset five to 15 years) to an adult-onset form. Both the childhood and juvenile forms have been observed in sibs; however, the infantile and juvenile/adult forms have never been observed within the same family. It should, however, be noted that in patients homozygous for the same mutation, for instance the T91A mutation in EIF2B5, the phenotype may vary from childhood to presymptomatic adult. The neurologic signs include ataxia, spasticity, and variable optic atrophy. In the early-onset forms, decline is rapid and followed quickly by death; in the later-onset forms, mental decline is usually slower and more mild. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma. Other eIF2B-related forms likely exist.This new entity, defined based on clinicoradiological criteria, was first described in children. The onset is marked, after initially normal or only moderately retarded development, by the rapid appearance of a cerebellospastic syndrome before the age of 6 years. The occurrence of severe episodes of deterioration, after minor head trauma or banal infections, often lead to unexplained coma or episodes of lethargy with vomiting. Cognitive functions are preserved for a relatively long time. During the course of disease evolution, epileptic seizures, optic nerve atrophy and signs indicating involvement of the cerebral trunk (difficulty swallowing or breathing, ...) can occur. Death frequently occurs during the first decade of life. Clinical findings: Initial motor and mental development is normal or mildly delayed. Neurologic deterioration has a chronic progressive or subacute course. Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma. Clinical examination usually shows a combination of truncal and appendicular ataxia, pyramidal syndrome, and spasticity with increased tendon reflexes. The peripheral nervous system is usually not involved. Optic atrophy may develop. Epilepsy may occur, but is not the predominant sign of the disease. Mental abilities may be affected, but not to the same degree as motor functions. More recently, cases of later onset and slower progression have been reported, with a disease starting after 10 years, during adolescence or even in the young adult. The symptoms can, in these patients, start with moodiness and motor signs can appear later. Neuropathologic examination: The findings in general are a "cavitating orthochromatic leukodystrophy with rarity of myelin breakdown and relative sparing of axons". Cerebral and cerebellar myelin is markedly diminished, whereas the spinal cord is relatively spared. Vacuolation and cavitation of the white matter are diffuse giving a spongiform appearance. Oligodendrocytes are increased in number. The hallmark is the presence of oligodendrocytes with "foamy" cytoplasm and markedly hypotrophic and sometimes atypical astrocytes. Apparently the CACH syndrome represents 30% of leukodystrophies of unknown etiology.

Precipitants

Episodes of subacute deterioration may follow minor infection or minor head trauma and may lead to lethargy or coma.

Provocation Tests

none

Diagnostic Procedures

The diagnosis of childhood ataxia with central nervous system hypomyelination/leukoencephalopathy with vanishing white matter (CACH/VWM) can be made with confidence in patients with typical clinical findings, characteristic abnormalities on cranial MRI, and identifiable mutations in one of the five causative genes. Routine laboratory tests, including spinal fluid analysis, are normal.The diagnosis of CACH/VWM can be made with confidence in patients with typical clinical findings, characteristic abnormalities on cranial MRI, and identifiable mutations in one of five causative genes ( EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the five subunits of the eucaryotic translation initiation factor, eIF2B. Mutations have been found in more than 95% of patients, using sequence analysis or mutation scanning.