Satu Kivitie-Kallio

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular Protein Transport

Cohen syndrome is an uncommon autosomal recessive disorder whose diagnosis is based on the clinical picture of nonprogressive psychomotor retardation and microcephaly, characteristic facial features, retinal dystrophy, and intermittent neutropenia. We have refined the critical region on chromosome 8q22 by haplotype analysis, and we report the characterization of a novel gene, COH1, that is mutated in patients with Cohen syndrome. The longest transcript (14,093 bp) is widely expressed and is transcribed from 62 exons that span a genomic region of approximately 864 kb. COH1 encodes a putative transmembrane protein of 4,022 amino acids, with a complex domain structure. Homology to the Saccharomyces cerevisiae VPS13 protein suggests a role for COH1 in vesicle-mediated sorting and transport of proteins within the cell.

Cohen syndrome: Essential features, natural history, and heterogeneity

This article elucidates the clinical picture in Cohen syndrome (MIM 216550), an autosomal recessive disorder that is overrepresented in Finland. The diagnosis is based on the typical clinical picture: nonprogressive psychomotor retardation, motor clumsiness and microcephaly, typical facial features, childhood hypotonia and hyperextensibility of the joints, ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age, and granulocytopenia. In a nationwide study, 29 Finnish patients were investigated. Magnetic resonance images of the brain with quantitative structure analyses revealed a relatively enlarged corpus callosum (CC). The youngest patients had normal EEGs, while all others had low-voltage EEGs. Of the patients, 22% had profound, 61% severe, 6% moderate, and 11% mild retardation. In an adaptive behavior scale (AAMD), patients had high scores in the positive domains (self-direction, responsibility, and socialization), whereas maladaptive behavior was almost lacking. Only the youngest patients had unimpaired visual function. Vision started to deteriorate early but slowly. Progressive myopia and retinochoroidal dystrophy were found in all of the patients over 5 years of age. All of the patients had isolated granulocytopenia. The heart anatomy was normal. However, decreased left ventricular function with advancing age was found. No significant endocrine abnormalities were discovered. Fingers were slender but short, with a typical metacarpophalangeal pattern profile. The manifestations vary at different ages. The Finnish Cohen patients are clinically highly homogeneous, their disease gene being located on chromosome 8. Heterogeneity probably exists among other patients claimed to have Cohen syndrome.

A prospective study on buprenorphine use during pregnancy: effects on maternal and neonatal outcome.

Background. Exposure to illicit drugs in utero is associated with low birth weight and premature birth. Therefore, maintenance therapy for opioid dependence during pregnancy has been recommended to help withdrawal from street drugs, in order to improve maternal health and decrease risks to the fetus. Methods. In 2002–2005, 67 pregnancies of 66 buprenorphine users were followed prospectively in an outpatient multidisciplinary antenatal setting by an obstetrician, a midwife, a psychiatric nurse and a social worker. Decreasing doses or even abstinence from buprenorphine was encouraged. Outcome measures were daily buprenorphine dose, fetal growth, gestational age at birth, mode of delivery, birth weight, Apgar scores, umbilical pH values, and occurrence of neonatal abstinence syndrome [NAS]. National statistics were used as reference values. Results. The daily dose of buprenorphine decreased by 2.3 mg (median, range increase of 8 mg to decrease of 24 mg). There were no more incidences of premature birth, cesarean section, low Apgar scores (≤6) or umbilical artery pH <7.05 at birth than in the national register, despite the lower birth weight. A total of 91% of the infants needed treatment in a neonatal care unit, 76% had NAS, and 57% needed morphine replacement therapy. Seven infants were taken into care directly from the maternity hospital. Two sudden infant deaths occurred later. Conclusions. The pregnancies and deliveries of buprenorphine‐using women were uneventful, but severe NAS and need for morphine replacement therapy was seen in 57% of the buprenorphine‐exposed newborns. A high number of sudden infant deaths occurred.

Emotional Availability, Parental Self-Efficacy Beliefs, and Child Development in Caregiver-Child Relationships with Buprenorphine-Exposed 3-year-olds

SYNOPSIS Objective . The purpose was to compare emotional availability, maternal self-efficacy beliefs, and child developmental status in caregiver–child relationships with prenatally buprenorphine-exposed and nonexposed 3-year-old children. Design. We compared prenatally buprenorphine-exposed children living either with the biological mother (n = 7) or in foster care (n = 14) to nonexposed participants (n = 13). Emotional availability was coded from videotaped parent-child free-play interactions. Results. After controlling for covariates, buprenorphine-exposed children scored lower on maternal Sensitivity and Nonhostility and child Responsiveness and Involvement as well as lower on the Bayley Cognitive and Language scales than did nonexposed children. As compared to foster mothers, biological mothers scored lower on Sensitivity and Nonhostility and self-efficacy beliefs, and their children scored lower on Responsiveness and the Bayley Cognitive Scale. Regardless of group status, the parenting variables were meaningfully related to child socioemotional variables. Conclusions . Buprenorphine-exposed children experienced more environmental risks in emotional availability and parental self-efficacy and performed worse on the Bayley as compared to nonexposed children.

Neonatal outcome of 58 infants exposed to maternal buprenorphine in utero

Aim: To study the neonatal outcome of infants exposed to buprenorphine in utero.

Ophthalmologic findings in cohen syndrome: A long-term follow-up

OBJECTIVE To determine the nature and course of ophthalmologic abnormalities and their clinical significance in Cohen syndrome. STUDY DESIGN Observational case series. PARTICIPANTS Twenty-two Cohen syndrome patients aged 2 to 57 years were examined, and a retrospective review of ophthalmologic records was carried out for 14 of them. All but one were part of the Finnish study of refined mapping of the Cohen syndrome gene by linkage disequilibrium in chromosome 8. MAIN OUTCOME MEASURES Visual acuity (VA), cycloplegic refraction, biomicroscopy, lens opacitometry, ophthalmoscopy, and fundus photography. RESULTS With the exception of the two youngest patients, all had symptoms such as nyctalopia, impaired vision, and visual field loss. Progressive, often high-grade myopia, astigmatism, and retinochoroidal dystrophy resembling retinitis pigmentosa occurred in all, except for the youngest patients. The earliest fundus changes were pale disc and pale fundus with or without pigment granularity, followed by narrowed vessels, pigment clumps, and bone spiculelike pigment accumulations by 10 to 20 years of age. Pigment deposits increased and approached the posterior pole by 35 to 40 years of age. Patients more than 45 years of age had severe retinochoroidal atrophy. A bulls-eye macula was seen in most patients. Teenagers had peripheral lens opacities, and young adults had early nuclear sclerosis confirmed by lens opacitometry. Older patients also had posterior subcapsular cataracts, iris atrophy, and iridophacodonesis. Vision started to deteriorate at the age of 6 to 10 years, but remained relatively good (VA 0.5-0.1) in most patients until 30 and, in one case, 46 years of age. Older patients were severely visually handicapped (VA hand motion to light perception), but none were completely blind. CONCLUSIONS Progressive myopia and retinochoroidal dystrophy are essential features in Cohen syndrome and, together with early lens opacities, lead to deterioration of vision. Cohen syndrome patients need careful ophthalmologic follow-up at all ages. Nyctalopia and restricted visual fields should be considered when planning the patients daily activities.

Cohen syndrome: evaluation of its cardiac, endocrine and radiological features

Cohen syndrome (MIM no. 216550) is an autosomal recessive disorder with a typical clinical picture. Since the first report, most publications have represented single case reports. In this study, our aim was to describe cardiac, endocrine and radiological abnormalities in 22 Cohen patients of Finnish descent. Detailed investigations of the heart revealed the anatomy of the heart to be normal with no evidence for clinically significant mitral prolapse. However, a decreased left ventricular function with advancing age was identified. No significant endocrine abnormalities were found at the examination of pituitary, adrenal and thyroid function. The height was either normal or patients were moderately short (mean height standard deviation score (SDS) −2) at all ages, associated, however, often with the marked kyphosis. Truncal obesity was seen in 4/22 patients. X‐rays of the chest, lumbar and thoracic spine, long bones, ankles and metacarpophalangeal pattern profiles revealed kyphosis, scoliosis and calcaneo planovalgus as common features. Fingers of these patients were slender but short with a characteristic metacarpophalangeal pattern profile.

Early development of opioid‐exposed infants born to mothers in buprenorphine‐replacement therapy

The purpose of the study was to examine cognitive development (using the Bayley MDI) and mother–child interaction (using the Emotion Availability Scales, 3rd edition) among infants of opioid‐abusing mothers. Participants were 87 dyads (15 opioid‐exposed, 15 maternal depression and 57 unexposed mother–infant dyads). The study group included 15 infants (mean age=7.0 months, sd=2.8 months) of mothers who participated in buprenorphine‐replacement therapy. Study variables were evaluated during the second half of the first year and compared with the infants of depressed (mean age = 8.06 months, sd =2.4 months) and nonabusing mothers (mean age = 9.96 months, sd =2.9 months). The opioid‐exposed infants earned the lowest Bayley‐II MDI scores. Furthermore, they scored the lowest in infant involvement. The role of environmental risk factors, in turn, was highlighted in that the opioid‐abusing mothers scored the lowest in maternal sensitivity, structuring and nonintrusiveness. Maternal childhood foster care and criminal record were significantly related to lower sensitivity and higher intrusiveness. Finally, the environmental risk status of the opioid‐exposed infants was further underlined in that there were more separations from the mother in the end of the first year as well as an elevated risk for physical abuse.