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Hereditary diffuse leukoencephalopathy with spheroids
HDLS is a condition where white matter in the brain gradually deteriorates, leading to a range of neurological symptoms. It is an inherited condition that typically begins in adulthood, affecting a person's cognitive abilities, movement, and behaviour.
Overview
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare genetic disorder characterised by the progressive degeneration of the brain's white matter. White matter consists of nerve fibres, or axons, which are covered in a protective layer called myelin. This myelin sheath helps to speed up the transmission of electrical signals between different parts of the brain. In HDLS, the white matter is damaged, and abnormal structures called spheroids, which are swollen nerve endings, accumulate within the brain [PMID:33678036]. This damage disrupts normal brain function, leading to a variety of neurological symptoms.
HDLS is a progressive condition, meaning that symptoms typically worsen over time. While the exact prevalence of HDLS is not well established, it is considered a rare disease. It generally affects adults, with symptoms often beginning between the ages of 20 and 60, though onset can vary [PMID:24077465].
Symptoms & clinical features
The symptoms of HDLS can vary significantly between individuals, even within the same family. Early symptoms often involve changes in personality or behaviour, such as depression, anxiety, apathy, or irritability. Cognitive decline is also common, which may manifest as problems with memory, attention, executive function (planning and problem-solving), and language difficulties [PMID:24077465].
As the condition progresses, individuals may develop motor symptoms. These can include spasticity (muscle stiffness), problems with balance and coordination (ataxia), gait disturbances, and weakness in the limbs. Seizures can occur in some people with HDLS. The rate at which symptoms progress is also variable, with some individuals experiencing a more rapid decline than others.
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Affected organs
HDLS primarily affects the central nervous system, specifically the white matter of the brain. The degeneration of myelin and nerve fibres is widespread, although certain areas may be more severely affected. While the disease is largely confined to the brain, the progressive neurological dysfunction impacts a person's overall physical and mental capabilities.
Risks & severity
HDLS is a progressive disorder, and its severity tends to increase over time. The age of symptom onset is variable, but it commonly occurs in adulthood, ranging from the third to the sixth decade of life. There can be significant variation in the progression rate, even among family members with the same genetic change. Some individuals may experience a relatively slow decline over many years, while others may have more rapid progression of symptoms.
The long-term outlook for individuals with HDLS involves progressive neurological impairment. This can eventually lead to significant disability, impacting independence and quality of life. The condition is associated with a reduced life expectancy, although the precise duration varies considerably depending on the age of onset and rate of disease progression.
Genetic causes
Hereditary diffuse leukoencephalopathy with spheroids is caused by changes (variants) in the CSF1R gene. The CSF1R gene provides instructions for making a protein called the colony stimulating factor 1 receptor. This receptor protein is found on the surface of certain immune cells in the brain, called microglia.
Microglia are essential for maintaining the health of the brain, acting as its primary immune defence system. They help clear cellular debris, prune synapses (connections between nerve cells), and respond to injury or infection. Pathogenic variants in CSF1R lead to a faulty receptor protein, which disrupts the normal function of microglia. This impaired microglial function is thought to contribute to the damage and degeneration observed in the brain's white matter in HDLS, including the formation of spheroids [PMID:33678036].
- CSF1R colony stimulating factor 1 receptor
Inheritance pattern
HDLS is inherited in an autosomal dominant pattern. This means that only one altered copy of the CSF1R gene is sufficient to cause the condition. If a parent has HDLS, there is a 50% chance with each pregnancy that their child will inherit the altered gene and therefore be at risk of developing the condition. This inheritance pattern applies equally to male and female children.
Individuals who inherit the altered gene may experience varying degrees of symptom severity and different ages of onset, even within the same family. In some cases, HDLS can arise from a new genetic change (a de novo variant) in an individual, meaning neither parent carried the altered gene. However, this is less common for HDLS.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing HDLS typically involves a combination of clinical evaluation, brain imaging, and genetic testing. A neurologist will assess the individual's symptoms, medical history, and conduct a neurological examination. Magnetic Resonance Imaging (MRI) of the brain is a crucial diagnostic tool, as it can reveal characteristic white matter abnormalities and atrophy (shrinkage) in specific brain regions consistent with HDLS.
Confirmation of an HDLS diagnosis is made through genetic testing, which identifies pathogenic variants in the CSF1R gene. This testing is usually performed on a blood sample. In the UK, genetic testing for suspected leukodystrophies, which includes HDLS, can be accessed via the NHS Genomic Medicine Service (GMS) pathways. A specialist clinician, such as a neurologist or clinical geneticist, would typically refer an individual for genetic testing under the relevant GMS R-code (e.g., R118 Inherited white matter disorders).
Management & lifestyle
Currently, there is no specific cure for HDLS, and management focuses on alleviating symptoms and supporting individuals to maintain their quality of life. This often involves a multidisciplinary team approach, including neurologists, physiotherapists, occupational therapists, speech and language therapists, and mental health professionals. Medications may be prescribed to manage specific symptoms such as spasticity, seizures, depression, or anxiety.
Regular monitoring by a neurologist is important to track disease progression and adjust management strategies as needed. Supportive therapies, such as physiotherapy, can help maintain mobility and muscle strength. Occupational therapy can assist with adapting daily activities and maintaining independence. Genetic counselling is also an important part of care, providing information about the condition, inheritance patterns, and support for family planning decisions.
UK care pathway
In the UK, individuals suspected of having genetic conditions like HDLS would typically be referred by their GP or specialist to a clinical genetics service. This service can provide expert assessment, counselling, and access to genomic testing through the NHS Genomic Medicine Service (GMS). Genetic tests for inherited white matter disorders, including HDLS, are available via specific GMS R-codes (e.g., R118 Inherited white matter disorders), which guides the laboratory testing pathway. Genetic counsellors play a vital role in explaining complex genetic information, supporting individuals and families through the diagnostic process, and discussing implications for other family members.
Frequently asked questions
What is the life expectancy for someone with HDLS?
The life expectancy for individuals with HDLS can vary significantly. It depends on factors such as the age of symptom onset and the rate of disease progression. Generally, it is associated with a reduced life expectancy, but the exact duration differs greatly from person to person.
Can HDLS be passed down to children?
Yes, HDLS is inherited in an autosomal dominant pattern. This means if you have HDLS, each of your children has a 50% chance of inheriting the altered gene that causes the condition. Genetic counselling can provide more detailed information and support regarding family planning.
Are there any treatments to stop HDLS from progressing?
Currently, there is no specific treatment that can stop the progression of HDLS. Management focuses on relieving symptoms and providing supportive care to improve quality of life. This can involve various therapies and medications to manage specific neurological issues.
How is HDLS diagnosed?
HDLS is typically diagnosed through a combination of a neurological examination, characteristic findings on a brain MRI scan, and confirmed by genetic testing. Genetic testing identifies specific changes in the CSF1R gene that are known to cause the condition.
References
- Adam MP, Bick S, Mirzaa GM. CSF1R-Related Disorder. 1993. PMID: 22934315
- Shih HY, Raas Q, Bonkowsky JL. Progress in leukodystrophies with zebrafish. Development, growth & differentiation. 2024. PMID: 38239149
- Stabile C, Taglia I, Battisti C. Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): update on molecular genetics. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2016. PMID: 27338940
- Wang YL, Wang FZ, Li R. Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy. Frontiers in aging neuroscience. 2021. PMID: 34955818
- Wade C, Lynch DS. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Handbook of clinical neurology. 2024. PMID: 39322383
- Konno T, Kasanuki K, Ikeuchi T. CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. Neurology. 2018. PMID: 30429277
- Lin WL, Wszolek ZK, Dickson DW. Hereditary diffuse leukoencephalopathy with spheroids: ultrastructural and immunoelectron microscopic studies. International journal of clinical and experimental pathology. 2010. PMID: 20830237
- Guo L, Ikegawa S. From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R. Journal of human genetics. 2021. PMID: 34135456