脳腱黄色腫症

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).

High levels of low-density lipoprotein cholesterol (LDL-c) have been recognized as the main causal factor of atherosclerotic cardiovascular disease (ASCVD) and are influenced by both genetic and environmental factors. Among genetic determinants, Familial Hypercholesterolemia (FH) is the most common monogenic disorder, caused by rare high-impact variants in genes involved in LDL uptake. Other monogenic causes of hypercholesterolemia include sitosterolemia, cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency (LALD). However, monogenic disorders only account for a small proportion of inherited hypercholesterolemia. In many individuals, increased LDL-c levels are caused by the contemporary presence of different single-nucleotide polymorphisms (SNPs) with a moderate/low impact. These SNPs could be summarized through polygenic risk scores (PRS) that attribute relative weight to each of these. Another genetic determinant of hypercholesterolemic phenotypes is high levels of lipoprotein(a)-Lp(a). Lp(a) is an LDL particle modified by the binding of apolipoprotein(a)-apo(a)-which represents an independent risk factor for ASCVD. Lp(a) levels are mainly genetically determined by variation in the number of kringle IV type 2 (K-IV2) repeats, as well as by several SNPs, and remain stable throughout life. The aim of this narrative review is to report an updated overview of the genetic mechanisms underlying hypercholesterolemia, including monogenic disorders, PRS and Lp(a), focusing on their potential repercussion in clinical practice by the integration into cardiovascular risk stratification beyond traditional clinical assessment. This integration could lead to a more comprehensive and individualized approach to cardiovascular prevention, with emerging perspectives including the possible use of artificial intelligence (AI).

Cerebrotendinous xanthomatosis (CTX) is rare, autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in CYP27A1, which encodes sterile 27 hydroxylase, a key enzyme in bile acid biosynthesis. Enzyme deficiency results in reduced cholic and chenodeoxycholic acid synthesis with accumulation of cholestanol, bile acid intermediates, and bile alcohols, producing a progressive multisystem disorder characterized by chronic diarrhea, juvenile-onset cataracts, tendons xanthomas, and neurological dysfunction. Although CTX typically begins in childhood, diagnosis is frequently delayed until adulthood, limiting the benefit of effective disease modifying therapy with chenodeoxycholic acid. Since the identification of CYP27A1, more than 200 pathogenic variants have been reported, including canonical loss of function alleles and missense variants with variable residual enzyme activity. In this review, we summarize the medical genetics, population genetics and genotype phenotype relationships of CTX. We highlight insights from large population databases that refine global incidence estimates, revealing population-specific enrichment of pathogenic variants and persistent underdiagnosis. We further review functional and clinical data demonstrating that stratification of CYP27A1 variants by functional effect, complete loss of function versus hypomorph alleles, correlates with clinical severity and biochemical phenotype. Finally, we discuss emerging advances in biochemical testing and newborn screening strategies that offer the potential for presymptomatic diagnosis, enabling timely initiation of therapy and prevention of irreversible disease manifestations. Integrating molecular, functional, and population genetic data provides a framework for improved variant interpretation, earlier diagnosis, and optimized therapeutic intervention in CTX.