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.
Frequency of Clinical Features in Individuals with UNC80 Pathogenic Variants
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Clinical Feature | Frequency in Persons 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% |
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].