Table 1. [Single-Gene Disorders of Interest in the Differential Diagnosis of ALS]. - GeneReviews®

Gene ¹	Disorder	MOI	Clinical Features of Disorder
AR	Spinal and bulbar muscular atrophy	XL	LMN signs: weakness, atrophy, fasciculations	No UMN involvement Proximal weakness Sensory involvement Slowly progressive Males only affected May have gynecomastia, testicular atrophy, & ↓ fertility
BSCL2	BSCL2-related neurologic disorders ²	AD	UMN & LMN involvement	Slowly progressive Abnormal vibration sense Pes cavus
GBE1	Adult polyglucosan body disease	AR	UMN & LMN involvement, cognitive impairment	Slowly progressive Distal sensory loss Early neurogenic bladder Cerebellar dysfunction
HEXA	Chronic and adult-onset hexosaminidase A deficiency	AR	LMN > UMN involvement, possible cognitive impairment	Spinocerebellar degeneration Dystonia Slowly progressive
SMN1	Spinal muscular atrophy IV	AR	Proximal > distal muscle weakness & atrophy	Onset typically in 2nd-3rd decade No UMN involvement Symmetric weakness & atrophy

Gene ¹

Disorder

MOI

Clinical Features of Disorder

Overlapping w/ALS

Distinguishing from ALS

Spinal and bulbar muscular atrophy

LMN signs: weakness, atrophy, fasciculations

No UMN involvement
Proximal weakness
Sensory involvement
Slowly progressive
Males only affected
May have gynecomastia, testicular atrophy, & ↓ fertility

BSCL2

BSCL2-related neurologic disorders ²

UMN & LMN involvement

Slowly progressive
Abnormal vibration sense
Pes cavus

GBE1

Adult polyglucosan body disease

UMN & LMN involvement, cognitive impairment

Slowly progressive
Distal sensory loss
Early neurogenic bladder
Cerebellar dysfunction

HEXA

Chronic and adult-onset hexosaminidase A deficiency

LMN > UMN involvement, possible cognitive impairment

Spinocerebellar degeneration
Dystonia
Slowly progressive

SMN1

Spinal muscular atrophy IV

Proximal > distal muscle weakness & atrophy

Onset typically in 2nd-3rd decade
No UMN involvement
Symmetric weakness & atrophy

From: Amyotrophic Lateral Sclerosis Overview

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