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Pontocerebellar hypoplasia type 13 (PCH13) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development with...

Pontocerebellar hypoplasia type 13 (PCH13) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable (summary by Uwineza et al., 2019).

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

▼ Clinical Features
Gershlick et al. (2019) reported a 6-year-old Caucasian girl, born of unrelated parents, with a severe multisystemic disorder with prominent neurodevelopmental abnormalities. She presented in early infancy with feeding difficulties and failure to thrive associated with chronic cholestatic hepatitis. She had hypotonia, global developmental delay with an inability to sit or speak, nystagmus, seizures, status epilepticus during sleep, frequent body movements, cortical visual impairment, and was tube-fed. Dysmorphic features included brachycephaly, epicanthal folds, strabismus, long eyelashes, ptosis, overfolded ears, upturned nasal tip, facial hypotonia with full cheeks and open mouth, thin upper lip, high and narrow palate, low posterior hairline, and mild clubbing of the fingernails. Additional features included sleep apnea, gastric volvulus, constipation, asthma, recurrent respiratory infections, and lower extremity edema. Brain imaging was normal at age 4 months, but showed pontocerebellar hypoplasia, evidence of a Dandy-Walker variant, small hippocampus, thin corpus callosum, and periventricular white matter abnormalities at 4 and 6 years of age. Laboratory studies showed hypoglycosylation of serum transferrin and abnormal O- and N-linked glycosylation, suggesting a possible congenital disorder of glycosylation (see, e.g., CDG1A; 212065).

Uwineza et al. (2019) reported 2 sisters, born of distantly related parents from Rwanda, with variable manifestations of PCH13. The older 9-year-old sister had severely impaired global development with absent speech and walking achieved with an ataxic gait after 5 years of age. She had microcephaly (-3.23 SD) and dysmorphic features, including hypertelorism, upturned nasal tip, short philtrum, open mouth with thick vermilion of the upper lip, high-arched palate, large teeth with dental caries, strabismus, and pes planus. Brain imaging at age 5 years showed a Dandy-Walker anomaly and enlarged ventricles, whereas brain imaging at age 9 showed cerebellar atrophy, thin corpus callosum, and mega cisterna magna. The younger 30-month-old sister had early normal development until about 12 months of age, when she showed stagnation associated with a febrile illness. She had feeding problems, inability to walk, no language, poor overall growth, and microcephaly (-4.56 SD). Dysmorphic features included upturned nasal tip and strabismus. Brain imaging showed reduced white matter volume and a thin corpus callosum; the authors suggested that cerebellar atrophy may progress with age. Neither patient had nystagmus, optic impairment, edema, pyramidal signs, or hepatic involvement; seizures were not noted. Serum transferrin was normal.

▼ Inheritance
The transmission pattern of PCH13 in the family reported by Gershlick et al. (2019) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics
In a 6-year-old Caucasian girl, born of unrelated parents, with PCH13, Gershlick et al. (2019), identified compound heterozygous mutations in the VPS51 gene (c.2232delC, 615738.0001 and R490C, 615738.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent, confirming segregation. Analysis of patient fibroblasts showed decreased levels of VPS51 (about 25% of controls), as well as decreased levels of certain other VPS proteins (all about 50% of controls) associated with decreased levels of the GARP and EARP complexes (see 615738) and abnormal localization of the complexes in the cytosol rather than to the trans-Golgi network. Other abnormalities included altered levels and distribution of the cation-independent mannose 6-phosphate receptor (CIMPR; IGF2R; 147280) and TGN46 (603062), indicative of a recycling defect, and lysosomal swelling.

In 2 sisters, born of related parents from Rwanda, with PCH13, Uwineza et al. (2019) identified a homozygous mutation in the VPS51 gene (615738.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

Tags: 11q13.1