HSP

Hereditary spastic paraparesis (HSP): 

• Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse disorders that typically cause progressive symmetric, spastic paraparesis in the lower extremities more then apparent weakness.   It is a hereditary myelopathy, specifically a distal motor-sensory axonopathy predominantly affecting the CNS. 

• The HSPs are a group of nearly 100 disorders in which lower extremity spastic weakness is a major clinical feature.  There are autosomal dominant, autosomal recessive, X-linked, and maternally inherited (mitochondrial) forms of HSP.

• Clinically, it has been divided into uncomplicated and complicated forms. 

  • The uncomplicated form of HSP refers to the syndrome in which cavus foot deformities and mild vibratory sense loss may occur as the only other associated feature.

  • The complicated form has other neurologic features besides spasticity.   In addition to corticospinal tract and dorsal column disturbance.  These abnormalities include, for example, peripheral neuropathy, cerebellar ataxia, cognitive impairment, dementia, and distal muscle wasting. These include optic neuropathy, retinal pigmentary degeneration, deafness, amyotrophy, peripheral neuropathy, ataxia, dementia, mental retardation, extrapyramidal dysfunction, thinning of corpus callosum on MRI of brain, ichthyosis, epilepsy, swallowing,  speech, and breathing problems.   

  • Also divided by Genetic mode of inheritance: AD, AR, X-linked recessive.

  • As in most hereditary neuromuscular disorders, the absence of a positive family history does not exclude the disorder.

  • Some HSP variants, such as those caused by mutations of spastic paraplegia genes (SPGs) 9, 10, 14, 15, 20, 22, 26, and 30, may display lower motor neuron (LMN) signs, further complicating differentiation from ALS.

• Mutation analysis can detect 60% of the autosomal-dominant (AD) cases, but there is a high false negative rate.  A total of 10% of sporadically affected individuals turn out to have diagnostic dominant mutations. Whole exome sequencing will hopefully increase diagnostic yield.

• Based on age of onset it is classified into:

  • Type 1: age of onset <35 years

  • Type 2: age of onset >35 years

  • Several genetic mutations have been identified involving various HSP loci and genes. 

    • The most common mutation is on chromosome 2p22 involved with the SPAST gene encoding for the protein spastin, which is inherited in an autosomal dominant fashion. 

    • Other proteins involved include atlastin, paraplegin, spartin, and maspardin, among others. 

• Clinical features:  

  • Lower extremity spasticity which may be symmetric or near symmetric in distribution. 

  • Symptom onset typically occurs in 2nd or 3rd decades of life or as early as first decade or as late as 7th decade of life.  

  • Patient is unable to run, hop secondary to increased extensor tone in lower extremities.  Hip flexion and knee flexion is impaired.  There is reduced stride length and difficulty running.  There is dragging and stiffness in legs and a tendency to trip on uneven ground.  There is increased adductor tone in the legs and may be noted to scissor while walking.  Circumduction rather than linear advancement of the legs is a compensated attempt to avoid tripping.  The hips and knees are tonically extended and form tonic foot posture of inversion and plantar flexion (equinovarus posture). There is high arched feet and hammertoes but these are not in variable features.  

  • HSP symptoms beginning in early childhood, gait disturbance may be nonprogressive and resemble spastic diplegic cerebral palsy.  HSP symptoms that begin after early childhood typically progress slowly over a number of years.  Neurologic examination demonstrates signs of upper motor neuron impairment as various degrees of hyperreflexia, spasticity, and weakness that are exclusively present or markedly greater in the legs than the arms.  For example, in the presence of spasticity, weakness, and grade 3 to 4 reflexes in the legs, upper extremities are typically entirely asymptomatic yet show mildly brisk deep tendon reflexes.  This is often accompanied by subtle decrease in vibration perception in the toes.  HSP’s pattern of CNS-predominant motor and sensory axonopathy particularly affecting the distal ends of very long CNS fibers (corticospinal tracts and dorsal columns, respectively) can be considered analogous to Charcot-Marie-Tooth disease type 2, in which distal motor-sensory axonopathy is limited to the peripheral nervous system.

  • Low motor neuron involvement may occur but is overshadowed by spasticity.  

  • Upper motor neuron weakness: Hip flexion, knee flexion, and the foot dorsiflexion typically weaker than the antagonists is seen.  Hyperreflexia of lower extremities, extensor plantar responses, hyperreflexia of upper extremity with Hoffmann sign and reflex spread.

  • Posterior column-vibration and joint position sensation loss in toes.  Urinary frequency, urgency and urgency incontinence are common.  Rectal urgency and incontinence and sexual dysfunction are uncommon.

  • Length-dependent axonopathy predominantly involving distal ends of corticospinal tracts may be apparent as an upper-to-lower extremity gradient of upper motor neuron signs; much greater (or much earlier onset) upper motor neuron–pattern impairment is seen in the legs compared to the arms.

  • Think of an alternative diagnosis if there is significant loss of upper extremity function associated with weakness, increased tone, or impaired coordination.  Rarely sensory ataxia and Romberg is positive.

• Patients with HSP are referred to neuromuscular clinics due to:

  • Suspicion of progressive lateral sclerosis, a variant of ALS characterized by progressive upper motor neuron (UMN) signs such as spasticity and hyperreflexia.

  • Suspicion of polyneuropathy due to gait imbalance and mild impairment of vibratory sensation in the feet.

• Delayed somatosensory-evoked responses and the presence of Charcot joint deformities are useful in differentiating HSP from other diagnostic considerations such as primary lateral sclerosis.

• Differences between HSP and PLS

  • Clinical features of HSP and PLS overlap when there is no apparent family history of spastic paresis.

  • Slow progression, high foot arches, and mild sensory impairment in the feet due to dorsal column dysfunction favor HSP, while involvement of the arms and bulbar muscles favor primary lateral sclerosis (PLS). The only feature unique to HSP was cerebellar signs which may be seen in complicated forms of HSP.  

  • In primary lateral sclerosis (PLS), upper motor neuron–pattern motor impairment is severe and occurs in the absence of significant dorsal column or lower motor neuron impairment which may be seen in HSP.

• SPG11: HSP, CMT (AR): patient may have pes-cavus, hammer toes; axonal neuropathy, allelic to AR juvenile ALS (ALS5).  Patient's with SPG11/spatacsin mutation in addition to neurologic deficits involving corticospinal tracts serving all extremities (with earlier appearing and more severe deficits affecting the legs compared to the arms), corticobulbar tracts, extrapyramidal system (dystonia and tremor), and cerebral hemispheres (serving cognition).  In addition, EMG and nerve conduction studies provide evidence of motor neuropathy.  Although some individuals have uncomplicated spastic paraparesis, it is typical for patients with SPG11 HSP to have complicated phenotypes in which progressive spastic paraplegia is associated with other deficits, including cognitive impairment, a thin corpus callosum, extrapyramidal features (which may resemble dopa-responsive dystonia and dopa-unresponsive parkinsonism, upper extremity and bulbar muscle involvement, and peripheral motor neuropathy.  Motor neuron degeneration in SPG11 HSP may mimic ALS.

• SPG7:  Insidiously progressive bilateral leg weakness and spasticity.  Most affected individuals have decreased vibration sense and cerebellar signs.  Onset is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years.  Additional features including ataxia (gait and limbs), spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, ptosis, hearing loss, motor and sensory neuropathy, amyotrophy, scoliosis, pes cavus, and urinary sphincter disturbances may be observed. 

• SPAST mutations are the single most common cause of dominantly inherited HSP, present in approximately 35% to 45% of individuals with HSP.  Individuals with SPAST HSP typically manifest with a slowly progressive uncomplicated spastic paraparesis.

• Troyer syndrome

•  MRI of brain, spinal cord, EMG/NCS, neuropsychological testing, ophthalmological evaluation, urodynamics, VEP, SSEP, ENMG, clinical geneticist, genetic counselor for carrier testing in other family members. 

• Recognizing HSP is straightforward when the patient has similarly affected first-degree relatives, neurologic involvement is limited to progressive corticospinal tract impairment (often accompanied by urinary urgency and subtle impairment of vibration perception), and other disorders are excluded by laboratory testing and neuroimaging.  Recognizing HSP is more difficult when patients have no family history (which may be the case when HSP is autosomal recessive, X-linked, or due to de novo mutation and when diverse neurologic symptoms are (or eventually become) indicative of more extensive CNS involvement.

• DDx:  It is useful to think about DDx of HSP considering that many hereditary myelopathies conform to one of four clinical paradigms: (1) spinocerebellar ataxia, (2) motor neuron disorder, (3) leukodystrophy, or (4) distal motor-sensory axonopathy predominantly affecting the central nervous (HSP included) system.  Myelopathies are recognized by variable combinations of upper motor neuron–pattern functional motor disturbance, impaired vibration or proprioception, and lower motor neuron–pattern motor impairment that are not attributable (by the remainder of neurologic symptoms and examination findings) to another localization (ie, brain or peripheral nerve).

  • Childhood onset: diplegic cerebral palsy, AC malformation, atlanto-axial subluxation, Leukodystrophy (Krabbe), abetalipoproteinemia, arginase deficiency, levodopa-responsive dystonia, MS, primary or secondary spinal tumor.

  • Adult onset: cervical disc disease, MS, NMOD, MND, PLS, parasaggital meningioma, spinal tumors, myelitis, dural AVM, adrenoleukodystrophy, HSP, Friedreich ataxia, SCA type 3 (Machado-Joseph disease),, vit B12, E, deficiency, lathyrisim , Konzo, levodopa-responsive dystonia, syphilis, HTLV1/2, HIV, copper deficiency, adrenomyeloneuropathy, cerebral palsy, tropical spastic paraplegia and sarcoidosis.

  • Distinguishing between leukodystrophies and CNS-predominant motor-sensory axonopathies at the bedside may be difficult but is important in formulating a differential diagnosis.  Signs of corticospinal tract impairment (eg, spastic weakness, hyperreflexia, extensor plantar responses, Hoffman and Trömner signs) are typical of both leukodystrophies and axonopathies.  Clinically distinguishing leukodystrophies from CNS-predominant distal motor-sensory axonopathies is based on the presence of additional neurologic findings, particularly cognitive impairment and sensory disturbance.  For example, patients with generalized leukodystrophies (those affecting myelin of both the CNS and peripheral nervous system) may also have (although not always) progressive cognitive impairment and may have demyelinating peripheral neuropathy, which usually manifests as stocking distribution of hypesthesia and a gradient of deep tendon reflexes, being reduced in the ankles compared to the knees. On the other hand, sensory impairment in motor-sensory axonopathies (eg, uncomplicated forms of HSP) is typically predominantly limited to dorsal column impairment affecting longer fibers (fasciculus gracilis) and manifests as mildly impaired vibration perception in the toes with preservation of other sensory modalities. Note is made, however, that peripheral neuropathy may be a complicating feature of many forms of HSP.    Thus, it is noted that spastic gait disturbance is an early and prominent symptom. Identifying associated features (eg, subtle dorsal column signs in HSP; cognitive impairment in cerebral adrenoleukodystrophy; marked dorsal column impairment in Friedreich ataxia; upper extremity and bulbar muscle involvement in PLS; and cognitive, extrapyramidal, and peripheral motor neuropathy in SPG11 HSP) is essential to clinical recognition of these disorders.

• Labs:   

  • MRI of brain, C and T-spine w/wo contrast, CSF,  HTLV 1/2, syphilis, GAD-64, SPS panel (Mayo), HIV, Hep-C, Vit E, folate, VLCFA, lactate, pyruvate, plasma amino acids, copper, ceruloplasmin, paraneoplastic, SPEP/SIFE, homocystine, rheumatoid factor, CRP, ANA, lipoprotein a, vitamin D, lysosomal acid lipase.

  • Commercial labs may not be able to detect partial deletions of these SPAST gene (SPG4 locus).  The yield is high for autosomal dominant-75% can be genotyped.  60% are attributed to 4 HSP types: SPG3A, 4, 6 and 31.  Test SPG 4, 6 and 31 first.  SPG3A (atlastin) mutation frequently manifests in childhood and can be avoided testing initially in adults.

  • SPG11 is thought to be responsible for approximately 50% of recessively inherited cases.  This should be their first gene tested in any recessive or sporadic case with a thin corpus callosum, if genotyping is performed.

  • SPG7 is the second most common autosomal recessive genotype representing 6% or less of these cases.

  • 10 to 20% of apparent sporadic cases of SPG will be found to have a gene mutation more typically associated with either a dominant or recessive inheritance pattern with SPG4 and SPG 7 being the most commonly recognized examples.  SPG 4 is reported to demonstrate phenomenon of anticipation.

  • Genetic testing is often able to establish a precise diagnosis for patients with hereditary myelopathy.  Depending on the clinical syndrome (ie, whether cerebellar ataxia, spastic paraparesis, or cognitive impairment is the predominant symptom), the clinician may choose to either analyze a large panel of genes implicated in spinocerebellar ataxias, HSPs, leukodystrophies, or motor neuron disorders or proceed with whole-exome analysis.  Next-generation sequencing (either of gene panels or whole-exome analysis) may not sensitively detect gene copy number variation (deletion or duplication). Chromosome microarray analysis may be useful in this regard.  It is often difficult to interpret the significance of gene variations (such as those identified in whole-genome or whole-exome sequencing) that have little or no known association with the specific syndrome.  It is important to note that identifying a precise genetic cause of the syndrome often does not indicate the extent and severity of the individual’s symptoms.  Each of these syndromes is highly variable.  Significant variation may be seen even between individuals who share exactly the same mutation.  For most conditions, little is known about genotype-phenotype correlation and the contribution of modifying genes and potentially modifying environmental factors.  For this reason, a cautious approach to prognosis is advised.

  • Financial burden, natural history of disease that is unlikely to be favorably altered by knowledge of genotype are rationales for not routinely testing HSP suspects.

  • Imaging and HSP is typically normal with the exception of occasional atrophy of the thoracic cord which may be seen in some uncomplicated cases.

  • In complicated cases, MRI of the brain may show atrophy of the corpus callosum, hydrocephalus, or white matter changes.

• Histopathology:

  • Dying back myelopathy.  There is degeneration of both crossed and uncrossed corticospinal tracts at the level of the lumbosacral and thoracic segments.  Degeneration of posterior column is most evident in the cervical medullary junction.  There is decreased numbers of AHC and/or cortical motor neurons have been reported.

Allelic forms: 

• SPG3A and HSN1: Mutation in a atlastin gene.

Pathogenesis:

• SPG 4 (spastin) fracture microtubule dynamics.

• SPG 10 (kinesin 5A gene) has a role in axonal transport.

• 3 SPG genes: paraplegin, chaperonin 60, receptor expression enhancing protein 1, and mitochondrial ATPase 6 (SPG7, 13, 31) code for mitochondrial proteins. L1 cell adhesion molecule (SPG1) effects corticospinal tract development.  PLP gene, gap junction protein gamma 2 genes (SPG2, SPG42) affects myelination.

• SPG 8, 17 abnormality of stumpellin and seipin gene function causing disturbances of membrane trafficking, protein accumulation and endoplasmic reticulum stress response.

Treatment is symptomatic, with pharmacologic treatment of spasticity and supportive care for disability.

• • Baclofen 5 mg p.o. 3 times daily up to a maximal dose of 20 mg p.o. 4 times daily.  SE: Constipation, nausea, emesis, decreased muscle tone, dizziness, headache, somnolence, coma, seizure, and abrupt withdrawal syndrome.

  • Tizanidine 4 mg p.o. daily up to a maximal dose of 12 mg p.o. 3 times daily.  SE: Hypotension, xerostomia, asthenia, dizziness, and sedation.

  • Botulinum toxin type A.  It varies with product.  1 unit/kg.  Maximal total dose per treatment averages 250 to 400 units.  SE: Decreased muscle tone and allergy.

  • Benzodiazepines (diazepam) 2 mg p.o., IM or IV daily up to a maximal dose of 15 mg p.o. 4 times daily.  SE: Sedation, ataxia, hypotension, fatigue, respiratory depression, and withdrawal symptoms.

  • Dantrolene 25 mg p.o. daily up to a maximal dose of 100 mg p.o. 4 times daily.  SE: Lightheadedness, constipation, diarrhea, asthenia, headache, sedation, diplopia, visual, CHF and arrhythmia, myelosuppression, and hepatotoxicity.

  • Intrathecal baclofen 50 mcg test dose at a dose, 25 mcg children, increase dose by 10 to 30%/day in adults, 5 to 15 mcg and children titrated to response.  Up to 2000 mcg/day.  SE: Pump failure, catheter fracture, CNS infection, CSF leak with intracranial hypotension, and complications of baclofen.

  • Rhizotomy.  Complications can be CSF leak with intracranial hypotension.

https://mnglabs.labcorp.com/tests/NGS337/spastic-paraplegia-ngs-panel-and-copy-number-analysis-mtdna  

TEST: NGS337 Test number copied CPT: 81448, 81460, 81465