Hereditary Spastic Paraplegia and Genetic Ataxias Flashcards
What is hereditary spastic paraplegia?
Definition and Etymology : Hereditary spastic paraplegia is clinically and genetically an heterogeneous condition in which the patient presents with bilateral lower limb spasticity and weakness (main feature of the disease) and genetic alterations. These symptoms worsen over time as it is progressive.
General feature : Although the main feature is bilateral lower limb spasticity, UMN are also associated with the disease. Unlike ALS, HSP has a very slow progression and has quite subtle onset. It is a much rarer disease. Onset is between early childhood and 70 years of age, so a veyr wide range of presentation.
Pathophysiology : The common pathological feature of these conditions is retrograde degeneration of the longest nerve fibers (reaching the lower limbs) in the corticospinal tracts and posterior columns. Since the posterior columns are also involved, so also proprioception and sensing vibration will be involved. Axon degeneration involving the lateral corticospinal tracts which is severe at distal ends, degeneration of axons in fasciculus gracilis, demyelination and gliosis of corticospinal tract is also noted.
Classification of HSP?
Hereditary Spastic Paraplegia (HSP) is clinically classified into two main categories :
- “Uncomplicated” (or “Pure”) HSP :Characterized by bilateral lower limb spasticity and weakness, with mild dorsal column impairment. Key features include:
• Lower limb spasticity (most pronounced in hamstrings, quadriceps, adductors, and gastrocnemius-soleus muscles).
• Weakness (mainly affecting iliopsoas, hamstrings, and tibialis anterior muscles).
• Hyperreflexia and extensor plantar responses (Babinski sign).
• Mild vibration sensation impairment in the toes.
• Mild upper limb hyperreflexia (without increased tone, weakness, or dexterity loss).
• Urinary urgency (up to 50% in later stages).
• Pes cavus (high-arched foot).
• No cranial nerve involvement → no dysarthria, no dysphagia, no chewing or speech impairment.
• Normal cognitive function. - “Complicated” HSP : In addition to spastic paraplegia, neurological and/or systemic abnormalities are present. These may include:
• Cognitive impairment or dementia.
• Extrapyramidal disturbances (e.g., dystonia, tremors).
• Ataxia.
• Peripheral neuropathy.
• Optic neuropathy or Retinitis Pigmentosa.
• Ichthyosis (thick, dry, scaly skin).
• Distal muscle wasting.
• Deafness.
Upper limbs may be involved in later stages, but the bulbar district is always preserved, distinguishing HSP from ALS.
Genetics of HSP?
HSP has a complex genetic basis with all modes of inheritance described, including autosomal dominant, autosomal recessive, and X-linked recessive transmission. Over 50 genes have been identified, each designated by their Spastic ParapleGia (SPG) number (e.g., SPG1, SPG2), which reflects the order of discovery rather than functional similarities.
Mutations of HSP affects various cellular functions like : axon transport, ER morphology, mitochondrial function, myelin formation, protein folding and degradation.
Key Genes Associated with HSP
Autosomal Dominant HSP (Most Common Form)
SPG4 (2p22) – Spastin
• Most common HSP gene (≈40% of cases).
• Primarily linked to uncomplicated HSP.
SPG3A (14q11-q21) – Atlastin
• Related to early-onset, uncomplicated HSP.
Autosomal Recessive HSP (More Often Complicated Forms)
SPG7 – Paraplegin
• Frequently associated with complicated HSP.
SPG11 – Spatacsin
• Strongly linked to complicated HSP, often with mental retardation and cognitive impairment.
Diagnosis of HSP and DDX?
The diagnosis of HSP is based on clinical presentation and family history. Given the heterogeneous genetic basis, distinguishing between uncomplicated and complicated forms is crucial.
Imaging :
• Spinal cord MRI → Gold standard for pure HSP, typically shows spinal cord atrophy, similar to ALS.
• Brain MRI → Performed in suspected complicated HSP, may reveal:
• White matter hyperintensities
• Cerebral and cerebellar atrophy
• Thinning of the corpus callosum
• Cortical grey matter atrophy
Electrophysiology :
• Central motor conduction times → Delayed from lower limbs.
• Somatosensory evoked potentials → Reduced amplitude in lower limbs.
Differential Diagnosis : HSP must be differentiated from other disorders with progressive spasticity, including:
• Structural abnormalities → Spinal cord compression.
• Motor neuron diseases → Slowly progressive ALS, primary lateral sclerosis (PLS).
• Demyelinating/white matter diseases → Multiple sclerosis (MS), B12 deficiency, Krabbe disease, leukodystrophies, adrenomyeloneuropathy.
• Spinocerebellar ataxias → Friedreich ataxia.
• Infections → HIV/AIDS, HTLV-1-associated myelopathy (tropical spastic paraplegia), neurosyphilis.
• Early-onset dementias → Frontotemporal dementia-ALS, familial Alzheimer’s disease (mutations in PSEN1, PSEN2, APP).
Treatment of HSP?
Currently, no curative or disease-modifying therapy exists for HSP, and treatments focus on symptom management.
Pharmacologic Management
Spasticity management:
• Baclofen (oral or intrathecal) → Reduces muscle stiffness.
• Botulinum toxin injections → Selective muscle relaxation.
Urinary urgency:
• Oxybutynin (Ditropan®) → Anticholinergic drug that reduces bladder overactivity.
Physical Therapy & Rehabilitation
• Goal: Improve range of motion, strength, and cardiovascular conditioning.
What is ataxia? Types?
Ataxia is defined as impaired coordination of movements, leading to unsteady gait, poor limb coordination, and dysarthria. It can result from cerebellar dysfunction, spinal cord lesions, or peripheral sensory deficits.
Ataxia is classified into two main groups:
1. Non-hereditary (Acquired) degenerative ataxias.
2. Inherited ataxia syndromes :
• Congenital ataxias
• Autosomal recessive cerebellar ataxias
• Autosomal dominant cerebellar ataxias
• X-linked ataxia syndromes
• Ataxias due to mitochondrial DNA mutations
Causes of non hereditary degenerative ataxias?
• Vitamin B12 deficiency → Causes posterior column degeneration, leading to sensory ataxia.
• Chronic alcohol abuse → Leads to cerebellar degeneration.
• Repeated head trauma → Seen in boxers or MMA fighters, requiring multiple injuries to induce ataxia.
• Paraneoplastic cerebellar degeneration → Due to autoimmune response against cerebellar neurons in cancer patients.
• Celiac disease → Associated with gluten ataxia, an immune-mediated condition.
• Normal pressure hydrocephalus → Causes gait ataxia, dementia, and urinary incontinence.
• Cerebellitis → Inflammation of the cerebellum, often due to viral infections.
Most common autosomal recessive cerebellar ataxias?
Autosomal Recessive Cerebellar Ataxias
1. Friedreich’s Ataxia (FRDA)
• Most common hereditary ataxia.
• Caused by GAA trinucleotide repeat expansion in the FXN gene (frataxin).
• Progressive limb ataxia, dysarthria, loss of deep tendon reflexes, and cardiomyopathy.
• Spinal cord degeneration affects both the corticospinal tracts and posterior columns → motor and sensory impairment.
2. Ataxia Telangiectasia (AT)
• Caused by mutations in the ATM gene involved in DNA repair.
• Early childhood onset.
• Ataxia, telangiectasias (dilated blood vessels), immunodeficiency, and increased cancer risk.
Friedreich’s ataxia? Clinical features? Pathology?
Epidemiology : Most common cause of ARCA, accounting for ~40% of cases, estimated prevalence: 1 in 30,000–50,000.
Clinical features :
• Early-onset, progressive gait and limb ataxia.
• Dysarthria.
• Abnormal eye movements, including fixation instability.
• Loss of vibration and proprioceptive sense.
• Areflexia.
• Pyramidal weakness of the feet.
Systemic complications :
• Cardiomyopathy (leading cause of mortality).
• Diabetes mellitus (10%) or impaired glucose tolerance.
• Scoliosis and pes cavus.
• Sensorineural hearing loss and vertigo.
Autopsy findings:
• Degeneration of the spinal cord and myocardial fibers.
• Fibrous replacement of myocardial muscle fibers.
Pathology
Degeneration of spinal cord pathways:
• Posterior columns → sensory ataxia.
• Spinocerebellar tracts → limb ataxia.
• Corticospinal tracts → pyramidal signs.
• Dentate nucleus degeneration → cerebellar dysfunction.
Cerebellar involvement:
• Purkinje cell loss in the superior vermis.
• Reduced size of middle and superior cerebellar peduncles.
Systemic findings:
• Myocardial hypertrophy & fibrosis.
• Iron-reactive granules in cardiomyocytes.
Friedreich’s ataxia genetics? Diagnosis?
Caused by a mutation in the frataxin (FXN) gene on chromosome 9q13.
• >95% of cases: GAA trinucleotide repeat expansion in intron 1 of both alleles.
• Repeat expansion impairs FXN transcription, leading to decreased protein production.
• Frataxin protein is involved in mitochondrial iron metabolism.
Loss of frataxin leads to:
• Mitochondrial dysfunction.
• Oxidative stress and cell damage (affecting myocardium and nervous tissue).
• Neurodegeneration—affecting the cerebellum, spinal cord (posterior columns, spinocerebellar tracts, corticospinal tracts), and Clarke’s column.
• Repeat size correlates with disease severity:
• Normal range: 11–30 repeats.
• Pathogenic range: 100–2000 repeats (longer repeats → earlier onset, more severe phenotype).
Diagnosis
• Clinical suspicion based on symptoms.
MRI findings:
• Spinal cord atrophy (early, hallmark feature).
• Cerebellar & cortical atrophy (later, more common in complicated forms).
• Thinning of the corpus callosum (SPG11 mutation cases).
Genetic testing confirms GAA repeat expansion in FXN.
Prognosis and treatment of freidreichs
Progressive neurodegeneration.
• Mean survival ~30–40 years, with cardiomyopathy as the main cause of death.
• Multidisciplinary care required (neurology, cardiology, endocrinology, orthopedics).
Treatment : No disease-modifying therapy available.
Symptomatic treatment:
• Antioxidants (Coenzyme Q10, Vitamin E, Idebenone) → limited evidence for cardiac function improvement.
• Physical therapy to improve gait & reduce spasticity.
• Baclofen or botulinum toxin for spasticity.
• Oxybutynin for urinary urgency.
• Cardiac monitoring & management.
