Hereditary Spastic Paraplegia 56

Hereditary spastic paraplegia 56 is one of the many subtypes of hereditary spastic paraplegias (HSP), which are a rare group of genetic neurologic disorders characterized by progressive degeneration of the corticospinal tracts (i.e., the major neuronal pathway responsible for voluntary motor function). HSP has an overall prevalence of approximately 1 to 10 per 100,000 individuals and results in gait impairment, bilateral lower extremity weakness, and spasticity (i.e., stiff, rigid muscle tone).  

HSP can be clinically classified as either “pure” or “complicated.” In its pure form, spasticity-related symptoms are localized to the bladder, exclusively. If other systemic (e.g., intellectual disability, dementia, skeletal dysmorphic features) or neurologic (e.g., peripheral neuropathy) symptoms are present, it is then classified as the complicated form.  

The “56” of “hereditary spastic paraplegia 56” is based upon the order of locus discovery (i.e., 56th genetic locus discovered), and to date, there are over 87 genetic loci that have been identified. Specifically, HSP 56 follows an autosomal recessive inheritance and is classified as “complicated” because it has been associated with peripheral neuropathy (i.e., damage to nerves outside of the brain and spinal cord), intellectual disability, extrapyramidal symptoms (e.g., continuous spasms or muscle contractions, restlessness, or tremors) in addition to lower extremity weakness and spasticity.  

The diagnosis of HSP 56 begins with a thorough review of characteristic symptoms and medical history. A neurologic exam may demonstrate bilateral leg weakness or spasticity, hyperreflexia, and positive Babinski reflex (i.e., stimulating the sole of the foot results in upward extension of the toes), which is an abnormal finding in adults suggestive of nervous system dysfunction. Molecular genetic testing confirms the diagnosis. For example, a multigene panel targeting known HSP-related genes is initially used to screen for pathogenic variants. Whole-genome sequencing is another option when multigene panel screening is equivocal. 

Magnetic resonance images (MRI) of the brain and spine may help exclude differential diagnoses including demyelinating and degenerative central nervous system lesions (e.g., multiple sclerosis, an autoimmune disease in which the body attacks its own nerves) and structural lesions (e.g., intracranial tumor). Laboratory blood tests can help exclude nutritional deficiency (e.g., vitamin B12 or copper deficiency) and cerebrospinal fluid studies can rule out chronic infections (e.g., HIV or neurosyphilis), which can present with similar symptoms. Nerve conduction studies can help exclude motor neuron disease (e.g.,  amyotrophic lateral sclerosis, [ALS] a progressive neurodegenerative disorder) since ALS can also present with muscle twitching and weakness.