Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report

The proband, a 32-year-old Japanese man, was the first child of non-consanguineous healthy parents (Supplementary Fig. 1A). There was no past medical history of neonatal jaundice or cholestasis. He had chronic unexplained diarrhea starting within the first year of life. In addition to having learning disabilities, he noted an enlarging tuberous xanthoma on the left knee at the age of 13. At age 31, he underwent bilateral cataract surgery, and developed a gait disturbance, which worsened gradually. At age 32, he visited our hospital. A physical examination revealed a pes cavus deformity of the left foot besides xanthomas of the left knee and bilateral Achilles tendons. On neurological examination, he exhibited impaired smooth pursuit eye movements, dysarthria, ataxia in the trunk and bilateral lower extremities, and spastic paraplegia. Vibration sense in the lower extremities was impaired, while joint position sense was preserved. There was generalized hyperreflexia of all four extremities with bilateral ankle clonus and positive Babinski signs. Parkinsonism was not evident. He had a score of 20/30 on the Mini-Mental State Examination (MMSE). On the Wechsler Adult Intelligence Scale-III (WAIS-III), verbal and performance IQs were 58 and 54, respectively (Fig. 2C). Brain magnetic resonance imaging (MRI) showed hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted (Fig. 1A) and fluid-attenuated inversion recovery images. Mild cerebral and cerebellar atrophy was also evident. T2-weighted spinal cord MRI revealed hyperintense lesions localized in the lateral corticospinal tracts and gracile tracts, longitudinally extending from the C1 to Th10 level (Fig. 1C and D). An electroencephalogram (EEG) revealed slow background activity composed of theta and delta waves with bursts of high voltage activity. Epileptic discharges were not present (Fig. 2B). Nerve conduction studies (NCSs) revealed a slightly decreased motor nerve conduction velocity in the posterior tibial nerve, with normal amplitude of compound muscle action potential. Bone mineral density (BMD) at the lumbar spine assessed by dual-energy X-ray absorptiometry was slightly decreased (0.894 g/cm², T-score = -1.3). His serum cholestanol level was elevated to 27.5 µg/mL (normal range, 1.91–3.51 µg/mL) (Fig. 2A).

After obtaining written informed consent, genomic DNA was extracted from the peripheral blood of the patient and his parents. The CYP27A1 gene was amplified by PCR from the genomic DNA. Sequence analysis identified a compound heterozygous mutation in the proband. One was a novel c.1176_1177delGA mutation in exon 6, resulting in a frame shifting change with a glutamic acid to aspartic acid substitution at position 392 and the new reading frame ending in a stop at position 20, p.(Glu392Asp*20). The other mutation was the known c.1420C > T mutation (p.Arg474Trp) in exon 8. The former mutation was inherited from his mother and the latter from his father (Supplementary Fig. 1B).

The patient was diagnosed with CTX and treated with CDCA at 15 mg/kg daily (750 mg/day), leading to immediate disappearance of the diarrhea. The serum cholestenol concentration gradually decreased in the first year of CDCA treatment and was well-controlled during the follow-up period (Fig. 2A). In EEG after one year of treatment, diffuse slow background activity with bursts of high voltage activity remained evident (Fig. 2B). Despite treatment with CDCA and normalization of serum cholestanol, neuropsychiatric manifestations including dysarthria, dysphagia, and spastic paraplegia continued to worsen. Percutaneous endoscopic gastrostomy was performed due to exacerbating dysphagia. Although an initial improvement in WAIS-III scores was observed with CDCA therapy, scores tended to decrease, particularly for VIQ. However, we could not obtain IQ scores four years after starting therapy because of conversion disorder (Fig. 2C). Follow-up MRI demonstrated progressive signal abnormalities and diffuse brain atrophy especially in the cerebellum (Fig. 1A). Brain ⁹⁹mTc-ethyl cysteinate dimer (⁹⁹mTc-ECD) single photon emission computed tomography (SPECT) revealed marked cerebellar hypoperfusion, as well as mild frontoparietal hypoperfusion (Fig. 1E).

A 30-year-old woman, the younger sister of Case 1, presented to our hospital with suspected CTX. She had been able to attend regular school despite learning difficulties, and had no past medical history of neonatal jaundice or cholestasis. Bilateral juvenile cataracts were diagnosed at the age of 13, and she underwent surgery at the age of 18. At age 20, she had mild diarrhea, while there had been no history of diarrhea during early childhood. A physical examination revealed mild enlargement of both Achilles tendons. A neurological examination found no signs of spasticity, ataxia, or parkinsonism. Neither hyperreflexia nor the extensor plantar response was observed. Her MMSE score was 23/30. Her WAIS-III verbal and performance IQs were 69 and 53, respectively (Fig. 2C). Brain and spinal cord MRI revealed neither obvious signal intensity changes nor atrophy (Fig. 1B). EEG showed slow background activity with bursts of high voltage activity, without epileptic discharges (Fig. 2B). NCS findings were unremarkable. BMD at the lumbar spine measured by DEXA was within the normal range (0.929 g/cm², T-score = -0.7). Her serum cholestanol level was elevated to 33.6 µg/mL (Fig. 2A). Genetic analysis of the CYP27A1 gene revealed that she was compound heterogeneous for the two above mutations.

She was diagnosed with CTX and treated with CDCA at 15 mg/kg daily, which immediately improved the diarrhea. With treatment, the cholestanol level gradually decreased to within the normal range (Fig. 2A). One year after beginning treatment with CDCA, α-waves were clearly observed on EEG, instead of diffuse slow background activity (Fig. 2B). Her WAIS-III scores improved during the follow-up period (Fig. 2C). Other than a transient obsessive–compulsive disorder, no neurological manifestations were apparent. There was no significant deterioration on brain MRI (Fig. 1B) or in BMD. Brain 99mTc-ECD SPECT revealed mild frontoparietal hypoperfusion, without abnormal cerebellar hypoperfusion (Fig. 1F).