Clinical characteristics.

UNC80 deficiency is characterized by hypotonia, strabismus, oral motor dysfunction, postnatal growth deficiency, and developmental delay. The majority of individuals do not learn to walk. All individuals lack expressive language; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional features can include nystagmus, extremity hypertonia, a high-pitched cry, repetitive and self-stimulatory behaviors, constipation, clubfeet, joint contractures, and scoliosis. For most individuals the UNC80 deficiency syndrome is not progressive. Individuals have slow acquisition of skills and do not have a loss of skills suggestive of neurodegeneration.

Diagnosis/testing.

The diagnosis of UNC80 deficiency is established in a proband with developmental delay and hypotonia by identification of biallelic pathogenic variants in UNC80 on molecular genetic testing.

Management.

Treatment of manifestations: G-tube feeding as needed for oral feeding difficulties; antiepileptic medications for seizure management; physical and occupational therapy for motor delay and sensory processing difficulties; ophthalmologic management for strabismus; braces and corrective surgeries as needed for orthopedic abnormalities; empiric management of constipation; sign language instruction or use of an alternate communication device for absent speech.

Surveillance: Annual evaluations for growth assessment, back exam for scoliosis, seizure management, evaluation of contractures, and ophthalmology examination.

Genetic counseling.

UNC80 deficiency is inherited in an autosomal recessive manner. 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. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants in a family are known.

Suggestive Findings

UNC80 deficiency should be suspected in individuals with the following clinical features:

• Developmental delay
• Moderate-to-severe intellectual disability
• Absent speech (<5 words)
• Hypotonia
• Joint contractures
• Postnatal growth restriction

Establishing the Diagnosis

The diagnosis of UNC80 deficiency is established in a proband with developmental delay and hypotonia by identification of biallelic pathogenic variants in UNC80 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive 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. Because the phenotypes of many disorders with hypotonia, developmental delay, and intellectual disability overlap, most children with UNC80 deficiency are diagnosed by the following genomic testing options:

• Comprehensive genomic testing (when clinically available) that includes exome sequencing and genome sequencing is one option.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A multigene panel that includes UNC80 and other genes of interest (see Differential Diagnosis) is another option. 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.

Note: Single-gene testing (sequence analysis of UNC80) is rarely useful and typically NOT recommended.

Clinical Description

UNC80 deficiency is a multisystem disorder. Table 2 indicates the frequency of clinical findings in this condition based on published reports. Clinical features vary and current evidence suggests dependency on the nature of the genetic variations.

Neurodevelopmental features. Individuals have congenital central hypotonia and strabismus. Some also manifest extremity hypertonia and a high-pitched cry. Seizures may develop during infancy or childhood. Focal seizures, generalized tonic-clonic seizures, myotonic seizures, aclonic seizures, and atypical absence seizures have been described. All respond well to anticonvulsive medications.

All individuals have developmental delay as well as severe intellectual disability. Oral motor dysfunction leads to difficulty with oral coordination, chewing, and swallowing. The majority of individuals do not learn to walk. All individuals lack expressive language, although many have expressive body language and a few have used signs to communicate.

For most individuals the UNC80 deficiency syndrome is not progressive. Individuals have slow acquisition of skills and do not have the loss of skills suggestive of neurodegeneration.

Behavioral features. Some individuals have behavioral difficulties including repetitive and self-stimulatory behaviors and difficulties with emotional regulation. The majority of individuals with UNC80 deficiency are social (i.e., they prefer people to objects). Some individuals show tactile aversion and hypersensitivity to stimuli. Some individuals seek significant oral stimulation.

Growth. All individuals have had normal prenatal growth. Postnatally, however, linear growth and weight remained below the 3rd centile. Poor feeding exacerbates the growth restriction; however, tube feedings with a calorie-rich diet generally do not result in weight for age above the 3rd centile. Individuals do not have evidence of endocrine anomalies that would account for the poor weight gain.

Gastrointestinal features. Constipation is common and has been attributed to hypotonia.

Musculoskeletal features. Many individuals have congenital clubfeet. Joint contractures (e.g., hip, elbow, knee) can present from an early age. Later-onset scoliosis can be seen. Ongoing physiotherapy, stretching, and bracing improves some of the limitations encountered with contractures and/or scoliosis. In individuals with more severe clubfeet or scoliosis, surgery may be considered.

Ophthalmologic features. Strabismus has been reported in all affected individuals and nystagmus is seen in half of affected individuals. One individual with structural ocular abnormalities (punctate keratopathy) has been reported. Vision is usually normal.

Facial features. The dysmorphic features reported appear to be nonspecific (see Table 2).

Radiographic features. Although most affected individuals have normal brain MRI findings, nonspecific abnormalities such as a thin corpus callosum, mild diffuse brain atrophy, and borderline mild enlargement of the lateral and third ventricles and of the extra-axial space have been reported [Perez et al 2016, Shamseldin et al 2016, Stray-Pedersen et al 2016]. The skeletal features seen in affected individuals to date are primarily identified by physical exam.

Prognosis. Reported individuals span ages from birth to 15 years [Perez et al 2016, Shamseldin et al 2016, Stray-Pedersen et al 2016, Valkanas et al 2016]. To date, only one individual has died, of complications from infection; postmortem studies of the brain, spinal cord, nerve, muscle, liver, skin, and myocardium did not identify evidence of central nervous malformations or findings attributable to the underlying neurologic disorder [Valkanas et al 2016].

Genotype-Phenotype Correlations

Correlations of genotype to phenotype have shown that genotype does not predict disease severity or outcome either within or among families.

Nomenclature

UNC80 deficiency is referred to as "infantile hypotonia with psychomotor retardation and characteristic facies 2" (IHPRF2) in OMIM (616801).

Prevalence

The prevalence is unknown. Nineteen individuals have been reported to date. UNC80 deficiency is presumed pan ethnic.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with UNC80 deficiency, the evaluations and referrals summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Annual evaluation with the following specialists is appropriate:

• Pediatrician for growth assessment
• Neurologist to identify and manage seizures
• Orthopedist for evaluation of contractures and back examination for scoliosis
• Ophthalmologist for ocular manifestations and corrective therapy if needed

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.

Mode of Inheritance

UNC80 deficiency 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 UNC80 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• The offspring of an individual with UNC80 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in UNC80.
• To date, no individuals diagnosed with UNC80 deficiency have been known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a UNC80 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the UNC80 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 UNC80 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Literature Cited

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Revision History

• 21 September 2017 (sw) Review posted live
• 17 January 2017 (cds) Original submission