Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not prevent postnatal losses

Mice with mucopolysaccharidosis type VII (MPS VII) are devoid of beta-glucuronidase and accumulate glycosaminoglycans in lysosomes resulting in bone dysplasia, learning disabilities, and decreased mobility. MPS VII males do not breed and, while MPS VII females occasionally mate with heterozygous males, they do not maintain their young postnatally. Heterozygous matings produce less than 25% MPS VII offspring, but until now it was unclear whether this results from prenatal or postnatal losses. The administration of recombinant beta-glucuronidase from birth significantly reduces glycosaminoglycan storage in most tissues, increases life span, and improves the animal's cognitive ability and mobility. To determine whether reproductive failure is corrected by such therapy, male and female MPS VII mice were injected with enzyme at weekly intervals from birth to 5 wk of age (6xinj). Enzyme-replaced MPS VII mice bred when mated together. The 6xinj MPS VII males mated repeatedly until they were killed 135 d postinjection. All mated 6xinj MPS VII females gave birth to two litters, but maintained few of their young. Selective loss of MPS VII offspring was observed in matings between heterozygotes. Analysis of 379 preterm fetuses from heterozygous matings showed a frequency of 24.6% MPS VII pups, indicating that the decreased number of MPS VII pups produced by mating heterozygotes results from postnatal losses. The ovaries of young adult MPS VII mice have follicles and corpora lutea, and the testes generate sperm. Results suggest that the reproductive failure in MPS VII mice is related to impaired mobility and/or impaired cognitive function, and enzyme replacement restores mating capacity.     

Restricted joint range of motion in patients with MPS II: correlation with height, age and functional status

Aim: The aims of the study were to assess shoulder range of motion (ROM) in patients with mucopolysaccharidosis type II (MPS II) and to correlate joint mobility with patients’ height, age and functional status. Methods: Passive ROM and Z‐score of height were followed in 29 patients with MPS II (mean age 11.5 years, range 2–29 years) between the years 2005 and 2010. Passive ROM was measured by a goniometer, and height, by a stadiometer. Functional status was assessed by an age‐appropriate health assessment questionnaire (HAQ). Results: (i) A strong correlation was observed between patients’ age and Z‐score of patients’ height (R = 0.78, p < 0.001). (ii) A medium correlation was observed between Z‐score of patients’ height and passive shoulder flexion and abduction (R = 0.697, p < 0.001 and R = 0.63, p < 0.001, respectively). The progression of restriction was slower in attenuated patients. (iii) Restrictions in shoulder flexion and abduction were already observed before the second year of life. (iv) ROM limitations intensified and became more severe with age. (v) Activities of daily living depended on cognitive impairment of patients with MPS II. Conclusion: Range of motion limitations in patients with MPS II correlate with patients’ height, increase with patients’ age and are more pronounced in a severe form of MPS II.     

Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls

Mucopolysaccharidosis II (MPS II), or Hunter syndrome, is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2-sulfatase. Affected patients suffer progressive damage to multiple organ systems and early mortality. Two thirds of patients also manifest cognitive impairment and developmental delays. MPS II can be extremely difficult to diagnose before irreversible organ and tissue damage has occurred because of an insidious onset and the overlap in signs and symptoms with common childhood complaints. This is particularly true of patients without cognitive impairment (attenuated phenotype). Although not curative, early treatment with enzyme replacement therapy before irreversible organ damage has occurred may result in the greatest clinical benefit. Here, the signs, symptoms, and surgical history that should trigger suspicion of MPS II are described, and the diagnostic process is reviewed with a focus on practical considerations and the avoidance of common diagnostic pitfalls. Once a diagnosis is made, multidisciplinary management with an extended team of pediatric specialists is essential and should involve the pediatrician or family practice physician as facilitator and medical home for the patient and family. Conclusion: Because routine newborn screening is not yet available for MPS II, the involvement and awareness of pediatricians, family practice physicians, and pediatric specialists is critical for early identification, diagnosis, and referral in order to help optimize patient outcomes.     

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??Neurocognitive developmental disorders in children include developmental dyslexia??developmental dyscalculia??attention deficit hyperactivity disorder and autism spectrum disorders??which have high incidence in children’s nervous system diseases. Neurocognitive developmental disorders affect the children’s academic performance and social skills??and are the challenge in the long-term social prognosis. At present??we are in lack of objective and effective tool for the clinical diagnosis and treatment of neurocognitive development disorders in children. In recent years??the development of brain science provides a new way to explore the mechanism and intervention of the neurocognitive developmental disorders. From the perspective of cognitive behavioral??neural mechanisms and intervention??this paper elaborates the research findings of brain science in neurocognitive developmental disorders. The evidence of brain science demonstrateds that neurocognitive developmental disorders present core cognitive impairment and abnormal brain structure or function. The intervention mainly involves cognitive behavior training??and the brain stimulation effect needs to be confirmed.     

52例黏多糖病酶学分型及临床特点分析

目的：探讨黏多糖病（MPS）疾病谱及其临床特点。方法：对2009年1月至2011年12月75例高度疑似MPS患儿同时进行尿黏多糖（GAG）定量和电泳分析以及7种MPS酶学分析。采用荧光分析法分别检测白细胞α-L-艾杜糖酶、艾杜糖-2-硫酸酯酶、α-N-乙酰氨基葡糖苷酶、半乳糖胺-6-硫酸酯酶、β-半乳糖苷酶、芳基硫酸酯酶B及β-葡萄糖醛酸酶活性。结果：根据临床、放射学及酶学检查确诊MPS 52例,年龄4.0±2.2岁,其中I型5例（10%）,Ⅱ型20例（38%）,ⅣA型20例（38%）,Ⅵ型6例（12%）,Ⅶ型1例（2%）,未发现ⅢB、ⅣB型患儿。除2例ⅣA型患儿外,其余50例MPS 患儿尿GAG/Gr比值均较同龄儿增高。尿GAG定量增高者均确诊为MPS。绝大多数患儿于生后1~2岁起病,常伴有疝、心脏瓣膜病。Ⅰ、Ⅱ、Ⅵ 型患儿表现面容丑陋、皮肤粗糙、矮小、关节僵硬及活动受限,ⅣA型主要表现为矮小、骨骼畸形及关节松弛。结论：MPS Ⅱ型和ⅣA型是MPS最常见类型,其次是Ⅵ型及Ⅰ型。MPS患儿以特殊外貌为临床特点,包括面容丑陋、皮肤粗糙、矮小、骨骼畸形等。尿GAG定量测定可作为一种简便、快速、可靠的MPS筛查方法在临床上推广应用。     

Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy.

We have previously shown that mucopolysaccharidosis type VII (MPS VII) mice receiving six weekly injections of recombinant beta-glucuronidase from birth had improved cognitive ability and reduced central nervous system lysosomal storage. However, a single beta-glucuronidase injection at 5 wk of age did not correct neuronal storage. We define the age at which central nervous system storage in MPS VII mice becomes resistant to beta-glucuronidase therapy and determine the effect of enzyme on other tissues by comparing the histology of mice begun on therapy at various times after birth. MPS VII mice received injections on the day of birth and then weekly for 5 wk with 16,000U/g beta-glucuronidase had reduced lysosomal storage in brain. The same therapy begun on d 14 of life or thereafter failed to correct neuronal storage, even when treatment was continued for six doses. Glial responsiveness or accessibility to enzyme also depended on early treatment. In contrast, leptomeningeal, osteoblast, and retinal pigment epithelial storage reduction depended on enzyme dose rather than age at initiation of therapy. Fixed tissue macrophage storage was reduced in all treated MPS VII mice, even those receiving a single dose. These observations indicate that fixed tissue macrophages in MPS VII mice remain sensitive to enzyme replacement therapy well into adulthood although neurons are responsive or accessible to enzyme therapy early in life. Because early initiation of enzyme replacement is important to achieve a central nervous system response, these studies emphasize the importance of newborn screening for lysosomal storage diseases so that early treatment can maximize the likelihood of a favorable therapeutic response.     

Reconsidering the impact of preterm birth on language outcome

Background

Since preterm birth is associated with a constellation of pre-, peri- and post-natal risk factors, we hypothesised that prematurity may continue to impact the development of linguistic abilities even up to the end of the preschool years and beyond, giving rise to an atypical developmental trajectory. The study tested this hypothesis at six years of age, investigating whether language is affected by preterm birth and how different linguistic abilities are interrelated.

Method

Seventy monolingual Italian preterms and 34 age-matched controls were recruited. Linguistic abilities (vocabulary, grammar, and phonological awareness) as well as general cognitive developmental levels were measured.

Results

No general cognitive delay emerged, but less developed abilities in vocabulary, grammar, and phonological awareness were found in preterms compared to fullterms. Moreover, the relations among the different linguistic competences differed across groups.

Conclusions

Our study shows that even without brain damage, preterm birth continues to affect linguistic development up to the end of the preschool years, and probably beyond, highlighting a continuity between pre- and peri-natal life and subsequent development, and pointing to an atypical developmental trajectory in this population compared to fullterms (different rates of development, different strategies employed, and differences in the relationships among linguistic abilities).     

Cognitive abilities associated with the Silver-Russell syndrome.

There is no consensus opinion on whether or not cognitive impairments are found in the Silver-Russell syndrome. An investigation of a substantial sample was undertaken, using standardised assessments, in 20 boys and five girls aged 6.0 years to 11.8 years. Mean (SD) birth weights were -2.65 (0.95) SD scores, corrected for gestation. At evaluation the children had a mean (SD) age of 8.8 (1.8) years and a mean height of -2.26 (1.5) SD scores. Tests of cognitive abilities included assessments of general intelligence, reading and arithmetic attainments, and a cognitive processing task. Most had some degree of developmental delay: mean (SD) full scale IQ was 86 (24); 32% scored within the learning disability range (that is, IQ < 70); 40% were reading at least 24 months below their chronological age. Current head circumference correlated highly with full scale IQ. Assessments of special educational needs had been completed on 36%; 48% were receiving speech therapy. Approximately half of children with the Silver-Russell syndrome have significant impairment of their cognitive abilities.     

Cardiovascular changes in children with mucopolysaccharide disorders

The aims of this study were to evaluate cardiac involvement, assess risk factors and mortality, and define the outcome of cardiac abnormalities with age in the different types of mucopolysaccharidoses (MPS). The echocardiograms of 99 patients with MPS, aged 1-24 y (median age 10.3 y) were reviewed between 1978 and 2000. Mitral regurgitation (MR) was detected in 29 patients (29%). MR was more frequent in types IH [ n = 11 (38%)], II [ n = 10 (24%)] and III [ n = 4 (20%)]. Sixteen patients (16%) developed aortic regurgitation (AR), seen mostly in types II [ n = 9 (56%)] and IV [ n = 4 (24%)]. AR and/or MR was detected in 37 patients and 8 had both abnormalities of borderline significance (odds ratio 2.95, 95% confidence interval 1.0-8.85, p = 0.05). Of 99 patients, 47 had a normal study on their first echocardiogram, whereas only 7 had a normal study on subsequent echocardiograms. Fifty-four (54%) had a single echocardiogram. Of these, 27 (50%) were abnormal and 27 normal. Forty-five patients had more than one echocardiogram, of which 25 (56%) were abnormal and 20 normal. In 13/20 (65%) a cardiac abnormality developed on a subsequent echocardiogram which was statistically significant ( p = 0.002). Overall mitral and aortic valve abnormalities showed a positive association with age. Univariate analysis of risk factors showed that increasing age, MPS I and ejection fraction were significant risk factors for death. However, left ventricular hypertrophy, mitral valve abnormalities and type II MPS were not significant risk factors for death, with borderline significance for aortic valve abnormalities.

Conclusion: This study demonstrates the evaluation of ventricular function, which is a significant risk factor for death, along with increasing age and MPS I, and outlines the borderline significance of aortic valve abnormalities, which has not been mentioned in previous studies. It also shows that mitral valve lesions, commonly seen in MPS, were not a significant risk factor for death. The results emphasize the importance of performing serial echocardiograms in patients with MPS to assess ventricular function and the progression of cardiac abnormalities with age.     

The presenting features of mucopolysaccharidosis type IH (Hurler syndrome)

The presenting features of 39 patients with mucopolysaccharidosis (MPS) type IH are described. The mean age at diagnosis was approximately 9 months and it is difficult to see how this can be reduced without consideration of newborn screening. An earlier age at diagnosis is likely to lead to better results following therapy such as bone marrow transplantation. Clinical features which should arouse suspicion of MPS IH include frequent ENT surgery and recurrent herniae. Clinical vigilance is needed for early diagnosis     

Enzyme replacement therapy: from concept to clinical practice

In the early 1960s, the first lysosomal storage disease was identified. Since then over 40 such diseases have been reported. The common feature is that enzyme deficiency leads to accumulation of undegraded macromolecules and lysosomal engorgement, resulting in organ dysfunction. Enzyme replacement therapy (ERT) is being developed for many of these disorders. The present paper summarizes the history of the development of ERT, with particular reference to the mucopolysaccharidoses, and specifically, to mucopolysaccharidosis type VII (MPS VII). The rarity of MPS VII has meant that ERT is not yet available for the small number of affected patients, although the study of MPS VII and murine models of the disease have played an important part in the development of treatment for related disorders, including Gaucher disease. CONCLUSION: Much progress has been made in our understanding of lysosomal storage diseases over the past 40 years. This has led to the development of effective ERT for some of the more common storage diseases, such as Fabry disease and Gaucher disease. Treatment is still awaited, however, for many of the other rare disorders in this area, such as MPS VII.     

Mucopolysaccharidosis type VII in the developing mouse fetus

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of beta-glucuronidase (1). MPS VII is a fatal, progressive degenerative disorder, and a number of patients die of hydrops fetalis. Thus an approach to treating this disease may be by transplantation or gene therapy in utero. A mouse model of MPS VII has been studied extensively but the disease in affected fetal mice has not been characterized, which is essential for evaluation of therapeutic efficacy. Fetal and newborn mice affected with MPS VII were examined for lysosomal enzyme activities and for the presence of typical storage lesions in comparison to normal and carrier littermates. No beta-glucuronidase enzymatic activity was detected in any of the tissues of affected mice, indicating that transplacental transfer of beta-glucuronidase from the dam did not occur. Lesions were not detected in affected fetuses of 13.5 d gestational age on light or electron microscopy. Vacuolation in cells, typical of lysosomal accumulation of substrate, was first seen in a small number of cells of the reticulo-endothelial system in 15.5 d gestational age livers and in 18.5 d gestational age brains. Storage lesions were not seen consistently in endothelial and Kupffer cells of fetal livers until 18.5 d gestational age and in brains until birth. The results suggest that treatment of affected mice performed at 13.5 d gestational age may be effective in forestalling disease manifestations.     

Sanfilippo syndrome: Overall review

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of the four enzymes involved in the catabolism of glycosaminoglycan heparan sulfate. It is characterized by progressive cognitive decline and severe hyperactivity, with relatively mild somatic features. This review focuses on clinical features, diagnosis, treatment, and follow‐up of MPS III, and provides information about supplementary tests and differential diagnosis. Given that few reviews of MPS III have been published, several studies were compiled to establish diagnostic recommendations. Quantitative urinary glycosaminoglycan analysis is strongly recommended, and measurement of disaccharides, heparin cofactor II–thrombin complex and gangliosides is also used. Enzyme activity of the different enzymes in blood serum, leukocytes or fibroblasts, and mutational analysis for SGSH, NAGLU, HGSNAT or GNS genes are required to confirm diagnosis and differentiate four subtypes of MPS III. Although there is no global consensus for treatment, enzyme replacement therapy and gene therapy can provide appropriate results. In this regard, recent publications on treatment and follow‐up are discussed.     

The development of pragmatic communication skills in head injured children

This study investigated the developmental levels of pragmatic language skills in children following head injury (HI), in comparison to their uninjured peers. Participants were 30 head-injured and 19 healthy controls, classified into a 'young' age group, 8-9 years, and an 'old' age group, 11-12 years. Participants were administered the WISC- III, a negotiating requests task and a hint task, the latter two assessing verbal reasoning skills and abilities to be indirect, respectively. It was found that negotiation and hinting strategies were rapidly developing in these age groups, where abilities to hint were less mature for all groups. Results found a main effect for injury on cognitive and functional language tasks, reflected by lower performance levels and inflexibility in reasoning for the head-injured group. Injury sustained at an earlier age consistently predicted poorer performance on the language tasks, complicating the ongoing development of generalized and higher-order communicative skills. Severity of injury did not predict performance on either language task.     

A clinical study of 77 patients with mucopolysaccharidosis type II

AIM: This study aims to assess the clinical features of 77 South American patients (73 Brazilian) with mucopolysaccharidosis type II (MPS II). METHODS: Details of the patients and their disease manifestations were obtained from a review of medical records, interviews with the patients and/or their families, and physical examination of the patients. RESULTS: Mean birth weight was 3360 g, median age at onset of symptoms was 18 months and median age at diagnosis was 6 years. For the whole sample (median age, 8.2 years; range, 2.8-53.0 years), neurological degeneration, typical pebbly skin lesions, seizures and extensive dermal melanocytosis were found in 23.3, 13.0, 13.0 and 1.3% of the cases, respectively. The most frequently reported echocardiogram abnormality was mitral valve regurgitation. Refraction errors were the most common ophthalmological manifestation. The following characteristics were found to be associated with the severe form of MPS II: earlier age at biochemical diagnosis, higher levels of urinary glycosaminoglycans, language development delay, behavioural disturbances, poor school performance and mental retardation. CONCLUSION: Our results suggest that there is a considerable delay between the onset of signs and symptoms and the diagnosis of MPS II in Brazil (and probably in South America as well), and that many complications of this disease are underdiagnosed and undertreated. Therefore, the implementation of programmes aiming to increase the awareness of the disease, the availability of biochemical diagnostic tests and the provision of better support to affected patients is urgently needed.     

Mitral and aortic regurgitation in 84 patients with mucopolysaccharidoses

In echocardiographic and necropsy studies nodular thickening of the mitral valve and, less frequently, of the aortic valve has been found in 60%–90% of patients with mucopolysaccharidoses (MPS). Little is known about the haemodynamic consequences of these morphological changes. In this study 84 unselected patients with different enzymatically proven MPS and 84 age and sex matched, healthy persons were studied prospectively by colour Doppler flow mapping. The patients' age ranged from 1 to 47 years (median 8.1 years). Mitral and aortic regurgitation were defined as a holosystolic or holodiastolic jet originating from the valve into the left atrium or the left ventricular outflow tract, respectively, with peak velocities exceeding 2.5 m/s. Of the 84 patients with satisfactory studies, mitral regurgitation was detected in 64.3% and aortic regurgitation in 40.5%, respectively. Regurgitation was severe in 4.8% of mitral valves and 8.3% of aortic valves. The frequency of aortic and/or mitral regurgitation was 75% in all patients, 89% in MPS I, 94% in MPS II, 66% in MPS III, 33% in MPS IV, and 100% in MPS VI. Combined mitral and aortic regurgitation was present in 29% of our patients. None of the control persons showed mitral or aortic regurgitation.     

Long term developmental outcomes of pre-school age children following laser surgery for twin-to-twin transfusion syndrome

BackgroundLaser therapy is now a well recognised treatment for twin-to-twin transfusion syndrome (TTTS). We investigated the early childhood neurodevelopmental outcome of children post laser treatment for TTTS in our centre.MethodsChildren of women who had laser therapy for TTTS between March 2006 and June 2008 were assessed at 30–69 months of age with WPPSI-III and a general health questionnaire. Major neurodevelopmental impairment (NDI) was reported as IQ < 70 or cerebral palsy (CP). Borderline cognitive impairment was defined by IQ 70–79.ResultsAmongst the 37 pregnancies treated, 62 infants were discharged home and the overall foetal survival rate was 84%. A total of 50 children (84%) from 31 pregnancies were assessed. Average age at assessment was 47 months. Two children with late treatment of congenital hypothyroidism were excluded. The majority of pregnancies were Quintero Stage III (74%). There was a significant trend for worse outcome with higher Quintero stage. The average gestational age at birth was 32 weeks. The majority (39, 78%) of children were found to be neurodevelopmentally normal; 9 (18%) had borderline cognitive development; and 2 (4%) had a major NDI, including one with cerebral palsy (2%).ConclusionsThere was a modest level of neurocognitive impairment post laser therapy for TTTS, mainly borderline cognitive development, lesser so major NDI. There was a low incidence of cerebral palsy. Routine developmental and neurological follow-up of these children is recommended.     

Effects of intraventricular hemorrhage and socioeconomic status on perceptual, cognitive, and neurologic status of low birth weight infants at 5 years of age.

A prospective longitudinal study assessed the effects of intraventricular hemorrhage (IVH) and socioeconomic status on the perceptual, cognitive, and neurologic status of preterm infants at 5 years of age. The preterm group consisted of infants with no IVH, grade I to II IVH, and grade III to IV IVH; a control group of normal term infants was also studied. Outcome was evaluated at 3, 4, and 5 years of age. Twenty-four percent of infants with grade III to IV IVH had abnormal neurologic diagnoses at 5 years of age. Correlations of predictor variables including IVH status, latency of visual evoked response, days of hospitalization, and socioeconomic status with 5-year neurologic outcome indicated that IVH status and visual evoked response at 1, 2, and 3 years continued to have an effect on neurologic outcome, but socioeconomic status and days of hospitalization did not; socioeconomic status did have a significant effect on the McCarthy cognitive scores but not on the perceptual scores at 5 years. Multiple regression analyses revealed that duration of hospitalization (reflecting neonatal morbidity), visual evoked response, and socioeconomic status all have independent effects on the cognitive index, whereas only duration of hospitalization has an independent effect on the perceptual index. These data support the concept that a complex interaction of biologic and environmental risk factors determines the degree of recovery from IVH by high-risk preterm infants.     

Predictors of neurodevelopmental outcome of Malaysian very low birthweight children at 4 years of age

OBJECTIVE: To determine neonatal, early developmental and social risk factors that predict the neurocognitive and behavioural outcome of very low birthweight (VLBW) preschool children at four years of age. METHODOLOGY: From a cohort of 151 eligible VLBW survivors born in Kuala Lumpur Maternity Hospital, 116 (76.8%) were prospectively followed up from birth till four years. A standardised neurological examination was performed at one and four years to determine the presence of impairment and cerebral palsy, respectively. Cognitive development was assessed using the Mental Scale of the Bayley Scales of Infant Development (MDI) at one year and the Weschler Preschool and Primary Scale of Intelligence-Revised (WIPPSI-R) at four years. Motor coordination was assessed using the Movement Assessment Battery for Children (Movement-ABC). Mothers completed the Child Behaviour Checklist (CBCL) and Parenting Stress Index (PSI) questionnaires. Logistic and multiple regression analyses were used to determine factors associated with cerebral palsy, IQ scores, Movement-ABC and CBCL scores. RESULTS: Factors associated with cerebral palsy were lower MDI scores at one year (P = 0.001) and late neonatal cranial ultrasound abnormalities (P = 0.036). Minor (P = 0.016) or major impairment (P = 0.003) at one year of age and a low level of paternal education (P = 0.01) were associated with poor motor function on the Movement-ABC scale. Lower levels of maternal education (P < 0.001), impairment at one year (P = 0.002) and late neonatal cranial ultrasound abnormalities (P = 0.039) predicted Full Scale IQ scores. Higher PSI scores (P = 0.001), younger mothers (P = 0.003) and late neonatal cranial ultrasound abnormalities (P = 0.009) were associated with worsened child behaviour scores on the CBCL scale. CONCLUSION: Social factors and the caregiving environment were important determinants of cognitive and behavioural outcome. Cranial ultrasound abnormalities in the late neonatal period and the developmental status at one year might be useful in identifying high risk infants in need of long-term surveillance.     

Language development in children with congenital heart disease aged 12–24 months

This longitudinal study aims to describe the trajectory of language development in children with CHD aged 12–24 months assessed through an early monitoring and individualized intervention program. We also sought to determine whether early language performances, at 12 months of age, predict 24-month language abilities.We conducted developmental assessments of 49 children with CHD using the Bayley Scales of Infant and Toddler Developmental, third edition (Bayley-III) at 12 and 24 months, and the MacArthur-Bates Communicative Development Inventories (MBCDI) at 12, 18 and 24 months.Compared to normative populations, CHD patients showed significantly lower mean scores in both receptive and expressive language scales of the Bayley-III and the MBCDI at 12 months, whereas at 18 and 24 months only expressive language scores were reduced. No differences were found in the cognitive scale. Communicative gestures at 12 months were significantly predictive of language skills at 24 months of age.Our findings indicate specific vulnerability of language outcome, especially in expressive skills, rather than a global cognitive impairment in our patients with CHD. We recommend using communicative gestures as an early marker of language development to improve our ability to detect language delays in this population.