Pontocerebellar hypoplasia type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement ... Pontocerebellar hypoplasia type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement (summary by Wan et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
Ryan et al. (2000) reported 5 patients, including 2 sibs, with pontocerebellar hypoplasia associated with anterior horn cell disease of the spinal cord. The 2 sibs died at ages 6 days and 5 months, respectively. They both had ... Ryan et al. (2000) reported 5 patients, including 2 sibs, with pontocerebellar hypoplasia associated with anterior horn cell disease of the spinal cord. The 2 sibs died at ages 6 days and 5 months, respectively. They both had severe hypotonia, were poorly responsive, and had respiratory insufficiency. Postmortem examination showed severe cerebellar atrophy with absent granular layer, decreased number of Purkinje cells, white matter gliosis, and a paucity of axons. Skeletal muscle showed neurogenic atrophy. Spinal cord examination in 1 sib showed decreased numbers of anterior horn cells. A third unrelated child had joint contractures, hip dislocation, and foot deformities at birth. He was severely hypotonic with only flickers of voluntary movement. He was visually nonreactive with nystagmus. He died of respiratory failure at age 3 months. Postmortem examination showed muscle atrophy, hypoplastic cerebellum, and degeneration of spinal cord anterior horn cells. A fourth infant had dysmorphic facies, foot deformities, poor feeding, and respiratory insufficiency. There was psychomotor delay with visual inattention. He was hypertonic but had progressive muscle weakness and died at age 11 months. The pons and cerebellum were hypoplastic and there was loss of anterior horn cells in the spinal cord. A fifth child was similarly affected. Ryan et al. (2000) noted the similar phenotype in these patients, with hypotonia and severe weakness in the neonatal period, occasional spasticity, and abnormal brainstem signs. All had severe global developmental delay. The spinal cord changes resembled spinal muscular atrophy (SMA; 253300), but the more severe phenotype in PCH type 1 reflected additional cerebellar and cerebral involvement. Salman et al. (2003) reported 2 sibs, born of unrelated Spanish-Cuban parents, with pontocerebellar hypoplasia type 1. A boy presented with nystagmus, axial hypotonia, and hypertonic lower extremities at age 3 months. He made little developmental progress and developed fatal respiratory failure due to pneumonia at age 14 months. CT scan at age 8 months showed generalized brain atrophy. His younger sister showed feeding difficulties, severe global developmental delay, and poor head control in infancy. She had increased tone in the lower extremities, brisk reflexes, nystagmus, microcephaly, and pontocerebellar hypoplasia on brain scan. Funduscopy suggested retinal dystrophy, and electroretinographic studies indicated a progressive rod/cone dystrophy. She also had an abnormal sleep breathing pattern. She died at age 40 months of respiratory failure. Postmortem examination showed anterior horn cell degeneration of the spinal cord and marked loss of Purkinje and granular cells with gliosis in the cerebellum. Skeletal muscles showed neurogenic atrophy, and sural nerve biopsy showed axonopathy. Wan et al. (2012) reported a family of American and European origin in which 4 brothers had PCH1B. All were hypotonic at birth and showed global developmental delay, without achieving any motor milestones. Although normal in size at birth, they all showed progressive microcephaly and severe growth retardation within the first year. Other features included oculomotor apraxia, progressive muscle wasting, and distal contractures. They never learned to speak. Brain MRI showed marked cerebellar atrophy with prominent sulci and decreased volume of folia. The brainstem and cerebral cortex appeared normal, but were small. The patients were 9, 16, and 18 years at the time of the report; 1 died at age 18 years. Electromyography in 2 patients showed neurogenic changes of denervation and reinnervation consistent with axonal loss. Nerve conduction studies showed impaired motor responses and normal sensory responses. Postmortem examination of 1 patient showed severe loss of cerebellar and spinal motor neurons.
In affected members of 9 families with autosomal recessive pontocerebellar hypoplasia type 1B, Wan et al. (2012) identified homozygous or compound heterozygous mutations in the EXOSC3 gene (see, e.g., 606489.0001-606489.0005). The first mutation was identified by genomewide scan ... In affected members of 9 families with autosomal recessive pontocerebellar hypoplasia type 1B, Wan et al. (2012) identified homozygous or compound heterozygous mutations in the EXOSC3 gene (see, e.g., 606489.0001-606489.0005). The first mutation was identified by genomewide scan and exome sequencing of a family with 4 affected brothers. One of the patients had been reported by Salman et al. (2003), and 2 by Ryan et al. (2000). The findings indicated that proper RNA processing is important for the development and survival of cerebellar and spinal motor neurons.