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Asparagine synthetase deficiency(ASNSD)

MedGen UID:
816301
Concept ID:
C3809971
Disease or Syndrome
Synonyms: ASNS DEFICIENCY; ASNSD
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): ASNS (7q21.3)
OMIM®: 615574
Orphanet: ORPHA391376

Disease characteristics

Excerpted from the GeneReview: Asparagine Synthetase Deficiency
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. [from GeneReviews]
Authors:
Majid Alfadhel  |  Ayman W El-Hattab   view full author information

Additional descriptions

From OMIM
ASNS deficiency is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder shows onset in utero or at birth and may result in early death (summary by Ruzzo et al., 2013).  http://www.omim.org/entry/615574
From GHR
Asparagine synthetase deficiency is a condition that causes neurological problems in affected individuals starting soon after birth. Most people with this condition have an unusually small head size (microcephaly) that worsens over time due to loss (atrophy) of brain tissue. They also have severe developmental delay that affects both mental and motor skills (psychomotor delay). Affected individuals cannot sit, crawl, or walk and are unable to communicate verbally or nonverbally. The few affected children who achieve developmental milestones often lose these skills over time (developmental regression).Most individuals with asparagine synthetase deficiency have exaggerated reflexes (hyperreflexia) and weak muscle tone (hypotonia). The muscle problems worsen through childhood and lead to muscle stiffness, uncontrolled movements, and ultimately, paralysis of the arms and legs (spastic quadriplegia). Many affected individuals also have recurrent seizures (epilepsy). Not all affected people experience the same type of seizure. The most common types involve a loss of consciousness, muscle rigidity, and convulsions (tonic-clonic); involuntary muscle twitches (myoclonic); or abnormal muscle contraction (tonic). People with asparagine synthetase deficiency may have an exaggerated startle reaction (hyperekplexia) to unexpected stimuli. Some affected individuals have blindness due to impairment of the area of the brain responsible for processing vision, called the occipital cortex (cortical blindness).People with asparagine synthetase deficiency typically do not survive past childhood.  https://ghr.nlm.nih.gov/condition/asparagine-synthetase-deficiency

Clinical features

Large hands
MedGen UID:
98097
Concept ID:
C0426870
Finding
Long foot
MedGen UID:
154365
Concept ID:
C0576225
Finding
Increased back to front length of the foot.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Slower than normal rate of weight increase.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Macrotia
MedGen UID:
349900
Concept ID:
C1860838
Finding
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Underdevelopment of the cerebellum.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
A type of spastic cerebral palsy characterized by increased muscle tone of all four extremities.
Cortical dysplasia
MedGen UID:
98129
Concept ID:
C0431380
Congenital Abnormality
Malformation of the cerebral cortex due to improper migration of neurons in utero.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Delayed myelination
MedGen UID:
224820
Concept ID:
C1277241
Finding
Delayed myelination.
Exaggerated startle response
MedGen UID:
329357
Concept ID:
C1740801
Finding
An exaggerated startle reaction in response to a sudden unexpected visual or acoustic stimulus, or a quick movement near the face.
Hypoplasia of the pons
MedGen UID:
341246
Concept ID:
C1848529
Finding
Underdevelopment of the pons.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Finding
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Cortical gyral simplification
MedGen UID:
413664
Concept ID:
C2749675
Finding
An abnormal reduction of the number and complexity of the pattern of gyrations of the cerebral cortex.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Profound global developmental delay
MedGen UID:
766364
Concept ID:
C3553450
Disease or Syndrome
A profound delay in the achievement of motor or mental milestones in the domains of development of a child.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Failure to adequately provide oxygen to cells of the body and to remove excess carbon dioxide from them. (Stedman, 25th ed)
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
A type of spastic cerebral palsy characterized by increased muscle tone of all four extremities.
Muscular hypotonia of the trunk
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
A congenital abnormality of the jaws (particularly the mandible) in which they are unusually small. This condition is not always pathological and may correct itself as the patient matures; however, it may also present as a birth defect in multiple syndromes.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Finding
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
A congenital abnormality of the jaws (particularly the mandible) in which they are unusually small. This condition is not always pathological and may correct itself as the patient matures; however, it may also present as a birth defect in multiple syndromes.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Finding
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Sloping forehead
MedGen UID:
346640
Concept ID:
C1857679
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
Cortical visual impairment
MedGen UID:
57834
Concept ID:
C0155320
Disease or Syndrome
Total loss of vision in all or part of the visual field due to bilateral OCCIPITAL LOBE (i.e., VISUAL CORTEX) damage or dysfunction. Anton syndrome is characterized by the psychic denial of true, organic cortical blindness. (Adams et al., Principles of Neurology, 6th ed, p460)

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAsparagine synthetase deficiency
Follow this link to review classifications for Asparagine synthetase deficiency in Orphanet.

Recent clinical studies

Etiology

Yamamoto T, Endo W, Ohnishi H, Kubota K, Kawamoto N, Inui T, Imamura A, Takanashi JI, Shiina M, Saitsu H, Ogata K, Matsumoto N, Haginoya K, Fukao T
Brain Dev 2017 Mar;39(3):236-242. Epub 2016 Oct 12 doi: 10.1016/j.braindev.2016.09.010. PMID: 27743885

Diagnosis

Yamamoto T, Endo W, Ohnishi H, Kubota K, Kawamoto N, Inui T, Imamura A, Takanashi JI, Shiina M, Saitsu H, Ogata K, Matsumoto N, Haginoya K, Fukao T
Brain Dev 2017 Mar;39(3):236-242. Epub 2016 Oct 12 doi: 10.1016/j.braindev.2016.09.010. PMID: 27743885
Alrifai MT, Alfadhel M
Pediatr Neurol 2016 May;58:98-100. doi: 10.1016/j.pediatrneurol.2016.01.024. PMID: 27268761
Collardeau-Frachon S, Cordier MP, Rossi M, Guibaud L, Vianey-Saban C
J Inherit Metab Dis 2016 Sep;39(5):597-610. Epub 2016 Apr 22 doi: 10.1007/s10545-016-9937-x. PMID: 27106218
Ben-Salem S, Gleeson JG, Al-Shamsi AM, Islam B, Hertecant J, Ali BR, Al-Gazali L
Metab Brain Dis 2015 Jun;30(3):687-94. Epub 2014 Sep 17 doi: 10.1007/s11011-014-9618-0. PMID: 25227173Free PMC Article

Therapy

Lomelino CL, Andring JT, McKenna R, Kilberg MS
J Biol Chem 2017 Dec 8;292(49):19952-19958. Epub 2017 Oct 30 doi: 10.1074/jbc.R117.819060. PMID: 29084849Free PMC Article
Alrifai MT, Alfadhel M
Pediatr Neurol 2016 May;58:98-100. doi: 10.1016/j.pediatrneurol.2016.01.024. PMID: 27268761

Prognosis

Yamamoto T, Endo W, Ohnishi H, Kubota K, Kawamoto N, Inui T, Imamura A, Takanashi JI, Shiina M, Saitsu H, Ogata K, Matsumoto N, Haginoya K, Fukao T
Brain Dev 2017 Mar;39(3):236-242. Epub 2016 Oct 12 doi: 10.1016/j.braindev.2016.09.010. PMID: 27743885
Palmer EE, Hayner J, Sachdev R, Cardamone M, Kandula T, Morris P, Dias KR, Tao J, Miller D, Zhu Y, Macintosh R, Dinger ME, Cowley MJ, Buckley MF, Roscioli T, Bye A, Kilberg MS, Kirk EP
Mol Genet Metab 2015 Nov;116(3):178-86. Epub 2015 Aug 14 doi: 10.1016/j.ymgme.2015.08.007. PMID: 26318253
Ben-Salem S, Gleeson JG, Al-Shamsi AM, Islam B, Hertecant J, Ali BR, Al-Gazali L
Metab Brain Dis 2015 Jun;30(3):687-94. Epub 2014 Sep 17 doi: 10.1007/s11011-014-9618-0. PMID: 25227173Free PMC Article

Clinical prediction guides

Yamamoto T, Endo W, Ohnishi H, Kubota K, Kawamoto N, Inui T, Imamura A, Takanashi JI, Shiina M, Saitsu H, Ogata K, Matsumoto N, Haginoya K, Fukao T
Brain Dev 2017 Mar;39(3):236-242. Epub 2016 Oct 12 doi: 10.1016/j.braindev.2016.09.010. PMID: 27743885
Palmer EE, Hayner J, Sachdev R, Cardamone M, Kandula T, Morris P, Dias KR, Tao J, Miller D, Zhu Y, Macintosh R, Dinger ME, Cowley MJ, Buckley MF, Roscioli T, Bye A, Kilberg MS, Kirk EP
Mol Genet Metab 2015 Nov;116(3):178-86. Epub 2015 Aug 14 doi: 10.1016/j.ymgme.2015.08.007. PMID: 26318253
Ben-Salem S, Gleeson JG, Al-Shamsi AM, Islam B, Hertecant J, Ali BR, Al-Gazali L
Metab Brain Dis 2015 Jun;30(3):687-94. Epub 2014 Sep 17 doi: 10.1007/s11011-014-9618-0. PMID: 25227173Free PMC Article

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