Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia.

OBJECTIVE: Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia-spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity. METHODS: We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high-throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases. RESULTS: Six unreported CAPN1-associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs* 103, c.759+1G>A, and p.R285* ), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain-1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015). INTERPRETATION: Our study supports the clinically heterogeneous inter- and intra-family variability of SPG76 patients, and demonstrates that gender and calpain-1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

COVID-19 and the Field of Intellectual and Developmental Disabilities: Where Have We Been? Where Are We? Where Do We Go?

The coronavirus (COVID-19) pandemic has affected, and will continue to affect, every aspect of the intellectual and developmental disabilities (IDD) community. We provide recommendations to (a) support people with IDD and the broader of field of IDD during the course of the pandemic, and (b) place the IDD community in a strong position when the health threats associated with the pandemic abate and post-pandemic social and policy structures are formed.

COVID-19 outcomes among people with intellectual and developmental disability living in residential group homes in New York State.

BACKGROUND: People with intellectual and developmental disabilities (IDD) may be at higher risk of severe outcomes from COVID-19. OBJECTIVE: To describe COVID-19 outcomes among people with IDD living in residential groups homes in the state of New York and the general population of New York State. METHODS: Data for people with IDD are from a coalition of organizations providing over half of the residential services for the state of New York, and from the New York State Department of Health. Analysis describes COVID-19 case rates, case-fatality, and mortality among people with IDD living in residential group homes and New York State through May 28, 2020. RESULTS: People with IDD living in residential group homes were at greater risk of severe COVID-19 outcomes: case rates - 7,841 per 100,000 for people with IDD compared to 1,910 for New York State; case-fatality - 15.0% for people with IDD compared to 7.9% for New York State; and mortality rate - 1,175 per 100,000 for people with IDD compared to 151 per 100,000 for New York State. Differences in cases and mortality rate were confirmed across regions of the state, but case-fatality rate was only higher for people with IDD in and around the New York City region. CONCLUSIONS: COVID-19 appears to present a greater risk to people with IDD, especially those living in congregate settings. A full understanding of the severity of this risk will not be possible until US states begin publicly sharing all relevant data they have on COVID-19 outcomes among this population.

Secondary congenital aphakia.

UNLABELLED: Abstract PURPOSE: We present the clinical, paraclinical and therapeutic features in a patient with secondary congenital aphakia. METHODS: A 2-year-old patient, diagnosed with congenital rubella syndrome including sensorineural deafness, congenital heart disease, intellectual disability, microcephaly, microphthalmia, and congenital cataract, presented to our clinic for the surgical treatment of cataract. RESULTS: During the surgery, the absence of the lens' cortex was observed, hence, the final diagnose was of secondary congenital aphakia. Surgery was then continued with a posterior capsulorhexis and an anterior vitrectomy, deciding to postpone the implantation of the posterior chamber intraocular lens.

[Three cases of human herpesvirus-6 encephalopathy showing hyperperfusion in the acute phase on SPECT].

Brain hypoperfusion observed on single-photon emission computed tomography (SPECT) is a typical finding in the acute phase of human herpesvirus-6 (HHV-6) encephalopathy. However, from 2004 to 2010, we encountered three cases of HHV-6 encephalopathy in which hyperperfusion in the area of the brain lesion was observed on SPECT performed within 48 hours after disease onset. The hyperperfusion in the brain was followed by hypoperfusion in the recovery phase. These cases suggest that hyperperfusion may appear in damaged areas prior to the hypoperfusion that is normally associated with HHV-6 encephalopathy.

Congenital cytomegalovirus infection: new prospects for prevention and therapy.

Cytomegalovirus is the commonest congenital viral infection in the developed world, with an overall prevalence of approximately 0.6%. Approximately 10% of congenitally infected infants have signs and symptoms of disease at birth, and these symptomatic infants have a substantial risk of subsequent neurologic sequelae. These include sensorineural hearing loss, mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy. Antiviral therapy for children with symptomatic congenital cytomegalovirus infection is effective at reducing the risk of long-term disabilities and should be offered to families with affected newborns. An effective preconceptual vaccine against CMV could protect against long-term neurologic sequelae and other disabilities.

Cochlear implantation in children with congenital cytomegalovirus infection accompanied by psycho-neurological disorders.

CONCLUSION: Cochlear implantation was effective for deaf children with congenital cytomegalovirus (CMV) infection, but their cochlear implant (CI) outcomes were often impaired, depending on the types of CMV-associated psycho-neurological disorders. Evaluation of cognitive development and autistic tendency of implantees might be useful to predict their CI outcomes. OBJECTIVES: To reveal the influence of CMV-associated psycho-neurological disorders on CI outcomes. METHODS: This was a retrospective evaluation of 11 implantees with congenital CMV infection (CMV-CIs) and 14 implantees with autosomal recessive hearing loss (genetic-CIs). RESULTS: Nine of 11 CMV-CIs suffered from psycho-neurological disorders; one from attention deficit hyperactivity disorder, two from pervasive developmental disorder, and six from mental retardation. Aided hearing thresholds with CIs in the two groups did not differ, but two autistic and two mentally retarded CMV-CIs showed significantly low scores in speech discrimination tests. Language-Social (L-S) developmental quotients (DQs) evaluated by the Kyoto Scale of Psychological development were improved after the implantation in both groups, but the postoperative increase of L-S DQs was significantly smaller in the CMV-CIs than that of genetic-CIs. Interestingly, the postoperative L-S and Cognitive-Adaptive (C-A) DQs showed statistically significant correlation in all cases except for two autistic CMV-CIs whose L-S DQs were much lower than those expected from their C-A DQs.

Congenital cytomegalovirus virus infection.

A 14 months old male child with psychomotor retardation and hypotonia is reported, where computerized axial tomography revealed multiple calcification and ventriculomegaly secondary to cortical atrophy. Investigation suggested the diagnosis of cytomegalovirus infection. Importance of early diagnosis is emphasized as the potential long term sequelae can be prevented or reduced markedly with available therapeutic options.

[Cytomegalovirus (CMV) congenital infection]. / Infection congénitale à Cytomégalovirus (CMV).

Human Cytomegalovirus (CMV) is the main cause of mental retardation and sensorineural hearing loss related to congenital infections. Justification of systematic screening for fetal CMV infection is still controversial and is not recommended in most developed countries. This is mainly justified by the paucity of antenatal prognostic factors and the lack of established intrauterine treatment when fetal infection has been diagnosed. Our aim was to review the current state of the knowledge about the CMV congenital infection and to highlight recent advances in the diagnosis as well as in the identification of prognostic factors.

Trace elements and cytokine profile in cytomegalovirus-infected pregnancies: a controlled study.

OBJECTIVE: Qinba Mountain area of Shanxi Province, China, is one of the poorest, culturally backward regions in China with a high incidence of mental retardation. To investigate whether cytomegalovirus (CMV) plays a role in the high incidence of mental retardation in this region, we studied the incidence of CMV infection during pregnancy and possible risk factors associated with CMV infection. METHODS: 386 consecutive pregnant women in Qinba Mountain area were monitored for the level of a CMV-specific IgM antibody. Polymerase chain reaction was used to detect CMV in breast milk obtained within 2 weeks postpartum and urine samples of newborn infants born to actively CMV-infected mothers. Serum levels of TNF-alpha, IL-6, zinc, copper, iron and selenium were analyzed in CMV-infected pregnant women. RESULTS: The incidence of CMV-active infection during pregnancy, intrauterine transmission and excretion in breast milk were 15.03, 33.33, and 39.58%, respectively. Active CMV infection during pregnancy was correlated with maternal age, education and economic status, parity, and history of obstetric complications. Those women who had active CMV infection, intrauterine transmission, or CMV excretion in milk showed higher values of TNF-alpha and IL-6, lower values of zinc as compared with health age-matched controls (p < 0.05). No differences were identified between studied cases and controls in the level of copper, iron, and selenium (p > 0.05). CONCLUSION: The incidence of CMV-active infection during pregnancy was high in Qinba Mountain area of Shanxi Province. Zinc deficiency may be a risk factor for the development of CMV infection. TNF-alpha and IL-6 may be involved in the pathophysiologic process.

Congenital cytomegalovirus infection diagnosed by polymerase chain reaction with the use of preserved umbilical cord in sensorineural hearing loss children.

OBJECTIVES/HYPOTHESIS: Congenital cytomegalovirus (CMV) infection is estimated to account for 30% of sensorineural hearing loss (SNHL) cases. Differences in clinical characteristics between CMV-related and unrelated SNHL cases were scrutinized. METHODS: Using dried umbilical cord, we have recently developed a polymerase chain reaction (PCR)-based assay for the retrospective detection of congenital CMV infection. Medical records of 7 CMV-related patients identified from 31 SNHL patients by the assay were evaluated for the following: type and degree of hearing impairment, computed tomographic scan results, mental retardation, cerebral palsy, autism, and other multiple disorders. RESULTS: Clinical characteristics of the seven CMV-related SNHL cases were as follows: 1) six of the seven exhibited severe bilateral SNHL, whereas one had severe unilateral SNHL in the right ear. Although the hearing levels of CMV-related patients were more greatly impaired than those of CMV-negative patients, there was no hearing impairment pattern specific to the CMV-related patients; 2) five patients had mental retardation, which was more frequent than in CMV-negative patients; 3) birth weights of the CMV-positive cases were relatively lower. DISCUSSION: Although CMV-positive cases are clinically indistinguishable from CMV-negative cases, our PCR system allowed the retrospective diagnosis of CMV-related SNHL. CONCLUSION: CMV-related SNHL tends to accompany mental retardation and low birth weight more frequently than does CMV-negative SNHL.

Prevalence and genotypic distribution of hepatitis GB-C/HG and TT viruses in blood donors, mentally retarded children and four groups of patients in eastern Anatolia, Turkey.

We investigated the prevalence and genotypic distribution of GB virus-C/hepatitis G virus (GBV-C/HGV) and TT virus (TTV) in blood donors, mentally retarded children and four groups of patients living in Eastern Anatolia, Turkey. The prevalence and genetic analysis of TTV were determined by using the primers of the UTR and ORF1 regions of TTV, respectively. Reverse transcription nested (RT-n)-PCR was used to amplify 5' UTR of GBV-C/HGV. Genotyping of HGV was carried out by PCR-based genotyping assay while RFLP was conducted to determine the genotypes of TTV. TTV DNA was detected in 118 of 410 sera tested, giving an overall prevalence of 28.7%; GBV-C/HGV-RNA was detected in only 17 cases, giving an overall prevalence of 4.1%. No significant differences were observed in the number of positive or negative tests for GBV-C/HGV and TTV according to duration of illness or mean duration of institutionalization in any of the groups studied. Although all samples from the study population belonged to genotypes 1 and 4, the most common TTV genotype is G2. In conclusion, our results indicate a low endemicity of GBV-C/HGV and TTV infection in Eastern Anatolia, Turkey. The presence of G2 strains reveals the limited genetic diversity of the GBV-C/HGV circulating in Turkey. We suggest that TTV infection of genotypes 1 and 4 is prevalent in the same region.

Incidence and outcome of congenital cytomegalovirus infection in selected groups of preterm and full-term neonates under intensive care.

Congenital cytomegalovirus (CMV) infection is the leading cause of mental retardation and hearing impairment. Examination for the presence of CMV infection was carried out in a selected population of 70 neonates. Urine samples were tested for CMV by means of a nested polymerase chain reaction. CMV was detected in 6 (16.7%) of the 36 preterm newborns and in 5 (14.7%) of the 34 full-term newborns. One preterm neonate died and the remaining 10 newborns were followed up. Two children born at full-term did not excrete CMV at 2 years of age and were symptom-free. Of 8 CMV-excreting children (5 preterm and 3 full-term), 2 were symptom-free (1 preterm and 1 term). Symptomatic CMV disease developed in 6 children (4 preterm and 2 full-term), with mental retardation (n=4), hearing loss (n=1), strabismus (n=2) or bronchial asthma (n=1). Screening of such neonates is important; those identified as congenitally CMV-infected can be monitored to correct any sequelae immediately.

[Neurologic aspects of HIV infections--follow-up of pediatric patients]. / A HIV-fertózés neurológiai vonatkozásai. Gyermek betegek követésének tapasztalatai.

OBJECTIVES: Before the widespread introduction of combined antiretroviral therapy (1995) complications from HIV and AIDS in the central nervous system had been reported in larger proportion in infants and children than in adults: 80-90% versus 60-70%. Particular clinical manifestations tend to occur at different stages during the evolution of HIV infection. The authors review the neurological aspects of HIV infection. METHOD: First, a summary of the protocol of the neurological examinations and related experience is given. Then authors present the evaluation of neuro-psychological development, prevalence of neurological impairment and neuro-imaging of nine HIV infected children (seven boys, two girls) for the period of ten years (1991-2001). Three/ten children had vertically transmitted HIV six/nine were infected by a nosocomial route in their early childhood. Children were regularly followed up from the diagnosis of HIV. The median follow up time has been 79 month (range: 18-144 month). Four patients died during the study period. The neurological status, the motor and mental development were examined at three month intervals or monthly under one year of age. EEG was performed every six month and CT/MRI once a year. All patients received combined antiretroviral treatment and immunoglobulin therapy continuously. RESULTS: Three/nine children have normal development, one/nine has hyperactive and attention deficit disorder with normal IQ range, two/nine have slight, one/nine moderate and two/nine serious mental retardation. Mild neurological signs were found in two children, various moderate and serious neuro/psychological symptoms were found in four patients, one of them was treated with benign epilepsy too. There was also dose correlation between the clinical symptoms and the results of EEG examination (diffuse background slowing) and results of neuroimaging studies (cortical atrophy, calcification of the basal ganglia, toxoplasma abscesses). According to the results of different examinations three/nine children were found to be symptom-free, one/nine case showed the static form, two/nine patients showed the plateau form, two/nine the rapid progressive form and one/nine the progressive infantile form of AIDS encephalopathy. The majority of the patients suffered from adopting problems and difficulties of socialisation since their families lives were damaged by isolation and rejection from the community. CONCLUSION: The regular neurological and psychological examinations completed with EEG, CT/MRI were very informative to follow the course of neuro-psychological problems of HIV infected children. Symptom-free patients have to face psychosocial problems too, which cause much more damage in their mental progress than HIV itself.

Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection.

OBJECTIVE: To determine the ability of neonatal clinical, audiologic, and computed tomography (CT) findings to predict long-term neurodevelopmental outcome in children with symptomatic congenital cytomegalovirus (CMV) infection. METHODS: Longitudinal cohort study of children (n = 41) with symptomatic congenital CMV infection evaluated at birth and followed up with serial age-appropriate neurodevelopmental testing. The performance of birth characteristics as predictors of long-term outcome were determined, and clinical and CT scoring systems were developed and correlated with intellectual outcome. RESULTS: Microcephaly was the most specific predictor of mental retardation (100%; 95% CI 84.5-100) and major motor disability (92.3%; 95% CI 74.8-99). An abnormality detected by CT was the most sensitive predictor for mental retardation (100%; 95% CI 82.3-100) and motor disability (100%; 95% CI 78.2-100). A highly significant (P <.001) positive correlation was found between head size at birth and the intelligence/developmental quotient (IQ/DQ). Approximately 29% of children had an IQ/DQ >90. There was no association between sensorineural hearing loss at birth and cognitive outcome. However, children with sensorineural hearing loss on follow-up (congenital and late-onset) had a lower IQ/DQ (P =.006) than those with normal hearing. CONCLUSIONS: The presence of microcephaly at birth was the most specific predictor of poor cognitive outcome in children with symptomatic congenital CMV infection, whereas children with normal findings on head CT and head circumference proportional to weight exhibited a good cognitive outcome.