Clinical manifestations

Presentation and course

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder that manifests with a wide range of systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and multiple neurologic and neuropsychiatric manifestations (69).

Cerebrotendinous xanthomatosis usually manifests in the first decade of life with diarrhea, cataracts, and mild intellectual disability (69). Diarrhea develops within the first year of life, followed by motor and psychiatric symptoms, then cataracts and school difficulties between 5 and 15 years of age (34). Adolescent-to-young-adult-onset tendon xanthomas and adult-onset progressive neurologic dysfunction are typical manifestations. The clinical course of the disease is slowly progressive. Individual and intrafamilial variability is considerable (86; 129; 44; 82). It is inherited in an autosomal recessive manner. Considerable clinical heterogeneity can occur even in identical twins (140). Early treatment with chenodeoxycholic acid may stabilize or improve metabolic and clinical abnormalities (107).

In a review of the clinical features in 55 individuals with cerebrotendinous xanthomatosis by Mignarri and colleagues, cataracts were present in 49 (89%), tendon xanthomas in 43 (78%), osteoporosis in 20 of 30 assessed (67%), and diarrhea in 22 (40%). Neurologic involvement included peripheral neuropathy in 21 of 30 assessed (70%), paraparesis in 35 (64%), intellectual disability in 33 (60%), psychiatric disturbances in 24 (44%), ataxia in 20 (36%), seizures in 18 (33%), and parkinsonism in five (9%) (80).

A study of four Chinese pedigrees reported xanthomas and pyramidal signs in all identified cases, cerebellar ataxia in 67%, cognitive impairment in 67%, cataracts in 50%, peripheral neuropathy in 33%, and chronic diarrhea in only 6% (26). In a review of the clinical features in 43 individuals with cerebrotendinous xanthomatosis by Duell and colleagues, chronic diarrhea was present in 23 (53%), cognitive impairment in 32 (74%), premature cataracts in 30 (70%), tendon xanthomas in 33 (77%), neurologic disease in 35 (81%), and premature cardiovascular disease in three (7%) (42).

A multicenter, cross-sectional descriptive study documented the clinical characteristics of cerebrotendinous xanthomatosis patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid treatment (66). Of 11 patients, three (27%) had neonatal cholestasis, seven (64%) had a history of frequent watery defecation that started in the infantile period, and eight (73%) had juvenile cataract. Seven (64%) were diagnosed in childhood. Four adults had pyramidal signs and parkinsonism symptoms.

The natural history varies for different phenotypes of cerebrotendinous xanthomatosis (ie, the classical, spinal, and “non-neurological” forms) (91); different symptoms and signs also have typical time windows of onset.

Systemic manifestations

Xanthomas. Tendon xanthomas, which are a hallmark of the disease, usually appear in the second or third decade of life. First estimated to be almost invariably present (16; 26), they were found in 78% of patients in a study of 55 cases (80) and less than 50% of a series of Dutch patients (132). They are usually localized at the Achilles tendon; however, they have also been described on the extensor tendons of the elbow and hand, as well as the patellar and neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Adult patients with cerebrotendinous xanthomatosis may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia (115). Diagnosis may be further delayed in patients with the cerebrotendinous xanthomatosis sans xanthomas (52).

Enterohepatic system. Chronic intractable diarrhea from infancy may be the earliest clinical manifestation of cerebrotendinous xanthomatosis (132; 28). Neonatal cholestasis has been reported (35). Gallstones have occasionally been reported.

Eye. In most affected individuals, cataracts are the first clinically documented finding, often appearing in the first decade of life (132; 123; 05; Fernandez‐Eulate et al 2022).

Cataracts may be visually significant opacities requiring lensectomy or visually insignificant cortical opacities. The appearance can include irregular cortical opacities, anterior polar cataracts, and dense posterior subcapsular cataracts (30). Other ophthalmological findings include palpebral xanthelasmas (96), optic nerve atrophy (108), and proptosis (85). In a series of patients reported by Dotti and colleagues (age range 32 to 54 years), ocular manifestations included cataracts in all cases, optic disc paleness in about 50%, and signs of premature retinal senescence with retinal vessel sclerosis in 30% (40). Cholesterol-like deposits along vascular arcades and myelinated nerve fibers were present in some patients.

Cardiovascular system. Premature atherosclerosis and coronary artery disease have been reported (124; 50). Lipomatous hypertrophy of the atrial septum has been described (39; 50).

Skeleton. Bone involvement is characterized by granulomatous lesions in the lumbar vertebrae and femur, osteopenia with increased risk of bone fractures, and impaired adsorption of calcium, which improves with chenodeoxycholic acid treatment (17; 45). Osteopenia is evident by total body densitometry in untreated individuals. Some patients may have marked thoracic kyphosis.

Endocrine abnormalities. Hypothyroidism has occasionally been reported (96; 20; 62).

Premature aging signs. Early-onset cataract, osteopenia with bone fractures and loss of teeth, atherosclerosis, and neurologic impairment with dementia or parkinsonism that are associated with the characteristic facies may suggest a generalized premature aging process (41).

Neurologic manifestations

The neurologic manifestations may include ataxia, dystonia, epilepsy, intellectual disability, dementia, peripheral neuropathy, and parkinsonism (24; 46). In a systematic review of 91 cases of cerebrotendinous xanthomatosis, the most common neurologic abnormalities were corticospinal tract abnormalities (60%), ataxia (59%), cognitive decline (46%), and gait difficulty (38%); 68 (35.0%) had baseline cognitive problems (136). Ataxia, gait difficulties, and corticospinal tract abnormalities develop throughout life, whereas cognitive decline tend to begin later in life (136). Although less common, neurologic abnormalities, seizures, psychiatric changes, and speech changes develop throughout life, whereas parkinsonism and sensory changes generally begin later in life (136). The absence of neurologic symptoms at onset does not rule out the development of future neurologic symptoms (115).

Mental retardation and dementia. Mental retardation, or dementia following slow deterioration in intellectual abilities in the second decade of life, occurs in over 50% of individuals (132; 80; 26). Some individuals show mental impairment from early infancy, whereas the majority has normal or only slightly subnormal intellectual functions until puberty (55). In some cases, cognitive functions are nearly normal.

Neuropsychiatric symptoms. Neuropsychiatric symptoms such as behavioral changes, personality disorders, agitation, aggression, depression, suicide attempts, hallucinations, and psychotic disorders may be prominent (48; 55).

Pyramidal and cerebellar signs. Pyramidal signs (ie, weakness and spasticity) and cerebellar signs (eg, ataxia) are almost invariably present starting at 20 or 30 years of age (64; 139; 26), although some studies reported lower frequencies (80).

A spinal form occurs in which spastic paraparesis is the main clinical symptom (130; 08; 138; 122; 04; 52; 57). In the absence of xanthomas, the diagnosis of spinal cerebrotendinous xanthomatosis can be easily missed or delayed (04; 52).

Extrapyramidal manifestations. Extrapyramidal manifestations, including dystonia and atypical parkinsonism, corticobasal syndrome, postural tremor, ataxia, and myoclonus have occasionally been reported (37; 87; 56; 70; 102; 109; 80; 139; 118; 06). Parkinsonism is the most frequently reported movement disorder in patients with cerebrotendinous xanthomatosis, followed by dystonia, myoclonus, and postural tremor. Movement disorders are mixed in a quarter of the cerebrotendinous xanthomatosis patients with movement disorders and are usually part of a complex clinical picture (118). A movement disorder may be the presenting symptom in a significant proportion of cases (118).

Other neurologic manifestations. Other neurologic manifestations include epilepsy, dysphagia, dysarthria, and peripheral neuropathy (65; 94; 121; 54; 80; 90; 26; 36; 142).

Prognosis and complications

If untreated, cerebrotendinous xanthomatosis is a slowly progressive lethal disease (125; 78; 104; 11; 113; 09). Long-term treatment may stop the deterioration and improve the neurologic functions (107; 25). Neurologic improvement is more likely when treatment is started in young patients (14; 12; 09; 126). Decrease of the size of tendon xanthomas was reported (88; 134). Complications of cerebrotendinous xanthomatosis include deterioration of vision, recurrent falls and bone fractures, urinary tract infections, pneumonia, cachexia, and heart attacks.

Clinical vignette

Case 1. A 40-year-old man had a 2-year history of progressive difficulty with walking and reduced balance (75). Physical examination demonstrated bilateral egg-sized, hard, smooth, and painless masses in the Achilles tendons. Neurologic examination showed mild cognitive and language impairment, gait ataxia, inability to perform tandem gait smoothly, mild muscle hypertonia, and pathologically brisk muscle stretch reflexes with extensor plantar responses and ankle clonus bilaterally.

MRI of the brain showed symmetric hyperintensities in the posterior limbs of internal capsules, paraventricular white matter, cerebral peduncles, and anterior pons on T2W and FLAIR images, with corresponding hypointensities on T1W images, which are along corticospinal tracts.

CT and MRI revealed cerebellar parenchymal abnormalities consistent with cerebrotendinous xanthomatosis.

MRI of an Achilles tendon xanthoma showed fusiform enlargement of the right Achilles tendon. The xanthoma was relatively isointense compared to muscle. An axial proton density image shows diffuse fat infiltration with low-intensity tendon bundles interspersed within.

An unspecified mutation was identified in the CYP27A1 gene.

He was started on chenodeoxycholic acid treatment (250 mg three times per day). His xanthomas of the Achilles tendons began to diminish with treatment, but no improvement was observed in his neurologic signs after more than 3 months of treatment.

Case 2. A 30-year-old Indian man, born to second-degree consanguineous parents, presented with progressive incoordination and gait ataxia since puberty (76). Examination revealed moderate intellectual disability, an immature cataract in the right eye, pseudophakia in the left eye, bilateral tendon xanthomas on the Achilles and patellar tendons, and cerebellar ataxia.

Laboratory investigations further revealed normal hematological parameters, a basic metabolic profile, and a normal lipid profile. Fine-needle aspiration cytology from an Achilles tendon xanthoma revealed foamy histiocytes in clusters and occasional inflammatory cells consistent with fibroxanthoma. T1-weighted MRI of the right ankle showed tendon enlargement with tendon xanthoma showing intermediate signal intensity. T2-weighted MRI of the brain showed bilateral dentate nucleus calcification and bilateral cerebellar atrophy.

Genetic testing identified the pathogenic homozygous missense variant c.380G>A in exon 2 of the CYP27A1 gene, which results in the substitution of amino acid at codon position 127 (p.Arg127Gln). This patient was treated with atorvastatin 80 mg once daily and clopidogrel 75 mg once daily as chenodexycholic acid was unavailable in India.

Case 3. A 27-year-old man, the younger sibling of Case 2, presented with bilateral Achilles and patellar tendon xanthomas since childhood (76).

He also developed early-onset cataracts in both eyes, status post posterior chamber intraocular lens placement. Examination revealed moderate intellectual disability, an otherwise normal neurologic examination, and bilateral xanthomas. Fine-needle aspiration cytology of a xanthoma was consistent with fibroxanthoma. T1-weighted MRI of the left ankle revealed tendon enlargement with Achilles tendon xanthoma showing intermediate signal intensity. FLAIR images of the brain revealed normal bilateral dentate nucleus with no cerebellar atrophy.

Diagnosis of cerebrotendinous xanthomatosis was confirmed by genetic testing, which revealed the same homozygous missense pathogenic variant c.380G>A (p.Arg127Gln) in the CYP27A1 gene.

Biological basis

Etiology and pathogenesis

Cholesterol chemical structure and metabolism. Cholesterol (5-cholesten-3 β-ol) is a C27 alicyclic compound with a fused 4-ring structure (labeled A-D), a single hydroxyl group at C-3, an unsaturated center between C-5 and C-6, an 8-carbon branched hydrocarbon chain attached to the D ring at C-17, and two methyl groups at positions 10 and 13 (numbered C-19 and C-18, respectively). The fused 4-ring structure with a hydroxyl group at C-3 is a sterol; there are three 6-carbon rings and a single 5-carbon ring. The letter identification of the rings is standardized, as is the numbering of the individual carbons, which applies to the sterol ring structure and to cholesterol itself.

Cholesterol is excreted in the bile, primarily as bile acids conjugated to glycine or taurine, the end products of cholesterol metabolism. Primary bile acids are synthesized in hepatocytes directly from cholesterol. The primary bile acids are 24-carbon compounds containing two or three hydroxyl groups, and a side chain ending in a carboxyl group. The carboxyl group is ionized at physiological pH, meaning bile acids are anions (even if the terms “bile acids” and “bile salts” are generally used interchangeably). The most abundant primary bile acids are cholic acid and chenodeoxycholic acid.

Hepatic production of primary bile acids is not sufficient to meet physiologic needs, so the enterohepatic circulation transports most of the excreted primary bile acids back to the liver. Bile acids that are not reabsorbed are converted to various secondary 24-carbon bile acids by gut bacteria. A portion of these secondary bile acids (particularly deoxycholic acid and lithocholic acid) is also passively reabsorbed and returned to the liver, where they are excreted into the gall bladder.

Bile acids serve several physiological functions: (1) the only significant means of cholesterol excretion; (2) solubilizing and transport agents (eg, preventing cholesterol from precipitating from solution in the gall bladder); and (3) a "biological detergent" (in the form of micelles) that facilitates hydrolysis of dietary fats.

Classic pathway of bile acid biosynthesis. Bile acid synthesis proceeds in the liver through a series of chemical steps beginning with cholesterol.

The classic (or neutral) pathway of bile acid biosynthesis produces about 90% of the bile acids.

The first several steps occur in the cytosol. The first and rate-limiting enzyme of the pathway is cholesterol 7α-hydroxylase (CYP7A1; cytochrome P450, family 7, subfamily A, polypeptide 1; also known as cholesterol 7α -monooxygenase), which catalyzes the hydroxylation of cholesterol to 7α-hydroxycholesterol. This step effectively determines the size of the bile acid pool. 7α-hydroxycholesterol then undergoes isomerization to form 7α-hydroxy-4-cholesten-3-one.

What follows is a complicated series of chemical reactions catalyzed by different enzymes. The net result, though, is synthesis of almost equal amounts of the two primary bile acids: cholic acid and chenodeoxycholic acid.

First branch. In one branch of the classic pathway, 7α-hydroxy-4-cholesten-3-one is converted into 7α,12α-dihydroxy-4-cholesten-3-one in the endoplasmic reticulum by the action of the enzyme CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1; also known as sterol 12-alpha-hydroxylase).

7α,12α-dihydroxy-4-cholesten-3-one is then converted into 5β-cholestan-3α,7α,12α-triol by reduction and dehydrogenation through the actions of 5β-reductase (AKR1D1, ie, aldo-keto reductase family 1 member D1) and 3α-hydroxysteroid dehydrogenase (3α-HSD; or AKR1C4, ie, aldo-keto reductase family 1 member C4).

5β-cholestan-3α,7α,12α-triol is converted into 3α,7α,12α-trihydroxy-5β-cholestanic acid (THCA) in the mitochondria through the action of CYP27A1 (cytochrome P450, family 27, subfamily A, polypeptide 1; commonly known as sterol 27-hydroxylase).

THCA then undergoes side-chain cleavage through peroxisomal β-oxidation followed by amino-conjugation (in the cytosol/peroxisome) to form cholic acid.

Second branch. In the other branch of the classic pathway, 7α-hydroxy-4-cholesten-3-one is converted into 5β-cholestan-3α,7α-diol. 5β-cholestan-3α,7α-diol is converted into 3α,7α-dihydroxy-5β-cholestanic acid (DHCA) in the mitochondria through the action of CYP27A1. Finally, DHCA is converted to chenodeoxycholic acid.

Alternate pathway of bile acid biosynthesis. An alternative pathway (also known as the acidic pathway due to the synthesis of acidic intermediates) generally produces less than 10% of available bile acids in normal adults but may be relatively more important than the classic pathway in patients with liver dysfunction and is the predominant pathway in neonates.

The alternative pathway is initiated by mitochondrial sterol 27-hydroxylase (CYP27A1).

The key regulatory steps of the alternative pathway are the first two steps: (1) 27-hydroxylation by mitochondrial sterol 27-hydroxylase (CYP27A1) to form 27-hydroxycholesterol, and (2) the subsequent 7α-hydroxylation by oxysterol 7α-hydroxylase (CYP7B1). CYP7B1 serves as the ultimate controller of cellular oxysterol levels.

Cerebrotendinous xanthomatosis, an inborn error of bile acid synthesis. Cerebrotendinous xanthomatosis, due to 27-hydroxylase deficiency, is a rare familial sterol storage disease with accumulation of cholestanol and cholesterol in most tissues, particularly in xanthomas, bile, and brain. Clinically, this disorder is characterized by dementia, spastic paresis, cerebellar ataxia, tendon xanthomas, early atherosclerosis, and cataracts.

Cerebrotendinous xanthomatosis is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding a cytochrome p450 oxidase, a mitochondrial enzyme commonly known as sterol 27-hydroxylase. More than 20 different mutations have been defined in the sterol 27-hydroxylase gene (CYP27A1) of patients with cerebrotendinous xanthomatosis. A symptomatic heterozygote carrier with clinical disease and decreased enzyme function has also been reported; no second mutation was identified despite an extensive search (120).

The defect in sterol 27-hydroxylase leads to a block in bile acid biosynthesis, with a drop in levels of primary bile acids, accumulation of substrates for the mitochondrial 27-hydroxylase, and a pathologic and toxic increase in otherwise uncommon metabolites. In particular, cholesterol metabolism in cerebrotendinous xanthomatosis proceeds by otherwise minor metabolic pathways to form bile alcohols rather than bile acids. The absence of the negative feedback mechanism of chenodeoxycholic acid on 7α-hydroxylase, the rate-limiting enzyme in bile acid synthesis, augments the accumulation of intermediates as precursors for cholestanol. In cerebrotendinous xanthomatosis, these bile alcohols are excreted in gram amounts in bile and feces.

In cerebrotendinous xanthomatosis, the levels of cholestanol in serum are markedly increased, whereas the levels of cholesterol are generally normal. Metabolism of cholesterol in cerebrotendinous xanthomatosis includes, sequentially, the intermediaries cholest-4-en-3-one, 5α-cholestan-3-one, and, ultimately, 5α-cholestan-3β-ol (cholestanol) (106).

However, at least part of the excess cholestanol in patients with cerebrotendinous xanthomatosis is formed from the accumulated 7α-hydroxycholesterol and 7α-hydroxy-4-cholesten-3-one, the first two metabolic intermediates of the classic pathway of cholesterol metabolism (112). 7α,12α-Dihydroxy-4-cholesten-3-one, the product of CYP8B1 in the classic pathway of bile acid biosynthesis, is the most prominently elevated metabolite in serum and CSF of drug-naive patients with cerebrotendinous xanthomatosis (60).

In cerebrotendinous xanthomatosis, some intermediary metabolites from the classic pathway are metabolized into 5β-cholestane-3α,7α,12α,25-tetrol, 5β-cholestane-3α,7α,12α,23-tetrol, and 5β-cholestane-3α,7α,12α,24,25-pentol.

Cholestanol and 7α-hydroxycholesterol accumulate in many tissues (18), including the brain, leading to progressive neurologic dysfunction. The increased bile alcohol level may lead to disruption of the blood-brain barrier, which, in turn, may facilitate brain deposits of these substances (105). The storage of cholestanol in other tissues causes tendon xanthomas, atherosclerosis, lipomatous hypertrophy of the atrial septum, and cataracts (22). The reason for the accumulation of cholestanol and cholesterol in certain tissues in cerebrotendinous xanthomatosis is not understood.

Epidemiology

The estimated prevalence of cerebrotendinous xanthomatosis in the general population is 3 to 5 per 100,000 but may be 500-fold higher (1.6% to 1.8%) among patients with acquired juvenile-onset idiopathic bilateral cataracts (49; 05). Prevalence estimates are highest in Asians (1:44,407–93,084) and lowest in the Finnish population (1:3,388,767), whereas intermediate estimates are found in Europeans, Americans, and Africans/African Americans (1:70,795–233,597) (98). The prevalence of cerebrotendinous xanthomatosis related to the p.Arg395Cys mutation alone is approximately 1 per 50,000 among the Caucasian population (73).

Some ethnic subgroups have a high cerebrotendinous xanthomatosis gene frequency. The prevalence in Sephardic Jews of Moroccan extraction was estimated to be 1 in 108 (10). In Jewish Moroccans, there is an estimated prevalence of 4 in 100,000, with cases resulting from the two mutant alleles in nonconsanguineous marriages (72). In a high-risk Israeli population, a 1 in 30 carriership frequency was determined for the c.355delC CYP27A1 gene variant newborns identifying as Druze (an Arabic-speaking ethnoreligious group originating in Western Asia), providing an estimated disease prevalence of 1 in 3600 in this population (32).

Prevention

Early diagnosis of at-risk family members using biochemical testing, or molecular genetic testing if the two disease-causing mutations in the proband are known, allows initiation of treatment that may prevent or limit disease manifestations. Prenatal diagnosis may be possible.

Different newborn screening biomarkers for cerebrotendinous xanthomatosis have been described. Both 5β-cholestane-3α,7α,12α,25-tetrol glucuronide (GlcA-tetrol) and the ratio of GlcA-tetrol to tauro-chenodeoxycholic acid (t-CDCA) (GlcA-tetrol/t-CDCA) are excellent cerebrotendinous xanthomatosis biomarkers suitable for newborn screening (61).

Differential diagnosis

Sitosterolemia is an inherited sterol storage disease characterized by tendon xanthomas and by a strong predisposition to premature atherosclerosis. Serum concentration of plant sterols (sitosterol and campesterol) is increased. Primary neurologic signs and cataracts are not present. Spastic paraparesis may occur as a result of spinal cord compression by multiple intradural, extramedullary xanthomas (59).

Cerebrotendinous xanthomatosis is the second most common cause of early-onset cataract and neurologic disease (myotonic dystrophy type 1 is the most common cause). Unexplained juvenile-onset cataracts associated with infantile-onset chronic diarrhea and mental retardation or deterioration strongly suggest the possibility of cerebrotendinous xanthomatosis (29; 30; 132).

In hypercholesterolemia and hyperlipemia (especially type IIa) the plasma cholestanol level is normal. When xanthomas are not evident, the differential diagnosis includes all forms of progressive mental deterioration (53; 131).

When xanthomas are not evident, the differential diagnosis includes all forms of progressive mental deterioration or mental retardation (53; 141), and in one such case, the findings suggested mitochondrial disease and, specifically, myoclonic epilepsy with ragged-red fibers (MERRF) (67).

Diagnostic workup

Cerebrotendinous xanthomatosis is underrecognized (71). Improved screening, clinical awareness, and prompt treatment are needed to prevent unnecessary and irreversible disease progression (07; 90; 03; 34; 107; 123; 31). The average age at diagnosis is 32 to 35 years, with a mean delay in diagnosis of 16 to 17 years (80; 90; 42; 110). A 2-tiered newborn screening approach may be feasible (32). Forme frustes and the marked clinical heterogeneity can make diagnosis difficult (119); delays can result in worse clinical outcomes, so early diagnosis and treatment initiation are critical.

Cerebrotendinous xanthomatosis should be suspected in individuals with the following findings:

Clinical prediction rule (suspicion score; Mignarri score; Mignarri index). Mignarri and colleagues devised a clinical prediction tool or “suspicion index” that is simple, inexpensive, and yet highly effective as a diagnostic aid (80); this is now sometimes referred to as the Mignarri score or Mignarri index. Clinical features were classified as moderate, strong, or very strong and weighted accordingly with weights of 25, 50, and 100, respectively. An equivalent method would be to weight these as 1, 2, and 4 points, respectively. Strong indicators included early systemic signs (eg, cataract, diarrhea, and neonatal cholestatic jaundice) and neurologic features (eg, intellectual impairment, psychiatric disturbances, ataxia, spastic paraparesis, and dentate nuclei abnormalities at MRI). Very strong indicators included tendon xanthomas and a sibling affected with cerebrotendinous xanthomatosis. A total score of 100 or more (or equivalently, 4 points) warrants serum cholestanol assessment, and either an elevated cholestanol level or a total score of 200 or more (or equivalently, 8 points), with at least one very strong or four strong indicators, warrants CYP27A1 gene analysis. Using this tool (albeit retrospectively), the mean age at diagnosis could be reduced from 36 years to 11 years.

Neuroimaging. Neuroimaging (CT and especially MRI) illustrates cerebral, cerebellar, and spinal cord atrophy; T2-weighted/FLAIR hyperintensities involving subcortical, periventricular, and cerebellar white matter; and the brainstem and dentate nuclei (90; 63; 75; 117).

Typically, there are lesions in the cerebellar dentate nuclei (hyperintense on T2-weighted images and hypointense on T1-weighted images) associated with diffuse white matter abnormalities (01; 64; 99; 90; 139; 79; 77; 63; 75; 117).

T1-weighted/FLAIR hypointensities consistent with cerebellar vacuolation and T1-weighted/FLAIR/susceptibility-weighted hypointense alterations compatible with calcifications are seen in the dentate nuclei in a small subgroup of patients (79; 63; 75; 117). Cerebellar vacuolation is a useful biomarker of disease progression and unsatisfactory response to therapy, whereas the absence of dentate nuclei signal alteration is a good prognostic indicator (79).

MRI abnormalities may also involve the spinal cord and, in particular, may show signal changes affecting mainly the lateral corticospinal tracts (63).

Treatment initiation at a younger age markedly decreases evident progression on serial MRI studies (116; 117). It can reverse and even prevent the development of neurologic symptoms.

Diffusion tensor imaging and tractography can (1) detect changes in the brain when the conventional MRI is unremarkable and (2) provide potential neuroimaging biomarkers for monitoring treatment response in cerebrotendinous xanthomatosis, even when conventional MRI remains unchanged (25).

PET imaging of the brain may show hypometabolism in the cerebrum (especially in the frontal and temporal lobes) (90).

Multinodular thickening of the nerve roots and trunks of the lumbosacral plexus may be detected without gadolinium enhancement on MRI and MR neurography (58).

Multifocal, hypoechogenic nerve thickening of peripheral nerves and nerve roots may be demonstrated using high-resolution ultrasound (100).

Xanthomas. MRI of tendon xanthomas generally shows fusiform enlargement of the tendon, particularly the Achilles tendon. The xanthomas are relatively isointense compared to muscle, and there may be evidence of fat infiltration of the tendon.

Histology of tendon xanthomas shows accumulation of xanthoma cells and dispersed lipid crystal clefts.

Although not needed in most clinical situations, PET imaging, if conducted, may show unusually high radioactivity in the xanthomas (90).

Diagnostic testing for cerebrotendinous xanthomatosis. Genetic analyses or determination of serum cholestanol levels should be used to diagnose cerebrotendinous xanthomatosis (115).

Dried bloodspot testing should facilitate detection in newborns (115).

Biochemical testing. Cerebrotendinous xanthomatosis is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase, with resulting cholestanol and cholesterol accumulation in virtually every tissue. Plasma cholestanol should be measured in any patient with infantile chronic diarrhea or jaundice, juvenile cataract, learning disability or autism spectrum disorder, pyramidal signs, cerebellar syndrome, or peripheral neuropathy (02).

The main laboratory abnormalities that distinguish cerebrotendinous xanthomatosis from other conditions with xanthomas include the following:

Some additional studies are abnormal and may be useful in certain circumstances, but they are currently less commonly used for general clinical diagnosis and management.

Other laboratory abnormalities that are not diagnostic include the following:

Genetic testing. Sequence analysis of the CYP27A1 gene detects mutations in 90% to 100% of affected individuals.

Phenotypic heterogeneity may occur among affected siblings (57; 68; 76). In one family, one sibling had the spinal xanthomatosis phenotype and the other had a very mild form of cerebrotendinous xanthomatosis manifesting as minor tendon xanthomatosis and gastrointestinal complaints (57). However, biochemical analysis revealed normal levels of serum cholestanol and relatively mild elevations of the bile acid precursors 7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one. Nevertheless, both siblings had compound heterozygous variants in CYP27A1. The atypical biochemical findings illustrate that cholestanol is not a perfectly sensitive test for cerebrotendinous xanthomatosis. Therefore, patients with symptomatology consistent with cerebrotendinous xanthomatosis should have bile acid precursor biochemical testing and molecular analysis (57).

Electrophysiology studies. Decreased nerve conduction velocities as well as abnormal somatosensory, motor, brainstem, and visual evoked potential may improve or resolve with chenodeoxycholic acid therapy.

Dual-energy x-ray absorptiometry (DEXA) studies. Osteoporosis is common, so consideration should be given to screening for this with DEXA of the femoral neck and lumbar spine.

Other diagnostic findings. Large paranasal sinuses may be noted on brain imaging or skull x-rays.

Histology of xanthomas. Histological findings from tendon xanthomas show foamy macrophages and lipid crystal clefts (27).

Potential for newborn screening. Because delayed diagnosis and treatment worsens the prognosis, cerebrotendinous xanthomatosis is an excellent candidate disorder for newborn screening using recently developed methods for newborn dried bloodspot analysis (33; 32; 19; 116; 61; 31; 127). Unfortunately, this has not yet been implemented.

Management

Age at diagnosis and early treatment initiation (at birth, where possible) have the biggest impact on treatment outcomes (115).

Beginning treatment as early as possible is essential for preventing neurologic damage and deterioration from cerebrotendinous xanthomatosis (137; 02; 35; 68; 103). Once significant neurologic pathology has been established, the effect of treatment is limited, and progressive neurologic deterioration may continue even despite treatment (137; 42). Indeed, patients who started treatment after the age of 25 years had worse outcomes, were significantly more limited in ambulation and more cognitively impaired, and were more likely to continue to deteriorate despite treatment (137).

The recommended therapy for patients with cerebrotendinous xanthomatosis is chenodeoxycholic acid, which inhibits the 7-alpha-hydroxylation of cholesterol (a normal negative feedback mechanism), thereby reducing the formation of cholestanol and the excretion of bile alcohols in feces and urine.

The importance of early treatment initiation is emphasized by two siblings reported by Koyama and colleagues (68). Two siblings with cerebrotendinous xanthomatosis had differing clinical features at diagnosis and different responses to chenodeoxycholic acid treatment; they shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20). The proband, a 32-year-old man, had chronic diarrhea, bilateral cataracts, and xanthomas, and developed progressive neurologic abnormalities, including ataxia, spastic paraplegia, and cognitive decline during a 5-year period, despite normalization of serum cholestanol after initiation of chenodeoxycholic acid treatment. Serial brain MRI studies over this period revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions on T2-weighted images in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives.

Brain 99mTc-ethyl cysteinate dimer (99mTc-ECD) single photon emission computed tomography (SPECT) revealed marked cerebellar hypoperfusion, as well as mild frontoparietal hypoperfusion.

In contrast, his 30-year-old sister presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but had no other neurologic symptoms at the time of diagnosis. Chenodeoxycholic acid treatment lead to improvement of cognitive function, and there were no characteristic CTX-related MRI features during a 5-year period.

Brain 99mTc-ECD SPECT revealed mild frontoparietal hypoperfusion, without abnormal cerebellar hypoperfusion.

Both siblings had an excellent and sustained biochemical response to chenodeoxycholic acid.

However, the proband, who had more advanced neurologic manifestations at the time of treatment initiation developed progressive neurologic abnormalities, including cognitive decline, whereas his sister avoided these adverse outcomes and showed steady improvement in verbal and performance IQ.

Chenodeoxycholic acid is a lifetime replacement therapy that, if initiated early, can considerably improve outcomes because it may be capable of arresting, or in some cases, reversing the pathophysiological process in cerebrotendinous xanthomatosis (115). Clinical improvement of individuals with cerebrotendinous xanthomatosis following treatment with chenodeoxycholic acid was first reported by Berginer and colleagues (16). Chenodeoxycholic acid is effective in the long-term treatment of cerebrotendinous xanthomatosis, with an acceptable safety profile (128). Long-term chenodeoxycholic acid treatment (750 mg/day in adults) normalizes bile acid synthesis (leading to disappearance of abnormal metabolites from serum, bile, and urine), normalizes plasma and CSF concentration of cholestanol by suppressing cholestanol biosynthesis, and improves neurophysiologic findings and other clinical manifestations, including osteoporosis (83; 45; 84; 128). In a study of treatment with chenodeoxycholic acid over 11 years, nerve conduction velocities normalized after 4 months of treatment and subsequently remained stable; motor-evoked potentials and sensory-evoked potentials slowly and continuously improved; and clinical manifestations stabilized, even though neurologic deficits did not improve (84; 54). The contrast between two untreated siblings whose symptoms progressed and a third treated sibling whose symptoms stabilized suggests that treatment is beneficial.

Although chenodeoxycholic acid treatment seems to stabilize or improve clinical symptoms in most patients, sudden interruption of chenodeoxycholic acid may lead to irreversible neurologic complications.

Although chenodeoxycholic acid has been approved for gallstone dissolution, the U.S. Food and Drug Administration (FDA) has not yet approved it for cerebrotendinous xanthomatosis, despite long-term efficacy and safety data (42). Instead, chenodeoxycholic acid has an orphan drug designation by the FDA. Drug company manipulation resulted in dramatic escalation (500%) in the price for the drug, compromising the health of affected individuals, sometimes with very negative neurologic consequences (97; 21).

Monitoring plasma cholestanol levels is recommended during chenodeoxycholic acid treatment (115).

Presumably, cholic acid (the other primary bile acid) could have negative feedback effects, like chenodeoxycholic acid, on the classic pathway of bile acid synthesis. However, there is presently no consensus on the value of cholic acid therapy alone (115).

Inhibitors of HMG-CoA reductase alone or in combination with chenodeoxycholic acid are also effective in decreasing cholestanol concentration and improving clinical signs (95; 133). However, because of clinical evidence that HMG-CoA reductase inhibitors may induce muscle damage and even rhabdomyolysis, caution is required in the use of these drugs (43).

Riluzole has been proposed as a potential adjunctive therapy, but the only anecdotal case utilized this in conjunction with chenodeoxycholic acid, so its marginal benefit is not clear (135).

Other possible treatments include LDL apheresis, but the results are controversial (81; 15; 38).

Liver transplantation, although not yet performed in individuals with cerebrotendinous xanthomatosis, remains a possibility.

Cataract extraction is typically required in at least one eye by 50 years of age.

Symptomatic treatments for epilepsy, spasticity, and parkinsonism have been utilized. Parkinsonism in individuals with cerebrotendinous xanthomatosis is poorly responsive to levodopa, whereas an antihistamine drug, diphenylpyraline hydrochloride, had an excellent effect in three individuals (93).

Endoscopic resection of tendon xanthoma in the elbow or ankle is less invasive than open resection (89).

Special considerations

Pregnancy

The clinical status of pregnant women with cerebrotendinous xanthomatosis does not deteriorate as a result of pregnancy, and elevated serum cholestanol concentration slightly decreases (10; 74; 13). Perhaps this occurs because the liver of the fetus partially compensates for the defect in bile acid synthesis of the pregnant woman. Treatment with chenodeoxycholic acid should not be discontinued during pregnancy.