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Pontocerebellar hypoplasia type 6
A rare, genetic form of pontocerebellar hypoplasia (PCH) characterized by neocortical and severe cerebral cortical atrophy associated with pontocerebellar hypoplasia with the pons and cerebellum equally affected. Clinically the disorder manifests at birth with hypotonia, clonus, epilepsy, impaired swallowing and from infancy by progressive microcephaly, spasticity and lactic acidosis.
ORPHA:166073Classification level: Disorder
Pontocerebellar hypoplasia type 6 (PCH6) is reported in at least 31 cases to date.
PCH6 manifests at birth by generalized hypotonia, lethargy and dysphagia. The clinical profile is characterized from infancy by a profound developmental delay, progressive microcephaly, hypotonia or spasticity and treatment-resistant epilepsy.
PCH6 is caused by nonsense, missense and splice site mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene located to 6q16.1.
MRI demonstrates neocortical and severe cerebral cortical atrophy (more severe than in other types of PCH) as well as pontocerebellar hypoplasia with the pons and cerebellum equally affected. In some patients, early MRI is normal or only shows mild vermal hypoplasia, followed by rapidly progressive brain atrophy. Lactic acid is elevated in cerebrospinal fluid in the majority of patients, which can be accompanied by respiratory chain enzyme deficiency in muscle or fibroblasts. Genetic testing is recommended to confirm the diagnosis
Due to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the genes encoding mitochondrial aminoacyl-tRNA synthetases, which can also cause early onset mitochondrial epileptic encephalopathies.
Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal genetic testing or pre-implantation genetic diagnosis should be offered.
PCH6 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH6. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.
Management and treatment
Treatment is symptomatic in PCH.
Prognosis is poor, exact life expectancy is unknown but in most cases does not exceed infancy.
A summary on this disease is available in Español (2021) Français (2021) Nederlands (2021)
Disease review articles
- Review article
- English (2011) - Orphanet J Rare Dis
: produced/endorsed by FSMR(s)