The case histories

Patient 1

A 37-year-old woman presented to the ataxia clinic with 1 year of increasing unsteadiness and episodes of recent falls. She had behavioural problems from an early age and had Asperger's syndrome. She had undergone bilateral cataract extraction at the age of 10 years. She also had diarrhoea as a child. She had three older siblings all of whom were well with no other family history of neurological illness.

On examination, she had an ataxic gait, increased tone in all four limbs with brisk reflexes and bilaterally extensor plantars. Despite the absence of tendon xanthomata, the combination of ataxia and early-onset cataracts prompted testing for serum cholestanol. This was significantly raised, in keeping with the diagnosis of CTX. She also had significantly increased urinary bile acids.

MRI of the brain showed diffuse symmetrical high T2 signal changes affecting the deep cerebellar nuclei and extending into the white matter of both cerebellar hemispheres (figure 1). In addition, there were multiple white matter lesions in both cerebral hemispheres, which were largely peripheral. There was mild cerebellar atrophy. The patient was treated with chenodeoxycholic acid (CDA) and statins. On follow-up, she appeared to stabilise, with no progression of her ataxia.

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Figure 1

MRI of the cerebellum (patient 1) showing hyperintensities within the cerebellar white matter. These are thought to be due to accumulation of cholestanol.

Patient 2

A 38-year-old man presented to the ataxia clinic with a long history of progressive ataxia (over 20 years), cognitive impairment, epilepsy, and speech and swallowing difficulties. His problems dated to primary school. He had significant behavioural problems requiring a child psychologist's input. He had needed special tuition at school and had been very disruptive in class. He had a history of juvenile cataracts and complained of loose bowel motions. His condition had gradually deteriorated over the years to the point that he could walk only with the support of a person. There was no family history of neurological illness.

On examination, he had severe dysarthria, marked ataxia of the limbs and gait along with bilateral pes cavus and increased tone in the legs. He had brisk reflexes and very prominent xanthomata over his Achilles tendons (figure 2).

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Figure 2

Tendon xanthoma of the Achilles tendon in patient 2.

MRI of the brain showed extensive signal changes in the white matter of the cerebellum (figure 3) and in the brain stem. The triad of juvenile cataracts, tendon xanthomata and progressive ataxia was strongly suggestive of CTX. His serum cholestanol was significantly raised, confirming the diagnosis.

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Figure 3

MRI of the cerebellum (patient 2) showing symmetrical and extensive hyperintensities within the cerebellum. There is also cerebellar atrophy.

He was treated with CDA. Despite normalisation of the serum cholestanol over a follow-up period of 7 years, the patient progressively deteriorated, lost the ability to walk and to communicate verbally, and is now confined to a wheelchair. His swallowing problems progressed and required a gastrostomy for feeding. While repeat MRI showed no change in the white matter abnormalities, there was increased atrophy of the cerebellum and brain stem along with atrophy of the cerebellar peduncles.

Pathophysiology

CTX is an autosomal recessive disease with an estimated prevalence of 1 in 70 000. It is caused by mutations in the CYP27A1 gene, located on chromosome 2q and results in inactivation of the mitochondrial enzyme 27-hydroxylase.1 Loss of function of this enzyme results in decreased synthesis of CDA and accumulation of the intermediary metabolite cholestanol (figure 4), which is deposited in lipophilic tissues such as the brain and tendons. The biochemical abnormalities seen in CTX are important in confirming the diagnosis. The serum cholesterol and triglyceride levels are normal, but serum cholestanol levels are elevated. Cholestanol levels are particularly high in the bile, tendon xanthomata and brain tissue. Bile acid production is markedly decreased, leading to reduced CDA concentration in the bile. Excretion of bile acid precursors is increased in bile and urine.

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Figure 4

The metabolic pathway of cholesterol demonstrating how the enzymatic defect of 27-hydroxylase results in high levels of cholestanol, which accumulates in lipophilic tissues (eg, brain, tendons). HMGCoA, hydroxy methylglutaryl coenzyme A.

Clinical features, diagnosis and management

The disease is characterised by the triad of neurological dysfunction (usually cerebellar ataxia, but also pyramidal signs), early-onset cataracts and tendon xanthomata. Patients with CTX usually present towards the end of their first decade of life, and most individuals live beyond middle age. Clinical manifestations vary greatly, apart from the triad mentioned above. Patients also complain of gastrointestinal symptoms such as diarrhoea, thought to be secondary to impaired bile production.2 While juvenile cataracts are characteristic, other ophthalmological findings including optic disc atrophy occasionally occur.3 Tendon xanthomas tend to develop after the second decade of life. The Achilles tendons are the most commonly affected but other tendons can also be affected. Although such xanthomata may have the same appearance as those found in patients with familial hypercholesterolaemia or hyperlipoproteinaemia, biochemical analysis shows that they contain high amounts of cholestanol and little cholesterol. Progressive neurological impairment also includes dementia, myelopathy and peripheral neuropathy. However, the presentation can vary widely and the condition is almost certainly underdiagnosed. The cognitive/behavioural problems associated with CTX can be the earliest manifestation of the disease, but are not readily recognised and often attributed to other causes, resulting in delay in the diagnosis, as in two of our three cases.

These cases illustrate the diversity of presentation that contributes to the delay of the diagnosis. The only consistent finding in all three patients was the early onset of cataracts. Only two of the three patients had ataxia (the other had spastic paraparesis) and only one had tendon xanthomata. Only one patient had a family history. The patient presenting with spastic paraparesis had normal imaging of both brain and spine. In contrast, the other two patients had clear evidence of abnormal white matter primarily affecting the cerebellum, and less so the rest of the brain. The same patient had clinical evidence of a peripheral neuropathy. While two of the patients appeared to stabilise on the treatment, the third (most severely affected at diagnosis) seemed to progress neurologically. The reason for this is not clear. This patient, however, had the longest disease duration, the most severe neurological disability at diagnosis and the most abnormal brain scan. It is possible that extensive cholestanol deposition within the cerebellum exerts a local toxic effect that continues to cause damage to the cells despite normalisation of the serum cholestanol.

The diagnosis, if suspected, is easily confirmed by an elevated serum cholestanol, and an increased urinary excretion of bile acids (the Children's Hospital, Sheffield, is the national UK centre for these biochemical assays). Treatment with CDA improves bile acid metabolism with normalisation of serum cholestanol. Such treatment may halt the disease progression or even reverse some of the deficits. The sooner the diagnosis is made and treatment given, the more favourable the response is likely to be.

In a study involving 17 patients with CTX published in 1984, 15/17 (88%) had tendon xanthomata, 12/17 (71%) had cataracts and 13/17 (76%) had cerebellar dysfunction. In addition, 13/17 (76%) had cognitive problems and all patients had pyramidal signs with 7/17 having a mild peripheral neuropathy.4 After treatment with CDA (recommended dose is 250 mg three times daily), the authors reported that the cognitive deficits resolved in 10 patients, the pyramidal and cerebellar signs disappeared in 5 and improved in another 8. The improvement was associated with normalisation of the serum cholestanol and occurred within a year of starting treatment. In another series of 24 patients with CTX, 79% had an abnormal brain MRI, the most common finding being that of hyperintense lesions on T2-weighted images in the dentate nucleus. MRI also tends to demonstrate cortical volume loss in addition to the white matter changes implying axonal damage.5 MR spectroscopy also demonstrates an increase in brain parenchymal lactate implying diffuse brain mitochondrial dysfunction.6

While CTX is rare, it is one of the few genetic conditions that responds well to treatment, provided the diagnosis is made early. The diagnosis therefore should not be missed. The treatment with CDA is simple. Of interest, until the end of 2010, CDA was readily available from several different companies (estimated cost £375 (€425) per patient per year), but recently the supply has been limited with only one company still producing it and charging £15 000 (€17 000) per patient per year.