Clinical Diagnosis

The clinical diagnosis of pontocerebellar hypoplasia type 2 (PCH2) and type 4 (PCH4) is based on a combination of neuroradiologic and neurologic findings [Albrecht et al 1993, Barth et al 1995, Chaves-Vischer et al 2000, Steinlin et al 2007]. Longevity is the main difference between the two types: individuals with PCH2 usually live into childhood; those with PCH4 usually die as neonates.

Neuroradiologic findings in PCH2 and PCH4 [Barth et al 2007, Budde et al 2008]

• Major criteria
  • Cerebellar hypoplasia and varying degrees of cerebellar atrophy
  • Cerebellar hemispheres more affected than cerebellar vermis with relative sparing of the flocculi
  • Ventral pontine atrophy, present in the majority of cases
• Minor criteria (not present in all cases) (see Figure 1)
  • Striatal hypoplasia or atrophy
  • Cerebral cortical and hippocampal atrophy
  • Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4.
  • Exceptional: cerebellar hemispheric cysts in PCH2

Figure

Figure 1. MRI of the brain of a two-month-old with PCH2
a. Mid-sagittal image showing hypoplastic vermis and flat ventral pons (arrow)
b. Lateral sagittal image showing hypoplastic cerebellar hemisphere (arrow) leaving empty space in the (more...)

Neurologic findings in PCH2 [Barth et al 1995, Steinlin et al 2007]

• Major criteria
  • Progressive microcephaly
  • Extrapyramidal dyskinesia with mixed spasticity. Exceptional: pure spasticity
  • Impaired swallowing from bucco-pharyngeal incoordination
  • Central visual failure
  • Impaired statural motor development with failing head control
  • Absent voluntary hand control (present in exceptional cases)
  • Exclusion criteria: primary optic atrophy or retinopathy
• Minor criteria
  • Febrile and/or afebrile seizures
  • Excessive clonus in the neonatal period
  • Elevated plasma creatine kinase concentration [Barth et al 2008]

Neurologic findings in PCH4 [Albrecht et al 1993, Chaves-Vischer et al 2000]

• Prenatal signs: polyhydramnios and/or contractures
• Severe neonatal clonus
• Central apnea with absolute or relative dependency on mechanical ventilation

Neuropathology of PCH2 and PCH4 [Barth et al 2007]

• Cerebellum
  • Hypoplasia and reduced branching of the folia. Segmental degeneration of the cerebellar cortex and dentate nucleus. Variable degeneration of Purkinje cells. Relative sparing of flocculus and vermis.
  • PCH4: Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis. Loss of arcuate nucleus.
• Pons. Neuronal death within the ventral pons; relative sparing of the tegmentum
• Cerebral cortex and striatum. Variable neuronal degeneration
• Medulla oblongata. Variable neuronal degeneration;hypoplasia and segmental degeneration of the inferior olivary nuclei
• Myelin. Not involved in PCH2; widespread gliosis variably seen in individuals with PCH4

Testing

Biochemical testing. Plasma creatine kinase (CK) concentration can be elevated in individuals with PCH.

Molecular Genetic Testing

Genes. TSEN2, TSEN34, and TSEN54 are the only genes currently known to be associated with pontocerebellar hypoplasia types 2 and 4 [Budde et al 2008].

The genes of the TSEN complex encode subunits of tRNA splicing endonuclease.

Other loci. No other loci are known for PCH2 and PCH4. However, there are individuals with the clinical diagnosis of PCH2 and PCH4 in whom no mutations in TSEN2, TSEN34 or TSEN54 have been identified.

Clinical testing – sequence analysis

• PCH2 phenotype
  • TSEN54. The most common TSEN54 mutation, c.919G>T (p.Ala307Ser), accounts for 88.4% of mutant alleles in individuals with PCH2 [Budde et al 2008].
  • Mutations in two other subunits of the TSEN complex have been found to cause PCH2 in two individuals:
    • TSEN2. The homozygous c.926A>T (p.Tyr309Cys) mutation was found in one affected individual of Pakistani origin.
    • TSEN34. A homozygous c.172C>T (p.Arg58Trp) mutation was found in one affected individual of Turkish origin.
• PCH4 phenotype. In three individuals with PCH4, mutations have been identified in TSEN54 [Budde et al 2008].
  • One individual had one TSEN54 allele with two independent DNA changes resulting in p.Ala307Ser and p.Ser93Pro on one allele, while the second allele had a single DNA change resulting in p.Ala307Ser. This genotype is designated as p.[Ala307Ser;Ser93Pro] + [Ala307Ser]. This genotype results in a more severe disorder, and underscores the necessity of screening the entire gene for additional mutations [Budde et al 2008].
  • One individual was compound heterozygous for p.[Ala307Ser]+[Gln246X].
  • One individual was compound heterozygous for p.[Ala307Ser]+[Gln343X].

Table 1. Summary of Molecular Genetic Testing Used in PCH2 and PCH4

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Gene Symbol/Locus	Proportion of PCH2 & PCH4 Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
TSEN2	1.8%	Sequence analysis	Sequence variants 2	>95%	Clinical
TSEN34	1.8%	Sequence analysis	Sequence variants 2	>95%	Clinical
TSEN54	90.9%	Sequence analysis	Sequence variants 2	>95%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/establishing the diagnosis in a proband

1.

Perform TSEN54 sequencing for the common c.919G>T mutation.

2.

If the proband does not have the c.919G>T mutation, sequence the other exons of TSEN54.

3.

If no new mutations are found, consider sequencing of TSEN2, TSEN34, and TSEN15.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are currently known to be associated with mutations in TSEN2, TSEN34, and TSEN54.

Natural History

PCH2. Pregnancy is usually unremarkable. Newborns have no external dysmorphia and no visceral abnormalities. Birth is usually at term with normal weight, length, and head circumference, although the latter is always below the 50th centile.

Generalized clonus, often described as ''jitteriness'', is present in the majority. Swallowing is impaired with reduced grasping of the nipple and incoordination of sucking and swallowing. Motor and cognitive development is impaired in all children, with lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping are not achieved except in rare cases.

The occipitofrontal circumference drops below 2 SD in the course of the first year. During the first six months severe chorea often develops, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic.

Central vision is impaired. Primary optic nerve atrophy has not been seen in individuals with PCH2.

Epilepsy is present in approximately 50% of affected children, usually as generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms are possible.

Death is often before age ten years, although survival beyond age 20 years has been reported. Improved care, especially gastrostomy feeding, has probably improved survival. Typical complications are sudden and unexpected death while the child is sleeping (crib death) in infancy and death from hyperthermic crises. Subclinical myopathy, associated with elevated creatine kinase, may lead to death by malignant hyperthermia during anesthesia in which triggering agents are administered.

PCH4. Prenatal findings include polyhydramnios in many, but not all cases. In approximately 50% of neonates, contractures (''arthrogryposis'') are present at birth. Generalized clonus, provoked by handling or noise, may be extreme. Microcephaly is usually present at birth.

Central respiratory impairment (probably the result of brain stem failure) at birth results in prolonged or perpetual dependency on mechanical ventilation. Respiratory complications occur at a later stage when weaning is difficult or plainly impossible. Infants with PCH4 usually die in the neonatal period from these complications.

Genotype-Phenotype Correlations

TSEN54. In general, individuals with the PCH4 phenotype who have a nonsense mutation on one allele and a missense mutation on the other allele have poor survival compared to individuals with the PCH2 phenotype who are homozygous for a missense mutation [Budde et al 2008].

• In two individuals with PCH4, a nonsense mutation occurred with a missense mutation on the other allele. In one child with PCH4 the common TSEN54 missense mutation occurred with a second TSEN54 allele plus an additional missense mutation.
• In individuals with PCH2, no nonsense mutations have been described to date.

These clinical data, supported by pathologic data, strongly suggest a genotype-phenotype correlation.

Penetrance

Penetrance for PCH2 and PCH4 seems to be complete.

Nomenclature

OMIM maintains three different names for PCH2, depending on the mutated gene:

• PCH2A, caused by mutations in TSEN54
• PCH2B, caused by mutations in TSEN2
• PCH2C, caused by mutations in TSEN34

However, using these sub-classifications is not helpful clinically because it is not possible to predict which of the three genes will be mutated in any given individual with the PCH2 phenotype.

Prevalence

The prevalence of PCH2 and PCH4 is unknown. An estimation of the carrier frequency of the common TSEN54 mutation c.919G>T (p.Ala307Ser) can be made. Budde et al [2008] screened 451 Dutch and 279 German individuals for this mutation and found an allele frequency of 0.004.

Like many autosomal recessive disorders, PCH2 has been reported to be more common in isolated or inbred populations. PCH2 was originally reported by Barth et al [1995] in an isolated population in Volendam, The Netherlands.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with pontocerebellar hypoplasia type 2 (PCH2) or type 4 (PCH4), neurologic evaluation and assessment of feeding and respiratory function are recommended.

Treatment of Manifestations

PCH2. No specific therapy is available. Treatment is symptomatic and includes nutritional support by gastrostomy, treatment of seizures, and use of physiotherapy. Epilepsy is amenable to standard treatment. Chorea is refractory to treatment.

PCH4. No specific therapy is available. Respiratory support is usually given for a limited time.

Prevention of Secondary Complications

Electrolytes, creatine kinase concentration, hydration status, and urine production should be monitored during prolonged periods of high fever to avoid malignant hyperthermia. During episodes of hyperthermia sufficient fluid should be given to prevent dehydration.

Surveillance

Respiratory monitoring to detect sleep apnea may be necessary.

Agents/Circumstances to Avoid

Although malignant hyperthermia has been documented in individuals with PCH2, no special risk appears to be associated with generalized anesthesia (see Malignant Hyperthermia Susceptibility).

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Pontocerebellar hypoplasia type 2 and type 4 are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Children with PCH2 and PCH4 are not likely to have offspring because of severe intellectual disability and the likelihood of death before the age of fertility.

Other family members. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing for family members at risk of having a TSEN2, TSEN34, or TSEN54 mutation is available once the mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when the sensitivity of available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for TSEN2-, TSEN34-, and TSEN54-related pontocerebellar hypoplasia is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The tRNA splicing endonuclease (TSEN) complex has a role in RNA processing [Paushkin et al 2004, Trotta et al 2006].

• It is involved in tRNA maturation. Six percent of human tRNAs carry an intron in premature state that is spliced out by the tRNA splicing endonuclease (TSEN).
• The TSEN complex is also involved in mRNA 3’end formation. The precise role of the TSEN complex in this process remains elusive; however, it is known that in vitro knockdown of TSEN2 protein leads to impaired mRNA 3’end formation.

The TSEN complex comprises four different subunits: TSEN2 and TSEN34 are the two catalytic subunits; TSEN15 and TSEN54 are the two structural subunits.

Missense mutations in TSEN2, TSEN34, and TSEN54 are responsible for PCH2.

Analysis of steady state levels of tRNA tyrosine showed no major defects in tRNA tyrosine maturation in fibroblasts of individuals with PCH2; therefore, the mechanisms by which TSEN mutations result in PCH are still unknown.

TSEN2

Normal allelic variants. Multiple transcript variants encoding different isoforms have been found for this gene. Paushkin et al [2004] described an isoform of TSEN2 lacking exon 8. This isoform is not likely to be involved in tRNA splicing and probably has another, unknown, function.

Pathologic allelic variants. A missense mutation in TSEN2 has been identified in one Pakistani individual with PCH2. See Table 3.

Normal gene product. See Table 2.

Abnormal gene product. It is unknown how c.926A>G (p.Tyr309Cys) can lead to PCH, since the TSEN complex is expressed.

Literature Cited

1. Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Acta Neuropathol. 1993;85:394–9. [PubMed: 8480512]
2. Barth PG, Aronica E, de Vries L, Nikkels PG, Scheper W, Hoozemans JJ, Poll-The BT, Troost D. Pontocerebellar hypoplasia type 2: a neuropathological update. Acta Neuropathol (Berl). 2007;114:373–86. [PMC free article: PMC2039791] [PubMed: 17641900]
3. Barth PG, Blennow G, Lenard HG, Begeer JH, van der Kley JM, Hanefeld F, Peters ACB, Valk J. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from ten pedigrees. Neurology. 1995;45:311–7. [PubMed: 7854532]
4. Barth PG, Ryan MM, Webster RI, Aronica E, Kan A, Ramkema M, Jardine P, Poll-The BT. Rhabdomyolysis in pontocerebellar hypoplasia type 2 (PCH-2). Neuromusc Disord. 2008;18:52–8. [PubMed: 17825555]
5. Budde BS, Namavar Y, Barth PG, Poll-The BT, Nürnberg G, Becker C, van Ruissen F, Weterman MA, Fluiter K, te Beek ET, Aronica E, van der Knaap MS, Höhne W, Toliat MR, Crow YJ, Steinling M, Voit T, Roelenso F, Brussel W, Brockmann K, Kyllerman M, Boltshauser E, Hammersen G, Willemsen M, Basel-Vanagaite L, Krägeloh-Mann I, de Vries LS, Sztriha L, Muntoni F, Ferrie CD, Battini R, Hennekam RC, Grillo E, Beemer FA, Stoets LM, Wollnik B, Nürnberg P, Baas F. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008;40:1113–8. [PubMed: 18711368]
6. Chaves-Vischer V, Pizzolato GP, Hanquinet S, Maret A, Bottani A, Haenggeli CA. Early fatal pontocerebellar hypoplasia in premature twin sisters. Europ J Paediatr Neurol. 2000;4:171–6. [PubMed: 11008260]
7. Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, Saada A, Elpeleg O. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007;81:857–62. [PMC free article: PMC2227936] [PubMed: 17847012]
8. Forman MS, Squier W, Dobyns WB, Golden JA. Genotypically defined lissencephalies show distinct pathologies. J Neuropathol Exp Neurol. 2005;64:847–57. [PubMed: 16215456]
9. Jissendi-Tchofo P, Kara S, Barkovich J. Midbrain-hindbrain involvement in lissencephalies. Neurology. 2009;72:410–8. [PMC free article: PMC2677533] [PubMed: 19020296]
10. Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am J Med Genet A. 2006;140:594–603. [PubMed: 16470708]
11. Paushkin SV, Patel M, Furia BS, Peltz SW, Trotta CR. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3’end formation. Cell. 2004;117:311–21. [PubMed: 15109492]
12. Rajab A, Mochida GH, Hill A, Ganesh V, Bodell A, Riaz A, Grant PE, Shugart YY, Walsh CA. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology. 2003;60:1664–7. [PubMed: 12771259]
13. Steinlin M, Klein A, Haas-Lude K, Zafeiriou D, Strozzi S, Müller T, Gubser-Mercati D, Schmitt Mechelke T, Krägeloh-Mann I, Boltshauser E. Pontocerebellar hypoplasia type 2: variability in clinical and imaging findings. Eur J Paediatr Neurol. 2007;11:146–52. [PubMed: 17320436]
14. Trotta CR, Paushkin SV, Patel M, Li H, Peltz SW. Cleavage of pre-tRNAs by the splicing endonuclease requires a composite active site. Nature. 2006;441:375–7. [PubMed: 16710424]

Revision History

• 22 September 2009 (cd) Revision: sequence analysis and prenatal testing is available clinically for TSEN2 and TSEN34 mutations.
• 8 September 2009 (me) Review posted live
• 1 May 2009 (fb) Original submission