9% had QTc interval >450 msec The authors found a positive

9% had QTc interval >450 msec. The authors found a positive

dose-dependent relationship between methadone dose and QTc interval lengthening (Pearson r=0.37, p<0.01; multiple regression analysis B=0.37, p<0.01). A case control study was not performed. During the first month of methadone maintenance treatment, two deaths occurred among 3850 initiations of methadone maintenance. One patient died from intracranial bleeding and one cause of death was unknown. Anchersen et al. [2009] concluded that death due to methadone during the first month of treatment was low and did not exceed 0.06 per 100 patient-years. The authors did not report the presence or absence of risk factors associated Inhibitors,research,lifescience,medical with TdP and attendant QTc interval prolongation in this paper but did look at their patients with QTc interval >500 msec in a second paper [Anchersen et al. 2010]. Anchersen et al. [2010] provided a detailed review of their earlier subjects with QTc interval >500 msec with a particular focus on risk factors. Assessment included a detailed medical Inhibitors,research,lifescience,medical and cardiac history, genetic testing for the five most common long QT syndrome mutations, cardiac exercise testing and 24-hour Holter selleck monitor records. The authors assessed seven subjects and found that two were heterozygous long QT syndrome mutation

Inhibitors,research,lifescience,medical carriers who had both experienced cardiac complaints before and during opioid maintenance treatment. The authors detected no additional risk factor among these seven patients. In six subjects, QTc intervals fluctuated widely during 24-hour Holter monitor recording and exercise testing [Anchersen et

Inhibitors,research,lifescience,medical al. 2010]. Methadone-associated QTc interval prolongation More than 80% of patients receiving long-term methadone maintenance therapy may have QTc interval Inhibitors,research,lifescience,medical prolongation compared with reference values for patients of the same age and sex and there may be no correlation between QTc interval measurement and methadone dose [Maremmani et al. 2005]. However, others have reported a positive relationship between methadone dose and QTc interval duration [Kornick et al. 2003; Krantz et al. 2003]. Among our 21 cases of methadone-associated TdP, we failed to identify any relationship between QTc interval prolongation and methadone dose. Perhaps, multiple risk factors present may explain this finding. A paper recently published by Roy et al. [2012] studied 180 subjects (69.1% men) in a methadone maintenance therapy program. Mean see more QTc interval was 420.9 ± 21.1 msec and the mean daily methadone dose was 80.4 ± 27.7 mg. There was no significant correlation between these two measurements (p = 0.33) with 8.8% of patients demonstrating QTc interval prolongation (8.3% men and 0.5% women). In contrast to the uneven findings of the relationship between QTc interval prolongation among TdP patients and methadone dose in our and other studies, Miceli et al.

21 Broadly, the goal of this effort has been to identify “endophe

21 Broadly, the goal of this effort has been to identify “endophenotypes” or to uncover basic mechanisms that underlie psychiatric conditions, and that would provide potential targets for biomedical treatments.20 Social neuroscience has proven effective in eliciting general cognitive and neural mechanisms involved in processing “socially relevant” material. Nonetheless, well-controlled

Inhibitors,research,lifescience,medical laboratory procedures are most often devoid of personal relevance for the examined participants. This limits the specificity of the emotional resonance (and thus the self-relevance) of the experimental results.22 The current social cognitive approach leaves self, self-awareness, and inter-subjectivity unaccounted for in the background where they (as self-image and self-esteem) influence perception, memory, and other cognitive processes concerning socially relevant Inhibitors,research,lifescience,medical interactions.14,15,23 We argue that a mature social cognitive neuroscience aimed at having fundamental relevance to psychiatry should therefore not deliberately choose to ignore it for methodological and epistemological convenience. There is a fundamental gap between the type of phenomena currently studied and the type of psychological

models that would be necessary to understand and approach human social cognition. The Inhibitors,research,lifescience,medical knowledge accumulated by general cognitive and social neuroscience and its application to psychiatry, while representing progress, remains inadequate to address the challenges faced by psychiatry or more INCB028050 cost generally by any field striving to understand human psychology and psychopathology. Relevant levels of integration such as self-awareness and inter-subjectivity Inhibitors,research,lifescience,medical still escape Inhibitors,research,lifescience,medical the reach of biomedical science, and integrating such levels into research will be a challenge. Models integrating social cognition with aspects of the self and psychopathology have been proposed for brain damage occurring during developmental ages.24 Yet, it will

be essential to invest in research and clinical practice seeking a more comprehensive why understanding of the levels of representation and mechanisms at stake in human social cognition as it relates to psychopathology, including in individuals without gross brain damage. We argue that no satisfactory understanding of human social cognition and psychopathology will be possible without making psychological constructs such as the self, self-awareness, and more generally consciousness, the unconscious and inter-subjectivity integral to (formal) models of social cognitive neuroscience. It will be essential to understand how the self, as a socially laden system, structures its relationships to the categories of self and otherness, in the context of the processes that are central to the making of human identity, representations and coping strategies, throughout development.

Specific measures are taken to ensure compliance of the clinicia

Specific measures are taken to ensure compliance of the clinician with the protocol and adherence of the patient with the procedures and treatments. Formally, efficacy studies define optimal treatment outcomes for narrowly selected patients treated under rigidly controlled and ideal conditions. With a primary focus on symptoms, the assessment of efficacy is based upon the degree to which the level of symptomatology is reduced or eliminated.6,7

Inhibitors,research,lifescience,medical In an efficacy trial, treatment is provided by specially selected and trained clinicians who provide optimal treatment and expend substantial resources to ensure compliance and minimize drop out. Research supported for commercial purposes, particularly that supported by the drug companies themselves, has, of necessity, conformed to the regulatory model. This is the case regardless of whether the site of the study is an academic health center or a community- treatment facility, and regardless of whether the coordination of the study Inhibitors,research,lifescience,medical is done directly by the sponsor or by an intermediary (contract research organization,

or CRO). It is worth noting that those doing clinical Inhibitors,research,lifescience,medical psychotherapeutic or behavioral research have not (yet) adopted this CRO type of arrangement. The regulator)- model has also been carried over into research that has no industrial sponsorship, even to research on mental disorders that has been directed to government Inhibitors,research,lifescience,medical agencies or foundations. In a treatment study driven by a regulatory model of investigation, there is no minimum effect size or minimum pro portion of rcsponders necessary. In addition,

there is no requirement that the subject population be representative of the kind of patient seen in actual practice. As such, a trial done in accordance with the regulatory model represents only the beginning of a process of clinical development. Inhibitors,research,lifescience,medical Efficacy studies define optimal treatment outcomes for narrowly selected patients treated under rigidly controlled and ideal conditions. The from classic efficacy trial is used to define the gold standard of the best outcome under ideal Selleck Dorsomorphin circumstances. Because of the tight standard of control required in efficacy studies, the policy and practice relevance of these trials will always be limited.8 The clinical trials of cognitive enhancers provide a useful example of the differences between regulatory and public health research. The trials of cognitive enhancers seek to show slowing or reversal of the progression of Alzheimer’s disease or to demonstrate improved management of the symptoms of the disease. These trials typically attempt to show that the course of a progressive disease has been modified. The design of such trials involves great complexities even under optimal conditions.

Results have indicated that, compared with the traditional struc

Results have indicated that, compared with the traditional structured models, interventions that are less structured and more child-focused result not only

in faster learning by children with ASD,20,27 but also result in children displaying higher levels of affect21 and engaging in less avoidant and Fasudil molecular weight disruptive behavior.20,28 As our ability to accurately diagnose autism in the first few years of life has improved, there has been an increased Inhibitors,research,lifescience,medical demand for intervention approaches that integrate developmental and behavioral approaches to target social communication skills in toddlers and preschoolaged children with ASD. Kasari’s JASPER (joint attention, symbolic play, emotion regulation) program resulted in increased expressive language skills with continued gains 1 year post study completion.29 This combined developmental and naturalistic behavioral approach Inhibitors,research,lifescience,medical was more effective than a more traditional applied

behavioral intervention preschool program. Similarly, the Early Start Denver Model30 incorporates behavioral and developmental strategies and has been associated with increased cognitive development and adaptive behavior. While not Inhibitors,research,lifescience,medical directly targeting requesting behavior, the focus on facilitating early social communication skills is designed to increase spontaneous communication skills and decrease challenging behaviors. Most of these naturalistic interventions include a caregiver Inhibitors,research,lifescience,medical education/training component. The caregiver has an advantage as s/he can optimize learning moments throughout naturally occurring opportunities during Inhibitors,research,lifescience,medical daily activities within the home and community. This may be more successful than instruction occurring only during specified times, which may burden the family by requiring extra time and effort.31 Thus,

naturalistic approaches are Tryptophan synthase ideally suited for caregivers.7,32 Recently, a large community-based study found improvements for up to 1 year in children’s expressive and receptive communication and decreases in problem behavior with parents who learned how to implement pivotal response treatment.33 Similarly, Minjarez and colleagues32 found significant increases in children’s functional spontaneous speech for parents who participated in a communication intervention training where feedback was delivered based on the videotapes they brought in. However, more research is needed to determine whether caregiver-mediated interventions that combine developmental and behavioral approaches are effective at decreasing challenging behaviors.

33 Two clinically distinct disorders, Prader-Willi

and An

33 Two clinically distinct disorders, Prader-Willi

and Angelman syndromes (PWS and AS) , arise from abnormalities of a small region in 15ql l-ql3.34 These syndromes have characteristic and distinct neurobehavioral profiles: in AS the retardation is severe (very few affected individuals can talk) and there is ataxia, seizures, abnormal EEG, microcephaly, facial dysmorphism, Inhibitors,research,lifescience,medical hyperactivity and paroxysmal laughter. By contrast, in PWS, the MR may be only mild; there is a characteristic facial appearance and a specific behavioral abnormality, ie, hyperphagia resulting in severe obesity. Despite the phenotypic differences, the basic defect is the same in the Inhibitors,research,lifescience,medical two disorders: a failure of parent-of-origin-specific gene expression. If both copies of chromosome 15 derive

from the mother then the individual will have PWS; if both are from the father then the phenotype is AS. The basic defect is not simply a dosage effect; it turns out that about a find more quarter of cases of PWS are not due to a deletion Inhibitors,research,lifescience,medical but to the inheritance of two maternal copies of chromosome 15 (rather than the usual situation of one maternal and one paternal). Conversely, two paternal copies of chromosome 15 result in AS. The chromosomal region is said to bear a parent-of-origin imprint, of which the molecular signature is a difference in DNA methylation.35 Mutations in a ubiquitin protein ligase gene (UBE3A) have been found in a few rare families with AS.36 The gene product is

part of a widely used ubiquitin-mediated protein Inhibitors,research,lifescience,medical degradation pathway. PWS is probably not the result of a defect in a single gene. Seven genes (and candidate genes) have been identified in the PWS region, all of Inhibitors,research,lifescience,medical which appear to be brain specific.29 It is not known if the phenotype is due to an abnormality in a single gene. However, there is now some evidence to suggest that abnormal RNA editing, due to misregulation of guide RNAs, mediates the defect in PWS. The nucleolus contains a large number of small RNAs, termed small nucleolar RNAs (snoRNAs); the majority of these snoRNAs function in the posttranscriptional modification of rRNA nucleotides. However, it is now clear that the action of methylation guide snoRNAs goes beyond the field of ribosome biogenesis. Recently three brain-specific snoRNAs, which are subject Terminal deoxynucleotidyl transferase to genomic imprinting in mice and humans, have been discovered within the 15qll critical region for PWS and AS.37 Unusually, they do not have appropriate antisense elements, so their function is not clear, but one has a similarity to the mRNA encoded by the gene for the serotonin receptor-2C. The sequence matches a conserved region subject to both alternative splicing and adenosine-to-inosine editing.

Subgroup 2 consists of individuals who had a viral illness (Guill

Subgroup 2 consists of individuals who had a viral illness (Guillain-Barre, mononucleosis, hepatitis, atypical viral pneumonia) followed by persistent EDS. Subgroup 3 includes patients with no family history or viral

infection prior to onset of EDS. The PSG demonstrates a combination of normal or long nocturnal sleep, and the MSLT performed the day after the PSG shows short SOL without sleep-onset REM periods.139 Pharmacological treatment involves use of stimulants, starting Inhibitors,research,lifescience,medical with either modafinil or methylphenidate and switching to dexedrine spansules if initial treatment is ineffective. Nonpharmacological treatment includes one scheduled daily Inhibitors,research,lifescience,medical nap (noon or late afternoon) no longer than 45 min; avoidance of alcohol, sleep deprivation, heavy meals and shift work; and observance of regular sleep (at least 8.5 h per night) and wake schedules. Parasomnias Parasomnias are characterized by undesirable physical phenomena or behaviors that occur predominantly during sleep. Skeletal muscle activity and autonomic nervous system changes are prominent. Parasomnias are composed of disorders of arousal, partial arousal, and sleepstage transition (Table I). Disorders of arousal are the most common form of parasomnia.They Inhibitors,research,lifescience,medical usually occur during SWS (NREM stages III and IV),

and symptoms typically present in the first third of the night. Studies of twin cohorts and families with sleep terror and sleepwalking suggest that genetic factors Inhibitors,research,lifescience,medical may be involved, and there may be a family history of the same or other NREM arousal parasomnia.140-142 Factors that increase SWS, such as young age, natural deep sleeper, recoverd Inhibitors,research,lifescience,medical from sleep deprivation, central nervous system (CNS) depressant medications (sedatives, hypnotics, alcohol), fever, and the hypersomniac

period in Klcine-Levin syndrome, may aggravate the arousal disorder. Factors that lead to sleep fragmentation, including stress, environmental LY335979 molecular weight stimuli, endogenous stimuli, pain, pregnancy, stimulants, thyroxine taken in the evening, migraine headaches, or Tourcttc’s syndrome, may trigger the parasomnia. Megestrol Acetate Confusional arousals (nocturnal sleep drunkenness) This disorder is more common in children younger than 5 years of age, becomes less frequent during adolescence, and is rare in adulthood. The patient partially awakens from a deep sleep during the first third of the night, is confused and slow in mentation, disoriented to time and space, poorly/partially responsive to external stimuli, manifests automatic behavior (picking at bedclothes), and moans and mumbles incomprehensibly. Attacks last from 30 s to 10 min, and the patient is amnesic for the behavior and for any dream-like or thought-like mentation.

The antidotal potency of pyridinium oximes is as a result of reac

The antidotal potency of pyridinium oximes is as a result of reactivation of the phosphorylated cholinesterases.96,97 Oximes can reactivate phosphorylated cholinesterases via replacing the phosphoryl moiety from the enzyme. Phosphorylated oximes are produced during this reaction and some of them seem to be potent inhibitors of AChE.98 The choice of oximes is based on the data presently available and may also be dependent on factors other than Inhibitors,research,lifescience,medical protection against lethality, such as cost and availability of the oximes and their side effects. Obidoxime (Toxogonin) is likely to cause more toxic effects than

pralidoxime and HI6. asoxime is the least toxic, but is less unstable in solution and is not commercially available in many parts of the

world.18 In soman-intoxicated guinea pigs, HI6 was therapeutically slightly more effective than HLo7, but was less effective than HLo7 against tabun intoxication.99 Pyridinium oximes are mostly used against OP-inhibited AChE in Inhibitors,research,lifescience,medical the peripheral nervous system and not as much in CNS. This is due to a limited penetration across the blood–brain Inhibitors,research,lifescience,medical barrier (BBB). However, it appears that the oximes penetrate BBB more than expected, since in soman poisoning oxime concentration in the brain was high.100 Recent studies in rats have shown that modulation of the BBB by a drug like tariquidar is of great value in enhancing the efficacy of oximes.101 The induction of local inflammatory processes and increase of brain–blood flow may also have some roles in enhancing the penetration of oximes through BBB. Sakurada et al have determined the amount of PAM-2 passing across the BBB at approximately 10% of the given dose. This amount may be effective in the reactivation of OP-inhibited AChE in

the brain. Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical A new class of amidine-oxime HA1077 reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) have been reported to have increased BBB penetration with greater reactivation rates for OP-BuChE than pralidoxime (2-PAM) and monoisonitrosoacetone, but lower rates for OP-AChE reactivation compared to 2-PAM.102 In another study, the authors demonstrated that purified human and rabbit serum paraoxonase1 significantly protected against sarin and soman exposure in guinea pigs.103 Newly developed oximes (K206, K269) are relatively effective in reducing nearly cyclosarin-induced lethal toxic effects in mice. Their therapeutic efficacies exceed the therapeutic potency of obidoxime but not HI-6.104 Relative therapeutic effects of oximes in different OPs are presented in table 3. Table 3: Relative therapeutic effects of different oximes in organophosphate nerve agents poisoning Pralidoxime should be administered intravenously at 30 mg/kg initially over 30 min, followed by constant infusion of 8 mg/kg/hr in dextrose 5% solution.105 It could be continued until the full recovery or until atropine is required.

85 6%, P=0 304) survival rates, suggesting that RFA is an accepta

85.6%, P=0.304) survival rates, suggesting that RFA is an acceptable alternative treatment in patients with solitary CRHM smaller than 3 cm who are not candidates for resection. In another study, Otto et al. (63) showed that there is no difference in overall 3-year survival between resection and RFA for early CRHM, even though RFA was associated with higher local tumor recurrence rates and shorter time to progression. In yet another recent study, Kim et al. (52)

suggest that RFA may be a safe alternative treatment for solitary CRHM <3 cm, with equivalent outcomes Inhibitors,research,lifescience,medical (overall and disease-free survival) compared to resection. These data suggest that RFA represents an effective local treatment for patients who are unsuitable for conventional surgical treatment. However, caution is warranted in using CI-1033 datasheet ablation Inhibitors,research,lifescience,medical in lieu of resection for patients who are suitable candidates for surgical treatment. Ablation should NOT be seen as a replacement for hepatic resection and does not preclude the need of systemic chemotherapy. Furthermore, the candidates for this specific approach are likely to be few. Important clinical and technical considerations for thermal tumor ablation

Just as the vast majority of patients with CRHM are not candidates for potentially curative resection, most will also Inhibitors,research,lifescience,medical not be candidates for evolving strategies that includes staged hepatic resection with or without tumor ablation, regional infusion therapies, and the preceding approaches in the context of systemic regimens. The evolving field of regional hepatic therapies lacks mature data to guide the Inhibitors,research,lifescience,medical approach, such as the

optimal sequence of therapies and defining the target patient population that may be most likely to benefit. As such, we put forth a few caveats, which are critical in the treatment planning process for these complex patients. The most important determinant of outcome for patients with CRHM is the biology or extent of disease. Regardless of the treatment efficacy of any one modality at the local level (liver), the presence of progressive, persistent, or chemotherapy-refractory systemic disease should in most instances preclude the use of resection or thermal Inhibitors,research,lifescience,medical tumor ablation. heptaminol Assuming the conditions described in the previous paragraph are met, the limitations of thermal tumor ablation are straightforward, and by no means complete in the listing that follows: (I) At any given time, there must be sufficient hepatic reserve to ensure adequate function. (II) The use of ablation as a prelude to resection should encompass the principles of known treatment failures, such as heat sinks. Basing a future liver remnant on a portion of liver at high risk for persistent or recurrent tumor in the ablation zone should be avoided. (III) The potential for inadvertent for injury to vital hepatic structures needs to be carefully considered utilizing TTA for CRHM, particularly in the context of a staged approach to ensure adequate inflow and outflow for the liver remnant.

Imaging results Consistent groups The first comparison of interes

Imaging results MS-275 cell line Consistent groups The first comparison of interest was activation to all DD task trials versus SMC trials. In the within-group results, consistent HC qualitatively showed more widespread activation, such as in putative executive function areas (the inferior and middle

frontal gyri, dorsal anterior cingulate cortex or dACC, and inferior parietal lobule), attention-related areas (precuneus), and midbrain, to the task than did consistent SZ (Table S2, Fig. S1). In the consistent between-group analysis (Table ​(Table2,2, Fig. ​Fig.6),6), significantly enhanced activation in DD over SMC trials in the HC (Fig. ​(Fig.6,6, red) occurred in regions including the inferior frontal gyrus; Inhibitors,research,lifescience,medical medial wall locations such as dACC extending into supplementary motor area (SMA) Inhibitors,research,lifescience,medical and pre-SMA motor areas; posterior parietal cortex extending into occipital cortex; and subcortically, in the ventral striatum, thalamus, and midbrain. By contrast, greater activation in the SZ group (Fig. ​(Fig.6,6, blue) was found in the insula, with the cluster extending Inhibitors,research,lifescience,medical into the frontal operculum and superior temporal gyrus, and in a more posterior medial wall cluster that included the precuneus and posterior and middle cingulate gyrus. Table 2 Consistent patients and consistent

controls: between-group fMRI results for DD task>SMC trials1 Figure 6 Between-group results for activation to task>SMC trials revealed more activation in controls (red) in frontoparietal areas, including inferior frontal gyrus and medial areas of the prefrontal cortex, and subcortically in the striatum and thalamus; … Additional contrasts of interest

were related to DD trial difficulty. Although the within-group analyses of activation to hard>easy trials were not significant Inhibitors,research,lifescience,medical in HC or in Inhibitors,research,lifescience,medical SZ, the reverse contrast of easy>hard trials revealed significant results in both groups (Table S3). HC exhibited activation in areas including the middle cingulate gyrus, superior parietal cortex, insula, and middle temporal cortex. SZ showed activation in the superior and middle frontal gyri, middle and posterior cingulate gyrus, inferior parietal Bay 11-7085 cortex, and middle temporal cortex. Comparing groups for the difference in activation to easy versus hard trials (Fig. ​(Fig.7,7, Table ​Table3)3) showed an interaction between group and difficulty in one large cluster that included lateral frontal regions such as the superior and middle frontal gyri, medial wall regions such as the dACC extending into the SMA/pre-SMA areas, and parietal locations such as inferior parietal lobule. Table 3 Consistent patients and consistent controls: between-group fMRI results for trial difficulty1 Figure 7 Between-group results for activation to hard>easy trials revealed an interaction between difficulty and group. For controls>consistent patients, the contrast is hard>easy; for consistent patients>controls, the contrast …

In keeping with the hypothesis of a common pathogenetic pathway,

In keeping with the hypothesis of a common pathogenetic pathway, allelic mutations of any of these genes results in conditions of variable severity broadly correlated with the degree of ADG hypoglycosylation. Molecular genetic PH-797804 supplier analysis of patients with a dystroglycanopathy therefore should include all these 6 genes; however, approximately 35% of patients have no identifiable mutations, Inhibitors,research,lifescience,medical strongly pointing towards further genetic heterogeneity. Genetic analysis suggests that the possibility of a single major locus accounting for the remaining dystroglycanopathies

is unlikely and we must be prepared to search for multiple genes associated with the glycosylation of ADG. Acknowledgement

The authors wish to thank the ENMC CMD consortium Inhibitors,research,lifescience,medical for the ongoing collaboration. The financial support of the Muscular Dystrophy Campaign and of the Department of Health (NCG) is gratefully acknowledged. The group at Guy’s Hospital Trust London involved in the NCG diagnostic work (Dr Stephen Abbs; Mrs Rachael Mein; Miss Judith Pagan) is also gratefully acknowledged.

This very rare disease has a frequency estimated at 1 in 8 million births. This, however, seems to be underestimated due to misdiagnosed or non-recognized cases and could Inhibitors,research,lifescience,medical be 1 in 4 million. The disease affects mainly Caucasians, slightly more boys (M:F = 1.5:1). HGPS is a multisystem disorder affecting

various organs – muscles, bones, skin, subcutaneous Inhibitors,research,lifescience,medical tissue, heart, etc. The classic symptoms are: short stature, bird-like faces, cranio-facial disproportion, baked beak nose, micrognathia, graying sparse hair, wrinkled tight skin with pigmentation and prominent vessels, in some cases scleroderma-like indurations, pear-shaped thorax, coxa valga, short clavicles, joint contractures, osteolysis of distal phalanges Inhibitors,research,lifescience,medical of fingers, delayed dentition, cataract (Fig. ​(Fig.1).1). Early atherosclerosis, leading to heart infarction or stroke is the main cause of death. Very characteristic is low weight and delayed growth. IQ is usually normal, no brain changes have been described (3–7). Figure 1 Hutchinson-Gilford progeria (from CYTH4 collection of prof. S. Jablońska). Most of these symptoms mentioned appear between 6 and 18 months of life, at birth the child is usually considered to be normal. The mean life-span in typical cases is estimated at about 11 years, but single older cases (even > 20 years old) with confirmed diagnosis have been reported (9). Most of the cases reported so far (no more than ± 110) were sporadic, products of consanguineous parents. The mode of transmission, according to most authors, is autosomal dominant (AD). In a few cases, the mode of transmission was autosomal recessive (10, 11). The risk of recurrence is estimated as lower than 3%.