脳腱黄色腫症

Cerebrotendinous xanthomatosis (CTX) is a treatable genetic disorder associated with deficiency of the sterol 27-hydroxylase enzyme (CYP27A1), important in bile acid synthesis. CTX may present in the newborn period as hepatic jaundice/cholestasis, that can resolve or can progress to fatal liver disease. Many cholestasis gene panel tests now include CYP27A1. For infants presenting with cholestasis that are identified to have CTX, follow-up biochemical testing is recommended. Here, we describe a case of an infant with neonatal jaundice genetically diagnosed with CTX through the use of cholestasis gene panel testing. Follow-up biochemical testing determined the infant had normal plasma cholestanol, inconsistent with a diagnosis of CTX according to expert guidance. We report that quantitative biochemical testing for bile acid precursors and bile alcohols provided definitive biochemical evidence of CTX and recommend that such testing is advised in infants with CYP27A1 gene analysis indicative of CTX.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of cholesterol metabolism, characterised by childhood-onset diarrhoea, juvenile cataracts, tendon xanthomas, and progressive neuropsychiatric symptoms. CTX is caused by mutations in the sterol 27-hydroxylase gene (CYP27A1) and sterol 27-hydroxylase deficiency. CTX is particularly rare in the Chinese population; to the best of our knowledge, this is the first report of identical twins with CTX in China. The present study also includes a review of the literature on the clinical presentation, imaging findings, and genetic results in identical twins and triplets with CTX. Our twin patients carried a homozygous transition mutation in intron 7 and displayed clinical manifestations of atypical parkinsonism and cognitive impairment; furthermore, they exhibited different phenotypes, which may be attributed to lifestyle differences. Early diagnosis and treatment are crucial to the prognosis of CTX, and genetic testing should be conducted to confirm the diagnosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is caused by biallelic mutations in the CYP27A1 gene, which encodes sterol 27-hydroxylase. Reduced activity of this enzyme decreases bile acid synthesis and increases cholestanol production. Cholestanol, a metabolic intermediate, can be used as a diagnostic marker; however, patients with CTX have been reported to have normal cholestanol levels. Cholesterol and bile acid metabolism is likely to be extensively disrupted even in these patients with CTX. OBJECTIVE: We aimed to clarify whether sterol markers, including oxysterols, can be used to screen for and diagnose CTX and assess treatment efficacy. METHODS: Fourteen patients with CTX (homozygotes, n = 7; compound heterozygotes, n = 5; unidentified, n = 2), 6 carriers, and 24 healthy controls were enrolled. We analyzed 9 sterol markers, including 4 oxysterols, using gas chromatography-mass spectrometry. We measured these markers in patients with CTX before and after treatment with chenodeoxycholic acid (CDCA) and/or lipid-lowering agents. RESULTS: Cholestanol and sterol markers of cholesterol synthesis and absorption were 1.3 to 8.3 times higher in patients with CTX than in carriers and controls. These marker levels decreased significantly in patients with CTX after treatment. Compared to carriers and controls, patients with CTX had extremely low levels of 27-hydroxycholesterol (27-OHC) and extremely high levels of 7α-hydroxycholesterol (7α-OHC). During treatment, 7α-OHC levels decreased significantly, while 27-OHC levels remained low. Receiver operating characteristic analysis demonstrated excellent diagnostic performance. The area under the curve was 1.000 for low 27-OHC and 0.991 for elevated 7α-OHC, outperforming cholestanol (0.903). CONCLUSION: Sterol markers, including oxysterols, can be used to screen for and diagnose CTX and to assess treatment efficacy with CDCA and/or lipid-lowering agents.

BACKGROUND: Despite established clinical diagnostic criteria for Parkinson's disease and the neurodegeneration-related atypical parkinsonian syndromes (progressive supranuclear palsy/PSP, corticobasal degeneration syndrome/CBD, multiple system atrophy with parkinsonian or cerebellar predominance/MSA-P/C, and dementia with Lewy bodies/DLB), the differential diagnosis from rare hereditary and acquired disorders presenting with parkinsonism can be challenging. METHODS: Based on a PubMed search, relevant original studies and review articles were analyzed to identify rare hereditary and acquired disorders associated with parkinsonism. Secondary parkinsonian syndromes resulting from medication or toxin exposure were excluded but are summarized in an overview. RESULTS: Without claiming completeness, the major hereditary and acquired disorders associated with parkinsonism were summarized in tabular form. Selected entities were described in more detail in short profiles focusing on those with therapeutic modifiability, characteristic pattern-like constellations of findings, or notable pathophysiological mechanisms. Paradigmatic cerebral MRI patterns are illustrated. CONCLUSIONS: A broad spectrum of rare acquired and genetic entities can manifest with clinically relevant parkinsonian syndromes. Frequently, parkinsonism occurs in combination with other neurological features of variable severity, including extrapyramidal-hyperkinetic symptoms (dystonia/chorea), cerebellar signs (ataxia), pontomesencephalic involvement (oculomotor disturbances, bulbar dysarthria/dysphagia), motor neuron signs (spasticity and/or amyotrophic paresis), cognitive or neuropsychiatric symptoms, and epilepsy.For several disease groups - such as neurodegeneration with brain iron accumulation (NBIA), Wilson's disease, and primary familial brain calcification (PFBC) - distinctive MRI patterns are diagnostically informative.A relevant subset of disorders exhibits at least a partial and sometimes transient presynaptic dopaminergic deficit responsive to dopaminergic medication (e.g., certain NBIA forms, spinocerebellar ataxias/SCA, cerebrotendinous xanthomatosis/CTX).Neuropathologically, some of these disorders are associated with secondary synucleinopathies (e.g., MPAN), tauopathies (e.g., IgLON5 syndrome) or TDP-43 (e.g., Perry syndrome/DCTN1).