Review
Pontocerebellar Hypoplasias
Clinical features of the PCH subtypes
PCH1
PCH | Clinical features | Pathological features | Gene(s) | Ref. |
---|---|---|---|---|
PCH1 | Neonatal period: Hypotonia, impaired swallowing, congenital contractures and/or polyhydramnios, primary hypoventilation, progressive microcephaly. MRI: Pontocerebellar hypoplasia. | Cerebellar hypoplasia: hemispheres > > vermis, areas of stunted or absent folial development. Cerebellar dentate nucleus present as tiny remnants. Olivary nucleus: absent folding and gliosis. Pons: loss of ventral nuclei and transverse fibers. Spinal cord: Anterior horn cell degeneration. Peripheral nerves and muscle: chronic denervation. | One family with the common TSEN54 mutation. One case with missense plus splice site mutations in RARS2. One atypical mild family with nonsense mutations in VRK1. Locus unknown in the majority. | |
PCH2 | Neonatal period: Clonus, impaired swallowing. Infancy and later: Chorea, variable spastic pareses; progressive microcephaly. Severe impairment of cognitive and motor development. MRI: Variable neocortical atrophy, pontocerebellar hypoplasia. | Cerebellar hypoplasia: hemispheres > > vermis. Segmental degeneration of cerebellar cortex. Fragmentation of cerebellar dentate nucleus. Olivary nucleus: neuron loss and decreased folding. Pons: progressive loss of ventral nuclei and transverse fibers. Cerebral cortex: progressive atrophy | TSEN54: p.A307S, A307S most common in 75 families. Rarely: Other TSEN54 missense mutations in 3 families, TSEN2 mutations in 2 families, TSEN34 mutations in 1 family. | |
PCH3 | Neonatal period: Hypotonia, impaired swallowing. Infancy and later: Short stature progressive microcephaly, optic atrophy. MRI: Neocortical and cerebellar atrophy, pontocerebellar hypoplasia; Pons and cerebellum equally affected. | No autopsies performed. | Locus on chromosome 7 q in 2 families. | |
PCH4 | Neonatal period: Hypertonia, severe clonus, polyhydramnios and/or contractures; primary hypoventilation. MRI: Delayed neocortical maturation, pontocerebellar hypoplasia; microcephaly on autopsy. | Cerebellar hypoplasia: hemispheres > > vermis, areas of stunted or absent folial development. Cerebellar dentate nucleus present as tiny remnants Olivary nucleus: absent folding and gliosis. Pons: loss of ventral nuclei and transverse fibers. | TSEN54: Compound heterozygosity for p.A307S plus nonsense or splice site mutations in 10 families. Three missense mutations in 1 family. | |
PCH5 | Prenatal/neonatal period: Clonus or seizures. Neonatal period: Persistent clonus, microcephaly and pontocerebellar hypoplasia on autopsy. | Cerebellar hypoplasia: cortical involvement as in PCH4, but vermal cortex more extensively affected than hemispheric cortex; subtotal loss of cerebellar dentate nucleus. Olivary nucleus: absent folding. Pons: loss of ventral nuclei and transverse fibers. | TSEN54: Compound heterozygosity for p.A307S plus splice site mutation in 1 family. | |
PCH6 | Neonatal period: Hypotonia, clonus, impaired swallowing. Infancy and later: Progressive microcephaly, spasticity, elevated CSF lactate, edema of extremities. MRI: Neocortical and cerebellar atrophy, pontocerebellar hypoplasia; Pons and cerebellum equally affected. | No autopsies performed. | Missense and splice site mutations in RARS2 in 2 families. | |
PCH7 | Neonatal period: No palpable gonads with a micropenis. Hypotonia. Infancy and later: Regression of penis. Progressive microcephaly, seizures, respiratory distress, poor feeding. MRI: Pontocerebellar hypoplasia. | Cerebellar hypoplasia: absence of cerebellar hemispheres with neuronal loss. Olivary nucleus: absent. Pons: loss of ventral nuclei and transverse fibers. Cerebral cortex: progressive atrophy. | No locus. | [13] |
PCH2
PCH3
PCH4
PCH5
PCH6
PCH7
Genetics of PCH
TSEN-related PCH and genotype-phenotype correlations
Gene | Nucleotide position | Protein position | Subtype |
---|---|---|---|
TSEN54 | c.178_215del | p.E60AfsX109 | PCH4 |
TSEN54 | c.285G > C | p.A95A Splice site mutation | PCH4 |
TSEN54 | c.277T > C | p.S93P | PCH4 |
TSEN54 | c.371G > T | p.G124V | PCH2 |
TSEN54 | c.370-2A > G | p.G124_Q138del | PCH4 |
TSEN54 | c.468+2T > C | Splice site mutation | PCH5 |
TSEN54 | c.736C > T | p.Q246X | PCH4 |
TSEN54 | c.919G > T | p.A307S (common) | PCH1, PCH2, PCH4, PCH5 |
TSEN54 | c.953delC | p.P318QfsX23 | PCH4 |
TSEN54 | c.1027C > T | p.Q343X | PCH4 |
TSEN54 | c.1056_1057del | p.R353GfsX81 | PCH4 |
TSEN54 | c.1170_1183del | p. V390fsX39 | PCH4 |
TSEN54 | c.1251A > G | p.P417P Splice site mutation | PCH4 |
TSEN54 | c.1430+2T > A | Splice site mutation | PCH4 |
TSEN54 | c.1537T > G | p.Y513D | PCH4 |
TSEN34 | c.172C > T | p.R58W | PCH2 |
TSEN2 | c.926A > G | p.Y309C | PCH2 |
TSEN2 | c.960+1delGTAAG | Splice site mutation | PCH2 |
RARS2 | c.35A > G | p.Q12R | PCH1, PCH6 |
RARS2 | c.110+5A > G | Splice site mutation | PCH1, PCH6 |
RARS2 | c.1024A > G | p.M342V | PCH6 |
VRK1 | c.1072C > T | p.R358X | PCH1 |
RARS2-related PCH
Other genes and loci involved in PCH
Management and Treatment
Other diseases with (ponto)cerebellar hypoplasia
Differential diagnosis | Cerebellar Hypoplasia plus: | Gene(s) | Pathways involved | Key references |
---|---|---|---|---|
Genetic diseases with cerebellar hypoplasia and/or atrophy and variable cerebral cortical atrophy
| ||||
PCCA | Progressive Cerebello-cerebral atrophy, progressive microcephaly, spasticity, seizures, mental retardation and seizures. | Missense mutations in SEPSECS. | Selenocysteine synthesis | [53] |
ICCA | Severe atrophy of cerebrum and cerebellum. Psychomotor retardation, clonus, seizures, spasticity, progressive microcephaly. | Missense mutations in MED17 | Transcripition initiation | [54] |
CDG type 1A and 1D | Hypotonia, ataxia, developmental delay, failure to thrive, microcephaly. | PMM2 (type1a), ALG3 (type 1d) | Glycoprotein biosynthesis | |
Phosphoserine aminotransferase deficiency | Low CSF concentrations of serine and glycine, seizures, progressive microcephaly, hypertonia and psychomotor retardation. White matter immaturity and cerebral atrophy. |
PSAT
| Serine biosynthesis | [59] |
Different congenital mitochondrial disorders | Respiratory chain deficiencies plus several other abnormalities. | - | n/a | [60] |
PEHO-syndrome | Progressive cerebellar atrophy, progressive encephalopathy, hypsarrythmie, edema and optic atrophy. | Unknown | Unknown | |
Genetic diseases with cerebellar hypoplasia plus neocortical dysplasia
| ||||
Dystroglanopathies: Walker-Warburg syndrome, MEB-disease, Fukuyama | Neocortical dysplasia. Mental retardation, eye abnormalities, seizures, impaired motor control. |
FKRP, LARGE, POMGNT1, POMT1, POMT2, FKTN
| Dystroglycan synthesis | |
Lissencephaly | Lissencephaly phenotype. |
RELN
| Neuronal migration | [67] |
X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum | Microcephaly, optic atrophy, sensorineural hearing loss, simplified gyri, developmental delay. |
CASK
| Neuronal migration; Part of MAGUK protein family, involved in signaling in both, pre- and post-synapses. | [66] |
Congenital fibrosis of the extraocular muscles 3 with extraocular involvement | Ocular motility disorder, facial weakness, axonal peripheral neuropathy, delayed development, neocortical dysplasia and other neuronal migration disorders. |
TUBB3
| Neuronal migration | |
Acquired cerebellar hypoplasia
| ||||
Extreme prematurity (< 32 weeks) | Extreme prematurity. | n/a | n/a | [70] |
Genetic diseases with cerebellar hypoplasia and/or atrophy and variable cerebral cortical atrophy
Genetic diseases with cerebellar hypoplasia plus neocortical dysplasia
Pathogenesis
The function of the tRNA splicing endonuclease
Human tRNA species with an intron (anticodon) | Number of human tRNA genes with an intron | Number of the remaining human tRNA genes without an intron (same anticodon) |
---|---|---|
Pro - AGG | 1 | 9 |
Arg - TCT | 5 | 1 |
Leu - CAA | 5 | 2 |
Ile - TAT | 5 | 0 |
Tyr - ATA | 1 | 0 |
Tyr - GTA | 13 | 1 |
Cys - ACA | 1 | 0 |
Trp - CCA | 1 | 8 |