MALATTIE DA ACCUMULO DI OSSISTEROLI. RIUNIONE SNO TOSCANA VIAREGGIO, 06/04/2019 MALATTIE DA ACCUMULO DI OSSISTEROLI. L’ESEMPIO DI DUE FORME TRATTABILI: XANTOMATOSI CEREBROTENDINEA (CTX) E PARAPARESI SPASTICA TIPO 5 (SPG5) Andrea Mignarri U.O. Neurologia – P.O. Misericordia Grosseto

DISORDERS OF BILE ACID SYNTHESIS CTX SPG5

CEREBROTENDINOUS XANTHOMATOSIS (CTX) Autosomal recessive disease due to mutations of CYP27A1 (sterol-27-hydroxylase), which has a key role in bile acid biosynthesis. Brain storage of toxic bile acid precursors. Clinical manifestations: - Systemic: chronic diarrhoea, juvenile cataracts, tendon xanthomas, premature osteoporosis - Neurological: spasticity, ataxia, psychiatric and cognitive disturbances, epilepsy, polyneuropathy Treatable disease! Early diagnosis! Cholestanol accumulates in the brain as a consequence of the flux of its precursor 7αC4 across the BBB, and may induce apoptosis of neuronal cells.

Suspicion Index Indicators Family history Systemic Neurological (A) Very strong (score = 100) A1) Sibling with CTX A2) Tendon xanthomas (B) Strong (score = 50) B1) Consanguineous parents B2) Juvenile cataract B3) Childhood-onset chronic diarrhea B4) Prolonged neonatal jaundice B5) Ataxia (a) and/or Spastic paraparesis (b) B6) Dentate nuclei signal alterations at MRI B7) Intellectual disability (a) and/or Psychiatric disturbances (b) (C) Moderate (score = 25) C1) Early osteoporosis C2) Epilepsy C3) Parkinsonism C4) Polyneuropathy

Diagnostic flow chart

Application of the diagnostic tool Age at diagnosis was 35.5 ± 11.8 years. SI score at diagnosis was 298.2 ± 66.6. Serum cholestanol elevated in all patients: 2.94 ± 1.21 mg/dl against 0.22 ± 0.08 in controls (p<0.0001). Age at SI ≥100 was 10.6 ± 9.8 years; age at SI ≥200 was 24.1 ± 11.4 years. Difference between age at actual diagnosis and age at SI ≥100 and SI ≥200 was 25.1 ± 11.8 years and 12.0 ± 9.5 years, respectively (p<0.01).

cholestanol 7ɑC4 27OHC 24OHC t0 = baseline - t1 = 0-1.5 years - t2 = 1.5-2.5 years - t3 = 2.5-3.5 years - t4 = >4 years

cholesterol lathosterol campesterol sitosterol t0 = baseline - t1 = 0-1.5 years - t2 = 1.5-2.5 years - t3 = 2.5-3.5 years - t4 = >4 years

Neurologically stable patients Neurologically worsening patients

Most important biochemical findings We observed increase of cholestanol, 7α-hydroxy-4-cholesten-3-one (7αC4), lathosterol, and plant sterols 27-hydroxycholesterol (27-OHC) was extremely low or absent. CDCA treatment normalized all biochemical parameters except for - 7αC4 which persisted slightly higher than normal in most patients - 27-OHC which was not modified by therapy. Biochemical evaluation did not reveal significant differences between stable and worsening patients. Treatment with CDCA should aim at normalizing serum 7αC4 as well as cholestanol. 7αC4 mirrors 7α-hydroxylation rate and strictly correlates with brain damage. Assessment of serum 27-OHC is a very good tool for biochemical diagnosis.

MRI of the cerebellum in CTX: a wide spectrum of alterations Absence (A) Dentate T2/FLAIR hyperintensity (B) Vacuolation (C) Calcification (D)

Very strong correlation between the presence of cerebellar vacuolation at baseline and a clinical progression at follow up.

MRI findings and treatment response: highlights Dentate nuclei and cerebellar white matter can show different patterns of signal alterations, as well as no lesions. T2/FLAIR hyperintensities may be the initial result of abnormal lipid storage. Vacuolation and maybe also calcification could be the result of degeneration caused by cholestanol-induced apoptosis. Cerebellar vacuolation was predictive of clinical and MRI worsening with unsatisfactory response to CDCA therapy. Cerebellar vacuolation can be regarded as the first available biomarker of possible disease progression and poor response to CDCA treatment.

SPASTIC PARAPLEGIA TYPE 5 (SPG5) Spastic paraplegia type 5 (SPG5) is an autosomal recessive hereditary spastic paraparesis (HSP) caused by mutations in CYP7B1 gene, which is responsible for a specific step in the alternative pathway of bile acid synthesis. Phenotype: pure HSP or complicated HSP (cerebellar signs, sensory ataxia, urinary symptoms). EMG: very often normal. MRI: white matter signal alterations.

Increased levels of 27-hydroxycholesterol (27OHC) in plasma and cerebrospinal fluid are thought to represent the pathological hallmark of the disease, with relevant therapeutic implications. However, no treatment is available so far.

Clinical, laboratory, and instrumental follow up (48 months) After 4 years, 270HC – 50/60%!

Mignarri A, Carecchio M, Del Puppo M, Magistrelli L, Di Bella D, Monti L, Dotti MT

SPG5: strategies for a disease-modifying therapy