Cerebrotendinous xanthomatosis and Marfan syndrome – A picturesque combination
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.190260
Source of Support: None, Conflict of Interest: None
Cerebrotendinous xanthomatosis is an autosomal recessive disorder of cholesterol and bile acid metabolism caused by mutation in the sterol 27-hydroxylase gene (CYP27A1). It leads to the deposition of cholesterol and cholestanol in various tissues such as those of the central nervous system, tendons, lungs, liver, and kidneys.
Marfan syndrome is an autosomal dominant systemic disorder of the connective tissue having varied clinical manifestations, the prominent ones being musculoskeletal, cardiac, and ocular in nature. We describe a young man who had clinical and radiological characteristics of cerebrotendinous xanthomatosis along with Marfan syndrome.
A 24-year-old man presented with complaints of spastic paraparesis and gait ataxia for the past 6 months. He had a history of poor scholastic performance since 10 years of age and a spastic speech for the past 4 years. His mother also reported a history of frequent diarrhea in the past. His birth history was noncontributory. There was no history of consanguinity or similar illness in the family. The physical examination revealed a marfanoid habitus (arm span/height ratio >1) along with dysmorphic facies, high-arched palate, hyperextensible wrist joints, pectus excavatum, positive thumb and wrist sign [Figure 1]a and [Figure 1]b, pes cavus, hammer toes, and bilateral Achilles tendon xanthomas [Figure 1]d. Ophthalmological examination did not reveal any abnormality. The testicular size was normal.
Central nervous system examination showed the mini mental scale examination (MMSE) score of 28/30, with a spastic speech. Spasticity was also present in the lower limbs; power was grade 4+/5 in the lower limbs and normal in the upper limbs. Deep tendon reflexes were brisk, with bilateral extensor plantar response. Sensory examination showed impaired proprioception below the ankles bilaterally and a positive Romberg's sign. He also had bilateral intention tremors; tandem walking was impaired. Neuropsychological assessment revealed an intelligence quotient of 70, suggestive of mental retardation.
Investigations showed a normal lipid profile along with normal thyroid function tests. Nerve conduction studies showed a predominantly demyelinating motor neuropathy. Echocardiography revealed mild aortic regurgitation along with aortic root dilatation (diameter of 3.96 cm at the sinus of Valsalva) and mitral valve prolapse [Figure 1]c.
Magnetic resonance imaging (MRI) of the brain showed T1 hypo- and T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities in bilateral dentate nuclei of the cerebellum and globus pallidus and periventricular white matter without any contrast enhancement [Figure 1]g,[Figure 1]h,[Figure 1]i. MRI of the cervical and dorsal spine was normal.
MRI of the ankles showed T1 and T2 hypointensities along the posterior aspect of the Achilles tendon along with fat suppression characteristic of xanthomas [Figure 1]e and [Figure 1]f. Achilles tendon biopsy was also suggestive of xanthomas. Sural nerve biopsy was normal.
A diagnosis of cerebrotendinous xanthomatosis was considered in view of the constellation of clinical findings of mental retardation, chronic diarrhea, spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and Achilles tendon xanthomas along with the characteristic neuroimaging findings of dentate nucleus hyperintensities.
Serum cholestanol levels and cholestanol/cholesterol ratios were elevated. Urinary bile acid levels and genetic analysis for CYP27-A gene and 27-sterol hydroxylase could not be done due to unavailability of these investigations. The patient was started on atorvastatin, 40 mg at night time, as chenodeoxycholic acid was not available.
We describe a rare metabolic disorder and report its association with Marfan syndrome. To the best of our knowledge, cerebrotendinous xanthomatosis has been described in a patient with marfanoid habitus but not with Marfan syndrome. Our patient fulfilled the modified Ghents criteria for the diagnosis of Marfan syndrome (aortic root dilatation Z score >2 and systemic score of 7 points).
Cerebrotendinous xanthomatosis is a clinically heterogeneous and progressive disorder. The cardinal manifestations of the disorder include diarrhea, cataracts, mental retardation, myelopathy, peripheral neuropathy, cerebellar ataxia, seizures, dementia, and extrapyramidal syndrome along with tendon xanthomas. Diarrhea usually presents during infancy or childhood, with cataracts evident in adolescence. Tendon xanthomas and neurological involvement usually occurs in the second or third decade, which applies to our case also.
Investigations reveal a normal cholesterol and triglyceride concentration along with an elevated cholestanol level in the serum.
MRI demonstrates T1-weighted (W) hypointensities and T2W hyperintensities in bilateral cerebellar white matter and dentate nuclei along with involvement of bilateral globus pallidus and periventricular white matter, which was evident in our case also.
Treatment can dramatically alter the natural history, especially with an early initiation to prevent further progression of the disorder. Chenodeoxycholic acid (750 mg daily) has been commonly used as the standard therapy, which influences the negative feedback of cholesterol and bile acid synthesis.
Statins alone or in combination with chenodeoxycholic acid have also been shown to prevent further clinical deterioration. We started our patient on atorvastatin, 40 mg once daily, owing to nonavailability of chenodeoxycholic acid.
Pathogenesis of Marfan syndrome involves dysregulation of TGF-β metabolism, which also plays a role in fat metabolism. Cholesterol modulates cellular TGF-β responsiveness by altering TGF-β binding to TGF-β receptors. This can be a plausible explanation for the association between the two genetically different disorders.
To conclude, we describe a rare occurrence of cerebrotendinous xanthomatosis with Marfan syndrome. Cerebrotendinous xanthomatosis is a treatable neurodegenerative disorder and should be borne in mind as a differential diagnosis in patients presenting with the characteristic clinical and radiological findings.
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