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Eur J Paediatr Neurol. 2018 Jul;22(4):674-681. doi: 10.1016/j.ejpn.2018.03.011. Epub 2018 Apr 3.

Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature.

Author information

1
Department of Pediatrics, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: ivanovist@gmail.com.
2
VIB Center for Molecular Neurology, University of Antwerp, Belgium. Electronic address: derek.atkinson@molgen.vib-ua.be.
3
Department of Pediatrics, SBALDB "Prof. D-r Ivan Mitev", Medical University-Sofia, Sofia, Bulgaria. Electronic address: ilitvinenko@excite.com.
4
Department of Medical Genetics, University Hospital "St. Marina", Medical University of Varna, Varna, Bulgaria. Electronic address: lyudmila_angelova@abv.bg.
5
National Genetic Laboratory, Maichin Dom University Hospital, Sofia, Bulgaria. Electronic address: sandonova@netscape.net.
6
Department of Neonatology, Prof. Stoyan Kirkovich University Hospital, Medical Faculty of Tracian University, Stara Zagora, Bulgaria. Electronic address: hristom2000@yahoo.com.
7
Department of Pediatrics, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: inapatcheva@hotmail.com.
8
Department of Pediatrics, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: panova_marg@mail.bg.
9
Department of Pediatrics, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: ralitsa_iordanova@yahoo.com.
10
Department of Pathology, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: vesbel@abv.bg.
11
Department of Radiology, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: petrova_ar@abv.bg.
12
Department of Pediatrics, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: bosheva@mail.bg.
13
Department of Pediatrics, St. George University Hospital, Medical University-Plovdiv, Plovdiv, Bulgaria. Electronic address: t.shmilev@gmail.bg.
14
National Genetic Laboratory, Maichin Dom University Hospital, Sofia, Bulgaria. Electronic address: alexey.savov@abv.bg.
15
VIB Center for Molecular Neurology, University of Antwerp, Belgium; Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia, Bulgaria. Electronic address: albena.jordanova@molgen.vib-ua.be.

Abstract

Pontocerebellar hypoplasia type 1 (PCH1) is a major cause of non-5q spinal muscular atrophy (SMA). We screened 128 SMN1-negative SMA patients from Bulgaria for a frequent mutation -p.G31A in EXOSC3, and performed a literature review of all genetically verified PCH1 cases. Homozygous p.G31A/EXOSC3 mutation was identified in 14 Roma patients, representing three fourths of all our SMN1-negative Roma SMA cases. The phenotype of the p.G31A/EXOSC3 homozygotes was compared to the clinical presentation of all reported to date genetically verified PCH1 cases. Signs of antenatal onset of disease present at birth were common in all PCH1 sub-types except in the homozygous p.D132A/EXOSC3 patients. The PCH1sub-types with early death (between ages 1 day and 17 months), seen in patients with p.G31A/EXOSC3 or SLC25A46 mutations have a SMA type 1-like clinical presentation but with global developmental delay, visual and hearing impairment, with or without microcephaly, nystagmus and optic atrophy. Mutations with milder presentation (homozygous p.D132A/EXOSC3 or VRK1) may display additionally signs of upper motor neuron impairment, dystonia or ataxia and die at age between 5 and 18 years. Other EXOSC3 mutations and EXOSC8 cases are intermediate - SMA type 1-like presentation, spasticity (mostly in EXOSC8) and death between 3 months and 5 years. There is no correlation between neurological onset and duration of life. We add marble-like skin and congenital laryngeal stridor as features of PCH1. We show that imaging signs of cerebellar and pontine hypoplasia may be missing early in infancy. EMG signs of anterior horn neuronopathy may be missing in PCH1 patients with SLC25A46 mutations. Thus, there is considerable phenotypic variability in PCH1, with some cases being more SMA-like, than PCH-like. Detailed clinical evaluation and ethnicity background may guide genetic testing and subsequent genetic counseling.

KEYWORDS:

EXOSC3; Pontocerebellar hypoplasia; Roma population; Spinal muscular atrophy

PMID:
29656927
DOI:
10.1016/j.ejpn.2018.03.011
[Indexed for MEDLINE]

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