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Asparagine Synthetase Deficiency

Synonym: ASNS Deficiency


Author Information and Affiliations

Initial Posting: .

Estimated reading time: 15 minutes


Clinical characteristics.

Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern.


The diagnosis of ASD is established in a proband by identification of biallelic pathogenic variants in ASNS on molecular genetic testing.


Treatment of manifestations: Antispastic medication (baclofen, tizanidine, and/or Botox® injection) for spasticity; clonazepam for hyperekplexia; mechanical ventilation may be required for apnea; nasogastric or gastrostomy tube to support nutrition; standard treatment for seizures, hearing loss, gastroesophageal reflux disease, constipation, and kyphosis/scoliosis; supportive developmental therapies.

Prevention of secondary complications: Regular immunization to prevent life-threatening infections.


  • At each visit: evaluation of developmental progress and growth; assessment for progression of spasticity, contractures, and scoliosis/kyphosis.
  • Every six months: assessment of nutritional status through serum total protein, albumin, and prealbumin levels.
  • Annually: ophthalmologic evaluation.
  • As needed: EEG if there are concerns for new-onset seizure activity or progression of seizures; audiologic evaluation if there are concerns for hearing loss.

Genetic counseling.

Asparagine synthetase 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 testing for a pregnancy at increased risk are possible if the ASNS pathogenic variants in the family are known.


Suggestive Findings

Asparagine synthetase deficiency (ASD) should be suspected in individuals with the following clinical features, brain MRI findings, and supportive laboratory findings.

Clinical features

  • Congenital and progressive microcephaly
  • Severe global developmental delay
  • Hypotonia followed by spastic quadriplegia, seizures, jitteriness, and hyperekplexia
  • Intrauterine growth restriction with subsequent feeding difficulties, failure to thrive, and short stature
  • Cortical blindness

Brain MRI findings

  • Generalized brain atrophy (100%)
  • Simplified gyral pattern (81%)
  • Cerebellar vermis hypoplasia (41%)

Supportive laboratory findings

  • CSF asparagine level is typically low or not detected [Alfadhel et al 2015, Yamamoto et al 2017].
  • Plasma asparagine level is low in about half of affected individuals and is not as sensitive as CSF asparagine levels in supporting this diagnosis.
  • The following are unremarkable:
    • Plasma acylcarnitine profile
    • Creatine kinase (CK) level
    • Total homocysteine, lactic acid, and ammonia levels
    • Urine organic acids

Establishing the Diagnosis

The diagnosis of ASD is established in a proband with biallelic pathogenic (or likely pathogenic) variants in ASNS identified by molecular genetic testing (see Table 1).

Note: (1) 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. (2) Identification of biallelic ASNS variants of uncertain significance (or of one known ASNS pathogenic variant and one ASNS variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of ASNS is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multigene panel that includes ASNS and other genes of interest (see Differential Diagnosis) may be considered. 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 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.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    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 Asparagine Synthetase Deficiency

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
ASNS Sequence analysis 322/22 4
Gene-targeted deletion/duplication analysis 5None reported 6

See Molecular Genetics for information on variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Gene-targeted deletion/duplication analysis has not identified any pathogenic variants to date.

Clinical Characteristics

Clinical Description

Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low CSF asparagine level can help differentiate this disorder from others with similar clinical findings [Ruzzo et al 2013, Alfadhel et al 2015, Ben-Salem et al 2015]. Age of onset is soon after birth in the majority of reported individuals (median age of onset: 1 day; range 1 day – 9 months). Only three cases have presented after the neonatal period [Ruzzo et al 2013, Sacharow et al 2018]. Two neonates presented prenatally with microcephaly detected by antenatal ultrasound [Seidahmed et al 2016, Yamamoto et al 2017].

The common clinical manifestations summarized in Table 2 are discussed below the table.

Table 2.

Clinical Manifestations of 22 Individuals with Asparagine Synthetase Deficiency

Clinical ManifestationsFrequency (%)
Neonatal onset 117/18 (95%)
Severe global developmental delay22/22 (100%)
Congenital & progressive microcephaly 222/22 (100%)
Hyperreflexia22/22 (100%)
Axial hypotonia followed by spastic quadriplegia21/22 (95%)
Seizures16/22 (73%)
Jitteriness13/15 (87%)
Cortical blindness13/22 (60%)
Hyperekplexia7/22 (32%)

Congenital microcephaly, apnea, excessive irritability, and seizures


Head circumference is often 2 standard deviations (SD) below the mean at birth but may decline to 9 SD below the mean by early childhood.

Neurologic. All affected individuals reported have the following:

  • Congenital microcephaly, ranging between 26.5 and 33.4 cm (1-4 SD below the mean)
  • Severe global developmental delay with no acquisition of developmental milestones [Ruzzo et al 2013, Alfadhel et al 2015]
  • Axial hypotonia followed by spastic quadriplegia [Seidahmed et al 2016] leading to severe contractures of all limbs and neurogenic scoliosis

Seizures usually start in the neonatal period and mimic pyridoxine-dependent epilepsy [Gataullina et al 2016].

Brain MRI findings. The most common features are summarized in Suggestive Findings; other reported abnormalities (in <80%) include the following [Ruzzo et al 2013, Ben-Salem et al 2015, Gataullina et al 2016, Sun et al 2017]:

  • Delayed myelination (68%)
  • Small pons
  • Thin corpus callosum (55%)
  • Enlarged ventricular system (50%)
  • Left transverse sinus thrombosis and cerebral dysgenesis
  • Blake's cyst and/or arachnoid cyst
  • Bilateral caudate atrophy
  • Increased lactate peak on MR spectroscopy in four individuals studied [Ruzzo et al 2013, Palmer et al 2015]

Note: CSF asparagine level was normal in one reported individual [Seidahmed et al 2016].

Nonspecific dysmorphic facial features reported in approximately 50% of affected individuals include brachycephaly, pear-like head shape, sloping forehead, widely spaced eyes, big fleshy ears, prominent nasal tip, and micrognathia.

Gastrointestinal manifestations. Feeding difficulties are a major problem for most affected individuals. Contributing factors include hypotonia, gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination. Many affected individuals also have constipation.

Recurrent aspiration has been reported in eight individuals. Many require nasogastric tube feeding or gastrostomy [Ruzzo et al 2013, Sun et al 2017, Yamamoto et al 2017].

Ophthalmologic. Most individuals are unable to fix and follow with their eyes. Cortical blindness is reported in 65% of affected individuals. One affected person was reported to have left convergent squint [Gupta et al 2017].

Less frequently reported manifestations include the following [Ruzzo et al 2013, Ben-Salem et al 2015, Seidahmed et al 2016, Sun et al 2017]:

Prognosis. ASD is associated with a high rate of morbidity and mortality, where 50% of individuals die in the first year of life [Ruzzo et al 2013, Seidahmed et al 2016, Gupta et al 2017, Sun et al 2017]. However, because only a small cohort of affected individuals have been reported, it is possible that this represents the more severe end of a clinical spectrum.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported.


ASD has been reported in 22 individuals from 14 families to date. Consanguinity was reported in 50% of families. Affected individuals from Saudi Arabia, United Arab Emirates, Canada, France, Japan, and India have been reported [Ruzzo et al 2013, Alfadhel et al 2015, Ben-Salem et al 2015, Palmer et al 2015, Gataullina et al 2016, Seidahmed et al 2016, Gupta et al 2017, Sun et al 2017, Yamamoto et al 2017].

Differential Diagnosis

The differential diagnosis of ASD is wide, and the cardinal features of spastic quadriplegia, microcephaly, and low asparagine level can aid clinicians in differentiating this disorder from the other related disorders.

Note: Many chromosomal disorders present with features that overlap with asparagine synthetase deficiency; therefore, a chromosomal microarray could be considered.

Table 3.

Differential Diagnosis of Asparagine Synthetase Deficiency (ASD)

Gene(s) /
Genetic Mechanism
MOIClinical Features of the Phenotype/Disorder
Overlapping w/ASDDistinguishing from ASD
Primary autosomal recessive microcephaliesMultiple genes (See OMIM PS251200.)ARNo malformations in other organ systems
  • Normal CSF asparagine level
  • No spastic quadriplegia
Seckel syndrome ATR
  • Intrauterine growth restriction
  • Sloping forehead
  • Short stature
  • Normal CSF asparagine level
  • No spastic quadriplegia
Lissencephaly-pachygyria 1Multiple genes (See OMIM PS607432.)AR
  • Cerebellar hypoplasia
  • Simplified gyral pattern
  • Spastic quadriplegia
  • Lissencephaly & generalized polymicrogyria
  • Normal CSF asparagine level
Miller-Dieker syndrome
(See PAFAH1B1-Associated Lissencephaly / Subcortical Band Heterotopia.)
17p13.3 deletion
  • Hypotonia
  • Global DD
  • Spastic quadriplegia
  • Lissencephaly
  • Dysmorphic features
  • Normal CSF asparagine level
Smith-Lemli-Opitz syndrome DHCR7 ARGlobal DD
  • Prenatal & postnatal growth restriction
  • Dysmorphic features
  • Syndactyly of 2nd & 3rd toes
  • Postaxial polydactyly
  • Congenital heart defect
  • Hypospadias in males
  • No spastic quadriplegia
  • Low total cholesterol w/↑ 7-dehydrocholesterol
Cornelia de Lange syndrome HDAC8
  • Growth restriction
  • DD
  • Spastic quadriplegia
  • Distinctive facial features
  • Hirsutism
  • Upper-limb reduction defects ranging from subtle phalangeal abnormalities to oligodactyly
Serine biosynthesis defects PHGDH
  • Neonatal seizure
  • Global DD
  • Spastic quadriplegia
  • Low CSF serine & glycine level
  • Cataract
  • Nystagmus
Congenital disorders of N-linked glycosylation Multiple genes (See OMIM PS212065.)AR
  • Neonatal seizure
  • Failure to thrive
  • Hypotonia
  • DD
  • Spastic quadriplegia
  • Cerebellar hypoplasia
  • Hepatopathy
  • Hypoglycemia
  • Protein-losing enteropathy
  • Eye abnormalities
  • Immunologic findings
  • Skin abnormalities
  • Skeletal findings
  • Abnormal TIF
Early-infantile epileptic encephalopathy type 28 WWOX AR
  • Congenital microcephaly
  • Severe DD
  • Hypotonia
  • Spastic quadriplegia
  • Thin corpus callosum
  • Delayed myelination
Normal blood & CSF asparagine level

AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; MOI = mode of inheritance; TIF = transferrin isoelectrofocusing; XL = X-linked


Lissencephaly-pachygyria spectrum of cortical malformation is characterized by smooth cortex with simplified gyration appearance. "Lissencephaly" refers to a brain without sulci. Pachygyria (focal or diffuse) is a mild expression of lissencephaly in which sulci are shallow and reduced in number.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with asparagine synthetase deficiency (ASD), the following evaluations are recommended if they have not already been completed.

Table 4.

Recommended Evaluations Following Initial Diagnosis of Asparagine Synthetase Deficiency

Neurologic Brain MRI to evaluate extent of diseaseConsider neurologic consultation.
EEGIf seizures are suspected
Ocular Ophthalmologic evalConsider visual evoked potential.
ENT Audiologic eval
Assessment of growth parameters to identify those w/failure to thrive
Assessment for feeding problems incl difficulty w/sucking, swallowing, & GERDReferral to feeding therapist if feeding problems identified
Musculoskeletal Clinical eval for scoliosis &/or kyphosisConsider radiographic scoliosis survey (x-rays of the spine) based on clinical suspicion; consider referral to orthopedist if scoliosis is present.
Other Developmental assessmentTo provide a baseline level of functioning & recommendations for services (speech, occupational, physical therapy)
Consider referral to clinical geneticist &/or genetic counselor.

GERD = gastroesophageal reflux

Treatment of Manifestations

The management of ASD requires a multidisciplinary team approach; treatment is primarily supportive.

Note: Asparagine supplementation has not been effective and actually exacerbated seizures in affected individuals [Alrifai & Alfadhel 2016].

Table 5.

Treatment of Manifestations in Individuals with Asparagine Synthetase Deficiency

Seizures Standard treatment w/anti-seizure medication
Spastic quadriplegia Antispastic drugs (e.g., baclofen, tizanidine) &/or Botox® injection
Hyperekplexia Clonazepam appears to be the most effective treatment.
Hearing loss Hearing aidsSee Hereditary Hearing Loss and Deafness Overview.
Apnea Mechanical ventilation may be required.
Inadequate nutrition /
Feeding difficulties
Nasogastric tube or gastrostomy tube is frequently required.
reflux (GERD)
Standard pharmacologic treatmentFor severe GERD: consider Nissen fundoplication at the time of gastrostomy tube placement.
Constipation Standard treatment
Kyphosis/Scoliosis Standard treatment as recommended by orthopedist

Gross Motor Dysfunction

Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).

Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, Botox®, or orthopedic procedures.

Developmental Delay / 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. In the US, early intervention is a federally funded program available in all states.

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.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.

Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.

In the US:

  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Prevention of Secondary Complications

Regular immunization to prevent life-threatening infections is indicated.


Table 6.

Recommended Surveillance for Individuals with Asparagine Synthetase Deficiency

Neurologic Assessment of developmental progressAt each visit
Assessment for progression of spasticity & contractures
EEGIf concerns for new seizure activity or progression of seizures
Ocular Ophthalmologic evalAnnually
Hearing Audiologic evalIf concern for hearing loss
Measurement of growth parametersAt each visit
Eval of nutritional status 1Every 6 mos
Musculoskeletal Clinical assessment for scoliosis/kyphosisAt each visit

Serum total protein, albumin, and prealbumin levels

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Asparagine synthetase 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 ASNS 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. To date, individuals affected with asparagine synthetase deficiency are not known to reproduce.

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

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ASNS 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 the parents of an affected child.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the ASNS pathogenic variants have been identified in an affected family member, prenatal 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.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    Phone: 202-387-1968
  • American Epilepsy Society
  • Epilepsy Foundation
    Phone: 800-332-1000; 866-748-8008

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Asparagine Synthetase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Asparagine Synthetase Deficiency (View All in OMIM)


Gene structure. ASNS spans 35 kb and contains 13 exons. See Table A, Gene for a detailed summary of gene and protein information. ASNS is expressed in most mammalian cells. The gene was transcribed into an mRNA of 2 kb that was expressed in all human, hamster, and mouse cell lines tested. It encodes a protein of about 550 amino acids [Greco et al 1987].

Pathogenic variants. Eighty-eight percent of reported pathogenic variants are missense. Others include pathogenic nonsense and frameshift variants [Ruzzo et al 2013, Alfadhel et al 2015, Ben-Salem et al 2015, Palmer et al 2015, Gataullina et al 2016, Seidahmed et al 2016, Gupta et al 2017, Sun et al 2017, Yamamoto et al 2017].

Normal gene product. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate [Ruzzo et al 2013].

Abnormal gene product. ASNS pathogenic variants result in loss of enzyme function, which in turn results in impaired synthesis of asparagine. Insufficient physiologic levels of arginine cause neurologic impairment [Ruzzo et al 2013, Alfadhel et al 2015].

Chapter Notes

Revision History

  • 20 September 2018 (mpa) Review posted live
  • 8 January 2018 (ma) Original submission


Literature Cited

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  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
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