Sptbn4 Disorder
Summary
Clinical characteristics.
SPTBN4 disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported.
Diagnosis/testing.
The diagnosis of SPTBN4 disorder is established in a proband with congenital hypotonia and biallelic pathogenic variants in SPTBN4 identified by molecular genetic testing.
Management.
Treatment of manifestation: Hearing aids may be helpful for those with hearing loss; ventilator support (e.g., BiPAP) for respiratory distress; consideration of Robinul® or Botox® injections for severe sialorrhea; feeding therapy and consideration of gastrostomy tube placement for persistent feeding difficulties and/or concern about aspiration; standard treatment for developmental delay/intellectual disability, epilepsy, cortical vision impairment, constipation, and spasticity / joint contractures.
Surveillance: Assessment for new neurologic manifestations and/or adequacy of seizure control, developmental progress, growth and nutritional status, constipation, and joint mobility at each visit; ophthalmology evaluation every one to two years in those with optic atrophy; audiology evaluation as clinically indicated; sleep study every one to two years.
Genetic counseling.
SPTBN4 disorder 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. Once the SPTBN4 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Formal clinical diagnostic criteria for SPTBN4 disorder have not been established. However, affected individuals often have profound congenital neurologic deficits (including hypotonia, neuromuscular weakness, hyporeflexia/areflexia), severe cognitive delays, and seizures.
Suggestive Findings
SPTBN4 disorder should be considered in individuals with the following clinical, supportive laboratory, imaging, and functional findings.
Clinical findings
- Severe-to-profound developmental delay / intellectual disability
- Congenital hypotonia
- Neuromuscular weakness
- Loss of deep tendon reflexes indicative of neuropathy
- Epilepsy, including both focal and/or generalized seizures (infantile spasms)
- Cortical visual impairment
- Hearing impairment characterized as central deafness or auditory neuropathy
- Respiratory difficulties
- Feeding difficulties
Supportive laboratory findings
- Normal serum CK level
- Muscle biopsy findings consistent with a neurogenic process with evidence of denervation, including fiber type disproportion and/or neurogenic changesNote: Muscle biopsy is not required to establish the diagnosis.
Imaging findings. Brain MRI ranging from normal during the neonatal/early-infancy period to nonspecific changes including delayed myelination, thin corpus callosum, prominent ventricles, and atrophy in older children and adults
Functional findings
- Electromyography (EMG) / nerve conduction studies (NCS) demonstrating an axonal motor neuropathy/neuronopathy
- Abnormal auditory brain stem response (ABR) suggestive of auditory neuropathy
Establishing the Diagnosis
The diagnosis of SPTBN4 disorder is established in a proband with congenital hypotonia and biallelic pathogenic variants in SPTBN4 identified by molecular genetic testing (see Table 1).
Because the phenotype of SPTBN4 disorder overlaps with many other inherited disorders with congenital hypotonia and neuromuscular weakness, a broad molecular genetic testing approach is often required, including use of a multigene panel or comprehensive genomic testing (exome sequencing).
Note: Single-gene testing (sequence analysis of SPTBN4, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
A hypotonia, neuropathy, intellectual disability, and/or epilepsy multigene panel that includes SPTBN4 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. (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.
Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible.
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 SPTBN4 Disorder
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| SPTBN4 | Sequence analysis 3 | 14/14 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | None reported 7 |
- 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.
Anazi et al [2017], Knierim et al [2017], Wang et al [2018], Monies et al [2019], Pehlivan et al [2019], Häusler et al [2020]
- 5.
To date, 14 different pathogenic variants have been described in 12 families; 8 are truncating variants, 4 are missense, and 2 are splice variants. The majority of affected individuals reported to date are homozygous (12/14).
- 6.
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.
- 7.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
Clinical Characteristics
Clinical Description
To date, 14 individuals from 12 families have been reported with pathogenic variants in SPTBN4 [Anazi et al 2017, Knierim et al 2017, Wang et al 2018, Monies et al 2019, Pehlivan et al 2019, Häusler et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Features of SPTBN4 Disorder
| Feature | # of Persons w/Feature | Comment |
|---|---|---|
| Congenital hypotonia | 14/14 (100%) | |
| Neuromuscular weakness | 14/14 (100%) | 1 affected person reported w/some ambulation 1 |
| Areflexia/Neuropathy | 13/14 (93%) | |
| Developmental delay / Intellectual disability | 13/14 (93%) |
|
| Feeding difficulties | 9/14 (64%) | |
| Respiratory difficulties | 8/14 (57%) | |
| Visual impairment | 6/14 (43%) | |
| Joint contractures | 5/14 (36%) |
|
| Seizures | 5/14 (36%) | |
| Hearing loss | 4/14 (29%) | Typically due to an auditory neuropathy |
In most reports the phenotypic details were limited and pertinent negatives were often not provided. Therefore, the number of individuals with a specific clinical feature likely represents a minimum proportion.
- 1.
Häusler et al [2020]
Developmental delay / intellectual disability. A vast majority of affected individuals reported to date have had severe-to-profound developmental delay and/or intellectual disability. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Speech and language skills are also severely limited, with very few reported individuals to date developing verbal language. In a recently reported family with two affected individuals, one individual had normal cognitive ability, including receptive language skills [Häusler et al 2020].
Neurologic
- Hypotonia is typically congenital and does not improve significantly over time. Some affected individuals may progress to develop appendicular hypertonia while axial tone remains low.
- Neuropathy. Hyporeflexia or areflexia due to axonal motor neuropathy and weakness on exam have been reported. Areflexia may be present at birth or becomes evident with age, suggesting a progressive neuropathy.
- Seizures. About half of affected individuals develop epilepsy, including generalized seizures (infantile spasms) and drug-resistant epilepsy. No clear preferred medications to treat epilepsy are known at this point.
- Brain MRI findings are variable and nonspecific, including thin corpus callosum. In the few affected individuals with serial imaging there has been evidence of cortical atrophy and prominent CSF spaces over time. One affected individual had prenatally identified hydrocephalus on ultrasound [Pehlivan et al 2019].
Growth. Details about growth have not been systematically reported. Anazi et al [2017] reported weight, height, and head circumference as below the third centile in a single affected individual, while Pehlivan et al [2019] reported an affected individual with normal length, but weight and head circumference well below the third centile (3.9 SD below the mean for length and 6.6 SD below the mean for head circumference).
Eyes. Cortical visual impairment is common. Reports of optic atrophy are rare and it is unclear if this is progressive. Affected individuals are not known to have retinal involvement but this has not been thoroughly evaluated.
Hearing. Auditory neuropathy leading to hearing loss has been reported.
Respiratory difficulties. Affected children may need ventilator support due to neuromuscular weakness. Respiratory issues do not appear to be due to primary lung pathology. Many children also experience sialorrhea (excessive salivation or drooling), which needs to be monitored and managed due to aspiration risk. Two reported individuals died of respiratory failure.
Feeding difficulties. Dysphagia usually results from hypotonia and neuromuscular weakness. Most affected individuals reported to date received nutrition via feeding tube due to aspiration risk.
Musculoskeletal. Scoliosis due to neuromuscular weakness has been reported. Joint contractures (including congenital arthrogryposis) and spasticity (likely secondary to neuropathy) also occur.
Nonspecific dysmorphic features. Myopathic facies and highly arched palate have been noted in four affected individuals [Knierim et al 2017, Pehlivan et al 2019, Häusler et al 2020].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Prevalence
The prevalence of this condition is unknown. To date, only 14 individuals from 12 families have been reported in the literature. Most affected individuals reported to date have been from consanguineous families.
Differential Diagnosis
Table 3.
Genes of Interest in the Differential Diagnosis of SPTBN4 Disorder
| Gene(s) / Genetic Mechanism | Disorder | MOI | Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/SPTBN4 Disorder | Distinguishing from SPTBN4 Disorder | |||
| Abnormal parent-specific imprinting 1 | Prader-Willi syndrome | See footnote 2. | Congenital hypotonia, poor feeding | Hyperphagia, obesity, cognitive delay in childhood |
| CRPPA 2 DAG1 FKRP FKTN 3 LARGE1 POMGNT1 POMT1 POMT2 | Muscular dystrophy-dystroglycanopathy, type A (OMIM PS236670) | AR | Congenital hypotonia w/cognitive delays, often assoc w/hyporeflexia |
|
| DMPK | Myotonic dystrophy type 1 | AD | Congenital hypotonia, weakness, & cognitive delays | Myotonia, cataracts |
| SMN1 | Spinal muscular atrophy | AR | Congenital hypotonia, areflexia, & nonspecific dysmorphic features | Normal cognition & hearing |
| TBCK | Hypotonia, infantile, w/psychomotor delay, & characteristic facies 3 (OMIM 616900) | AR | Congenital hypotonia w/hyporeflexia, cognitive delays, & seizures |
|
| UFC1 | Neurodevelopmental disorder w/spasticity & poor growth (OMIM 618076) | AR | Contractures, hypotonia, delayed psychomotor development, inability to sit or walk, poor or absent speech, poor head control, seizures, poor feeding | Significant growth deficiency |
| UNC80 | UNC80 deficiency | AR | Congenital hypotonia, developmental delay, seizures, poor feeding | Dysmorphic facial features & skull deformities |
AR = autosomal recessive; AD = autosomal dominant; MOI = mode of inheritance
- 1.
Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.
- 2.
Listed genes represent a subset of those associated with muscular dystrophy-dystroglycanopathy, type A; for other genes associated with this phenotype in OMIM see Phenotypic Series: Muscular dystrophy-dystroglycanopathy, type A.
- 3.
See Fukuyama Congenital Muscular Dystrophy.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SPTBN4 disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with SPTBN4 Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Neurologic eval | Consider EEG if seizures a concern. |
| Development | Developmental assessment |
|
| Eyes | Ophthalmologic eval | To assess for ↓ vision, cortical visual impairment, & optic nerve abnormalities |
| Hearing | Audiologic eval |
|
| Respiratory | Sleep study |
|
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team eval |
|
| Musculoskeletal | Orthopedist / physical medicine & rehab / PT/OT eval | Incl assessment of:
|
| Genetics/ Other | Consult w/clinical geneticist &/or genetic counselor | Incl genetic counseling. |
| Family support / resources | Assess:
|
ABR = auditory brainstem response; BAER = brain stem auditory evoked potential; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations
Table 5.
Treatment of Manifestations in Individuals with SPTBN4 Disorder
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Developmental delay / Intellectual disability | See Developmental Delay / Intellectual Disability Management Issues. | |
| Epilepsy | Standardized treatment w/AEDs by experienced neurologist |
|
| Cortical visual impairment |
| |
| Hearing loss | Hearing aids may be helpful per otolaryngologist. | Community hearing services through early intervention or school district |
| Respiratory distress/failure | Ventilatory support (e.g., BiPAP) as needed | |
| Sialorrhea | Consider medical mgmt (Robinul® or Botox® injections) if severe. | |
| Poor weight gain / Failure to thrive |
| Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia |
| Bowel dysfunction | Stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation | |
| Spasticity / Joint contractures | Orthopedist / physical medicine & rehabilitation / PT/OT incl stretching |
|
| Family / Community |
|
|
AED = antiepileptic drugs; OT = occupational therapy; PT = physical therapy
- 1.
Education of parents regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Developmental Disability / 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:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine if any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible