Extended phenotype of pontocerebellar hypoplasia with infantile spinal muscular atrophy.

Pontocerebellar hypoplasia (PCH) is rarely associated with anterior horn cell disease and designated as PCH-1. This phenotype is characterized by severe muscle weakness and hypotonia starting prenatally or at birth with a life span not exceeding a few months in most cases. Milder disease courses with later onset and longer survival are normally not diagnosed as PCH-1. We describe the clinical and neuroradiological findings in nine patients out of six siblingships with evidence of cerebellar defects and early onset spinal muscular atrophy (SMA), representing a broad spectrum of clinical variability. In all patients, the diagnosis of SMA (Werdnig-Hoffmann disease) was made on the basis of electrophysiological data and muscle biopsy; however, genetic testing failed to confirm the diagnosis of infantile SMA with a gene defect on chromosome 5q and resulted in clinical reevaluation. Age at onset was after a normal period in the first months of life in three siblingships and pre- and postnatally in the other three families. Life span was 2-4 years in patients with later onset, and age at death occurred after birth or within months in the more severe group. Two siblingships showed discordant ages at death despite similar treatment. In contrast to the previous definition of PCH-1, our observations suggest the existence of milder phenotypes with pontocerebellar hypoplasia or olivopontocerebellar atrophy in combination with anterior horn cell loss. A pontine involvement is not necessarily seen by neuroimaging methods. The genetic basis of PCH-1 remains to be determined. The gene locus for infantile SMA on chromosome 5q could be excluded by linkage studies. Parental consanguinity and affected siblings make autosomal recessive inheritance most likely.