Clinical characteristics.

EXOSC3-related pontocerebellar hypoplasia (PCH) is characterized by abnormalities in the posterior fossa and degeneration of the anterior horn cells. At birth, skeletal muscle weakness manifests as hypotonia (sometimes with congenital joint contractures) and poor feeding. In persons with prolonged survival, spasticity, dystonia, and seizures become evident. Within the first year of life respiratory insufficiency and swallowing difficulties are common. Intellectual disability is severe. Life expectancy ranges from a few weeks to adolescence. To date, 51 individuals with PCH from 36 families with mutation of EXOSC3 have been described.

Diagnosis/testing.

The diagnosis is suspected in infants and children with characteristic clinical findings (including evidence of anterior horn cell disease) and characteristic neuroradiologic findings (hypoplasia and/or atrophy of the cerebellum and pons in varying degrees; equal involvement of the cerebellar vermis and cerebellar hemispheres). The diagnosis is established by identification of biallelic EXOSC3 pathogenic variants on molecular genetic testing.

Management.

Treatment of manifestations: No specific therapy is available. Treatment is symptomatic. Contractures and scoliosis are managed by passive or active movement and bracing as needed. Aspiration risk and seizures are managed in a routine manner. Education is adapted to the level of cognitive handicap.

Surveillance: Regular examinations to address: growth and nutritional status (including problems with feeding and risk of aspiration); respiratory function; joint contractures and scoliosis. Observation for and management of epileptic seizures.

Genetic counseling.

EXOSC3-related PCH is inherited in an autosomal recessive manner. 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. If the EXOSC3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible.

Suggestive Findings

Diagnosis of EXOSC3-related pontocerebellar hypoplasia (PHC) should be suspected in individuals with the following findings.

Neurologic findings

• Major criteria
  • Hypotonia (onset is usually at birth, but a later onset is possible)
  • Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes
  • Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival
  • Lower motor neuron involvement, proven by EMG (abnormal EMG potentials, increased motor unit potentials [MUPs], fasciculations)
• Minor criteria (present in some individuals)
  • Joint contractures (can be present at birth or develop later)
  • Swallowing insufficiency
  • Ophthalmologic findings of:
    • Small or pale optic discs indicative for optic atrophy
    • Nystagmus
    • Strabismus
  • Seizures

Neuroradiologic findings consistent with PCH1

• Major criteria
  • Hypoplasia and/or atrophy of the cerebellum in varying degrees
  • Hypoplasia and/or atrophy of the pons in varying degrees
  • Cerebellar vermis and cerebellar hemispheres equally affected
• Minor criteria (present in some individuals)
  • Intracerebellar cysts [Eggens et al 2014]
  • Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia

Neuropathologic findings

• Major criteria
  • Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy
  • Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn
  • Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers
• Minor criterion (present in some individuals)
  • Spinal cord. Depletion of neurons in the dorsal spinal horn [Eggens et al 2014]

Establishing the Diagnosis

The diagnosis of EXOSC3-related pontocerebellar hypoplasia is established in a proband by identification of biallelic EXOSC3 pathogenic variants on molecular genetic testing (see Table 1).

• One molecular genetic testing strategy is sequence analysis of EXOSC3, followed by deletion/duplication analysis if only one pathogenic variant is identified.
• An alternative genetic testing strategy is use of a multigene panel that includes EXOSC3 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

EXOSC3-related pontocerebellar hypoplasia (PCH) is characterized at birth by skeletal muscle weakness manifest as hypotonia (sometimes with congenital joint contractures) and poor feeding. In children with prolonged survival, spasticity, dystonia, and seizures become evident. Respiratory insufficiency and swallowing difficulties are common. Intellectual disability is severe.

To date, 51 individuals (in 36 families) with EXOSC3-related PCH have been described [Wan et al 2012, Biancheri et al 2013, Rudnik-Schöneborn et al 2013, Schwabova et al 2013, Zanni et al 2013, Eggens et al 2014]. In children with the pontocerebellar hypoplasia type 1 (PCH1) phenotype who have identifiable EXOSC3 pathogenic variants, neonatal death, delayed nerve conduction velocities (NCVs), and congenital respiratory and feeding difficulties occur less frequently than in those without identifiable EXOSC3 pathogenic variants [Rudnik-Schöneborn et al 2014].

Pregnancy is unremarkable in the majority. Fetal akinesia resulting in prenatal-onset joint contractures and polyhydramnios may occur in 1%-2% of cases.

Birth weight and length are normal; birth head circumference varies from normal to small. Hypotonia, the most common initial finding, is present at birth in most infants and not evident until age three to six months in the remainder.

Motor milestones are delayed or not achieved at all. Unsupported sitting and walking, observed in only a few children with prolonged survival, are often lost as the disease progresses. Speech is usually absent, but may be limited to short sentences in a few.

In relatively older individuals, central motor (pyramidal or extrapyramidal) and signs of peripheral motor involvement may coexist.

Infections and respiratory failure due to muscle weakness are among the reported causes of death. In most severe cases, respiratory problems start soon after birth. In the majority of children onset of respiratory failure begins within the first year of life. In rare cases, onset is during childhood [Rudnik-Schöneborn et al 2013].

Joint contractures can be present at birth in the most severe cases, or can develop after a few years. Unsupported crawling, sitting, or walking is reported in a few [Zanni et al 2013]; however, these abilities are often lost when disease progresses. In individuals who are able to sit or stand upright, scoliosis can arise due to muscle weakness.

Some infants can be bottle fed or breast fed in the first weeks of life [Eggens et al 2014]. Although on occasion infants are able to eat without aid [Zanni et al 2013], swallowing insufficiency in the majority necessitates tube feeding. Age of onset varies from birth to a few years of age [Rudnik-Schöneborn et al 2013].

Vision is hard to assess in young children. Many are unable to fix and follow, and many show strabismus and/or nystagmus. Possibly, the nystagmus in some children results from early-onset visual impairment, but clear evidence is lacking.

Seizures are mainly reported in individuals who survive beyond infancy [Rudnik-Schöneborn et al 2013, Eggens et al 2014]. A few instances of infantile spasms (West syndrome) are described. Around 25% of those with prolonged survival develop spasticity or epileptic seizures.

Age of death ranges from a few weeks of age to adolescence and can be correlated with certain pathogenic variants (see Genotype-Phenotype Correlations).

Genotype-Phenotype Correlations

Clear genotype-phenotype correlations are present in certain EXOSC3 pathogenic variants.

Phenotypes associated with the pathogenic variant c.395A>C (p.Asp132Ala)

• Children homozygous for the pathogenic variant c.395A>C (p.Asp132Ala) could be described as having a relatively "mild" clinical course. Some have the ability to walk or speak single words. The disease course is prolonged with possible survival into puberty.
• Brain MRI shows a pons of normal size, and cerebellar hypoplasia is mild compared to that observed in children with other EXOSC3 pathogenic variants.
• One child who was a compound heterozygote for the pathogenic variants c.395A>C (p.Asp132Ala) and p.Val80Phe had a similarly "mild" phenotype.

Other pathogenic variants. Children with other EXOSC3 pathogenic variants have a more severe phenotype that includes severe pontine and cerebellar hypoplasia, joint contractures, and death in infancy.

Penetrance

Males and females are affected equally.

Nomenclature

Pontocerebellar hypoplasia 1 (PCH1) refers to the phenotype; its subtypes, designated by letter (e.g., PCH1B), are identified by the gene in which causative pathogenic variants occur.

Prevalence

The prevalence of EXOSC3-related PCH in the general population is unknown.

About 50% of individuals with pontocerebellar hypoplasia type 1 (PCH1) have pathogenic variants in EXOSC3.

To date, 51 individuals from 36 families with PCH and biallelic pathogenic variants EXOSC3 have been described [Wan et al 2012, Biancheri et al 2013, Rudnik-Schöneborn et al 2013, Schwabova et al 2013, Zanni et al 2013, Eggens et al 2014].

c.395A>C (p.Asp132Ala) is the most prevalent pathogenic variant with an ancestral origin [Wan et al 2012, Rudnik-Schöneborn et al 2013], with an allele frequency of 0.1% among European Americans (Exome Variant Server).

Of note, c.395A>C (p.Asp132Ala) is associated with survival beyond infancy.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EXOSC3-related pontocerebellar hypoplasia, the following are recommended:

• Optionally to evaluate disease progress: neurologic evaluation (EMG, NCV) and brain MRI.
• Pediatric evaluation, including assessment of feeding, pulmonary function, and nutritional status
• Ophthalmologic examination including fundoscopy to assess the optic nerve and measurement of visual acuity.
• Orthopedic evaluation to assess joint contractures and scoliosis.
• Electroencephalography in those with suspected liability of seizures
• Clinical genetics consultation, including counseling and prenatal advice regarding future pregnancies and counseling of related family members.

Treatment of Manifestations

No specific therapy is available. Treatment is symptomatic. The main problems to manage are:

• Contractures, including scoliosis, due to neurogenic atrophy, by passive or active movement and if necessary by bracing.
• Prevention of aspiration due to bulbar muscle and respiratory muscle involvement
• Adaptation of education to the level of cognitive handicap
• Epilepsy, which is amendable to standard treatments

Surveillance

Regular examinations to address:

• Growth and nutritional status, including problems with feeding and risk of aspiration
• Respiratory function
• Joint contractures and scoliosis
• Development or management of epileptic seizures

Evaluation 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 in the US and www.ClinicalTrialsRegister.eu in Europe 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.

Mode of Inheritance

EXOSC3-related pontocerebellar hypoplasia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 and are not at risk of developing the disorder.

Offspring of a proband. Individuals with EXOSC3-related pontocerebellar hypoplasia are not likely to have offspring because of severe intellectual disability and the likelihood of early death.

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

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the EXOSC3 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Molecular Genetic Pathogenesis

EXOSC3 encodes a subunit of the exosome complex which plays a role in RNA processing and degradation. Other PCH types are caused by mutation of genes involved in RNA processing as well; for example, mutation of TSEN54 causes PCH2, PCH4, and PCH5. The exact molecular pathway underlying PCH is unknown.

Gene structure. The longest transcript variant, NM_016042.3, is 1857 bp, comprising four exons. Alternatively spliced transcript variants encoding different isoforms are known. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Identified pathogenic variants include missense variants (which can be homozygous or compound heterozygous), protein truncating variants (as a compound heterozygote with a missense variant), and a large partial deletion of EXOSC3.

The most common pathogenic variants in EXOSC3 are c.395A>C (p.Asp132Ala) and c.92G>C (p.Gly31Ala). The latter is prevalent among the Roma population.

Normal gene product. The normal gene product of EXOSC3 comprises 275 amino acids.

Abnormal gene product. The authors suggest that EXOSC3 pathogenic variants lead to loss of function or reduced function of the EXOSC3 protein, since individuals with a nonsense allele are more severely affected than those with missense alleles.

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Revision History

• 21 August 2014 (me) Review posted live
• 11 February 2014 (vrce) Original submission