Pontocerebellar Hypoplasia, Type 1b

A number sign (#) is used with this entry because pontocerebellar hypoplasia type 1B (PCH1B) is caused by homozygous or compound heterozygous mutation in the EXOSC3 gene (606489) on chromosome 9p13.

Description

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). PCH1B can be divided into mild, moderate, and severe subgroups that vary in age at onset, progression, clinical and neuroradiologic severity, and survival (summary by Halevy et al., 2014).

For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).

Clinical Features

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.

Rudnik-Schoneborn et al. (2003) described 6 patients from 4 families (3 German and 1 Norwegian) with pontocerebellar hypoplasia associated with infantile spinal muscular atrophy. The patients presented at birth or within the first 6 months of life with profound hypotonia followed by severely delayed psychomotor development and absent speech. Brain imaging showed cerebellar hypoplasia. In addition, 2 sisters also had a retrocerebellar cyst and another patient had profound pontocerebellar hypoplasia with a hypotrophic brainstem. All patients underwent testing for infantile SMA1 (253300), and homozygous absence of the SMN1 gene (600354) was excluded in all. In a review of these patients, Rudnik-Schoneborn et al. (2013) noted that all but 1 of the children died within the first years of life. One had epilepsy, 2 had infantile seizures, and 3 had nystagmus.

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.

Schwabova et al. (2013) reported 3 unrelated Czech children of Roma descent with PCH1B. One of the patients had previously been reported by Wan et al. (2012). All presented at birth with severe hypotonia, muscle weakness with areflexia, and sucking difficulties. Two patients had congenital contractures. The infants later showed progressive microcephaly, severe global developmental delay, weak cry, growth retardation, and visual impairment. None had spontaneous antigravity movements; 1 had tongue fasciculations. Brain imaging showed cerebellar hypoplasia, severe hypoplasia of the vermis, and mild hypoplasia of the brainstem. All patients died of respiratory insufficiency before 2 years of age. Postmortem examination of 2 patients showed short cerebellar folia with poor branching, loss of Purkinje cells and neurons in the granular layer, pontine hypoplasia, segmental loss of the inferior olivary nucleus, and loss of motor neurons in the anterior horn cells of the spinal cord.

Clinical Variability

Zanni et al. (2013) reported 2 sibs, born of unrelated Bangladeshi parents, with a relatively mild form of PCH1B confirmed by genetic analysis (D132A, 606489.0001 and V80F, 606489.0006 in the EXOSC3 gene). Both patients had delayed motor development, difficulty walking, and distal amyotrophy. The older sib had severe spasticity and became wheelchair-bound in his teens; his younger sister retained ambulation with support in her teens. Both had mild to moderate intellectual disability, but the sister was able to attend school. Other features included adducted thumbs, talipes valgus, tongue atrophy, fasciculations, brisk tendon reflexes, and gaze-evoked nystagmus. Brain imaging showed cerebellar atrophy with normal brainstem. Neither patient had hypotonia or microcephaly. The report expanded the phenotypic spectrum associated with EXOSC3 mutations to include hereditary spastic paraplegia.

Halevy et al. (2014) reported 2 pairs of sibs from a large consanguineous family of Arab origin with a mild form of PCH1B presenting as complicated hereditary spastic paraplegia with variable cognitive impairment. Whole-exome sequencing identified a homozygous missense mutation in the EXOSC3 gene (G191C; 606489.0007) that segregated with the disorder, but functional studies were not performed. The patients were 12 to 21 years of age at the time of the report. All showed delayed motor development with late walking and eventual deterioration of walking ability. All patients had mild cerebellar signs, including nystagmus with or without intention tremor and dysmetria, and brain imaging of all patients showed mild hypoplasia and atrophy of the lower part of the vermis with a normal pons. None had microcephaly or lower motor neuron signs, and spinal imaging was normal. Halevy et al. (2014) emphasized the mild phenotype in these patients.

Inheritance

The transmission pattern of PCH in the families reported by Wan et al. (2012) is consistent with autosomal recessive inheritance.

Molecular Genetics

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.

Genotype/Phenotype Correlations

Rudnik-Schoneborn et al. (2013) identified biallelic EXOSC3 mutations in 10 (37%) of 27 families with PCH with spinal muscular atrophy. Seven of the mutation-positive families had previously been reported (Rudnik-Schoneborn et al., 2003; Wan et al., 2012). The most common mutation was D132A (606489.0001), found in 11 (55%) of 20 mutated alleles, and haplotype analysis suggested a founder effect for this mutation. All patients had hypotonia, progressive muscular atrophy, and global developmental delay, but there was variation in the clinical presentation and survival. Individuals homozygous for the D132A mutation had the mildest phenotype; they presented in the first 6 months of life, had preserved respiratory function and cerebellar hypoplasia with a well-structured pons, and survived beyond infancy, even up to 20 years of age in 1 patient.

Biancheri et al. (2013) reported 2 sets of brothers from 2 unrelated families with PCH1B and spinal anterior horn involvement associated with a homozygous D132A mutation in the EXOSC3 gene. The patients had onset of microcephaly in the first months of life, delayed psychomotor development, and severe axial muscle hypotonia with variable limb hypertonia and extensor plantar responses, but they had prolonged survival compared to some previously reported patients. One 14-year-old patient could walk with support until age 10. None of the patients had seizures. Brain imaging showed isolated cerebellar hypoplasia with normal pontine volume. Biancheri et al. (2013) noted the genotype/phenotype correlation of a comparatively mild form of PCH1B associated with a homozygous D132A mutation.

Eggens et al. (2014) reported 14 patients from 12 families with PCH1B. Six patients from 5 families, all of Roma descent, carried the same homozygous G31A mutation in EXOSC3 (606489.0004). All of these patients had a severe form of the disorder, with hypotonic paresis at birth, areflexia, variable microcephaly and contractures, and death by 7 months of age. In contrast, 3 patients from 2 Caucasian families who were homozygous for the D132A mutation (606489.0001) showed a milder course, with dyskinesia, dystonia, brisk tendon reflexes in 2, and visual and auditory responses; these children survived until later childhood (up to 12 years of age). Four additional children who were compound heterozygous for D132A and a truncating mutation or a missense mutation had a severe clinical course, with hypotonia at birth, contractures, and death in infancy. Two patients had seizures. Finally, a patient who was homozygous for a G135E mutation had hypotonia, contractures, and no response to external stimuli; he died at age 8 weeks. Brain imaging showed differing patterns of cerebellar atrophy in all patients studied. In addition, 3 patients who were compound heterozygous for D132A and a truncating mutation had cerebellar cysts, while patients homozygous for D132A had a normal pons. Eggens et al. (2014) concluded that homozygosity for the D132A mutation leads to PCH with possible survival into early puberty and preservation of the pons, whereas other mutations cause the more severe phenotype. Functional studies of the variants were not performed.

Population Genetics

Schwabova et al. (2013) identified a homozygous G31A mutation in the EXOSC3 gene (606489.0004) in 32 unrelated Czech children of Roma descent with PCH1B. The heterozygous mutation was found in 4 (4.4%) of 90 unrelated Roma control individuals, and haplotype analysis suggested a founder effect. The patients had a severe form of the disorder, with death in the first year of life.