Pontocerebellar hypoplasia: review of classification and genetics, and exclusion of several genes known to be important for cerebellar development.

The pontocerebellar hypoplasias are a heterogeneous group of rare and devastating conditions characterized by multiple structural abnormalities of the ventral pons, inferior olive, and cerebellum. Here, we briefly review these conditions and discuss genes recently discovered to be involved in pontocerebellar hypoplasia pathogenesis. We then present data that exclude several genes important for cerebellar development as causes of pontocerebellar hypoplasia-4 and pontocerebellar hypoplasia-5, and we demonstrate that not all cases of clinically defined pontocerebellar hypoplasia-4 result from mutations in TSEN54. We conclude that classification based on clinical, imaging, and neuropathological findings does not differentiate between pontocerebellar hypoplasia subtypes with different genetic causes.

Congenital pontocerebellar atrophy and telencephalic defects in three siblings: a new subtype.

We report three siblings, two of whom had a neuropathological study, with a new subtype of congenital ponto-cerebellar atrophy (PCH). In addition to the brain stem and cerebellar anomalies common to all types of this heterogeneous condition, there were unique developmental defects in the telencephalon: absence of the claustrum, diffuse cortical changes particularly in the insula and an extremely small brain. In an attempt to shed some light on the pathogenesis of this developmental disorder, we have analyzed the pattern of brain stem and cerebellar abnormalities in ours and in previously reported patients with PCH, to possibly distinguish primary from secondary effects of the mutant gene upon the cerebellar circuitry, and compared our patients' cerebellar and cerebral defects to those of some other human brain malformations and to mutant mice with both hindbrain and forebrain anomalies. Although this and previous observations of familial congenital PCH with apparent autosomal recessive inheritance spawn the endeavor to compare and classify patients into subgroups, any final classification must await identification and molecular characterization of the causal gene(s).

Leukodystrophies: clinical and genetic aspects.

The leukodystrophies comprise an ever-expanding group of rare central nervous system disorders with defined clinical, pathological, and genetic characteristics. The broader term, leukoencephalopathy, is applied to all brain white matter diseases, whether their molecular cause is known. Magnetic resonance imaging has helped to elucidate new forms of leukodystrophy as well as to permit longitudinal studies of disease progression. The white matter abnormality may appear similar in different forms of leukodystrophy so that in most cases, further studies such as magnetic resonance spectroscopy, tissue biopsies, enzyme studies, and molecular DNA analyses are needed to pinpoint the specific diagnosis. The primary inherited leukoencephalopathies include dysmyelinating, hypomyelinative, and vacuolating forms. Metabolic and vascular causes account for most of the secondary forms, but other inherited syndromes are recognized that have their onset in childhood or adult life and are characterized by distinctive clinical and neuropathologic features. This review discusses some of the mechanisms that have been proposed to explain deficiencies of myelin and the molecular genetic bases underlying these disorders.