NORD gratefully acknowledges Lia Boyle, MD/PhD Candidate, Columbia University Vagelos College of Physicians & Surgeons; Wendy Chung, MD, PhD, Clinical and Molecular Geneticist, Kennedy Family Professor of Pediatrics and Medicine, Columbia University Medical Center; and KIF1A.org, for assistance in the preparation of this report.
KIF1A-related disorder is a group of genetic disorders caused by one or more variations (mutations) in the KIF1A gene. Researchers have determined that different variations of this gene have been associated with different signs and symptoms, progression, and severity of disease. Although different variations lead to many of the same signs and symptoms, the specific symptoms that develop, the progression of the symptoms and the overall severity can vary greatly. This is true for people in different families with the same genetic variation and members within the same family with the same variation in the KIF1A gene. The differences are based, in part, on where in the gene the variation occurs and the type of variation that occurs. In some people, a KIF1A-related disorder is inherited in an autosomal recessive pattern and, in other people it can be inherited in an autosomal dominant pattern. KIF1A-related disorder can best be thought of as a spectrum of disease that can range from mild symptoms to severe, life-threatening complications. Treatment for these disorders is geared toward the specific symptoms that develop.
Originally, changes in the KIF1A gene were thought to lead to three different disorders: the autosomal dominant condition nonsyndromic intellectual disability 9 (MRD9), and the recessive conditions hereditary sensory neuropathy type IIC (HSNIIC) and hereditary spastic paraplegia 30 (SPG30). HSNIIC and SPG30 are typically inherited in an autosomal recessive pattern. There are several reports in the medical literature of individuals with disease-causing variations in the KIF1A gene that occur sporadically (i.e. new mutations) that could then be passed on in an autosomal dominant pattern. Originally, these reports detailed individuals with intellectual disability and the disorder was classified nonsyndromic intellectual disability 9 (MRS9). However, autosomal dominant variations in the KIF1A gene are now understood to cause a complex, neurological disorder. While some affected individuals may have symptoms and inheritance patterns that fit neatly into these categories, others do not. Some individuals with a recessive form of the disease can have symptoms that look more like MRD9, and some individuals with a dominant form of the disease can have symptoms that look more like SPG30 or HSN2C.
The signs and symptoms of KIF1A-related disorder can vary greatly from one person to another depending on the specific variation in the gene that is present, the inheritance pattern, and other factors. Much about KIF1A-related disorder is not fully understood. Several factors including the small number of identified patients prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals most likely will not have all of the symptoms discussed below and that every person is unique. Parents should talk to their children’s physician and medical team about their specific situation, associated symptoms and overall prognosis.
AUTOSOMAL DOMINANT FORMS OF KIF1A-RELATED DISORDERS
Some affected individuals have an autosomal dominant form of the disorder that has been associated with a variety of symptoms. These symptoms include intellectual disability, delays in reaching developmental milestones (developmental delays), diminished muscle tone (hypotonia), and delays in developing language. Additional symptoms include exaggerated reflexes (hyperreflexia) and, as infants or children age, increased muscle tone (hypertonia). Eventually, affected children may develop spastic paraplegia, a condition in which people have difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. Spastic paraplegia can become progressively worse, significantly affecting the ability walk and get around.
Spastic paraplegia is classified as “uncomplicated” or “pure” when symptoms are confined to leg weakness and tightness. Spastic paraplegia is classified as “complicated” when leg weakness and tightness (spasticity) are accompanied by other neurologic disturbances. Some individuals eventually develop contractures. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.
Some affected individuals have optic nerve atrophy, which is degeneration of the main nerve that carries nerve impulses from the eyes to the brain. Sometimes, the field of vision can be reduced. Some affected individual experience progressive deterioration of the nerves cells of cerebellum (cerebellar atrophy), which can cause problem with balance and coordination, and peripheral neuropathy. Peripheral neuropathy is a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain in the affected extremities.
Other symptoms that have been reported in the medical literature include poor coordination (ataxia), rapid, involuntary eye movements (nystagmus), crossed eyes (strabismus), drooping of the upper eyelid (ptosis), weakness or paralysis of half of the facial muscles (facial diplegia), clumsiness when trying to use their hands to manipulate or hold objects, and tremors that occur when attempting to make deliberate actions (intention tremors). A variety of different seizure types have also been described and seizures during sleep can be a particular problem. Some individuals have abnormal electrical activity in their brain that is not a seizure but is not normal. Some individuals have developed abnormal sideways curvature of the spine (scoliosis). Some infants have microcephaly, a condition in which the circumference of the head is smaller than would otherwise be expected based on age and gender. Some infants and children experience backflow or regurgitation of the contents of the stomach into the esophagus (gastroesophageal reflux). Some males have had small testes or penis, or there is failure of the testes to descend into the scrotum (cryptorchidism).
AUTOSOMAL RECESSIVE FORMS OF KIF1A-RELATED DISORDERS
Individuals with recessive forms of KIF1A-related disorder may have symptoms that fit neatly into the categories described, or may have symptoms that look more like the autosomal dominant form of the condition described above.
HEREDITARY SENSORY NEUROPATHY IIC
Some individuals with variations in the KIF1A gene develop a form of hereditary sensory and autonomic neuropathy, specifically type IIC. Hereditary sensory neuropathies are a group of rare neurological disorders characterized by degeneration of the nervous system that frequently progresses to loss of feeling, especially in the hands and feet. Symptoms usually start with inflamed fingers or toes, especially around the nails. Numbness and tingling sensations in the hands and feet may also occur. Eventually, affected individuals lose feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Chronic infection of the affected areas is common and worsens as ulcers form on the fingers or the soles of the hands and feet. NORD has a separate report on hereditary sensory and autonomic neuropathy type II. For more information, choose the exact disorder name as your search term in the Rare Disease Database.
HEREDITARY SPASTIC PARAPLEGIA 30
Some individuals with variations in the KIF1A gene develop a form of hereditary spastic paraplegia, specifically hereditary spastic paraplegia type 30, or autosomal recessive spastic paraplegia 30, or SP30. The hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share the primary symptom of difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of HSP. There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe), and the occurrence of other neurologic symptoms between different genetic types of HSP; as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of HSP. NORD has a separate report on hereditary spastic paraplegia. For more information, choose “hereditary spastic paraplegia” as your search term in the Rare Disease Database.
KIF1A-related disorders are caused by a variation in the KIF1A gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation in a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The KIF1A gene produces a protein that is expressed solely in the brain and nerves. The exact function of this protein is not fully understood. The protein has a role in transporting or carrying substances within cells (intracellular transport), specifically these protein helps to transport substances through a tubular structure in nerve fibers (axonal microtubules). Some studies suggest that this protein is essential for the function and survival of sensory nerve cells (neurons). Sensory neurons are the nerves cells that respond to stimuli like pain or temperature.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease, while recessive disorders occur when an individual inherits two copies of an abnormal gene, one from each parent. In dominant disorders, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Some people with a KIF1A-relataed disorder have a variation in the KIF1A gene that is inherited in an autosomal dominant pattern. This almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all families the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The gene variation can then be passed on by the affected person in an autosomal dominant pattern. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
At least two distinct disorders are associated with variations in the KIF1A gene that are inherited in an autosomal recessive pattern. These disorders are hereditary sensory and autonomic neuropathy IIC and hereditary spastic paraplegia 30. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Some affected individuals are compound heterozygotes, which means that they have inherited two different autosomal recessive mutations that have the combined effect of causing disease.
KIF1A-related disorder is extremely rare. The number of people affected by these disorders is unknown. Rare disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population. As of November 2018, according to KIF1A.org, there are more than 150 people known to have a disease-causing variation in the KIF1A gene.
A diagnosis of a KIF1A-related disorder is suspected based upon the identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. A diagnosis is confirmed through molecular genetic testing on a blood sample, which can detect mutations in the KIFA1 gene, but is available only as a diagnostic service at specialized laboratories.
Some individuals will have tests that cover a subset of genes related to the individual’s symptoms (panel testing) while others will have whole exome sequencing (WES). Sometimes blood from the parents is requested for comparison as part of WES. WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the KIF1A gene that are known to cause disease, or variations in other genes known to cause symptoms similar to KIF1A-related disorder.
Clinical Testing and Workup
Affected individuals may undergo additional tests to assess the extent of the disease. Two of the more common symptoms of the condition are problems with vision due to issues with the nerves of the eye (optic nerve atrophy) and seizures. Optic nerve atrophy can be difficult to detect so individuals may be referred to see an eye doctor specializing in neurological conditions that affect the eyes (neuro-ophthalmologist). Since seizures and abnormal brain activity during sleep are common, longer electroencephalograms (EEG) that last 24-48 hours may be recommended. An EEG records the brain’s electrical activity and can detect seizures that might not be obvious, as well as detect abnormal brain activity that is not a seizure.
Neurologic examination is important for individuals with the symptoms of a KIF1A-related disorder. Neurologic examination helps identify the specific features affecting a person. Laboratory tests, neurophysiologic testing, and neuroimaging; routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions); and analysis of cerebrospinal fluid (obtained by “spinal tap”) may be conducted to help exclude alternate and co-existing diagnoses.
The treatment of KIF1A-related disorder is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists), neurologists, physicians who specialize in the diagnosis and treatment of eye disorders (ophthalmologists), speech pathologists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials will be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with KIF1A-related disorder.
Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.
Medications may be tried to treat seizures, spasticity and certain neurological aspects of KIF1A-related disorder. Orthopedic devices including braces, crutches, canes and other devices may help children walk. Additional treatment is symptomatic and supportive.
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