Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia

Abstract

Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

“…Including the two patients we report here, 29 patients with RARS2 mutations are described in literature so far (Namavar et al 2011a;Cassandrini et al 2013;Rankin et al 2010;Glamuzina et al 2012;Kastrissianakis et al 2013;Joseph et al 2014;Li et al 2015;Lax et al 2015;Nishri et al 2016;Ngoh et al 2016;Alkhateeb et al 2016). Splice site, nonsense, or missense mutations are identified throughout the RARS2 gene, but no patients with biallelic null mutations were identified, supporting the assumption that complete abolishment of tRNA-arg would be lethal.…”

“…These patients present with severe mental and motor retardation, progressive microcephaly, and dystonia/chorea (Namavar et al 2011a, b). MR imaging typically shows a "dragonfly" or "butterfly" configuration of the cerebellum (Namavar et al 2011a). New subtypes of PCH, based on differences in phenotypes and/or genotype were described over the past years, and we showed that the same genetic variant can be responsible for different forms of PCH (Namavar et al 2011b).…”

Cerebellar Cysts in Children: A Pattern-Recognition Approach

“…Large cysts were seen on MRI in one patient at the age of 1 month, located at the lateral aspects of the hemispheres [15]. A further patient was illustrated in a subsequent larger cohort [16]. The overall prevalence of cysts in PCH1 and PCH2 is rather low.…”

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

“…These are characterized by congenital hypotonia, progressive postnatal weakness and areflexia with anterior horn cell degeneration. The differential diagnosis includes X-linked infantile SMA with arthrogryposis (XL-SMA) [4,5], SMA due to mitochondrial dysfunction [6][7][8], SMA with pontocerebellar hypoplasia (SMA-PCH/PCH1) [9][10][11][12][13], and SMAwith respiratory distress (SMARD) ( Table 1) [14][15][16]. SMARD1 (or HMN type VI) is probably the second most commonly encountered pediatric from of SMA due to mutations in IGHMBP2 [14].…”