Table 5.

Disorders to Consider in the Differential Diagnosis of Spinal Muscular Atrophy (SMA)

Age of OnsetDisorderGene(s) or RegionMOIClinical Features of
Differential Diagnosis Disorder
Overlapping w/SMADistinguishing from SMA
Congenital to <6 mos X-linked infantile SMA UBA1 XLHypotonia, weakness, areflexiaMultiple congenital contractures, intrauterine fractures
SMARD1 1 (OMIM 604320) IGHMBP2 ARWeakness, respiratory failure, hypo- or areflexiaDistal predominant weakness, diaphragmatic paralysis
GARS1-related infantile-onset SMA 2 (OMIM 619042) GARS1 ADHypotonia, weakness, areflexiaDiaphragmatic paralysis, sensory involvement
Prader-Willi syndrome 15q11.2-q13 3See footnote 3.Hypotonia, feeding difficultiesPoor respiratory effort is rare.
Myotonic dystrophy type 1 DMPK ADHypotonia, muscle weaknessMarked facial weakness
Congenital muscular dystrophyMany genesAR
AD		Hypotonia, muscle weaknessCNS, eye involvement, possible increased tone
Zellweger spectrum disorder PEX family of genesARHypotoniaHepatosplenomegaly, CNS
Congenital myasthenic syndromes CHAT
CHRNE
COLQ
DOK7
GFPT1
RAPSN 4		AR
AD		HypotoniaOphthalmoplegia, ptosis, episodic respiratory failure
Pompe disease GAA ARHypotoniaCardiomegaly
Other: congenital myopathies, 5 metabolic/mitochondrial myopathies, 6 peripheral neuropathies 7
>6 mosBotulismNANAProximal muscle weakness, decreased reflexesProminent cranial nerve palsies, acute onset
Later childhoodGuillain-Barré syndromeNAMuscle weaknessSubacute onset, sensory involvement
Duchenne muscular dystrophy DMD XLMuscle weakness, motor regressionSerum creatine kinase concentration 10-20x > normal
Hexosaminidase A deficiency (juvenile, chronic, & adult-onset variants) HEXA ARLower motor neuron diseaseSlow progression, progressive dystonia, spinocerebellar degeneration, cognitive/psychiatric involvement
Fazio-Londe syndrome (See Riboflavin Transporter Deficiency Neuronopathy.) SLC52A2
SLC52A3 		ARProgressive bulbar palsyLimited to lower cranial nerves; progresses to death in 1-5 yrs
Monomelic amyotrophy (Hirayama disease) (OMIM 602440)UnknownMuscle weaknessPredominantly cervical; tongue may be affected (rare); other cranial nerves spared
Other: peripheral neuropathies, 7 muscular dystrophies 8
AdulthoodSpinal and bulbar muscular atrophy (Kennedy disease) AR XLProximal muscle weakness, muscle atrophy, fasciculationsGradually progressive; gynecomastia, testicular atrophy, ↓ fertility
Amyotrophic lateral sclerosis Many genes 9AD
AR
XL		May begin w/pure lower motor neuron signsProgressive neurodegeneration; involves both upper & lower motor neurons

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SMARD = spinal muscular atrophy with respiratory distress; XL = X-linked

1.

SMARD spans a phenotypic spectrum [Guenther et al 2007].

2.

Pathogenic variants in GARS1 are also associated with Charcot-Marie-Tooth neuropathy type 2D (CMT2D) and distal spinal muscular atrophy V (dSMA-V) (see GARS1-Associated Axonal Neuropathy). CMT2D and dSMA-V are characterized by adolescent or early-adult onset of unique patterns of motor and sensory manifestations with age of onset ranging from eight to 36 years.

3.

Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS / Angelman syndrome region (15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.

4.

Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS. The most commonly associated genes include those listed in the table (see Congenital Myasthenic Syndromes).

5.

Congenital myopathies: see X-Linked Centronuclear Myopathy

6.

Metabolic/mitochondrial myopathies: see Glycogen Storage Diseases (GSD I, GSD II, GSD III, GSD IV, GSD V, GSD VI) and Mitochondrial Disorders Overview

7.
8.

Muscular dystrophies: see Dystrophinopathies

9.

See Amyotrophic Lateral Sclerosis: Phenotypic Series to view genes associated with this phenotype in OMIM.

From: Spinal Muscular Atrophy

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.