Differential Diagnosis
Hereditary spastic paraplegia (HSP) is a progressive condition with a gradual worsening of spasticity and weakness of the lower extremities. Overall, the age of onset, disease severity, and rate of progression differ among different types of autosomal dominant (AD) HSP; there is also considerable variability within the same genetic forms of HSP. For a general discussion of the differential diagnosis of spastic paraplegia/paraparesis syndrome, see Hereditary Spastic Paraplegia Overview. ATL1 pathogenic variants have been confirmed as the most common cause of early-onset HSP, accounting for approximately 30%-50% of all AD HSP with onset before age ten years . Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) accounts for approximately 5% of all AD HSP , which is lower than previous estimates of 10%-15% . In an analysis of a large cohort of individuals in whom a SPAST (formerly known as SPG4) pathogenic variant was not identified, 40% had pathogenic variants in ATL1 . ATL1-HSP needs to be differentiated from other forms of AD HSP . Table 2. Autosomal Dominant Hereditary Spastic Paraplegias of Interest in the Differential Diagnosis of Spastic Paraplegia 3A
Gene | Disorder | Clinical Features of Differential Diagnosis Disorder1 |
|---|
KIF5A | SPG10 | Axonal motor neuropathy common2; Probably 2nd most common cause of early-onset AD HSP |
NIPA1 | SPG6 | Occasionally manifests in infancy3; Probably most aggressive form of AD HSP; wheelchair dependency in a relatively short period of time |
REEP2 | SPG72 | Early age of onset (age 4 yrs); Mild postural tremor common4 |
SLC33A1 | SPG42 | May have onset in 1st decade; Mild, minimally progressive clinical course; Pes cavus distal amyotrophy common5; Reported in a single family SPAST |
RTN2 | SPG12 | Usual onset age 10 yrs6; Uncomplicated phenotype AD HSP = autosomal dominant hereditary spastic paraplegia 1. See Hereditary Spastic Paraplegia Overview. 2. 3. 4. 5. Cerebral palsy. |
Source: GeneReviews — "Spastic Paraplegia 3A"
