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 (or likely 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.

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 changes
  Note: 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 (or likely pathogenic) variants in SPTBN4 identified by molecular genetic testing (see Table 1).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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 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.

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.

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 become 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.

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.

Treatment of Manifestations

Surveillance

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

SPTBN4 disorder is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one SPTBN4 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 SPTBN4 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 SPTBN4 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with SPTBN4 disorder are not known to reproduce (currently the majority of identified individuals with SPTBN4 disorder are severely affected children).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SPTBN4 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SPTBN4 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/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.

Prenatal Testing and Preimplantation Genetic Testing

Once the SPTBN4 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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.

Molecular Pathogenesis

Spectrin proteins are actin cross-linking and molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and function in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. A spectrin molecule is a tetramer consisting of two alpha and two beta subunits.

SPTBN4 is one member of a family of beta-spectrin genes that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle. Wang et al [2018] concluded that pathogenic variants in SPTBN4 disrupt the cytoskeletal machinery that controls proper localization of ion channels and function of axonal domains, resulting in severe neurologic dysfunction.

Mechanism of disease causation. The majority of affected individuals have biallelic SPTBN4 pathogenic variants with pathogenic nonsense or frameshift variants predicted to result in a complete loss of function.

Revision History

• 16 July 2020 (ma) Review posted live
• 24 October 2019 (kw) Original submission

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