Unc80 Deficiency
Summary
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.
Diagnosis
No formal diagnostic criteria have been published.
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.
Table 1.
Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
---|---|---|
UNC80 | Sequence analysis 3 | 19/19 4 |
Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.
Valkanas et al [2016]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
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).
Table 2.
Clinical Feature | Frequency in Individuals w/UNC80 Pathogenic Variants 1 | ||
---|---|---|---|
# w/feature / # reported 1 | % w/feature | ||
Neurodevelopmental & behavioral | Severe ID or DD | 19/19 | 100% |
Hypotonia | 19/19 | 100% | |
Global motor delay | 13/13 | 100% | |
Feeding difficulties | 5/6 | 83% | |
Walking achieved | 3/6 | 50% | |
Absent speech or <5 words | 19/19 | 100% | |
Dystonic posture of limbs | 9/9 | 100% | |
Seizures | 10/19 | 53% | |
Arm flapping | 2/2 | 100% | |
Happy disposition | 2/2 | 100% | |
Self-injurious behaviors | 2/2 | 100% | |
Sensory hypersensitivities | 5/6 | 83% | |
Growth | Normal birth parameters | 12/12 | 100% |
Postnatal height <3rd centile | 11/12 | 92% | |
Postnatal weight <3rd centile | 11/12 | 92% | |
Postnatal microcephaly | 11/19 | 58% | |
Gastrointestinal | Constipation | 5/6 | 83% |
Musculoskeletal | Scoliosis | 10/13 | 77% |
Joint contractures | 10/10 | 100% | |
Clubfeet | 6/9 | 67% | |
Long, thin fingers | 9/9 | 100% | |
Tapering of distal phalanx | 9/9 | 100% | |
Small hands & feet | 5/6 | 83% | |
Ophthalmologic | Strabismus | 11/11 | 100% |
Nystagmus | 2/4 | 50% | |
Nonspecific facial features | Triangular face | 16/19 | 84% |
Frontal bossing | 5/9 | 56% | |
Downslanted palpebral fissures | 10/19 | 53% | |
Low-set/posteriorly rotated ears | 10/17 | 59% | |
Broad nasal bridge | 11/19 | 58% | |
Anteverted nares | 11/19 | 58% | |
Enlarged nares | 7/19 | 37% | |
Short & smooth philtrum | 10/13 | 77% | |
Thin vermilion of upper lip | 8/18 | 44% | |
Tented vermilion of upper lip | 10/13 | 77% | |
Micrognathia | 10/19 | 53% |
Adapted from Valkanas et al [2016]
DD = developmental delay; ID = intellectual disability
1: Total number of individuals with UNC80 deficiency who were assessed for the feature
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.
Differential Diagnosis
Based on affected individuals described to date [Perez et al 2016, Shamseldin et al 2016, Stray-Pedersen et al 2016, Valkanas et al 2016], UNC80 deficiency does not have pathognomonic features distinguishing it from the many disorders in which central hypotonia, intellectual disability, and developmental delay are observed. Description of additional affected individuals may eventually identify such pathognomonic features; however, until then UNC80 deficiency is best considered as clinically indistinguishable from many other genetic causes of hypotonia, developmental delay, and intellectual disability (some of which are listed in Table 3).
Table 3.
Disorder 1 | Gene / Genetic Mechanism | Distinguishing Clinical Features |
---|---|---|
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (OMIM 615419) | NALCN | Distinctive facial features incl prominent forehead, short nose, wide mouth, micrognathia, & large, low-set ears; neuroaxonal dystrophy; optic atrophy |
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (OMIM 616900) | TBCK | Distinctive facial features incl coarse face, bitemporal narrowing, highly arched eyebrows, deeply set eyes, high nasal bridge w/anteverted nares, macroglossia, gingival hyperplasia, & exaggerated cupid's bow; abnormal brain imaging; optic atrophy |
Phelan-McDermid syndrome | Terminal or interstitial deletion of chromosome 22q13.3 | Normal or accelerated growth, dolichocephaly, ptosis, epicanthal folds, large or prominent ears, pointed chin, fleshy hands, dysplastic toenails, tendency to overheat |
Ring chromosome 22 | Mild prenatal growth deficiency; mild dysmorphic features incl hypertelorism, epicanthal folds, depressed nasal bridge, & micrognathia; genitourinary anomalies; coloboma of the iris, choroid, &/or optic nerve; microphthalmia; cleft palate; congenital heart malformations; hernias; internal & external ear anomalies | |
Prader-Willi syndrome | Abnormal parent-specific imprinting w/in PWCR | Polyphagia & obesity, thin vermilion of upper lip w/down-turned corners of the mouth, genitourinary anomalies, acquisition of speech & mobility |
Angelman syndrome | Deficient expression or function of the maternally inherited UBE3A allele | Bursts of laughter, macrostomia, tongue protrusion, prognathism, widely spaced teeth, mild cortical atrophy |
Glass syndrome (OMIM 612313) | SATB2 | Cleft palate, arachnodactyly, joint laxity, ectodermal anomalies |
Rett syndrome | MECP2 | Postnatal microcephaly, seizures, poor growth, esotropia, scoliosis, repetitive behaviors |
PWCR = Prader-Willi critical region
- 1.
See hyperlinked GeneReview or OMIM phenotype entry for more information.
Management
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.
Table 4.
System/Concern | Evaluation | Comment |
---|---|---|
Constitutional | Growth assessment incl height, weight, & head circumference | |
Eyes | Ophthalmologic eval | |
Gastrointestinal | Feeding eval | |
Musculoskeletal | Orthopedic eval | If clubfeet &/or scoliosis is present |
Neurologic | EEG | If neurologic history suggests presence of seizures |
Psychiatric | Psychiatric eval | If behavioral problems are present |
Miscellaneous/ Other | Psychoeducational &/or developmental evals (physical therapy, occupational therapy, speech therapy evals) to assess developmental delays & facilitate appropriate interventions | |
Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 5.
Manifestation/Concern | Treatment |
---|---|
Ocular abnormalities (nystagmus/strabismus) |