hereditary spastic paraplegia 3A

Hereditary Spastic Paraplegia 3A (SPG3A) is a rare genetic disorder that affects the nervous system, causing progressive weakness and stiffness in the lower limbs.

Characteristics:

• Progressive bilateral and mostly symmetric spasticity and weakness of the legs: SPG3A is characterized by a slow, gradual progression of symptoms, starting with difficulty with balance, weakness, and stiffness in the legs.
• Diminished vibration sense: Degeneration of the corticospinal tracts and dorsal columns can lead to diminished vibration sense, which is a common feature in other forms of autosomal dominant hereditary spastic paraplegia (HSP).
• Variable rate of progression and severity of symptoms: The rate at which symptoms progress and their severity can vary significantly among individuals with SPG3A.

Age of onset:

• Early childhood: Symptoms typically begin to appear in early childhood, with the average age of onset being around 4 years.
• More than 80% of cases show symptoms before the age of 10: A significant proportion of children with SPG3A will exhibit symptoms before reaching the age of 10.

Genetic basis:

• Autosomal dominant inheritance: SPG3A is inherited in an autosomal dominant pattern, meaning that a single copy of the mutated gene (ATL1) is sufficient to cause the condition.
• Mutation in the ATL1 gene: The condition is caused by mutations in the ATL1 gene, which codes for a protein involved in axonal transport and maintenance.

References:

• [5] A rare, pure or complex form of hereditary spastic paraplegia, with variable phenotype, typically characterized by childhood-onset of minimally progressive, ...
• [10] Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in ...
• [11] Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns ...
• [13] Description of SPG3A HSP. Early onset but normally uncomplicated. Disease characteristics: Spastic paraplegia 3A (SPG3A) is a hereditary spastic paraplegia (HSP) characterized by progressive bilateral and mostly symmetrical spasticity and weakness of the legs, diminished vibration sense caused by degeneration of the corticospinal tracts and ...
• [15] WHAT IS SPASTIC PARAPLEGIA 3A? SPG3A (also known as ATL1-HSP) is the most common type of autosomal dominant HSP in children. Average age of onset for SPG3A is 4 years and more than 80% of cases show symptoms before the age of 10.

Hereditary Spastic Paraplegia (HSP) type 3A, also known as SPG3A or ATL1-HSP, is a genetic disorder that affects the nervous system. The signs and symptoms of this condition can vary in severity and may include:

• Progressive spasticity and weakness of the legs: This is the most common symptom of HSP type 3A, with affected individuals experiencing stiffness and contraction in their lower limbs.
• Impaired walking: As the condition progresses, individuals may experience difficulty walking or may need to use a walking aid.
• Muscle weakness: Some people with HSP type 3A may experience muscle weakness, particularly in the legs.
• Spasticity: This is characterized by increased muscle tone, leading to stiffness and rigidity in the affected limbs.
• Hyperreflexia: Affected individuals may exhibit exaggerated reflexes in their lower limbs.

These symptoms typically appear before the age of 10, with an average age of onset being around 4 years. In some cases, the condition may slowly worsen over time, leading to a need for walking support.

It's worth noting that HSP type 3A is one of a group of genetic disorders known as hereditary spastic paraplegias, which are characterized by progressive lower extremity weakness and stiffness. The severity and progression of symptoms can vary significantly between individuals and even within the same family.

References:

• [1] (12) Hereditary spastic paraplegia is a group of inherited diseases whose main feature is a progressive gait disorder.
• [11] Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs.
• [13] The signs and symptoms of spastic paraplegia type 3A usually appear before the age of 10; the average age of onset is 4 years.

Hereditary Spastic Paraplegia 3A (SPG3A) is a rare genetic disorder that affects the nervous system, causing progressive weakness and stiffness in the legs. Diagnostic tests for SPG3A are crucial for accurate diagnosis and management of the condition.

Diagnostic Tests:

• Genetic Testing: Molecular genetic testing is the only way to establish a definitive diagnosis of SPG3A [8]. This test can detect mutations in the ATL1 gene, which is associated with SPG3A.
• Clinical Evaluation: A thorough clinical evaluation by a neurologist or a geneticist is essential to diagnose SPG3A. This includes a detailed medical and family history, neurological examination, and assessment of symptoms [13].
• Imaging Studies: MRI scans of the brain and spine may be used to rule out other conditions that can cause similar symptoms [7]. However, these tests are not specific for SPG3A.
• Cerebrospinal Fluid Analysis: In some cases, cerebrospinal fluid analysis may be performed to rule out other conditions that can cause similar symptoms [6].

Specialized Tests:

• A 75 gene panel that includes assessment of non-coding variants is ideal for patients with a clinical suspicion of spastic paraplegia, including SPG3A [5].
• Deletion/duplication analysis and Multiplex Ligation-dependent Probe Amplification (MLPA) are specialized genetic tests offered by Sheffield Diagnostic Genetics Service for the diagnosis of SPG3A [10].

It's essential to note that a definitive diagnosis of SPG3A can only be established through molecular genetic testing. A comprehensive clinical evaluation, including imaging studies and cerebrospinal fluid analysis, may help rule out other conditions that can cause similar symptoms.

References: [5] - A 75 gene panel that includes assessment of non-coding variants is ideal for patients with a clinical suspicion of spastic paraplegia. [6] - In some cases, cerebrospinal fluid analysis may be performed to rule out other conditions that can cause similar symptoms. [7] - MRI scans of the brain and spine may be used to rule out other conditions that can cause similar symptoms. [8] - Molecular genetic testing is the only way to establish a definitive diagnosis of SPG3A. [10] - Deletion/duplication analysis and Multiplex Ligation-dependent Probe Amplification (MLPA) are specialized genetic tests offered by Sheffield Diagnostic Genetics Service for the diagnosis of SPG3A.

Hereditary Spastic Paraplegia (HSP) type 3A is a genetic disorder that affects the nervous system, leading to progressive muscle weakness and paralysis in the legs. While there is no cure for HSP, various treatments can help manage symptoms and improve quality of life.

Medications:

• Oral medications such as Baclofen, Tizanidine, Gabapentin/Pregabalin are prescribed as muscle relaxants to reduce spasticity [3].
• Botulinum toxin injections or anesthetics may be used to relieve muscle spasms and pain [3].

Other Therapies:

• Rapamycin (RM), N-Acetyl Cysteine (NAC), Guanabenz (GA), and Methylene blue (MB) have shown potential in treating neuronal disorders, including HSP [6].
• L-Dopa, an amino acid precursor to dopamine commonly used to manage Parkinson's disease symptoms, has been explored for its potential in HSP treatment [7].

Gene Therapy:

• A gene therapy treatment called MELPIDA is currently undergoing Phase 2 clinical trials for Hereditary spastic paraplegia [9].

It's essential to note that each individual with HSP may respond differently to these treatments, and a healthcare professional should be consulted to determine the best course of treatment.

References: [3] - Oral medications such as Baclofen, Tizanidine, Gabapentin/Pregabalin are prescribed as muscle relaxants to reduce spasticity. [6] - A few drugs, such as Rapamycin (RM), N-Acetyl Cysteine (NAC), Guanabenz (GA), and Methylene blue (MB), have shown good scope in the treatment of neuronal disorders, including HSP. [7] - L-Dopa, an amino acid precursor to dopamine commonly used to manage PD symptoms, has been explored for its potential in HSP treatment. [9] - The second case study revolves around a gene therapy treatment called MELPIDA, which is currently undergoing Phase 2 clinical trials for Hereditary spastic paraplegia.

Hereditary spastic paraplegia 3A (SPG3A) is a genetic disorder characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. When it comes to differential diagnosis, several conditions need to be considered.

Conditions to consider:

• Multiple sclerosis [1]
• Structural abnormalities involving the spinal cord [9]
• B12 deficiency [9]
• Adrenomyeloneuropathy [9]
• Other hereditary spastic paraplegias (HSPs) [11]

These conditions can present with similar symptoms, making differential diagnosis a challenge. To narrow down the possibilities, it's essential to consider factors such as:

• Age at onset: SPG3A typically presents before the age of 10 [2, 3]
• Accompanying clinical features: Diminished vibration sense and urinary bladder hyperactivity are common in other forms of autosomal dominant HSP [14]
• Possible abnormalities on MRI
• Family history

Genetic considerations:

Hereditary spastic paraplegias include autosomal dominant, autosomal recessive, and X-linked forms. SPG3A is inherited in an autosomal dominant pattern [4], which means one copy of the altered gene in each cell is sufficient to cause the condition.

Clinical characteristics:

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant HSP, SPG3A does not typically present with diminished vibration sense or urinary bladder hyperactivity [14].

References:

[1] Nicholson G, Sereda MW, Seeman P, Kremensky I, Mitev V, De Jonghe P. Hereditary spastic paraplegia 3A associated with axonal neuropathy.

[2] Ivanova N, et al. Hereditary spastic paraplegia 3A associated with axonal neuropathy.

[3] Clinical characteristics: Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs.

[4] The genetic loci are designated as SPG (for SPastic parapleGia) and are numbered sequentially as SPG1, SPG2, SPG3, and so on.