Table 3.

Differential Diagnosis of Asparagine Synthetase Deficiency (ASD)

Phenotype/
Disorder		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
CENPJ
CEP152
CEP63
RBBP8
DNA2
NIN
NSMCE2
TRAIP 		AR
  • Intrauterine growth restriction
  • Sloping forehead
  • Short stature
  • Normal CSF asparagine level
  • No spastic quadriplegia
Lissencephaly-pachygyria 1Multiple genes (See OMIM PS607432.)AR
AD
XL
  • 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
LIS1 (PAFAH1B1)
YWHAE		AD
  • 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
NIPBL
RAD21
SMC1A
SMC3 		AD
XL
  • Growth restriction
  • DD
  • Spastic quadriplegia
  • Distinctive facial features
  • Hirsutism
  • Upper-limb reduction defects ranging from subtle phalangeal abnormalities to oligodactyly
Serine biosynthesis defects PHGDH
PSAT1
PSPH 		AR
  • 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
XL
  • 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

1.

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.

From: Asparagine Synthetase Deficiency

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