Spinal Muscular Atrophy Differential Diagnosis (Prenatal/Neonatal Onset)

Spinal Muscular Atrophy Differential Diagnosis (Prenatal/Neonatal Onset)

Spinal Muscular Atrophy (SMA) types 0 and 1 should be considered in the differential diagnosis of every newborn and infant < 6 months old with hypotonia, hyporeflexia, tongue fasciculations, weakness, respiratory distress, or contractures.1 Other potential diagnoses for hypotonia and weakness in the neonatal to < six months of age group are differentiated by category as follows:


Infants with congenital hypothyroidism may have decreased spontaneous activity before birth and in the neonatal period, but will rarely have the profound low tone, loss of reflexes, and need for respiratory support associated with SMA.2


The differential diagnosis for neonatal hypotonia includes many congenital causes associated with the prototypical “floppy infant.” Two rare variants of SMA must be considered.1 X-linked infantile spinal muscular atrophy and Spinal Muscular Atrophy and Respiratory Distress 1 (SMARD1) cause congenital weakness and are associated with genetic variants at SMA gene loci outside the most common occurring 5q SMN1 gene locus.3 SMARD1 typically has distal more than proximal weakness which can differentiate SMARD1 weakness from the more proximal weakness of classic SMA.4 Congenital myasthenic syndromes can cause symmetric weakness including respiratory insufficiency that resembles SMA.1 The presence of ptosis, ophthalmoplegia, and bulbar involvement would not be expected in SMA.5 Patients with a deletion at 15q11.2-q13 (i.e., Prader-Willi syndrome) will be profoundly hypotonic at birth but rarely experience respiratory difficulty.6 Infants with the most severe forms of the peroxisomal disorders (i.e., Zellweger syndrome) will be born hypotonic but will have other physical stigmata such as hepatosplenomegaly and chondroplasia punctata that do not occur in SMA.7 Infants with Trisomy 21 (Down syndrome) will be hypotonic but will have other dysmorphic features evident at birth to differentiate them from patients with SMA.8 Congenital myopathies (mitochondrial especially) and congenital muscular dystrophies can be associated with hypotonia, symmetric proximal>distal weakness, and depressed tendon reflexes but involvement of the central nervous system and eyes rules out SMA.1 Myotonic dystrophy type 1 can be distinguished from SMA by an absence of tongue fasciculations.1,9 Glycogen storage disease type 2 (Pompe disease) is associated with cardiomegaly, a feature not seen in typical SMA.10 


The newborn and neonate with respiratory distress and low tone obligates a broad workup for newborn sepsis due to bacterial (e.g., group B streptococcus) and viral (e.g., herpes simplex virus) infections.11 Enterovirus infection can occur in the newborn period but rapid bulbar involvement and asymmetric weakness can differentiate fulminant enteroviral infection from SMA.12


The infant with hypermagnesmia will be hypotonic and may have respiratory distress but in the setting of a history of maternal eclampsia treatment and an elevated serum magnesium will be diagnostic.13 Elevated bilirubin and kernicterus are associated with symmetric low tone and weakness but visible jaundice, hyperbilirubinemia, and seizures will exclude SMA as a cause.14


An infant who experiences a hypoxic-ischemic insult or an intracranial hemorrhage can present as hypotonic but may have encephalopathy, asymmetric weakness, seizures, or other end organ damage differentiating these presentations from that expected with typical SMA.15,16 Spinal cord trauma during birth can create symmetric weakness, areflexia, and low tone but will evolve into spasticity, hyperreflexia, and increased tone along with neurological deficits below the level of the injury.17


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