Spastic paraplegia type 3A

Spastic paraplegia type 3A is one of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by muscle stiffness (spasticity) and weakness in the lower limbs (paraplegia). Hereditary spastic paraplegias are often divided into two types: pure and complex. The pure types involve only the lower limbs, while the complex types also involve other areas of the body; additional features can include changes in vision, changes in intellectual functioning, difficulty walking, and disturbances in nerve function (neuropathy). Spastic paraplegia type 3A is usually a pure hereditary spastic paraplegia, although a few complex cases have been reported.

In addition to spasticity and weakness, which typically affect both legs equally, people with spastic paraplegia type 3A can also experience progressive muscle wasting (amyotrophy) in the lower limbs, reduced bladder control, an abnormal curvature of the spine (scoliosis), loss of sensation in the feet (peripheral neuropathy), or high arches of the feet (pes cavus). The signs and symptoms of spastic paraplegia type 3A usually appear before the age of 10; the average age of onset is 4 years. In some affected individuals the condition slowly worsens over time, sometimes leading to a need for walking support.

Spastic paraplegia type 3A belongs to a subgroup of hereditary spastic paraplegias known as autosomal dominant hereditary spastic paraplegia, which has an estimated prevalence of 2 to 9 per 100,000 individuals. Spastic paraplegia type 3A accounts for 10 to 15 percent of all autosomal dominant hereditary spastic paraplegia cases.

Mutations in the ATL1 gene cause spastic paraplegia type 3A. The ATL1 gene provides instructions for producing a protein called atlastin-1. Atlastin-1 is produced primarily in the brain and spinal cord (central nervous system), particularly in nerve cells (neurons) that extend down the spinal cord (corticospinal tracts). These neurons send electrical signals that lead to voluntary muscle movement. Atlastin-1 is involved in the growth of specialized extensions of neurons, called axons, which transmit nerve impulses that signal muscle movement. The protein also likely plays a role in the normal functioning of multiple structures within neurons and in distributing materials within these cells.

ATL1 gene mutations likely lead to a shortage of normal atlastin-1 protein, which impairs the functioning of neurons, including the distribution of materials within these cells. This lack of functional atlastin-1 protein may also restrict the growth of axons. These problems can lead to the abnormal functioning or death of the long neurons of the corticospinal tracts. As a result, the neurons are unable to transmit nerve impulses, particularly to other neurons and muscles in the lower extremities. This impaired nerve function leads to the signs and symptoms of spastic paraplegia type 3A.

Genetic Testing Information

• Genetic Testing Registry: Hereditary spastic paraplegia
• Genetic Testing Registry: Hereditary spastic paraplegia 3A

Genetic and Rare Diseases Information Center

• Hereditary spastic paraplegia
• Spastic paraplegia 3

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; SPG3A

Scientific Articles on PubMed

• PubMed

• Alvarez V, Sanchez-Ferrero E, Beetz C, Diaz M, Alonso B, Corao AI, Gamez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, Lopez de Munain A, Moris G, Ribacoba R, Marquez C, Rosell J, Marin R, Garcia-Barcina MJ, Del Castillo E, Benito C, Coto E; Group for the Study of the Genetics of Spastic Paraplegia. Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89. Citation on PubMed or Free article on PubMed Central
• Blackstone C. Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci. 2012;35:25-47. doi: 10.1146/annurev-neuro-062111-150400. Epub 2012 Apr 20. Citation on PubMed
• Ivanova N, Claeys KG, Deconinck T, Litvinenko I, Jordanova A, Auer-Grumbach M, Haberlova J, Lofgren A, Smeyers G, Nelis E, Mercelis R, Plecko B, Priller J, Zamecnik J, Ceulemans B, Erichsen AK, Bjorck E, Nicholson G, Sereda MW, Seeman P, Kremensky I, Mitev V, De Jonghe P. Hereditary spastic paraplegia 3A associated with axonal neuropathy. Arch Neurol. 2007 May;64(5):706-13. doi: 10.1001/archneur.64.5.706. Citation on PubMed
• Leonardi L, Marcotulli C, Santorelli FM, Tessa A, Casali C. De novo mutations in SPG3A: a challenge in differential diagnosis and genetic counselling. Neurol Sci. 2015 Jun;36(6):1063-4. doi: 10.1007/s10072-015-2097-1. Epub 2015 Jan 31. No abstract available. Citation on PubMed
• Leonardis L, Auer-Grumbach M, Papic L, Zidar J. The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features. Eur J Neurol. 2012 Jul;19(7):992-8. doi: 10.1111/j.1468-1331.2012.03665.x. Epub 2012 Feb 16. Citation on PubMed
• Namekawa M, Ribai P, Nelson I, Forlani S, Fellmann F, Goizet C, Depienne C, Stevanin G, Ruberg M, Durr A, Brice A. SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology. 2006 Jan 10;66(1):112-4. doi: 10.1212/01.wnl.0000191390.20564.8e. Citation on PubMed
• Zhu PP, Soderblom C, Tao-Cheng JH, Stadler J, Blackstone C. SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. Hum Mol Genet. 2006 Apr 15;15(8):1343-53. doi: 10.1093/hmg/ddl054. Epub 2006 Mar 14. Citation on PubMed