Persistent inflammation, immunosuppression and catabolism syndrome (PICS) in critically ill children is associated with clinical outcomes: a prospective longitudinal study.

BACKGROUND: Persistent inflammation, immunosuppression and catabolism syndrome (PICS) has been described in critically ill adults and may contribute to unfavourable outcomes. The present study aimed to describe and characterise PICS in critically ill children (PICS-ped) and to verify its association with clinical outcomes. METHODS: A prospective longitudinal study was conducted in a paediatric intensive care unit (PICU) with children aged between 3 months and 15 years. PICS-ped, based on adult definition, was described. PICS-ped was defined as PICU length of stay >14 days; C-reactive protein > 10.0 mg L-1 ; lymphocytes <25%; and any reduction of mid-upper arm circumference Z-score. Clinical, demographic, nutritional status, nutrition therapy parameters and clinical outcomes were assessed. Statistical analysis comprised Mann-Whitney and Fisher's chi-squared tests, as well as logistic and Cox regression. P < 0.05 was considered statistically significant. RESULTS: In total, 153 children were included, with a median age of 51.7 months (interquartile range 15.6-123.4 months), and 60.8% male. The mortality rate was 10.5%. The prevalence of PICS-ped was 4.6%. Days using vasoactive drugs and days using antibiotics were associated with PICS-ped. PICS-ped was associated with mortality in crude (odds ratio = 6.67; P = 0.013) and adjusted analysis (odds ratio = 7.14; P = 0.017). PICS-ped was also associated with PICU and hospital length of stay, as well as duration of mechanical ventilation. Similar results were found in a subset of critically ill children who required mechanical ventilation for more than 48 h. CONCLUSIONS: Children with PICS-ped required antibiotics or vasoactive drugs for a longer period. PICS-ped was associated with poor clinical outcomes in critically ill children. More studies are needed to properly define PICS-ped for this population.

Synaptotagmin 13 is neuroprotective across motor neuron diseases.

In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.

A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis.

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.

Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations.

Spastic paraplegia type 5 (SPG5) is caused by mutations in CYP7B1, a gene encoding the cytochrome P-450 oxysterol 7-α-hydroxylase, CYP7B1, an enzyme implicated in the cholesterol metabolism. Mutations in CYP7B1 were found in both pure and complicated forms of the disease with a mutation frequency of 7.7% in pure recessive cases. The mutation frequency in complex forms, approximately 6.6%, is more controversial and needs to be refined. We studied in more detail the SPG5-related spectrum of complex phenotypes by screening CYPB1 for mutations in a large cohort of 105 Italian hereditary spastic paraplegias (HSPs) index patients including 50 patients with a complicated HSP (cHSP) phenotype overlapping the SPG11- and the SPG15-related forms except for the lack of thin corpus callosum and 55 pure patients. Five CYP7B1 mutations, three of which are novel, were identified in four patients, two with a complex form of the disease and two with a pure phenotype. The CYP7B1 mutation frequencies obtained in both complicated and pure familial cases are comparable to the known ones. These results obtained extend the range of SPG5-related phenotypes and reveal variability in clinical presentation, disease course and functional profile in the SPG5-related patients while providing with some clues for molecular diagnosis in cHSP.

Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2.

Spastic paraplegia type 10 (SPG10) is an autosomal dominant form of hereditary spastic paraplegia (HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy chain implicated in anterograde axonal transport. KIF5A mutations were found in both pure and complicated forms of the disease; a single KIF5A mutation was also detected in a CMT2 patient belonging to an SPG10 mutant family. To confirm the involvement of the KIF5A gene in both CMT2 and SPG10 phenotypes and to define the frequency of KIF5A mutations in an Italian HSP patient population, we performed a genetic screening of this gene in a series of 139 HSP and 36 CMT2 affected subjects. We identified five missense changes, four in five HSP patients and one in a CMT2 subject. All mutations, including the one segregating in the CMT2 patient, are localized in the kinesin motor domain except for one, falling within the stalk domain and predicted to generate protein structure destabilization. The results obtained indicate a KIF5A mutation frequency of 8.8% in the Italian HSP population and identify a region of the kinesin protein, the stalk domain, as a novel target for mutation. In addition, the mutation found in the CMT2 patient strengthens the hypothesis that CMT2 and SPG10 are the extreme phenotypes resulting from mutations in the same gene.

An evolutionary history of the selectin gene cluster in humans.

Molecules involved in leukocyte trafficking have a central role in the development of inflammatory and immune responses. We performed F(ST) analysis of the selectin cluster, as well as of SELPLG, ICAM1 and VCAM1. Peaks of significantly high population genetic differentiation were restricted to two regions in SELP and one in SELPLG. Resequencing data indicated that the region covering SELP exons 11-13 displays high nucleotide diversity in Africans and Europeans (CEU), and a high level of within-species diversity compared with inter-specific divergence. Analysis of inferred haplotypes revealed a complex phylogeny with two deeply separated clades that coalesce at ~3.5 million years (MY) plus a minor clade with a TMRCA (time to the most recent common ancestor) of ~2.2 MY. A splicing assay indicated no haplotype-specific effect on SELP exon 14 inclusion. These data are consistent with a model of multiallelic balancing selection; single-nucleotide polymorphism analysis indicated that the Val640Leu variant represents a likely selection target. In populations of Asian ancestry a distinct haplotype, possibly carrying regulatory variants, has been driven to high frequency by positive selection. No deviation from neutrality was observed for the SELPLG region. Resequencing of SELP in chimpanzees revealed a haplotype phylogeny with extremely deep basal branches, suggesting either long-standing balancing selection or ancestral population structure. Thus, SELP has experienced a complex selective history, possibly as a result of local adaptation. Variants in the gene have been associated with autoimmune and cardiovascular diseases. Association studies would benefit from both taking the complex SELP haplotype structure into account and from analysis of possible regulatory variants in the gene.

Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy.

Fabry disease is a multisystem, X-linked, lysosomal storage disorder caused by a mutation in the GLA gene on chromosome Xq22 resulting in alpha-galactosidase A enzyme (α-Gal A) deficiency. Neurological manifestations other than cerebrovascular accidents include small fibre neuropathy and dysautonomic disorders, which may be the presenting clinical features in a proportion of patients. An atypical disease onset may be misdiagnosed until the emergence of a more typical clinical picture, characterized by chronic renal and cardiac failure. Thus, neurologists should consider Fabry disease in differential diagnosis and provide an appropriate diagnostic work up. This review focuses on central and peripheral nervous system involving available diagnostic tools and diagnostic work up in Fabry disease. It also covers the most recent evidence regarding enzyme replacement therapy.

Burden of rare coding variants in an Italian cohort of familial multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families. OBJECTIVE: to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families. METHODS: We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection. RESULTS: We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10-4 and 3 × 10-4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families. CONCLUSION: Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.

Growth factors in ischemic stroke.

Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1α and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects.

The genetic features of 24 patients affected by familial and sporadic hemiplegic migraine.

Familial hemiplegic migraine (FHM) is the only migraine subtype for which a monogenic mode of inheritance, autosomal dominant has been clearly established. It is genetically heterogeneous and at least three different genes exist (CACNA1A, ATP1A2, and SCN1A), the so-called FHM1, FHM2, and FHM3 genes, respectively. Sporadic hemiplegic migraine (SHM) is a disorder, in which some patients may have their pathophysiology identical to FHM, but others, possibly the majority, may have different pathophysiology, probably related to the mechanisms of typical migraine with aura. In our study, we have screened the DNA of 24 patients affected by FHM and SHM. Only in three patients, 2 sporadic and 1 familial cases, we have described genetic mutations, all of them in the ATP1A2 gene. In our opinion, these results demonstrate a more frequent involvement of the ATP1A2 gene not only in the sporadic form, but probably also in the Italian FHM patients without permanent cerebellar signs. Moreover, the absence of CACNA1A, ATP1A2 and SCN1A mutations in the other 12 familial cases suggests the involvement of still unknown genes.

The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.

BACKGROUND: Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT. While CMT4A shows recessive inheritance, CMT2K can present with either recessive (AR-CMT2K) or dominant segregation pattern (AD-CMT2K), the latter being characterised by milder phenotypes and later onset. The majority of the GDAP1 mutations are associated with CMT4A and AR-CMT2K, with only four heterozygous mutations identified in AD-CMT2K. METHODS: We screened GDAP1 gene in a series of 43 index patients, 39 with CMT2 and 4 with intermediate CMT, with sporadic and familial occurrence of the disease. RESULTS: Three novel mutations were identified in three families with dominant segregation of the disease: two missense changes, p.Arg226Ser and p.Ser34Cys, affecting the GST domain of the GDAP1 protein and a novel deletion (c.23delAG) leading to early truncation of the protein upstream the GST domain. Wide variability in clinical presentation is shared by all three families mostly in terms of age at onset and disease severity. A rare variant p.Gly269Arg, located within the GST domain, apparently acts as phenotype modulator in the family carrying the deletion. CONCLUSION: The results obtained reveal a GDAP1 mutation frequency of 27% in the dominant families analysed, a figure still unreported for this gene, thus suggesting that GDAP1 involvement in dominant CMT2 might be higher than expected.

A Multidisciplinary Evaluation of Patients with DMD in An Italian Tertiary Care Center.

With more widespread prolonged survival, Duchenne muscular dystrophy patients progressively experience multisystem complications. We retrospectively reviewed the charts of 132 Duchenne patients (112 alive/20 dead, age 3.5÷32.3 years) with the aims: 1) to provide a comprehensive description of the clinical status considering different aspects of the disease; 2) to propose a new scoring tool able to consider and pool together heterogeneous different functional. Five functions were analyzed: cardiac, respiratory, nutritional, ambulation and scoliosis. For each function, different items were considered and classified according to clinical severity (as indicated by international guidelines) and an incremental scoring was assigned. In addition, a global score incorporating all functions was defined. The scoring system confirmed that despite the significant protective role of steroids, all functions deteriorated with age. The severity of the global score became significantly higher since the age of 13 years. The severity of cardiac, respiratory and nutritional dysfunction was higher since 18 years. Deceased patients were characterized by significantly worse cardiac function, absence of steroid therapy and later use of respiratory assistive devices. The index proposed in this pilot study is a promising tool able to aggregate and correlate heterogeneous functions. It could become either an individual prognostic indicator of decline or a global score to evaluate changes in clinical trials therefore allowing multicenter studies, optimizing the management of both the primary and the secondary complications of the disease and understanding their relative impact.

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males.

Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P=0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P=0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P=0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P=0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P=0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P=0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.

Long-term balancing selection maintains trans-specific polymorphisms in the human TRIM5 gene.

The human TRIM5 genes encodes a retroviral restriction factor (TRIM5α). Evolutionary analyses of this gene in mammals have revealed a complex and multifaceted scenario, suggesting that TRIM5 has been the target of exceptionally strong selective pressures, possibly exerted by recurrent waves of retroviral infections. TRIM5 displays inter-individual expression variability in humans and high levels of TRIM5 mRNA have been associated with a reduced risk of HIV-1 infection. We resequenced TRIM5 in chimpanzees and identified two polymorphisms in intron 1 that are shared with humans. Analysis of the gene region encompassing the two trans-specific variants in human populations identified exceptional nucleotide diversity levels and an excess of polymorphism compared to fixed divergence. Most tests rejected the null hypothesis of neutral evolution for this region and haplotype analysis revealed the presence of two deeply separated clades. Calculation of the time to the most recent common ancestor (TMRCA) for TRIM5 haplotypes yielded estimates ranging between 4 and 7 million years. Overall, these data indicate that long-term balancing selection, an extremely rare process outside MHC genes, has maintained trans-specific polymorphisms in the first intron of TRIM5. Bioinformatic analyses indicated that variants in intron 1 may affect transcription factor-binding sites and, therefore, TRIM5 transcriptional activity. Data herein confirm an extremely complex evolutionary history of TRIM5 genes in primates and open the possibility that regulatory variants in the gene modulate the susceptibility to HIV-1.

Abdominal volume contribution to tidal volume as an early indicator of respiratory impairment in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterised by progressive loss of muscular strength that leads to an increasingly restrictive pulmonary syndrome. However, it is still not clear whether this determines alterations in the breathing pattern. We studied: 66 DMD patients at different stages of the disease (mean+/- sem age 12.6+/-0.6 yrs, range 5-22 yrs of age), subdivided into four groups according to age; and 21 age-matched healthy male controls. Spirometry, lung volumes and nocturnal oxygen saturation were measured in all DMD patients. Ventilatory pattern and chest wall volume variations were assessed by optoelectronic plethysmography during spontaneous breathing both in seated and supine positions. Whilst in a seated position, no significant differences were found between patients and controls or between different age groups. In the supine position, the average contribution of abdominal volume change (DeltaV(AB)) to tidal volume progressively decreased with age (p<0.001). The patients who showed nocturnal hypoxaemia showed significantly lower Delta V(AB). In conclusion, chest wall motion during spontaneous breathing in awake conditions and in supine position is an important indicator of the degree of respiratory muscle impairment in DMD. DeltaV(AB) is not only an important marker of the progression of the disease but is also an early indicator of nocturnal hypoxaemia.

Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.

Infantile neuroaxonal dystrophy, INAD, is a severe progressive psychomotor disorder with infantile onset and characterized by the presence of axonal spheroids throughout the central and peripheral nervous systems. A subset of INAD patients shows also brain iron accumulation which represents instead the distinctive feature of the idiopathic neurodegeneration with brain iron accumulation, NBIA. These diseases share the same causative gene, PLA2G6, encoding iPLA2-VIA, a calcium-independent phospholipase. Mutations that lead to a complete absence of protein are associated with a severe INAD profile, while compound heterozygous mutations with possibly a residual protein activity are instead associated with the less severe NBIA phenotype. Here we describe two INAD patients both with an unusually rapid disease progression and a peculiar neuroradiological presentation in one of them. Compound heterozygosity for a large intragenic deletion and a nonsense mutation was found in one of them while the other is carrying two novel splice-site mutations. Breakpoint-sequence analysis suggests a non-allelic-homologous-recombination (NAHR) event, probably underlying the rearrangement. These findings, while supporting the genotype-phenotype correlation already observed in INAD patients, provide the first sequence characterization of a genomic rearrangement in PLA2G6 gene, thus orienting the search for missing mutant alleles in PLA2G6 related diseases.

Stem cell therapy in stroke.

Recent work has focused on cell transplantation as a therapeutic option following ischemic stroke, based on animal studies showing that cells transplanted to the brain not only survive, but also lead to functional improvement. Neural degeneration after ischemia is not selective but involves different neuronal populations, as well as glial and endothelial cell types. In models of stroke, the principal mechanism by which any improvement has been observed, has been attributed to the release of trophic factors, possibly promoting endogenous repair mechanisms, reducing cell death and stimulating neurogenesis and angiogenesis. Initial human studies indicate that stem cell therapy may be technically feasible in stroke patients, however, issues still need to be addressed for use in human subjects.

CD20-related signaling pathway is differently activated in normal and dystrophic circulating CD133(+) stem cells.

Among the heterogeneous population of circulating hematopoietic and endothelial progenitors, we identified a subpopulation of CD133(+) cells displaying myogenic properties. Unexpectedly, we observed the expression of the B-cell marker CD20 in blood-derived CD133(+) stem cells. The CD20 antigen plays a role in the modulation of intracellular calcium homeostasis through signaling pathways activation. Several observations suggest that an increase in intracellular calcium concentration ([Ca(2+)](i)) could be involved in the etiology of the Duchenne muscular dystrophy (DMD). Here, we show that a CD20-related signaling pathway able to induce an increase in [Ca(2+)](i) is differently activated after brain derived neurotrophic factor (BDNF) stimulation of normal and dystrophic blood-derived CD133(+) stem cells, supporting the assumption of a "CD20-related calcium impairment" affecting dystrophic cells. Presented findings represent the starting point toward the expansion of knowledge on pathways involved in the pathology of DMD and in the behavior of dystrophic blood-derived CD133(+) stem cells.

Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus callosum.

BACKGROUND: Hereditary spastic paraplegia (HSP) with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterised by slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the gene associated with the major locus involved, encodes spatacsin, a protein of unknown function. METHODS: Different types of mutations were identified in patients with the complex form of HSP (cHSP) including TCC. We screened a series of 45 index patients with different types of cHSP with (n = 10) and without (n = 35) TCC. RESULTS: Ten mutations, of which five are novel, were detected in seven patients. Of importance, three out of seven mutated patients present with cHSP without TCC. Among the novel mutations identified, we characterised a large intragenic rearrangement deleting 2.6 kb of the SPG11 gene. The rearrangement is due to non-allelic homologous recombination between Alu sequences flanking the breakpoints. CONCLUSIONS: These findings expand the mutation spectrum of SPG11 and suggest that SPG11 mutations may occur more frequently in familial than sporadic forms of cHSP without TCC. This helps to define further clinical and molecular criteria for a correct diagnosis of the SPG11 related form of cHSP. In addition, the intragenic deletion detected here, and the mechanism involved, both provide clues to address the issue of SPG11 missing mutant alleles previously reported.

A population genetics study of the familial Mediterranean fever gene: evidence of balancing selection under an overdominance regime.

Familial Mediterranean Fever (FMF) is a recessively inherited systemic autoinflammatory disease caused by mutations in the MEFV gene. The frequency of different disease alleles is extremely high in multiple populations from the Mediterranean region, suggesting heterozygote advantage. Here, we characterize the sequence variation and haplotype structure of the MEFV 3' gene region (from exon 5 to the 3' UTR) in seven human populations. In non-African populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with two common haplotypes separated by deep branches. These features are suggestive of balancing selection having acted on this region to maintain one or more selected alleles. In line with this finding, an excess of heterozygotes was observed in Europeans and Asians, suggesting an overdominance regime. Our data, together with the earlier demonstration that the MEFV exon 10 has been subjected to episodic positive selection over primate evolution, provide evidence for an adaptive role of nucleotide variation in this gene region. Our data suggest that further studies aimed at clarifying the role of MEFV variants might benefit from the integration of molecular evolutionary and functional analyses.