Pontocerebellar Hypoplasia, Type 2a

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 2A (PCH2A) is caused by homozygous mutation in the TSEN54 gene (608755) on chromosome 17q25.

Description

Pontocerebellar hypoplasia (PCH) represents a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesia and chorea, epilepsy, and normal spinal cord findings (Barth, 1993).

For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

Genetic Heterogeneity of Pontocerebellar Hypoplasia Type 2

PCH2B (612389) is caused by mutation in the TSEN2 gene (608753) on chromosome 3p25, and PCH2C (612390) is caused by mutation in the TSEN34 gene (608754) on chromosome 19q13. PCH2D (613811) is caused by mutation in the SEPSECS gene (613009) on chromosome 4p15. PCH2E (615851) is caused by mutation in the VPS53 gene (615850) on chromosome 17p13. PCH2F (617026) is caused by mutation in the TSEN15 gene (608756) on chromosome 1q25. The TSEN2 and TSEN34 genes encode catalytic subunits of the tRNA splicing endonuclease, whereas the TSEN54 gene encodes a noncatalytic subunit. The SEPSECS gene is also involved in tRNA processing.

Clinical Features

In 2 males and 5 females in 5 sibships related as cousins, all with parents originating from the island community of Volendam, north of Amsterdam in the Netherlands, Barth et al. (1990) described a lethal progressive neurologic disorder with prenatal onset and characteristic abnormalities on CT scanning. Clinical features included microcephaly, spastic paresis, severe extrapyramidal dyskinesia, and failure to acquire any voluntary skills. Computed tomography of the brain showed marked pontocerebellar hypoplasia and progressive cerebral atrophy. Four died during childhood. Autopsy in 1 case showed widespread loss of neurons affecting the olivopontoneocerebellar system more severely than any other part of the brain and accounting for the macroscopic pontocerebellar hypoplasia. Biopsy of the neocortex from another patient suggested that the rough endoplasmic reticulum in neurons was the earliest 'ultrastructural target of the pathological process.' The closest parallel they could find was the disorder reported by Norman and Urich (1958) as 'cerebellar hypoplasia associated with systemic degeneration in early life.' They stated that they made the presumptive diagnosis of this disorder in another case in the Netherlands unrelated to the Volendam families, and that they were aware of at least 2 other probable cases.

Barth et al. (1995) described the clinical features of 16 patients with PCH2 from 10 unrelated pedigrees of European origin. Consanguinity was present in 2 kinships, suggesting autosomal recessive inheritance. Patients had microcephaly, restlessness in the neonatal period, poor sucking or swallowing, and severe extrapyramidal dyskinesia, with jerking and choreic movements. Motor and cognitive development was severely restricted and visual pursuit movements were abnormal. Most patients had seizures. Neuroimaging showed pancerebellar hypoplasia and hypoplasia of the ventral pons. The authors concluded that PCH2 is a distinct neurogenetic entity.

Cassandrini et al. (2010) reported 9 patients from 7 unrelated Italian families with PCH2A confirmed by genetic analysis. Two of the families were consanguineous with 2 affected sibs each. Clinical features included hypertonia at birth, progressive microcephaly, sucking and feeding problems, dyskinetic movements, variable seizures, absent or poor social interaction, and absent or poor postural control. Brain MRI showed hypoplasia of the cerebellum and of the ventral pons, as well as periventricular white matter abnormalities. Survival was variable: 2 sibs were alive at ages 11 and 17 years, respectively; 2 other sibs died at ages 15 and 17 years, respectively; and the earliest death was at age 7 months. Neuropathologic examination of a 36-month-old patient with a severe form of the disorder showed an abnormal cerebellar cortex with stunted folia and decreased branches, loss of Purkinje cells, and absence of the ventral pontine nuclei.

Namavar et al. (2011) reviewed the clinical features of 88 patients with PCH2A who were homozygous for the common TSEN54 A307S mutation (608755.0001). The patients had neonatal irritability with jitteriness and/or clonus as well as dyskinesia and/or dystonia; most had impaired swallowing leading to failure to thrive. Progressive microcephaly became more apparent with age. Other features included impaired head and hand control, central visual impairment in the absence of primary optic atrophy, and seizures. Pre- and perinatal complications, such as polyhydramnios and contractures, were rare in these patients. Brain imaging showed pontocerebellar hypoplasia with a 'dragonfly-like' pattern characterized by flattened cerebellar hemispheres and a relatively preserved vermis. There was a wide range of life expectancy: 1 patient died at age 2.5 weeks, whereas another was alive at age 31 years.

Diagnosis

Prenatal Diagnosis

Graham et al. (2010) concluded that prenatal diagnosis of PCH2 by ultrasound is difficult. They reported dizygotic twin boys, conceived through in vitro fertilization, who were born prematurely at age 30 4/7 weeks. Prenatal ultrasound until that time showed no abnormalities. In the intensive care unit, the infants showed mild respiratory distress, poor feeding, intermittent bradycardia, and developed jittery movements. Although initial brain ultrasounds looked normal, later review showed subtle cerebellar hypoplasia at 31 and 34 weeks from last menstrual period. Brain imaging at 9 weeks of life showed hypoplasia of the cerebellar hemispheres with normal appearing vermi and hypoplastic brainstem. The boys showed progressive microcephaly and later developed dyskinesias. Genetic analysis showed homozygosity for an A307S substitution in the TSEN54 gene (608755.0001), consistent with PCH2A. Diffusion tensor imaging in 1 of the twins showed loss of ventral pontine neurons and transverse pontine crossing fibers at the level of the pons at age 2.5 months (40 weeks after last menstrual period). Overall, the findings indicated that cerebellar degeneration in PCH2A is subtle and begins at the end of the second trimester, usually rendering prenatal diagnosis by imaging inconclusive.

Mapping

Budde et al. (2008) performed a genomewide scan in 2 families from the Volendam region of the Netherlands using 10K SNP arrays. They identified linkage to chromosome 17q25 with a maximum lod score of 5.81. Haplotype construction disclosed recombination events distal to rs2019877 and proximal to rs2889529, defining a disease interval of 13.4 cM. By fine mapping using microsatellite markers, they narrowed the locus to a 4.5-cM interval between markers D17S1301 and D17S937. This 2.7-Mb region encompasses 85 genes. By genotyping microsatellite markers in 9 more families, Budde et al. (2008) further narrowed the interval to a 3.4-cM region comprising 19 genes. All of these were sequenced in 5 affected subjects and their parents. Budde et al. (2008) identified 4 missense mutations, only 1 of which was present only in affected individuals.

Molecular Genetics

In 42 of 47 patients with PCH, Budde et al. (2008) identified a homozygous ala307-to-ser substitution in the TSEN54 gene (A307S; 608755.0001). The A307S mutation was likely due to a single founder mutation event that occurred at least 11 to 16 generations ago. Budde et al. (2008) also found this mutation in 3 patients with PCH4 (225753). In other patients with PCH2, Budde et al. (2008) found homozygous mutations in the TSEN2 (608753) and TSEN34 (608754) genes; see PCH2B (612389) and PCH2C (612390).

Cassandrini et al. (2010) identified a homozygous A307S mutation in 7 affected individuals from 6 unrelated Italian families with PCH2A. Two additional patients had a heterozygous A307S mutation: 1 patient with a PCH2A phenotype in whom the second mutation could not be detected, and another patient with a more severe phenotype (PCH4) who was compound heterozygous for A307S and a truncating mutation (608755.0005). Thus, A307S accounted for 16 (89%) of 18 mutant alleles, and haplotype analysis suggested a founder effect.

Namavar et al. (2011) identified homozygosity for the common A307S mutation in the TSEN54 gene in 88 (52.1%) of 169 patients with pontocerebellar hypoplasia.

Heterogeneity

Cassandrini et al. (2010) reported 2 Italian sibs, ages 11 and 8 years, respectively, with a phenotype consistent with PCH2 but who were negative for mutations in the TSEN complex and did not show linkage to the PCH3 locus (608027) on chromosome 7q. These patients also had additional features, including renal tubulopathy, oligohydramnios, optic atrophy, and abnormal hyperintensities of the pontobulbar areas on brain MRI.