Is it accurate to classify ALS as a neuromuscular disorder?

Figures & data

Figure 1. Overview of the peripheral nervous system and corresponding neuromuscular disorders.

Figure 2. Shows the main findings on EMG that may aid to differentiate ALS from important mimics such as multifocal motor neuropathy (MMN), myasthenia gravis (MG) and inclusion body myositis (IBM).

Figure 3. Comparison of cortical thickness between ALS patients (n = 456) and healthy controls (n = 294). Analyses were corrected for age and sex. Regions with a significantly lower cortical thickness are marked in blue (p < 0.05, Bonferroni-corrected). p-values were mapped onto the surface of the entire region of interest (ROI, 34 per hemisphere) to indicate significant regional differences between ALS patients and controls.

Table 1. Overview of ALS and pleiotropic effects.

FALS Gene	Type of variation	Associated with other disease or phenotypes?	Designation	Inheritance
SOD1[^77]	point mutations	Progressive spastic tetraplegia and axial hypotonia	ALS1	AD or AR
ALS2 (ALSin)[^78]	point mutations	Infantile-onset ascending spastic paralysis	ALS2	AR
SETX[^79]	point mutations	ataxia-oculomotor apraxia type 2	ALS4	AD
SPG11[^80]	point mutations	HSP type 11	ALS5	AR
FUS/TLS[^75]	point mutations	Hereditary Essential Tremor 4[^74]	ALS6	AD or AR
VAPB[^81]	point mutations	Late-onset SMA (Finkel type)	ALS8	AD
ANG[^82]	point mutations	Parkinsonism[^69]	ALS9	AD
TARDBP[^70]	point mutations	Parkinsonism, FTD[^72]	ALS10	AD
FIG4[^83]	point mutations	Bilateral temporooccipital polymicrogyria, CMT type 4 J, YVS	ALS11	AD
OPTN[^84]	point mutations	Adult-onset open angle glaucoma 1E, MSP	ALS12	AD or AR
ATXN2[^72]	repeat expansions	SCA type 2, Parkinsonism	ALS13	AD
VCP[^85]	point mutations	CMT type 2Y, MSP	ALS14	AD
UBQLN2[^86]	point mutations	-	ALS15	XD
SIGMAR1[^87]	point mutations	Autosomal recessive, distal SMA type 2	ALS16	AD
CHMP2B[^88]	point mutations	Dementia	ALS17	AD
PFN1[^89]	point mutations	-	ALS18	AD
ERBB4[^90]	point mutations	-	ALS19	AD
HNRNPA1[^91]	point mutations	MSP	ALS20	AD
MATR3[^92]	point mutations	MSP	ALS21	AD
TUBA4A[^93]	point mutations	-	ALS22	AD
ANXA11[^94]	point mutations	-	ALS23	Unknown
NEK1[^65]	point mutations	Short-rib thoracic dysplasia 6 with or without polydactyly	ALS24	Unknown
KIF5a[^64]	point mutations	HSP type 10, CMT type 2	ALS25	AD
C9orf72[^68]	repeat expansions	FTD, parkinsonism, Huntington phenocopies, psychiatric disorders	ALS-FTD1	AD
CHCHD10[^95]	point mutations	Mitochondrial myopathy, SMA (Jokela type), FTD	ALS-FTD2	AD
SQSTM1[^96]	point mutations	MSP	ALS-FTD3	AD
TBK1[^97^,^98^]	point mutations	FTD	ALS-FTD4	Unknown
SALS risk factor*	Type of variation	Associated with other disease or phenotypes?
NIPA1[^63]	repeat expansions	HSP type 6
ATXN1[^99]	repeat expansions	SCA type 1
unc13a[^62]	SNP	FTD
MOBP[^62]	SNP	MS, corticobasal degeneration, PSP, Lewy body dementia
SMN1[^26]	duplications	SMA
SARM1[^62]	SNP	-
SCFD1[^62]	SNP	-
C21orf2[^62]	SNP	Retinal dystrophy with macular staphyloma, ASD
KIF5a[^64]	SNP	HSP type 10, CMT type 2
NEK1[^65]	SNP	Short-rib thoracic dysplasia 6 with or without polydactyly
LOC101927815[^62]	SNP
TBK1[^62]	SNP	FTD

AD = autosomal dominant, AR = autosomal recessive, ASD = Axial Spondylometaphyseal Dysplasia, CMT = Charcot-Marie-Tooth disease, FALS = Familial ALS, FTD = Frontotemporal dementia, HSP = Heridatary spastic paraplegia, MSP = Multisystem proteinopathy, SCA = Spinocerebellar ataxia, SALS = Sporadic ALS, SMA = Spinal muscular atrophy, XD = X-linked dominant, YVS = Yunis Varon Syndrome. *For SALS risk factors the nearest or most likely associated gene is given. Potential pleiotropic effects of the listed genes were evaluated by searching Medline, Embase and OMIM.

Figure 4. FTD forms a clinical with motor neuron diseases as well as with movement disorders, such as CBD and PSP. The underlying pathology and underlying genetics are equally heterogeneous. This example illustrate how challenging it can be to classify diseases with heterogeneous which form a spectrum. ALS = amyotrophic lateral sclerosis, mnd-ftd = motor neuron disease frontotemporal dementia, SD = semantic dementia, bvFTD = behavioral variant frontotemporal dementia, PNFA = progressive non-fluent aphasia, CBD = corticobasal degeneration, PSP = progressive supranuclear palsy.

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