Introduction 

Cerebrotendinous Xanthomatosis (CTX) is a lipid storage disease characterised by infantile onset diarrhoea, childhood onset cataract, adolescent to-young adult-onset tendon xanthomas and adult onset progressive neurological dysfunction (dementia, psychiatric disturbances, pyramidal or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy and seizures. In approximately 75% of individuals cataract is the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade and they occur on the Achilles tendon, the extensor tendon of the elbow and hand. CTX is a rare, autosomal, recessive lipid storage disorder caused by CYP27A1 mutation.¹

People with cerebrotendinous xanthomatosis develop neurological problems in early adulthood which are caused by abnormal accumulation of fats and an increasing number of xanthomas in the brain. Xanthomas can accumulate in the fatty substance that insulates and protects nerves. (CTX) is a rare disorder due to defective sterol 27-hydroxylase causing a lack of chenodeosycholic acid ( CDCA) production and high plasma cholestanol levels.^1,2

Other features of cerebrotendinous xanthomatosis include clouding of the lenses, cataract and chronic diarrhoea in childhood, a reduced ability to produce and release a digestive fluid called bile (cholestasis), which can lead to yellowing of the skin or whites of the eyes and progressively brittle bones that are prone to fracture (osteoporosis). People with cerebrotendinous xanthomatosis are also at increased risk of developing cardiovascular disease or respiratory diseases. Juvenile cataracts, progressive neurological dysfunction and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders including familial dysbetalipoproteinaemia and homozygous familial hypercholesterolaemia. In adulthood: neurological dysfunction with a variable time of onset, mental retardation leading to dementia, psychiatric symptoms (including behavioural changes), hallucinations, agitation, epileptic seizures, premature retinal ageing, premature arteriosclerosis, chronic intractable diarrhoea, gallstones and the increased risk of bone fracture coronary artery disease are noticed.²

Causes

CTX is caused by disease-causing pathogenic variants in the CYP27 A1 Gene. When a pathogenic variant of the gene occurs, the protein product or enzyme may be faulty, inefficient, or absent. Depending on the functions of the particular protein, this can affect many organ systems of the body including the brain. In CTX the gene variant is inherited in an autosomal recessive manner. The condition is inherited as an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. People with cerebrotendinous xanthomatosis are also at an increased risk of developing cardiovascular disease or respiratory failure because of lipid accumulation in the heart or lungs, respectively. Other names of this condition are cerebral cholesterinosis, cerebrotendinous cholesterinosis and cholestanol storage disease.³ 

How common is the disease?

Worldwide this disorder affects approximately 1 person in every 1,000.000. There is much higher incidence in the Moroccan Jewish population, where it affects 1 in every 108 individuals. CTX is also more prevalent in Asians with higher carrier frequency. Prevalence varies a lot by ethnicity, especially high rates in Moroccan Jews.⁴

Signs and symptoms 

 A common first sign of cerebrotendinous xanthomatosis is neonatal cholestatic jaundice, showing yellowing of the skin and white of eyes, itchy skin, dark urine and light-coloured, foul-smelling stools. Chronic diarrhoea and liver dysfunction may also occur. While some intellectual impairment may be noticed in childhood, this is more common from puberty onwards. Dementia, psychiatric disturbances and nerve damage progress with age alongside behavioural changes. These changes may include hallucinations, aggression, depression and suicidal tendencies. The typical triad of symptoms include juvenile cataracts, tendon xanthomas, progressive neurologic dysfunction which includes Ataxia, peripheral neuropathy, cognitive decline, seizures and psychiatric symptoms. Other features include chronic diarrhoea in infancy, developmental delays, osteoporosis and premature atherosclerosis. It is believed that massive deposition of cholesterol and cholestanol in affected organs leads to dysfunction and clinical development of the disease because only trace amounts of cholestanol are normally found in mammalian tissues.³

Diagnosis and treatment of cerebrotendinous xanthomatosis

Diagnosis of CTX usually begins with a physical exam and review of patients medical history and symptoms. A thorough clinical evaluation which includes detailed genetic family history, identifying characteristic findings and conducting biochemical examinations on their blood and urine. The biochemical examinations include cholestanol, plasma bile and bile alcohol within blood. During childhood, the condition can be diagnosed through urine analysis. With adults, a positive diagnosis of CTX is based on identifying at least two of the five main symptoms: persistent diarrhoea, cataracts at a young age, fatty deposits in the tendon, neurological abnormalities and abnormal amounts of cholesterol in the tendons of the body. Diagnosis can be performed with a biochemical analysis of certain molecules in the blood and urine. Molecular tests are also available to confirm the diagnosis. An MRI or CT scan can be looked for areas of the brain that resemble stroke conditions. A cerebrovascular evaluation will look at the affected blood vessels and may include an angiography.^5,9

Treatment 

There is no cure for CTX, however, if the condition is treated early, its progression can be slowed or stopped.

The first treatment generally prescribed is chenodeoxycholic acid (CDCA) replacement therapy, which works to normalise the body's ability to break down cholesterol. Other medications include HMG-CoA reductase inhibitors to help lower cholesterol levels by blocking the enzyme responsible for the production of cholesterol. The dose of chenodeoxycholic acid (CDCA) is 750 mg/day in divided doses 250mg three times a daily.

Adjunct or supportive treatments

Statins (e.g simvastatins), sometimes added to further reduce cholesterol levels.

Because CTX can cause endocrine abnormalities.

• Vitamin D and calcium for osteopenia / Osteoporosis
• Thyroid hormone if hypothyroidism develops 
• Anti epileptic drugs for patients with seizures 

Surgical management 

• Used when structural complications occur 
• Cataract Surgery (often needed in childhood or young adulthood)
• Tendon xanthoma excision - If painful or impairing mobility 

Monitoring 

• Regular follow-up is essential 
• Serum cholesterol levels need to be checked
• Liver function tests monitoring 
• Ophthalmologic evaluation
• Bone density scans 

Treatment of manifestations 

Targeted therapy

 In gene reviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation regardless of whether the therapy is significantly efficacious for one or more of the genetic causations of the condition. Early treatment with chenodeoxycholic acid in presymptomatic individuals appears to prevent clinical manifestations. 

Genetic counselling

Genetic counselling is the process of providing individuals and families with information on the nature, mode of inheritance, and implications of genetic disorders to make informed medical and personal decisions.^5,9

Summary 

Selected monogenic disorders present with clinical features such as chronic diarrhoea (congenital diarrhoea), Neonatal cholestasis, juvenile cataract, xanthomas, spastic paraplegia, Ataxia, intellectual disability and leucoenchalopathies. Extrapyrmidal manifestations can be considered as late disease manifestations with parkinsonism followed by dystonia and myoclonus.

FAQs

Does the family need to be tested?

CTX is an autosomal recessive inherited metabolic condition. For an autosomal recessive condition to be passed on to the child, the child must inherit two faulty enzyme making genes. The parents don't have to have cerebrotendinous xanthomatosis in order to pass it on to their children. They can be carriers. Carriers are people who have one faulty gene and one working gene. They don't have the disorder as they have one working gene.

What are tendon xanthomas?

Tendon xanthomas are a key symptom of CTX, but are not widely understood or recognised. xanthomas are cholesterol deposits that form on tendons. A patient may find lumps on Achilles, patella, hand, elbow, or neck tendons. The deposits can be found as bumps on the tendons.

Why is early diagnosis important?

Early diagnosis and treatment are crucial to preventing irreversible damage and improving long-term outcomes.

Key lessons from CTX case studies 

Early diagnosis profoundly alters outcomes.

The most important lesson - Earlier treatment prevents disability, late treatment slows progression.

Treatment of CTX with replacement chenodeoxycholic acid can prevent development of irreversible neurological and non neurological symptoms if initiated early. Neurological symptoms that can develop include epilepsy, spasticity, hypokinetic and hyperkinetic disorders thought to be a late disease manifestation are treated symptomatically. Deep brain stimulation (DBS) is also an important movement disorder, which can be used for less common tremor disorders. Early diagnosis of CTX is crucial because CTX is a treatable disease and early and long-term treatment with chenodexycholic acid (CDCA) improves clinical outcome substantially.

According to studies, the prognosis of CTX patients is affected by the age at diagnosis and initiation of CDCA treatment. Patients should be evaluated by the detection of plasma cholestanol levels and through neurologic tests. Furthermore, clinical studies have provided powerful evidence showing that early recognition and treatment are critical to prevent or ameliorate disease progression and devastating neurological complications.

Case report

A 26 year old mentally retarded woman attended the emergency department with complaints of swelling along the course of both Achilles tendons of 16 years duration and at the upper end of left tibia, of three years duration. They were asymptomatic and gradually increasing in size. They were asymptomatic and gradually increasing in size. The patient gave a history of surgery for bilateral cataract at the age of eight years. She developed hyperirritable behaviour and poor scholastic performance so that she stopped going to school from fourth standard. She also had a decline of mental function, being bedridden at present. She had developed Achilles tendon swellings three years ago. The patient was the eldest of four siblings of consanguineous parentage. Her 24 year old sister had a history of seizures since the first month of life and had bilateral mature cataract from an early age. She also has a gradual decline from mental function. Her 20 year brother was on phenytoin sodium for Grand mal seizures for the past three years. The Achilles tendon swellings of both women and the swelling on the left tibial tuberosity of the index case were proved by biopsy to be tendinous xanthomas. MRI of the index patient's brain revealed severe cerebellar atrophy, abnormal signals in the dentate white matter with mild cerebral atrophy. A peripheral rim of marked hypointensity was seen around the hyperintense areas caused by xanthomas.

Discussion 

Cerebrotendinous xanthomatosis is a rare familial sterol storage disease. The primary biochemical defect is deficiency of hepatic mitochondrial enzyme sterol 27 hydroxylase which catalyses the hydroxylation of cholesterol and its deficiency decreases bile acid synthesis. Tendon xanthomas, especially over the Achilles tendon are characteristic of the disorder and clinically resemble those seen in familial hypercholesterolaemia or hyperlipoproteinaemia. Other reported manifestations of this rare syndrome include juvenile cataract, premature arteriovascular disease. Psychiatric manifestations may occur in patients with cerebrotendinous xanthomas. These include depressed mood, irritability, poor appetite, insomnia, fatiguability and pessimistic thinking. The diagnosis of CTX can be made biochemically by detecting increased serum levels of cholestanol or urine bile alcohol and genetically by detecting molecular defects in sterol 27 hydroxylase gene. Conventional MRI studies have shown focal diffuse white matter abnormalities and different degrees of cerebral and cerebellar atrophy in the brain of patients with CTX. The non homogenous hyperintense magnetic resonance signal in dentate nuclei and surrounding cerebellar white matter can be considered as a neuro radiological feature and important diagnostic marker.