a) Parametri Genetici delle Neuropatie Sensomotorie Ereditarie (HMSN)

ii) MORBO DI ALEXANDER
 (ALEXANDER'S DISEASE)

DEFINITION:

A neurodegenerative disorder characterized by degeneration of CNS white matter and specific CNS pathological findings.

EPIDEMIOLOGY:

incidence: rare
age of onset:
newborn to adulthood (depends on the Form)
risk factors:
sporadic

PATHOGENESIS:

1. Background

unknown etiology but thought to involve dysfunctional astrocytes

PATHOLOGY:

1. Rosenthal Fibres

refractile eosinophilic hyaline bodies found within the cytoplasm of astrocytes particularly in the subpial, subependymal, and perivascular regions required for definite diagnosis but not pathognomonic as seen in other disorders as well, i.e., Neurofibromatosis, MS

TYPES:

Type I: Infantile Form
Type II: Juvenile Form
Type III: Adult Form

CLINICAL FEATURES:

1. Type I - Infantile Form

onset: mean of 6 months but can range from shortly after birth to 2 years of age most common of the 3 variants and most are male death in 2nd to 3rd years of age

    1. Neurological Manifestations

    plateauing then delayed psychomotor development movement disorders - spasticity others - mental retardation, seizures, megalencephaly (+/- hydrocephalus) +/- increased ICP

2. Type II - Juvenile Form

onset: 7-14 years of age

    1. Neurological Manifestations

    plateauing then delayed psychomotor development movement disorders - ataxia, spasticity others bulbar or pseudobulbar dysfunction - dysphagia, facial diplegia, nasal speech, nystagmus, ptosis, tongue atrophy muscle weakness

INVESTIGATIONS:

1. Imaging Studies

    1. CT/MRI

    progressive leukodystrophy attenuation of affected areas initially then later low attenuation of affected areas
2. Others

    1. EMG

    delayed conduction velocities

MANAGEMENT:

1. Supportive

no treatment available treat movement disorders and seizures

DESCRIPTION AND CLINICAL HISTORY

This disorder, first described by Alexander (1949), is characterized clinically by development of megalencephaly in infancy accompanied by progressive spasticity and dementia.
The features are similar to those of Canavan disease. In both disorders, astrocytes show marked changes. Histologically Alexander disease is characterized by Rosenthal fibers, homogeneous eosinophilic masses which form elongated tapered rods up to 30 microns in length, which are scattered throughout the cortex and white matter and are most numerous in the subpial, perivascular and subependymal regions.
These fibers are located in astrocytes, cells that are closely related to blood vessels.
Demyelination is present, usually as a prominent feature. A few cases have had hydrocephalus. Rosenthal fibers are commonly found in astrocytomas, optic nerve gliomas and states of chronic reactive gliosis, but they are especially conspicuous in Alexander disease.
Herndon et al. (1970) expressed the view that Rosenthal fibers found in this situation are the result of degenerative changes in the cytoplasm and cytoplasmic processes of astrocytic glial cells.
Wohlwill et al. (1959) described a sibship of 9, of whom 1 sister and 3 brothers had large heads called hydrocephalic and died at ages 4, 5, 6 and 3, respectively.
Alexander disease was proven histologically in the last. Pyeritz (1987) informed me of 2 black brothers, aged 11 and 13, thought to have this disorder.
They had macrocephaly, developmental delay that was not progressive, and CT scan consistent with leukodystrophy. Iwaki et al. (1989) found that alpha-B-crystallin accumulates in the brain in Alexander disease.

REFERENCES

  1. Alexander, W. S. :
    Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant.
    Brain 72: 373-381, 1949.

  2. Herndon, R. N.; Rubinstein, L. J.; Freeman, J. N.; Mathieson, G. :
    Light and electron microscopic observations on Rosenthal fibers in Alexander's disease andin multiple sclerosis.
    J. Neuropath. Exp. Neurol. 29: 524-551, 1970.

  3. Iwaki, T.; Kume-Iwaki, A.; Leim, R. K. H.; Goldman, J. E. :
    Alpha-B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain.
    Cell 57: 71-78, 1989.

  4. Pyeritz, R. E. : Personal Communication. Baltimore, Md., 1987.

  5. Wohlwill, F. J.; Bernstein, J.; Yakovlev, P. I. :
    Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial type of leukodystrophy with megalobarencephaly.
    J. Neuropath. Exp. Neurol. 18: 359-383, 1959.