Kinesin Family Member 5A (KIF5A)-Related Disorder

Disease Overview

Summary

Kinesin family member 5A (KIF5A)-related disorder (KIF5A-RD) is a rare disease caused by a change (variant) in the KIF5A gene. The KIF5A gene has instructions to make (codify) the KIF5A protein. Depending on where the variant occurs in the KIF5A gene, the disorder can affect different parts (domains) of the KIF5A protein and result in different signs and symptoms. ^1-3 The protein encoded by KIF5A gene has three parts:^1,4,5

• Motor domain: Changes here usually cause spastic paraplegia type 10 (SPG10) or Charcot-Marie-Tooth disease type 2 (CMT2).
• Tail domain: Changes here typically lead to amyotrophic lateral sclerosis (ALS), with or without symptoms of frontotemporal dementia or in infant neonatal intractable myoclonus.

• Stalk domain: Changes here are rare and can cause a wide range of symptoms but do not seem to be linked to a specific set of symptoms.

The age of onset for KIF5A-RD varies widely, with symptoms appearing from childhood to late adulthood, but usually in middle age. Symptoms of KIF5A-ALS typically start in the mid-40s, which is younger than in classic ALS. KIF5A-SPG10 symptoms usually begin in childhood, but onset at adult age can also occur.

Diagnosing KIF5A-RD is challenging due to the wide range of symptoms, and genetic testing is required for a definitive diagnosis. Currently, there is no cure available.

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Synonyms

• KIF5A-related disorder
• KIF5A-RD

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Subdivisions

• KIF5A-amyotrophic lateral sclerosis
• KIF5A-Charcot-Marie-Tooth disease type 2
• KIF5A-spastic paraplegia type 10
• neonatal intractable myoclonus

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Signs & Symptoms

The symptoms of KIF5A-RD depend in part on the part of the protein (domain) that is affected by the variants in the KIF5A gene. ^5-15

A variant in part of the KIF5A gene that encodes the motor domain of the KIF5A protein usually causes SPG10 or CMT2.

A variant in the part of the KIF5A gene that encodes the tail domain of the KIF5A protein can cause ALS, that can be accompanied by symptoms of frontotemporal dementia.

Stalk domain variants are relatively rare and are less well characterized but can cause a range of different symptoms. However, it seems that these variants are not specifically linked to a particular group of signs and symptoms. The different conditions caused by variants in the KIF5A gene include:

• Spastic paraplegia type 10 that can be pure or complex (when associated with additional symptoms)
  • Pure spastic paraplegia type 10 (KIF5A-SPG10)
    • Muscle weakness: Usually present in lower limbs (paraplegia)
    • Lower limb spasticity: Stiffness and tightness in the leg muscles
    • Hyperreflexia: Exaggerated reflexes
    • Extensor plantar responses: a sign of damage to corticospinal tract – a major pathway in the central nervous system that carries movement-related information from the cerebral cortex to the spinal cord
  • Complex KIF5A-SPG 10: Symptoms of paraplegia might be accompanied by:
    • Peripheral neuropathy: Nerve damage causing weakness and muscle atrophy
    • Moderate intellectual disability
    • Attention-deficit/hyperactivity disorder (ADHD)
    • Behavioral changes
    • Autonomic dysfunction
    • Deafness
    • Retinitis pigmentosa: A progressive eye disease causing vision loss
• KIF5A-Charcot-Marie-Tooth disease type 2
  • Progressive weakness and atrophy of distal limb muscles, particularly in legs and feet
  • Mild sensory deficits affecting position, vibration and pain/temperature sensations
  • Pes cavus (high-arched feet)
  • Spasticity (muscle stiffness) and hyperreflexia (exaggerated reflexes)
  • Painand discomfort in the affected areas
• KIF5A-amyotrophic lateral sclerosis
  • Muscle weakness: Often starts in one limb and spreads to other parts of the body
  • Muscle atrophy: Wasting away of muscles reducing its strength and muscle bulk
  • Spasticity: Increased muscle tone leading to stiffness and tightness
    • Muscle weakness, atrophy and spasticity, which may affect any voluntary muscle and is rapidly progressive
  • Fasciculations: Muscle twitches often noticeable under the skin
  • Dysarthria: Slurred or slow speech due to weakened facial muscles
  • Dysphagia: Difficulty swallowing which can lead to choking or food aspiration
  • Breathing difficulties: Shortness of breath due to weakened respiratory muscles
    • On average, people with KIF5A-ALS develop respiratory failure within 3–4 years from onset, which is the most common cause of death.
  • Fatigue: General tiredness and reduced endurance
  • KIF5A-ALS usually has a rapid disease course; however, some people have a mild course and prolonged survival; the course can be different even in members of the same family.
• KIF5A-frontotemporal dementia
  • Progressive changes in behavior, personality and language
  • Inappropriate social behavior such as loss of empathy, apathy, compulsive behaviors
  • Language difficulties such as trouble finding words or understanding speech
• Parkinsonism
  • Muscle stiffness
  • Movement slowness
  • Tremor
• Ataxia and cerebellar symptoms
  • Difficulty coordinating movements
• Neonatal intractable myoclonus (NEIMY)
  • Uncontrollable muscle jerks right after birth
  • Breathing problems
  • Abnormal eye movements (nystagmus, abnormal saccades, ptosis)
  • Pale optic nerves
  • Abnormal growth
  • Most babies with NEIMY do not survive beyond infancy

Stalk domain variants are not associated with specific signs and symptoms and a wide range of symptoms have been identified. Some people have symptoms of ALS but most have a complex form of hereditary spastic paraplegia (HSP).

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Causes

KIF5A-RD is caused by changes (variants) in the KIF5A gene. The KIF5A gene encodes a protein that is a part of the kinesin family. These proteins are responsible for transporting cellular cargo (various cellular components like organelles and vesicles, that need to be transported within neurons) along microtubules. This transport is crucial for various cellular functions, including intracellular trafficking and cell division.^1,2,16 Different parts (domains) of this protein have different functions:

• Motor Domain: Moves cellular cargo along microtubules
• Stalk Domain: Helps in dimerization and cargo binding
• Tail Domain: Binds to cellular cargo to allow its transport

KIF5A variants affect this protein’s ability to transport cargo properly, leading to the accumulation of cellular waste or the failure to deliver essential components which cause the symptoms. Since individual parts of the KIF5A gene encode individual parts of the protein, the location of variants in the KIF5A gene will disrupt its function in different ways and lead to different symptoms. ^1,2,17

Inheritance

KIF5A-RD is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

KIF5A-RD is rare and exact prevalence rates are not available. Many affected people might not be diagnosed correctly or might be missed entirely, making it difficult to determine how often these conditions occur in the general population.

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Disorders with Similar Symptoms

The differential diagnosis of KIF5A-RD involves distinguishing them from other conditions with similar symptoms. The main sets of symptoms in people with KIF5A-RD can occur in other diseases, both genetic and sporadic.

Spastic paraplegias are a group of inherited disorders characterized by progressive stiffness (spasticity) and weakness in the leg muscles. These conditions primarily affect the lower limbs, leading to difficulties with walking and mobility. There are over 80 different types of spastic paraplegia.

Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders that affect the peripheral nerves, which are responsible for transmitting signals between the brain, spinal cord and muscles. They are usually associated with progressive muscle weakness, muscle atrophy and sensory loss and are usually characterized by slow progression. CMT is a heterogeneous group of genetic diseases that can be caused by variants in many different genes.

Polyneuropathy is a condition that affects multiple peripheral nerves throughout the body. It can cause a range of symptoms including pain, weakness and sensory disturbances. Polyneuropathy can be caused by various factors including diabetes, alcohol abuse, infections and autoimmune diseases. Genetic polyneuropathies are relatively rare.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurons in the brain and spinal cord. These neurons are responsible for controlling voluntary muscle movements such as walking, speaking and breathing. About 10% of ALS cases are familial (KIF5A is one of many genes that can cause ALS), while the remaining 90% are sporadic (occurring randomly without a clear genetic cause).

Multiple sclerosis (MS) can present with spasticity and weakness but it typically includes other symptoms like optic neuritis and often has relapsing-remitting episodes, which are not seen in KIF5A-related disorders.

Parkinson’s disease (PD) manifests as set of symptoms: slowness of motion, rigidity, tremor and postural abnormality. These symptoms might be present in KIF5A-RD, but other symptoms like spasticity, hyperreflexia, fasciculations and breathing difficulties are usually not present in PD.

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Diagnosis

• Diagnosis of KIF5A-RD should be done by a neurologist and involves a comprehensive approach with a detailed neurological exam to assess symptoms such as spasticity, muscle weakness and sensory deficits.
• A detailed patient and family history can help identify any patterns or presence of similar symptoms in family members, as KIF5A disorders are inherited in an autosomal dominant manner. However, it’s important to note that a lack of family history does not rule out KIF5A
• A neuropsychological evaluation can be helpful to detect cognitive impairment and signs of frontotemporal dementia

Diagnostic tools may include:

• Neuroimaging: MRI scans can help visualize brain and spinal cord abnormalities, though they are not specific to KIF5A-RD.
• Nerve conduction studies and electromyography (EMG): These tests can detect nerve and muscle dysfunction, providing supportive evidence for conditions like motor-sensory polyneuropathy or ALS.
• Muscle and nerve biopsy: Muscle biopsies, where a small sample of muscle tissue is removed for examination under a microscope may show atrophy; nerve biopsies in patients with KIF5A variants can show axonal neuropathy, which is characterized by damage to the axons, the long, slender projections of nerve cells, of the peripheral nerves.

Doctors should consider KIF5A-RD when a patient presents with:

• Typical signs of spastic paraplegia such as lower limb spasticity and increased reflexes (hyperreflexia)
• Motor-sensory polyneuropathy including muscle weakness, atrophy and sensory deficits
• ALS symptoms such as progressive muscle weakness, spasticity and respiratory difficulties

A diagnosis of KIF5A-RD is confirmed when a disease-causing variant in KIF5A is identified by genetic testing. Given the autosomal dominant inheritance pattern, each child of an affected parent has a 50% chance of inheriting the variant. However, sporadic cases can occur, making genetic testing essential even in the absence of family history.

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Standard Therapies

There is no cure or an FDA-approved disease modifying treatment for KIF5A-RD. Treatment is focused on managing the specific symptoms and improving the quality of life.

Appropriate therapies, such as occupational, physical, speech and feeding therapies can help to minimize the effect of symptoms on a person’s life. Regular reassessments and adjustments to these services are important.

Standard medications may be used to treat symptoms like seizures, spasticity, neuropathy and other neurological aspects of the disorder.

Genetic counseling is recommended for individuals with KIF5A-RD and their families. It’s also important to provide psychosocial support to the entire family.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Cozzi M, Magri S, Tedesco B, et al. Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders. Cell Death Dis. 2024;15(9):692. Published 2024 Sep 27. doi:10.1038/s41419-024-07096-5
2. Baron DM, Fenton AR, Saez-Atienzar S, et al. ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function. Cell Rep. 2022;39(1):110598. doi:10.1016/j.celrep.2022.110598
3. Fichera M, Lo Giudice M, Falco M, et al. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology. 2004;63(6):1108-1110. doi:10.1212/01.wnl.0000138731.60693.d2
4. Nicolas A, Kenna KP, Renton AE, et al. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. 2018;97(6):1267-1288. doi:10.1016/j.neuron.2018.02.027
5. de Boer EMJ, van Rheenen W, Goedee HS, et al. Genotype-phenotype correlations of KIF5A stalk domain variants. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22(7-8):561-570. doi:10.1080/21678421.2021.1907412
6. Brenner D, Yilmaz R, Müller K, et al. Hot-spot KIF5A mutations cause familial ALS. Brain. 2018;141(3):688-697. doi:10.1093/brain/awx370
7. Oliveira R, Maruta C, Gil-Gouveia R. A novel KIF5a mutation identified in two-family members with spastic paraplegia type 10. Rev Neurol (Paris). 2021;177(1-2):152-154. doi:10.1016/j.neurol.2020.04.026
8. Dellatte J, Lievens I, Wang FC. Could some mutations of the KIF5A gene be responsible for a dominant CMT2 phenotype? (Case report). Acta Neurol Belg. 2023;123(6):2435-2438. doi:10.1007/s13760-023-02248-4
9. Rydzanicz M, Jagła M, Kosinska J, et al. KIF5A de novo mutation associated with myoclonic seizures and neonatal onset progressive leukoencephalopathy. Clin Genet. 2017;91(5):769-773. doi:10.1111/cge.12831
10. Qiu Y, Zhong S, Cong L, et al. A novel KIF5A gene variant causes spastic paraplegia and cerebellar ataxia. Ann Clin Transl Neurol. 2018;5(11):1415-1420. Published 2018 Sep 17. doi:10.1002/acn3.650
11. Duis J, Dean S, Applegate C, et al. KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction. Ann Neurol. 2016;80(4):633-637. doi:10.1002/ana.24744
12. Liouta E, Poulidou V, Frontistis A, et al. Charcot-Marie-Tooth Disease Type 2-Like Phenotype due to a Novel Variant in the Stalk Domain of KIF5A. Neurol India. 2023;71(3):577-579. doi:10.4103/0028-3886.378650
13. Faruq M, Kumar D, Wadhwa S, et al. Intrafamilial variable spastic paraplegia/ataxia/ALS phenotype linked to a novel KIF5A mutation. Clin Genet. 2019;96(3):271-273. doi:10.1111/cge.13585
14. Dulski J, Strongosky AJ, Al-Shaikh RH, Wszolek ZK. Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(3-4):347-350. doi:10.1080/21678421.2022.2164204
15. Saez-Atienzar S, Dalgard CL, Ding J, et al. Identification of a pathogenic intronic KIF5A mutation in an ALS-FTD kindred. Neurology. 2020;95(22):1015-1018. doi:10.1212/WNL.0000000000011064
16. Liu M, Pi H, Xi Y, et al. KIF5A-dependent axonal transport deficiency disrupts autophagic flux in trimethyltin chloride-induced neurotoxicity. Autophagy. 2021;17(4):903-924. doi:10.1080/15548627.2020.1739444
17. Soustelle L, Aimond F, López-Andrés C, Brugioti V, Raoul C, Layalle S. ALS-Associated KIF5A Mutation Causes Locomotor Deficits Associated with Cytoplasmic Inclusions, Alterations of Neuromuscular Junctions, and Motor Neuron Loss. J Neurosci. 2023;43(47):8058-8072. Published 2023 Nov 22. doi:10.1523/JNEUROSCI.0562-23.2023

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