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EXOSC3 Pontocerebellar Hypoplasia

Synonym: Pontocerebellar Hypoplasia Type 1B (PCH1B)

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: September 24, 2020.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

EXOSC3 pontocerebellar hypoplasia (EXOSC3-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, 82 individuals (from 58 families) with EXOSC3-PCH have been described.

Diagnosis/testing.

The diagnosis of EXOSC3-PCH is suspected in children with characteristic neuroradiologic and neurologic findings, and is confirmed by the presence of biallelic EXOSC3 pathogenic variants identified by 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 abilities.

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-PCH is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EXOSC3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. Once the EXOSC3 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

Diagnosis of EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH) should be suspected in children with severe neurologic impairment and characteristic findings on brain imaging.

Neurologic Findings

Common

  • 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, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations)

Less common

  • Joint contractures (can be present at birth or develop later)
  • Swallowing insufficiency
  • Ophthalmologic findings of:
    • Small or pale optic discs indicative of optic atrophy
    • Nystagmus
    • Strabismus
  • Seizures

Brain MRI Findings Consistent with Pontocerebellar Hypoplasia Type 1 (PCH1) *

Common

  • 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

Less common

  • Intracerebellar cysts [Eggens et al 2014]
  • Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia

* See Nomenclature.

Family History

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of EXOSC3 pontocerebellar hypoplasia is established in a proband with suggestive findings and biallelic EXOSC3 pathogenic variants identified by molecular genetic testing (see Table 1).

Note: Identification of biallelic EXOSC3 variants of uncertain significance (or identification of one known EXOSC3 pathogenic variant and one EXOSC3 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of EXOSC3-PHC has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of EXOSC3 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

A cerebellar hypoplasia multigene panel that includes EXOSC3 and other genes of interest (see Differential Diagnosis) 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. 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. Of note, given the rarity of EXOSC3-PCH, some panels for cerebellar hypoplasia may not include this gene. (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.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in EXOSC3 Pontocerebellar Hypoplasia

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
EXOSC3 Sequence analysis 3~99% 4
Deletion/duplication analysis 5Partial-gene deletion in 1 person 6
1.
2.

See Molecular Genetics for information on allelic variants.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6.

Clinical Characteristics

Clinical Description

EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH) is characterized at birth by skeletal muscle weakness that manifests 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, 82 individuals (in 58 families) with EXOSC3-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, Halevy et al 2014, Di Giovambattista et al 2017, Schottmann et al 2017, Ivanov et al 2018, Le Duc et al 2020, Saugier-Veber et al 2020].

Pregnancy is unremarkable in the majority. Fetal akinesia resulting in prenatal-onset joint contractures and polyhydramnios may occur in 1%-2% of cases [Rudnik-Schöneborn et al 2013].

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.

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. Motor milestones are delayed or not achieved at all. Unsupported crawling, sitting, or walking is reported in a few [Zanni et al 2013, Le Duc et al 2020]; however, these abilities are often lost when the disease progresses. In individuals who are able to sit or stand upright, scoliosis can result from muscle weakness. Speech is usually absent, but may be limited to short sentences in a few.

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 sometime between birth and 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 mainly occur in individuals who survive beyond infancy [Rudnik-Schöneborn et al 2013, Eggens et al 2014]. A few have infantile spasms (West syndrome). Around 25% of those with prolonged survival develop spasticity and/or epileptic seizures.

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

Neuropathologic findings

  • Common
    • 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
  • Less common. Spinal cord. Depletion of neurons in the dorsal spinal horn [Eggens et al 2014]

Genotype-Phenotype Correlations

Clear genotype-phenotype correlations exist for certain EXOSC3 pathogenic variants.

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

  • Children homozygous for this variant could be described as having a relatively "mild" clinical course. Some have the ability to walk or speak single words, and the disease course is prolonged with possible survival into puberty. Brain MRI shows a normal-size pons and cerebellar hypoplasia that is mild compared to that observed in children with other EXOSC3 pathogenic variants [Biancheri et al 2013, Rudnik-Schöneborn et al 2013, Eggens et al 2014].
  • Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and c.238G>T (p.Val80Phe), had a similarly "mild" phenotype [Zanni et al 2013].
  • Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and c.572G>A (p.Gly191Asp), also had a mild disease course [Le Duc et al 2020].

Phenotypes associated with the pathogenic variant c.92G>C (p.Gly31Ala) include the following:

  • Individuals homozygous for this variant represent the severe end of the EXOSC3-PCH spectrum, often manifesting at birth or in the first months of life severe hypotonia and respiratory failure. Survival is poor [Rudnik-Schöneborn et al 2013, Eggens et al 2014].
  • More recently, two sibs with this variant had severe growth retardation, fetal akinesia, microlissencephaly, and cerebellar malformations consistent with rhombencephalosynapsis [Saugier-Veber et al 2020].

Nomenclature

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

Prevalence

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

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

To date, 82 individuals (in 58 families) have been described with EXOSC3-PCH [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, Halevy et al 2014, Di Giovambattista et al 2017, Schottmann et al 2017, Ivanov et al 2018, Le Duc et al 2020, Saugier-Veber et al 2020].

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). See Table 6.

The c.92G>C (p.Gly31Ala) pathogenic variant is a founder variant in the Roma population [Rudnik-Schöneborn et al 2013, Schwabova et al 2013]. A carrier frequency of about 4% was found in the Roma population of the Czech Republic [Schwabova et al 2013]. See Table 6.

Differential Diagnosis

Key disorders to consider in the differential diagnosis of pontocerebellar hypoplasia type 1 (PCH1) include EXOSC8-, SLC25A46-, and VRK1-related PCH1, PCH2/4 (TSEN54-related PCH), spinal muscular atrophy type 1, PCH10, and PCH12 (see Table 2).

PCH1. About 50% of individuals with PCH1 have pathogenic variants in EXOSC3 (i.e., EXOSC3-PCH). In children with EXOSC3-PCH, neonatal death, delayed nerve conduction velocities, and congenital respiratory and feeding difficulties occur less frequently than in those without identifiable EXOSC3 pathogenic variants [Rudnik-Schöneborn et al 2014].

PCH2/4. Dyskinesias and seizures are common in PCH2, the most common type of PCH. PCH4 is a severe form of PCH2, often with congenital contractures and polyhydramnios. In children with EXOSC3-PCH, central motor findings (together with the typical brain MRI findings of cerebellar or pontocerebellar hypoplasia) may falsely suggest a diagnosis of PCH2. Compared to findings in EXOSC3-PCH, the findings in PCH2 are:

  • No abnormalities of the spinal cord (whereas in PCH1 anterior horn cells are involved);
  • Attenuation of the pons on brain MRI (whereas in PCH1 the pons can be unaffected).

Table 2.

Genes of Interest in the Differential Diagnosis of EXOSC3 Pontocerebellar Hypoplasia

Gene(s)Phenotype/
Disorder		MOIBrain MRI FindingsClinical Characteristics
Key differential diagnosis disorders (in order of relevance)
EXOSC8
SLC25A46
VRK1 		PCH1 1, 2ARPontine atrophy may not be present in some individuals.
  • Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness & muscle hypotonia from birth
  • Mixed central (spastic, dystonic) & peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age. 3
TSEN54 TSEN54-PCH (PCH2, 4, & 5)AR
  • Severe pontocerebellar hypoplasia w/relative sparing of pons
  • Profound supratentorial atrophy in PCH4
  • Generalized clonus, impaired swallowing, dystonia, chorea, progressive microcephaly in PCH2
  • PCH4 is a severe type of PCH2, w/congenital contractures & polyhydramnios.
SMN1 Spinal muscular atrophy type 1 ARNormal
  • Early-onset (birth-6 mos) disease is characterized by muscle weakness & lack of motor development.
  • Cognitive function is normal.
  • EMG reveals denervation; muscle biopsy shows grouped atrophy.
CLP1 PCH10 (OMIM 615803)ARMild cerebellar atrophy/hypoplasiaVery rare disorder characterized by DD, microcephaly, spasticity, axonal motor & sensory neuropathy, abnormal muscle tone, seizures, motor neuron degeneration
COASY PCH12 (OMIM 618266)ARPrenatal-onset microcephaly; hypoplasia of cerebellum, brain stem, spinal cordSevere prenatal-onset PCH, microcephaly, arthrogryposis w/hypoplasia of spinal cord & brain stem, multiple congenital contractures, polyhydramnios, motor neuron degeneration
Other disorders to consider (in alphabetic order by gene)
B3GALNT2
B4GAT1
DAG1
FKRP
FKTN
GMPPB
ISPD
LARGE1
POMGNT1
POMGNT2
POMK
POMT1
POMT2
RXYLT1 4		Alpha-dystroglycanopathiesARWide spectrum of brain malformations incl cobblestone lissencephaly & hydrocephalusMuscle weakness & ophthalmologic abnormalities
CASK ID & microcephaly w/pontine & cerebellar hypoplasia (See CASK Disorders.)XLNeocortical dysplasia (simplified gyral pattern, thin brain stem w/flattening of pons) & severe cerebellar hypoplasia (PCH)
  • Heterozygous females have severe or profound ID & structural brain anomalies incl mild congenital microcephaly & severe postnatal microcephaly.
  • Hemizygous males are more severely affected.
CHMP1A PCH8 1ARMRI findings similar to PCH1BMicrocephaly, delayed walking, variable foot deformities, chorea, dystonic posturing, impaired cognition
PCLO PCH3 1AR
>40 genes (e.g., PMM2 5)Congenital disorders of glycosylation (CDG) (See also PMM2-CDG (CDG-Ia).)AR
(XL)		Pontocerebellar hypoplasia w/superimposed atrophy, delayed myelinationDysmorphic features, ataxia; organ failure in neonatal period
RARS2 PCH6 1AR
  • Very rare
  • ↑ CSF lactate concentration
RELN Lissencephaly 2 (OMIM 257320)ARClassic lissencephaly w/coexistent cerebellar & pontine hypoplasia
SEPSECS PCH2 1ARProgressive cerebello-cerebral atrophy closely resembles mild PCH.Clinical findings closely resemble mild PCH2.
TOE1 PCH7 1ARPCHDisorders of sex development
VLDLR VLDLR cerebellar hypoplasia ARGross cerebellar hypoplasia, flat ventral pons, simplified gyriAtaxia & ID

AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked

1.
2.
3.

Children with EXOSC3 pathogenic variants other than c.395A>C (p.Asp132Ala) have a more severe phenotype that includes severe pontine and cerebellar hypoplasia, joint contractures, and death in infancy.

4.
5.

PMM2-CDG (CDG-Ia) is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides.

Other conditions to consider in the differential diagnosis

  • Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [Forman et al 2005]
  • Pontocerebellar hypoplasia in extremely premature infants (gestational age <28 weeks); an acquired phenocopy to be considered [Volpe 2009, Pierson & Al Sufiani 2016]

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis of EXOSC3 Pontocerebellar Hypoplasia

System/ConcernEvaluationComment
Constitutional Measure length & weight.See Gastrointestinal/Feeding if evidence of failure to thrive.
Gastrointestinal/
Feeding 		Gastroenterology / nutrition / feeding team evalAssess swallowing & feeding to determine safety of oral vs gastrostomy feeding.
Respiratory Assess airway & pulmonary function & secretion management.Consult pulmonologist.
Neurologic Eval by pediatric neurologistAssess for:
  • Evidence of severe generalized clonus;
  • Chorea, spasticity;
  • Seizures (to incl EEG);
  • Impaired central vision.
Hearing loss Eval by audiologist
Vision Eval by pediatric ophthalmologist
  • Assess visual acuity.
  • Fundoscopy to assess optic nerve
Musculoskeletal Multidisciplinary neuromuscular clinic assessment by orthopedist, physical medicine, OT/PTTo incl assessment of:
  • Contractures, clubfoot, & kyphoscoliosis
  • Need for positioning devices
Palliative care Refer to palliative care specialist.When deemed appropriate by family & care providers
Genetic
counseling 		By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of EXOSC3-PCH to facilitate medical & personal decision making
Family support/
resources 		Assess:

MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

No specific treatment for EXOSC3-PCH exists; the goals are to maximize function and reduce complications.

Ideally, each affected individual is managed by a multidisciplinary team of relevant specialists including developmental pediatricians, neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, pulmonologists, and psychologists depending on the clinical manifestations (see Table 4).

Table 4.

Treatment of Manifestations in Individuals with EXOSC3 Pontocerebellar Hypoplasia

Manifestation/
Concern		TreatmentConsiderations/Other
Seizures Per standard practiceBy neurologist experienced in epilepsy management
Irritability NoneOften related to chorea (involuntary movements)
Musculoskeletal Multidisciplinary neuromuscular clinic physical medicine, OT/PT
  • Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices.
  • Alternative casting/splinting & stretching
OrthopedicsManage contractures, clubfoot, scoliosis w/bracing &/or surgical intervention.
Feeding/Dysphagia Gastroenterology / nutrition / feeding teamModify food consistency to ↓ aspiration risk &/or consider NG feeding & gastrostomy.
Speech Speech/language evalConsider involving speech therapist & OT to improve communication skills.
Respiratory
  • Manage pulmonary complications.
  • Treatment of respiratory infections
Per treating pulmonologist
Neurodevelopmental Early intervention / individual education program based on needsSee Developmental Delay / Intellectual Disability Management Issues.

NG = nasogastric; OT = occupational therapy, PT = physical therapy

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Surveillance

Table 5.

Recommended Surveillance for Individuals with EXOSC3 Pontocerebellar Hypoplasia

System/ConcernEvaluationFrequency
Respiratory Assess airway & pulmonary function & secretion management.Monitoring of respiratory function may be necessary to detect sleep apnea.
Gastrointestinal/
Feeding
  • Aspiration risk & nutritional status
  • Monitor for constipation.
Annually; more frequently if needed
Musculoskeletal
  • PT/OT eval
  • Assess for contractures, scoliosis, foot deformities.
  • Hip/spine x-rays
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Monitor for dystonia & choreic movements.
Development Monitor developmental milestones
Family support/
resources 		Family needs

OT = occupational therapy, PT = physical therapy

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 EU Clinical Trials Register 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH) 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., presumed to be carriers of one EXOSC3 pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EXOSC3 pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an EXOSC3 pathogenic variant, each sib of an affected individual has at conception 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.
  • Although some intrafamilial variability has been described, sibs who inherit biallelic EXOSC3 pathogenic variants typically have a clinical presentation similar to the proband (see Genotype-Phenotype Correlations).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with EXOSC3-PCH 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 of an EXOSC3 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the EXOSC3 pathogenic variants in the family.

See Related Genetic Counseling Issues, Population screening for information about carrier testing in individuals who do not have a family history of EXOSC3-PCH.

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/preimplantation genetic 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.

Population screening. Persons of Roma ancestry may choose to have carrier testing for the c.92G>C (p.Gly31Ala) founder variant (see Prevalence).

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 Testing

Once the EXOSC3 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

EXOSC3 Pontocerebellar Hypoplasia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
EXOSC3 9p13​.2 Exosome complex component RRP40 EXOSC3 @ LOVD EXOSC3 EXOSC3

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for EXOSC3 Pontocerebellar Hypoplasia (View All in OMIM)

606489EXOSOME COMPONENT 3; EXOSC3
614678PONTOCEREBELLAR HYPOPLASIA, TYPE 1B; PCH1B

Molecular Pathogenesis

EXOSC3 encodes a subunit of the exosome complex which plays a role in RNA processing and degradation. Other pontocerebellar hypoplasia (PCH) types are caused by variants in genes involved in RNA processing as well; for example, biallelic variants in TSEN54 cause PCH2, PCH4, and PCH5 (see TSEN54-Related Pontocerebellar Hypoplasia). The exact molecular pathway underlying PCH is unknown.

Mechanism of disease causation. The authors suggest that EXOSC3 pathogenic variants lead to loss of function or reduced function of the EXOSC3 protein, since individuals with a nonsense variant are more severely affected than those with missense variants.

Table 6.

Notable EXOSC3 Pathogenic Variants

Reference SequencesDNA Nucleotide
Change		Predicted
Protein Change		Comment [Reference]
NM_016042​.3
NP_057126​.2 		c.92G>Cp.Gly31AlaFounder variant in Roma population [Wan et al 2012, Rudnik-Schöneborn et al 2013]
c.238G>Tp.Val80PheMilder clinical course (see Genotype-Phenotype Correlations) [Zanni et al 2013]
c.395A>Cp.Asp132Ala
c.572G>Ap.Gly191AspMilder clinical course [Le Duc et al 2020] (see Genotype-Phenotype Correlations) [Zanni et al 2013]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Acknowledgments

We thank the patients and families and their doctors for their support and sharing of clinical information.

Author History

Frank Baas, MD, PhD (2014-present)
Peter G Barth, MD, PhD; University of Amsterdam (2014-2020)
Veerle RC Eggens, MSc; University of Amsterdam (2014-2020)
Tessa van Dijk, MD, PhD (2020-present)

Revision History

  • 24 September 2020 (bp) Comprehensive update posted live
  • 21 August 2014 (me) Review posted live
  • 11 February 2014 (vrce) Original submission

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