Multiple families have been described with an adult onset leukoencephalopathy and an autosomal domi- nant mode of inheritance. When there is no specific disease marker, it is hard to tell whether families have the same disease or different disorders. In hereditary diffuse leukoencephalopathy with spheroids (see Chap. 70), the white matter disease is histopathologi- cally accompanied by numerous neuroaxonal spher- oids within the affected white matter, which is the basis for the diagnosis. In pigmentary orthochromat- ic leukodystrophy (see Chap. 76), histopathological examination reveals demyelination accompanied by astrocytes and phagocytic cells that contain in their cytoplasm membrane-bound inclusions of brown- yellow, autofluorescent pigment, which has the ap- pearance of multilamellar material in a curved or straight parallel arrangement or with fingerprint pro- files on electron microscopy. However, in other fami- lies with adult-onset autosomal dominant leukoen- cephalopathy such characteristic histopathological findings are lacking. In the present chapter we focus on those families in which MRI findings have been re- ported.
Adult-onset autosomal dominant leukoencephalo- pathy has been described in multiple members of an American-Irish family (Eldridge et al. 1984;
Schwankhaus et al. 1988, 1994; Coffeen et al. 2000). In this family, the onset of clinical symptoms is in the fourth or fifth decade of life. The first symptoms con- sist of autonomic abnormalities, including bowel and bladder dysfunction, impotence, orthostatic hypoten- sion, and decreased sweating. After several years, other neurological symptoms appear, such as loss of fine motor skills. Subsequently, overt cerebellar and pyramidal dysfunction develops, eventually leading to complete loss of voluntary movements. Signs of posterior column dysfunction are frequent. Behav- ioral problems, cognitive deficits, and abnormalities of the central visual pathways are mild and of later onset. Sensorineural hearing loss is common. The peripheral nervous system is spared. The disease is slowly progressive, and survival of 20 years is com- mon. Laboratory tests are unrevealing. Evoked poten- tials show central conduction delays. Peripheral nerve conduction velocities are normal. A gene locus on chromosome 5q31 has been identified, but the gene itself has not yet been found.
Neuroimaging shows cerebral white matter changes with frontoparietal predominance in the ear-
ly stages. The abnormalities are patchy and inhomo- geneous in signal intensity. The deep white matter is most prominently affected. The cerebral white matter abnormalities are progressive and extend posteriorly.
They finally involve all cerebral white matter with rel- ative preservation of the U fibers. Signal abnormali- ties in the middle cerebellar peduncles are early find- ings. In the later stages, the cerebellar white matter is also affected. Brain stem abnormalities are frequent, including involvement of the pyramidal tracts, medi- al lemniscus, and cerebellar peduncles.
Autopsy reveals widespread myelin loss in isolated and confluent patches in the cerebral white matter and relative preservation of axons within the affected areas. Irregular islands of relatively normal white matter are seen within and at the margins of the af- fected regions. In the areas of myelin loss, oligoden- drocytes are abundant. The abnormal white matter is vacuolated. Despite the severity of the white matter abnormalities, macrophages, activated microglia, lipid accumulation, astrocytic proliferation, and fib- rillary gliosis are scarce. Inflammatory infiltrates are absent. The U fibers are relatively spared. Gray matter structures are intact. The cerebellar white matter and cerebellar peduncles are severely affected, similar to the cerebral white matter. Brain stem tracts are also affected, but the changes are milder than in the cere- bral and cerebellar white matter.
Calandriello et al. (1992) describe a family with an autosomal dominant leukoencephalopathy and a highly variable age at onset, ranging between 9 and 66 years, making evaluation of this family difficult.
Details concerning MRI findings are lacking.
Abe et al. (1993) describe a family with adult-onset autosomal dominant leukoencephalopathy and clini- cally progressive tetraparesis, dysarthria, dysphagia, and urinary incontinence. Mental capacities seem to be relatively better preserved. MRI shows diffuse sig- nal abnormalities of the cerebral white matter, brain stem tracts, and cerebellar white matter. A striking finding is the preservation of the optic radiation, con- sidered to be a distinct finding.
Quattrocolo et al. (1997) and Bergui et al. (1997) describe a large Italian family with adult-onset auto- somal dominant leukoencephalopathy and clinically progressive spasticity, pseudobulbar dysfunction, urinary incontinence, and sometimes action tremor.
Apart from slight memory impairment, no cognitive decline is noted and there are no behavioral changes.
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The peripheral nervous system is spared. The mean age at onset is 45 years and the duration of the disease 10 years. MRI of the brain shows diffuse signal abnor- malities within the cerebral white matter, most prominently involving the deep cerebral white matter.
The U fibers and corpus callosum are initially spared but become involved in the later stages of the disease.
Some cerebral hemispheric atrophy develops over time. The posterior limb of the internal capsule and brain stem tracts become affected. The cerebellum and the optic radiation remain spared, even in the late stages of the disease. There are no data on histo- pathology.
Fukazawa et al. (1997) describe a family with an autosomal dominant leukoencephalopathy. The onset of clinical symptoms in this family is in childhood, but the progression is extremely slow, over decades.
The first signs include cerebellar dysfunction and some mental deterioration. The subsequently devel- oping spasticity leads to serious disability in the third or fourth decade of life. The MRI shows diffuse white matter signal abnormalities, involving all cerebral white matter from cortex to ventricular lining and also the internal capsule and corticospinal tracts in the brain stem. The cerebellum and remainder of the brain stem have a normal signal, although the cerebellum shows some atrophy. The findings may be compatible with hypomyelination, but data on histopathology are lacking.
In 2001 Tagawa et al. described another family with an adult-onset autosomal dominant leukoencephalo-
pathy. The disease is characterized by cerebellar ataxia as the initial symptom and later dementia and signs of pyramidal dysfunction. MRI shows a diffuse leukoencephalopathy involving all cerebral and cere- bellar white matter and the brain stem. In addition, some cerebral atrophy develops. Histopathological examination reveals vacuolar degeneration of the white matter, sparing the U fibers.
In 2003, another family with adult-onset auto- somal dominant leukoencephalopathy was reported by Letournel et al. The patients have a variable combi- nation of dementia, motor signs, and epilepsy.
MRI findings have not been reported in detail and histopathological finding are nonspecific, showing an orthochromatic leukoencephalopathy involving the cerebral hemispheres, but sparing the cerebellum and brain stem.
It is hard to tell whether consistent differences in clinical and MRI findings are sufficient to distinguish different disease entities. For instance, in some fami- lies signs of autonomic dysfunction are consistently present, whereas they are absent in other families.
Likewise, the cerebellar white matter is consistently involved in some families, whereas in other families the cerebellum is consistently spared. It is presently important to document these families in every detail from clinical, MRI, MRS, and histopathological per- spectives. It is to be expected that the underlying gene defect(s) will soon be found in the larger fami- lies, facilitating further analysis of the remaining families.
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