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.

Diagnosis.

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

Management.

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.

Surveillance

• 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.

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.

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].

• The type of seizure is not specific and can include the following [Ruzzo et al 2013, Alfadhel et al 2015, Seidahmed et al 2016, Gupta et al 2017, Sun et al 2017, Yamamoto et al 2017]:
  • Generalized tonic-clonic (64%)
  • Myoclonic (50%)
  • Tonic (50%)
  • Partial complex seizure (21%)
  • Spasms (15%) that are refractory to anti-seizure medication
• EEG abnormalities are nonspecific [Ruzzo et al 2013, Alfadhel et al 2015, Ben-Salem et al 2015, Palmer et al 2015, Gataullina et al 2016, Gupta et al 2017, Yamamoto et al 2017]:
  • Multiple independent spike foci most commonly (65%)
  • Burst suppression
  • Hypsarrhythmia
  • Discontinuous EEG pattern
• Jitteriness and hyperekplexia are present in 78% and 35% of reported individuals, respectively.

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]:

• Intrauterine growth restriction [Sun et al 2017]
• Sensorineural hearing loss [Palmer et al 2015, Yamamoto et al 2017]
• Frequent apneas necessitating mechanical ventilation, reported in nine affected individuals [Ruzzo et al 2013, Gupta et al 2017, Sun et al 2017]
• Diaphragmatic eventration [Sun et al 2017]
• Phrenic nerve palsy [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.

Prevalence

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].

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.

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].

Prevention of Secondary Complications

Regular immunization to prevent life-threatening infections is indicated.

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

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.

Revision History

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

Literature Cited

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