Pontocerebellar Hypoplasia, Type 6

A number sign (#) is used with this entry because pontocerebellar hypoplasia type 6 (PCH6) is caused by homozygous or compound heterozygous mutation in the gene encoding mitochondrial arginyl-tRNA synthetase (RARS2; 611524) on chromosome 6q15.

Description

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007).

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

Clinical Features

Edvardson et al. (2007) investigated 3 patients, the products of a consanguineous Sephardic Jewish marriage, who had infantile encephalopathy and a putative defect in mitochondrial translation. The eldest of the 3 affected children showed generalized hypotonia and poor sucking at several hours of age, and brain magnetic imaging (MRI) at age 3 days showed cerebellar and vermian hypoplasia but normal brain volume. Recurrent apnea from age 1 week was controlled by phenobarbital, but intractable seizures starting at age 2 months were resistant to multidrug therapy. Microcephaly became evident at age 1 year. No developmental milestones were attained, and muscle tone became spastic. The results of funduscopic observations were normal. Serial brain MRI revealed progressive atrophy of the cerebellum, pons, cerebral cortex, and white matter. The patient died at age 16 months. Activities of mitochondrial complexes I, III, and IV in muscle from this patient were markedly reduced, but activity of complex II was relatively preserved. The fourth child in the family and the second to be affected was a boy who was markedly hypotonic and lethargic from birth. He was found dead in his crib at age 7 weeks. The fifth child in the family and the third to be affected was normal on neurologic examination on the first day of life, but an apneic episode occurred on the second day. At age 3 weeks, poor feeding, lethargy, and generalized hypotonia became evident. At 4 months, she developed generalized seizures, and head growth was arrested. Brain MRI at age 3 months revealed general atrophy, with most marked changes in the pons and cerebellum.

Rankin et al. (2010) reported a girl, born of unrelated British parents, with PCH6. After a normal birth, she was admitted after 19 hours with poor feeding and high respiratory rate. Laboratory studies showed increased serum lactate, which resolved with treatment. She later developed severe hypotonia, myoclonic seizures, profound developmental delay with absence of social smiling and poor head control, and poor feeding requiring gastrostomy. Brain MRI at age 14 months showed generalized cerebral atrophy, thinning of the pons, and atrophy of the cerebellar hemispheres. Examination at age 2 and 3 years showed severe progressive microcephaly and dysmorphic features, such as bitemporal narrowing, deep-set eyes with prominent nasal bridge, full cheeks, and narrow palate. She also had edematous hands and feet, and required a tracheostomy for upper airway obstruction due to hypotonia. Muscle biopsy showed normal respiratory chain activity. Rankin et al. (2010) noted some phenotypic overlap with PEHO syndrome (260565), but their patient lacked optic atrophy.

Li et al. (2015) reported 2 Hispanic sibs with PCH6. Both presented in the first year of life with hypotonia and delayed psychomotor development after normal early development in the first months of life. Variable features included head lag or poor head control, weak reflexes that progressed to increased reflexes, and dysconjugate eye movements. The brother developed seizures at age 9 months. At age 4.5 years, he had microcephaly, progressive visual loss, no functional speech, refractory seizures, clinodactyly, and adducted thumb, and he required tube feeding. Brain imaging showed small posterior fossa, cerebellar vermis hypoplasia, small pons, cerebellar atrophy, and increased subarachnoid space over the frontotemporal regions. The sister was less severely affected: at age 18 months, she was able to sit with support and had started to babble; brain imaging showed cerebellar hypoplasia. She did not have seizures or visual loss.

Inheritance

The transmission pattern of PCH6 in the family reported by Li et al. (2015) was consistent with autosomal recessive inheritance.

Mapping

In a consanguineous Sephardic Jewish family with pontocerebellar hypoplasia, Edvardson et al. (2007) identified an identical haplotype in a region of chromosome 6 within a 22.46-Mb region between markers D6S1546 and D6S268 in all 3 affected patients by homozygosity mapping.

Molecular Genetics

In a consanguineous Sephardic Jewish family with infantile encephalopathy mapping to chromosome 6q16.1 and a putative defect in mitochondrial translation, Edvardson et al. (2007) sequenced the RARS2 gene and identified a homozygous intronic mutation (611524.0001) that segregated with the disorder in the family.

In a British girl, born of unrelated British parents, with PCH6, Rankin et al. (2010) identified compound heterozygous mutations in the RARS2 gene (611524.0002 and 611524.0003). Each unaffected parent was heterozygous for 1 of the mutations.

In 2 Hispanic sibs with PCH6, Li et al. (2015) identified a homozygous mutation in the promoter of the RARS2 gene (611524.0004). Patient cells showed decreased expression of RARS2 compared to controls, and luciferase studies in HEK293 cells transfected with the mutation showed a 40% reduction of promoter activity compared to wildtype.