Alternative titles; symbolsPCH1PONTOCEREBELLAR HYPOPLASIA WITH INFANTILE SPINAL MUSCULAR ATROPHYPONTOCEREBELLAR HYPOPLASIA WITH ANTERIOR HORN CELL DISEASE▼ Descr...
Alternative titles; symbols
Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Different types were classified based on the clinical picture and the spectrum of pathologic changes. PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA; see SMA1, 253300); death usually occurs early.
Genetic Heterogeneity of Pontocerebellar Hypoplasia
Also see PCH1B (614678), caused by mutation in the EXOSC3 gene (606489); PCH1C (616081), caused by mutation in the EXOSC8 gene (606019); PCH1D (618065), caused by mutation in the EXOSC9 gene (606180); PCH1E (619303), caused by mutation in the SLC25A46 gene (610826); PCH1F (619304), caused by mutation in the EXOSC1 gene (606493); PCH2A (277470), caused by mutation in the TSEN54 gene (608755); PCH2B (612389), caused by mutation in the TSEN2 gene (608753); PCH2C (612390), caused by mutation in the TSEN34 gene (608754); PCH2D (613811), caused by mutation in the SEPSECS gene (613009); PCH3 (608027), caused by mutation in the PCLO gene (604918); PCH4 (225753), caused by mutation in the TSEN54 gene; PCH5 (610204), caused by mutation in the TSEN54 gene; PCH6 (611523), caused by mutation in the RARS2 gene (611524); PCH7 (614969), caused by mutation in the TOE1 gene (613931); PCH8 (614961), caused by mutation in the CHMP1A gene (164010); PCH9 (615809), caused by mutation in the AMPD2 gene (102771); PCH10 (615803), caused by mutation in the CLP1 gene (608757); PCH11 (617695), caused by mutation in the TBC1D23 gene (617687); PCH12 (618266), caused by mutation in the COASY gene (609855); PCH13 (618606), caused by mutation in the VPS51 gene (615738); PCH14 (619301), caused by mutation in the PPIL1 gene (601301); PCH15 (619302), caused by mutation in the CDC40 gene (605585); and PCH16 (619527), caused by mutation in the MINPP1 gene (605391).
▼ Clinical Features
The combination of autosomal recessive PCH and anterior horn cell disease was first described by Norman (1961) and was extensively reviewed by Chou et al. (1990) and Barth (1993).
Rudnik-Schoneborn et al. (2003) reported 5 patients from 2 consanguineous families, one Pakistani and the other Turkish, with pontocerebellar hypoplasia associated with spinal muscular atrophy. The patients presented at birth or in the first months of life with severe hypotonia and delayed psychomotor development. There was muscle wasting; some patients showed spasticity and contractures. The findings suggested an extended phenotype that includes major structural defects of the cerebellum as well as mild cerebellar hypoplasia in combination with anterior horn cell loss. All patients underwent testing for infantile SMA1 (253300), and homozygous absence of the SMN1 gene (600354) was excluded in all.
Renbaum et al. (2009) reported a consanguineous family of Ashkenazi Jewish origin in which 3 children had SMA-PCH. Early features included microcephaly, poor sucking, and developmental delay. In the first 2 years, the proband developed upper limb ataxia, brisk reflexes, and bilateral equinovarus. She was found to have motor and sensory neuropathy due to chronic denervation. Brain MRI showed a small cerebellar vermis and a large cisterna magna, compatible with cerebellar hypoplasia; she had mild mental retardation. Disease progression led to severe weakness, and the child became wheelchair-bound and incontinent, with sleep disturbance, increasing swallowing difficulties, severe ataxia, and progressive intercostal muscle weakness. She died at age 11.5 years. A previously deceased older sister had a similar phenotype, with tongue fasciculations, hypotonia with brisk reflexes, ataxia, and equinovarus deformities. She died at age 9.5 years. Their cousin, also the product of a consanguineous marriage within the extended family, reportedly had a similar phenotype and died at age 8 years. Skeletal muscle studies showed neurogenic atrophy.
By homozygosity mapping of 3 consanguineous Iranian families with what was reported to be mild to severe nonsyndromic mental retardation, Kuss et al. (2011) found linkage to a locus on distal chromosome 14q. In 1 family (M017N), the interval spanned 3.0 Mb between SNPs rs763357 and rs1956859 (lod score of 3.4). Lod scores in the other 2 families (M233 and M257) were 2.7 and 2.5, respectively, for SNPs in this region.
▼ Molecular Genetics
By linkage analysis followed by candidate gene sequencing of an affected Ashkenazi Jewish family with SMA-PCH, Renbaum et al. (2009) identified a homozygous mutation in the VRK1 gene (R358X; 602168.0001). The mutation was detected in heterozygosity in 2 of 449 unaffected Ashkenazi Jewish individuals.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M017N, previously mapped to distal chromosome 14q by Kuss et al. (2011), they identified a homozygous missense mutation in the VRK1 gene (602168.0002) in 4 sibs with moderate to severe intellectual disability and a phenotype compatible with pontocerebellar hypoplasia. The parents, who were first cousins once removed, were heterozygous for the mutation and had 3 healthy children.