Metabolic and Biochemical Aspects

Bile acids are synthesized via the classic pathway initiated by cholesterol 7-alpha-hydroxylase (CYP7A1) or via alternate pathways, one of which is initiated by sterol 27-hydroxylase (CYP27). Cerebrotendinous xanthomatosis (CTX) is due to bi-allelic pathogenic variants in the CYP27A1 gene, which encodes the mitochondrial cytochrome P-450 enzyme sterol 27-hydroxylase. Deficiency in this enzyme interferes with sterol intermediates in the alternative bile acid pathway. More specifically, CTX is associated with the reduced synthesis of 27-hydroxycholesterol (27-OHC) and chenodeoxycholic acid (CDCA), as well as the shunting of sterol intermediates into the microsomal pathway for cholic acid formation [1]. CTX is also characterized by the high production of cholestanol, which accumulates in various tissues, as well as increased levels of bile alcohols in the urine [2]. Evidence that cholestanol may be neurotoxic is supported by the finding of cholestanol deposition and apoptosis in neuronal cells, most notably Purkinje cells, in the cerebellum of rats fed a 1% cholestanol diet [3]. As the influx of 27-OHC may be involved in brain cholesterol homeostasis, the lack of 27-OHC may also impact cholesterol synthesis in the brain [4].

Clinical Description and Diagnosis

Patients with CTX typically manifest both systemic and neuropsychiatric symptoms. Systemic manifestations may include infantile cholestasis or liver dysfunction, juvenile-onset cataracts, Achilles tendon xanthomas, chronic diarrhea, osteoporosis, premature arteriosclerosis, and cardiovascular disease [5]. Neurological symptoms encompass learning disabilities and/or autism spectrum disorder, spastic paraplegia, cerebellar ataxia, peripheral neuropathy, bulbar palsy, epilepsy, parkinsonism, dementia, and psychiatric disturbances [5]. Wong et al. conducted a meta-analysis of 91 publications reporting on 194 CTX patients [6]. The study revealed that corticospinal tract abnormalities (59.8%) and ataxia (58.8%) were the most common neurological alterations followed by cognitive decline (46.4%), gait difficulties (38.1%), and cognitive delay (35.0%) [6]. In a natural history study, we highlighted that diarrhea often develops within the first year of life, cataract and school difficulties between 5 years and 15 years of age, usually preceding motor or psychiatric symptoms by about a decade [7]. Although some patients may have autistic features early in the disease course [8], there is a critical therapeutic window in most CTX patients before the onset of disabling neuropsychiatric symptoms [9]. Furthermore, the possibility to reverse the pathophysiological process in patients with CTX stresses that the disease must be diagnosed as early as possible. To help with this, a clinical suspicion index has been proposed [10]. In addition to the characteristic finding of tendon xanthomas, we propose to evaluate for CTX in all patients presenting with any of the following: infantile chronic diarrhea and/or jaundice, juvenile cataracts, a learning disability and/or autism spectrum disorder, pyramidal signs, cerebellar signs, parkinsonism, or peripheral neuropathy.

The most common biochemical diagnostic marker of CTX is increased plasma cholestanol. Two other plasma metabolites are of particular interested for the diagnosis of CTX: decreased 27-OHC and increased 7-alpha-hydroxy-4-cholesten-3-one (7αC4) [4]. Cholestanol and 7αC4 are good biomarkers to monitor the response to treatment. Because of the favorable outcome of CTX patients treated at an early stage of the disease, expert groups are advocating for newborn screening for CTX, based on the detection of bile alcohol glucuronides [11, 12]. The diagnosis of CTX is confirmed by the identification of two pathogenic bi-allelic variants (compound heterozygous or homozygous) in CYP27A1.

Management

CDCA remains the treatment of choice in CTX as it downregulates CYP7A, restores the imbalance between CDCA and cholic acid, and is the only drug that has shown beneficial effects on neurological symptoms so far [5, 13]. The exogenous supply of CDCA may act by restoring a negative feedback in the endogenous acid bile and cholestanol synthesis. This drastically lowers plasma cholestanol concentrations in patients and prevents its accumulation in tissues [2, 5]. CDCA nearly normalizes the aberrant sterols profile found in patients with CTX [4]. While initial studies with CDCA reported a clear short-term clinical improvement in most patients [2, 14], long-term studies have rather reported clinical stabilization [9, 15, 16] and, sometimes, neurological deterioration [17]. In fact, Stelten et al. emphasized that the response to treatment strongly depends on when CDCA is initiated [18]. In a cohort of 56 Dutch CTX patients treated by CDCA with a median follow-up time of 8 years (6 months to 31.5 years), they showed that neurological symptoms, assessed by the modified Rankin Scale and Expanded Disability Status Scale (EDSS) scores, disappeared in all patients who were diagnosed before the age of 24 and treated since [18]. Furthermore, treatment prevented the development of new neurological symptoms during the follow-up period. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurological symptoms, with parkinsonism as a prominent treatment-resistant feature [18]. A similar observation was made in a cohort of 43 CTX patients in the USA [19].

Electrophysiological studies using transcranial magnetic stimulation or electromyoneurography have highlighted that the effect of therapy may depend on the extent of irreversible structural damage to axons [15, 20]. Few studies have evaluated the effect of CDCA on quantitative brain structural metrics in CTX [21, 22]. In a series of 14 French patients with CTX treated by CDCA over a mean period of 5 years, we observed a significant clinical improvement on the EDSS and the Scale for the Assessment and Rating of Ataxia in patients up to 25 years old, whose treatment was initiated less than 15 years after the onset of neurological symptoms [23]. Eleven patients presented with a length-dependent peripheral neuropathy. Electrophysiological parameters improved significantly under CDCA [23]. On neuroimaging, volumetric analyses in a subset of patients showed no overt volume loss on CDCA. Moreover, diffusion-weighted imaging showed improved fiber integrity of the pontocerebellar connections and the internal capsule with CDCA [23].

Genetic Counseling

CTX is an autosomal-recessive disease. Parents are usually heterozygous carriers of one CYP27A1 pathogenic variant and are asymptomatic. At conception, each sibling of a CTX patient has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Presymptomatic testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if both CYP27A1 pathogenic variants in the family are known. Because CTX is treatable, and even more so when treatment is initiated in the early stage of the disease, it is important to advocate for testing of siblings from CTX patients, in line with guidelines for presymptomatic testing, especially in minors [24].

Cerebellar and Pyramidal Syndrome

Cerebellar and pyramidal involvement are frequent in CTX and often start between the second and fourth decade so that the majority of patients have cerebellar and pyramidal features before age 40 [6, 13, 15, 25].

Gait ataxia is the most frequent cerebellar manifestation and is often associated with ataxic dysarthria or dysmetria. Rarely, a low-frequency kinetic tremor of cerebellar origin may also be present. Cerebellar abnormalities seen on MRI may include cerebellar atrophy as well as abnormalities of the dentate nucleus and surrounding white matter [26]. Interestingly, the clinical expression of ataxia is linked to the presence and extent of these abnormalities. Typically, corticospinal tract dysfunction results in a slowly progressive spastic paraparesis, with spasticity predominating over weakness. Pyramidal features likely reflect white matter lesions of the spinal cord [27]. In such cases, increased central motor conduction times on neurophysiological examination and abnormal signal intensity of the lateral corticospinal tracts on spine MRI can be detected [15, 27]. Occasionally, patients have a spinal form of CTX with an isolated and chronic myelopathy [27, 28]. Early treatment with CDCA may prevent worsening of cerebellar and corticospinal tract manifestations or even allow some degree of recovery [2, 23]. In addition to this treatment, management of spasticity and cerebellar manifestations in CTX is symptomatic. The treatment approach should involve a proactive and goal-centered multidisciplinary strategy [29, 30]. Rehabilitation, particularly physical and occupational therapies, are the mainstay of treatment. Oral anti-spasticity medications are usually of limited benefit. Targeted botulinum toxin injections can be useful in patients with disabling spasticity. Intrathecal baclofen can relieve disability in patients with severe spasticity.

Parkinsonism

CTX patients can occasionally develop parkinsonism late in the disease course, usually after the age of 40 [31, 32]. The typical picture is one of a progressive, asymmetric, akinetic–rigid parkinsonism. Resting tremor is sometimes present. The presence of additional neurological manifestations early in the course of parkinsonism, such as ataxia, spasticity, or cognitive deterioration, suggest atypical parkinsonism and can be a helpful clue. A case of pure corticobasal syndrome with no additional clinical features of CTX has previously been reported [31]. Findings from dopamine transporter imaging have consistently shown features of presynaptic dysfunction in patients with CTX-related parkinsonism [31, 32]. A reduced homovanilic acid level has also been found in the CSF of such patients (n = 3/3) [32]. Together, these findings suggest substantia nigra degeneration or dysfunction as an important pathogenic mechanism. Rarely, signal changes in the subtantia nigra or striatum have been reported in patients with parkinsonism. Levodopa responsiveness and early motor fluctuations have been observed in some patients, which supports the presynaptic denervation hypothesis [31–33]. However, the effect of levodopa is usually mild or transient, suggesting more diffuse lesions or dysfunction and possible postsynaptic dysfunction. Unlike most neurological manifestations of CTX, parkinsonism usually has a poor response to CDCA, even when treated early. Two possible explanations may account for this. First, parkinsonism may reflect irreversible lesions (neuronal loss) so that restoring the metabolism has no effect on these symptoms. Second, pathogenic mechanisms unrelated to cholestanol accumulation may be involved in CTX-related parkinsonism.

Dystonia and Myoclonus

Dystonia and myoclonus are rare manifestations of CTX. They are usually mild to moderate and therefore do not represent the most disabling features of the disease. Dystonia, when present, is usually focal or multifocal and mainly affects the limbs or craniofacial area [32]. It can be isolated or mixed with subcortical myoclonus, resulting in myoclonic dystonia [34]. The movement disorder can also appear as an isolated distal myoclonus either because the myoclonus is genuinely isolated or because upper limb dystonia (particularly limb dystonia) is usually restricted to mild abnormal postures and may go unnoticed. In CTX patients, there is little evidence for lesions or dysfunction within the striato-pallido-thalamo-cortical network, an area frequently involved in dystonia. It has been speculated that, in these patients, dystonia and subcortical myoclonus are mainly linked to the lesions of the cerebellum (particularly the dentate nucleus), with the subsequent dysfunction of cerebello-thalamo-cortical pathways. A similar pathogenesis has been described in myoclonus–dystonia due to a mutation in the SGCE gene, another disorder with dystonia and subcortical myoclonus [35]. Symptomatic treatment of CTX-related dystonia is non-specific, and mainly involves botulinum toxin injections. Pharmacological treatments of subcortical myoclonus are usually disappointing, with a poor benefit:side effect ratio, but a few drugs can be considered including zonisamide, benzodiazepines, gabapentin, and levetiracetam [36]. To date, the effect of CDCA treatment on dystonia and myoclonus has not been determined.