Table 2.

Disorders with Spinal Muscular Atrophy and/or Contractures in the Differential Diagnosis of X-Linked Infantile Spinal Muscular Atrophy

MOIGeneDisorder 1Age of OnsetMultiple
Contractures 2		FracturesHypotoniaMuscle
Weakness		Motor
Regression		Absent
Tendon
Reflexes		Myopathic
Facies		Neurogenic
Atrophy		Denervation
(by EMG)		AHC Loss
XL UBA1 XL-SMA (topic of this GeneReview; incl for comparison)Neonatal-infantile++±+++±±++
ATP7A Occipital horn syndrome (See ATP7A-Related Copper Transport Disorders.)Neonatal+ 3NR++NRNR+NRNRNR
ZC4H2 Wieacker-Wolff syndrome (OMIM 314580)Neonatal+NR++++++ (Distal)NR±
AD BICD2 Lower extremity-predominant SMA 2A (OMIM 615290)Neonatal-infantile+NR++Delayed motor development+NR+++
Lower extremity-predominant SMA 2B (OMIM 618291)In utero 4++++Delayed motor developmentNR++‒
TRPV4 Scapuloperoneal SMA (See Autosomal Dominant TRPV4 Disorders.)NeonatalNRNR++Delayed motor development+++NRNR
AR ASCC1 SMA w/congenital bone fractures 2 (OMIM 616867)Prenatal++++NA+++++
CHRND See footnote 5.Neonatal 6
DNM2 Lethal congenital contracture syndrome 5 (OMIM 615368)Prenatal+NR++NA+NR+++
ERBB3 Lethal congenital contractural syndrome 2 (OMIM 607598)Neonatal+NRNANANANAMicrognathia+NA+
EXOSC3 EXOSC3 pontocerebellar hypoplasia Neonatal 6+NR++Delayed motor developmentNRNR+++
GLE1 Congenital arthrogryposis w/ anterior horn cell disease (OMIM 611890)Neonatal+NR++++++++
Lethal congenital contracture syndrome 1 7 (OMIM 253310)Neonatal death++NA+NANANA+NA+
IGHMBP2 SMA w/ respiratory distress type 1 (OMIM 604320)Early infancy+±++NR++NR++
RARS2 Pontocerebellar hypoplasia type 6 (OMIM 611523)Neonatal 6+NR+NA±+++NRNR
SMN1 SMA 0 Prenatal+±++±+±+++
SMA 1 Infancy (<6 mos)NRNR+±NR+NR+++
TRIP4 SMA w/congenital bone fractures 1 (OMIM 616866)Prenatal++++NA+++++
TSEN54 TSEN54 pontocerebellar hypoplasia type 2ANeonatal 6+NRNRNRNR+NRNRNRNR
VRK1 Pontocerebellar hypoplasia type 1A (OMIM 607596)Prenatal-neonatal 6+NR+++NRNR+++
+

= feature that is present in persons with this disorder; ± = feature that may or may not be present in persons with this disorder AD = autosomal dominant; AHC= anterior horn cell loss; AR = autosomal recessive; EMG = electromyogram; MOI = mode of inheritance; NA= not applicable or not available; NR = feature not reported in persons with this disorder; SMA = spinal muscular atrophy: XL = X-linked

1.

Following XL-SMA, disorders are ordered alphabetically by gene within inheritance groups.

2.

See following Note on arthrogryposis.

3.

Hyperextensibility of finger joints is often found, despite reports of limited elbow and knee extensions.

4.

Often associated with prenatal death

5.

Two boys with clinical findings identical to those associated with XL-SMA were found to have biallelic CHRND pathogenic variants (the mother and father were confirmed to be heterozygous for the CHRND pathogenic variants) [Authors, unpublished data]. See OMIM 100720 for other phenotypes associated with pathogenic variants in CHRND.

6.

Most die of respiratory failure in the first year of life. Survivors have failure to thrive and intellectual disability.

7.

The highest prevalence is in Finland (OMIM 253310).

From: Spinal Muscular Atrophy, X-Linked Infantile

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