Carol Macmillan

Eye movements in neurodevelopmental disorders

Purpose of reviewThe aim of this paper is to review the literature on eye-movement abnormalities associated with neurodevelopmental disorders. Eye-movement testing is a non-invasive quantitative approach for evaluating brain systems across the age spectrum. It thus provides a promising methodology for characterizing and documenting maturational abnormalities in brain systems associated with neurodevelopmental disorders. Recent findingsRecent oculomotor studies have made significant contributions to the understanding of neurodevelopmental disorders, most notably in autism, attention-deficit/hyperactivity disorder, and Tourettes syndrome. Notably different patterns of deficits have been found in these disorders and have helped to clarify their pathophysiology. SummaryEye-movement studies have begun to serve as a useful approach for studying cognitive and neurophysiological aspects of neurodevelopmental disorders. They also have potential as a strategy for establishing quantitative endophenotypes for genetic research, and for monitoring beneficial and adverse effects of pharmacotherapies. Studies are needed that involve larger patient populations, longitudinal characterization of developmental failures, patients free from central nervous system-active medications, and that use functional imaging, as patients perform eye-movement tasks, for direct identification of clinically relevant abnormalities in brain systems.

Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy

Objective: To report three unrelated infants with a distinctive phenotype of Leigh-like syndrome, neurogenic muscular atrophy, and hypertrophic obstructive cardiomyopathy. The patients all had a homozygous missense mutation in SCO2. Background: SCO2 encodes a mitochondrial inner membrane protein, thought to function as a copper transporter to cytochrome c oxidase (COX), the terminal enzyme of the respiratory chain. Mutations in SCO2 have been described in patients with severe COX deficiency and early onset fatal infantile hypertrophic cardioencephalomyopathy. All patients so far reported are compound heterozygotes for a missense mutation (E140K) near the predicted CxxxC metal binding motif; however, recent functional studies of the homologous mutation in yeast failed to demonstrate an effect on respiration. Methods: Here we present clinical, biochemical, morphologic, functional, MRI, and MRS data in two infants, and a short report in an additional patient, all carrying a homozygous G1541A transition (E140K). Results: The disease onset and symptoms differed significantly from those in compound heterozygotes. MRI and muscle morphology demonstrated an age-dependent progression of disease with predominant involvement of white matter, late appearance of basal ganglia lesions, and neurogenic muscular atrophy in addition to the relatively late onset of hypertrophic cardiomyopathy. The copper uptake of cultured fibroblasts was significantly increased. Conclusions: The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy. There is increased copper uptake in patients’ fibroblasts indicating that the G1541A mutation effects cellular copper metabolism.

Mitochondrial DNA depletion: Prevalence in a pediatric population referred for neurologic evaluation

Mitochondrial DNA depletion is a quantitative disorder of mtDNA, characterized by tissue-specific reductions in mtDNA copy number, that presents in infancy or early childhood. It is most likely transmitted as an autosomal recessive trait, although about half of the described cases are sporadic. To estimate its prevalence we measured relative mtDNA copy number (mtDNA: 18S rDNA ratio) by Southern blot analysis in muscle biopsy samples from all children with compatible histories referred between 1983 and 1994. Of the 304 biopsies evaluated, 54 met the study criteria. We found 6 patients (2 male, 4 female) with mtDNA depletion (relative mtDNA copy number 7.9-33.2% of control). Their clinical course and findings were heterogeneous, however all but one manifested weakness, hypotonia, and developmental delay. Clinical severity was not obviously related to the degree of mtDNA depletion. No patient had ragged-red fibers, although 2 had a lipid storage myopathy. Immunofluorescence with antibodies to double-stranded DNA, COX IV, and COX II demonstrated homogeneously reduced reactivity to all three antibodies compared with control. mtDNA depletion may be a relatively common neurogenetic disorder of infancy and early childhood and should be considered in children with unexplained weakness, hypotonia, or developmental delay.

Neurobehavioral Abnormalities in First-Degree Relatives of Individuals With Autism

CONTEXT Studying sensorimotor and neurocognitive impairments in unaffected family members of individuals with autism may help identify familial pathophysiological mechanisms associated with the disorder. OBJECTIVE To determine whether atypical sensorimotor or neurocognitive characteristics associated with autism are present in first-degree relatives of individuals with autism. DESIGN Case-control comparison of neurobehavioral functions. SETTING University medical center. PARTICIPANTS Fifty-seven first-degree relatives of individuals with autism and 40 age-, sex-, and IQ-matched healthy control participants (aged 8-54 years). MAIN OUTCOME MEASURES Oculomotor tests of sensorimotor responses (saccades and smooth pursuit); procedural learning and response inhibition; neuropsychological tests of motor, memory, and executive functions; and psychological measures of social behavior, communication skills, and obsessive-compulsive behaviors. RESULTS On eye movement testing, family members demonstrated saccadic hypometria, reduced steady-state pursuit gain, and a higher rate of voluntary response inhibition errors relative to controls. They also showed lateralized deficits in procedural learning and open-loop pursuit gain (initial 100 milliseconds of pursuit) and increased variability in the accuracy of large-amplitude saccades that were confined to rightward movements. In neuropsychological studies, only executive functions were impaired relative to those of controls. Family members reported more communication abnormalities and obsessive-compulsive behaviors than controls. Deficits across oculomotor, neuropsychological, and psychological domains were relatively independent from one another. CONCLUSIONS Family members of individuals with autism demonstrate oculomotor abnormalities implicating pontocerebellar and frontostriatal circuits and left-lateralized alterations of frontotemporal circuitry and striatum. The left-lateralized alterations have not been identified in other neuropsychiatric disorders and are of interest given atypical brain lateralization and language development associated with the disorder. Similar oculomotor deficits have been reported in individuals with autism, suggesting that they may be familial and useful for studies of neurophysiological and genetic mechanisms in autism.

Reversion of hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial copper binding protein Sco2: is there a potential effect of copper?

Summary: Mutations in Sco2, a protein involved in copper trafficking to the terminal enzyme of the respiratory chain, cytochrome c oxidase, results in infantile hypertrophic cardioencephalomyopathy. We have recently shown that copper-histidine (Cu-his) supplementation of Sco2-deficient myoblasts rescues COX activity in vitro. Here, we report a patient with SCO2 mutations and with resolution of severe hypertrophic cardiomyopathy. Weighing up the evidence, the most likely explanation for the improved cardiac function in this patient was the subcutaneous application of Cu-his.

Head growth and neurodevelopment of infants born to HIV-1–infected drug-using women

Objective: To describe neurodevelopment and head growth in HIV-1–infected and exposed uninfected infants with and without in utero exposure to opiates and cocaine. Methods: Using data from a multicenter cohort study of HIV-1–infected women and their children, the authors fit repeated measures regression models to estimate the effects of HIV-1 infection and in utero hard drug exposure on head circumference and Bayley Scales of Infant Development standard scores during the first 30 months. Results: Of the 1,094 infants included in the analysis, 147 (13%) were HIV-1–positive and 383 (35%) were exposed in utero to opiates or cocaine (drug-positive). Mean 4- month Bayley mental scores were lower in infants with only HIV-1 positivity (HIV-positive and drug-negative) (-8.2 points, p < 0.0001) or only drug exposure (HIV-negative and drug-positive) (−4.4 points, p = 0.0001) and tended to be lower in infants with both factors (HIV-positive and drug-positive) (−3.7 points, p = 0.0596), compared with those who were HIV-1-negative and not drug exposed (HIV-negative and drug-negative). However, by 24 months of age, there was no longer a decrement among HIV-negative and drug-positive infants, whereas HIV-1 infection was still associated with a decrement relative to uninfected infants. Similar results were seen for Bayley motor scores and for head circumference Z scores. Conclusions: HIV-1 infection and in utero opiate and cocaine exposure decrease birth head circumference and slow neurodevelopment at 4 months. At 24 months of age, however, only HIV-1 infection is associated with decreased neurodevelopment and head circumference. There may be some postnatal recovery from the effects of in utero hard drug exposure. Importantly, the detrimental effects of HIV-1 positivity and maternal hard drug use on neurodevelopment at 4 months are not additive, although they are additive for birth head circumference.

A “Fille du Roy” Introduced the T14484C Leber Hereditary Optic Neuropathy Mutation in French Canadians

The predominance of the T14484C mutation in French Canadians with Leber hereditary optic neuropathy is due to a founder effect. By use of genealogical reconstructions of maternal lineages, a woman married in Quebec City in 1669 is identified as the shared female ancestor for 11 of 13 affected individuals, who were previously not known to be related. These individuals carry identical mitochondrial haplogroups. The current geographic distribution of French Canadian cases overlaps with that of the founders female descendants in 1800. This is the first example of genealogical reconstruction to identify the introduction of a mitochondrial mutation by a woman in a founder population.

Genetics and developmental delay

The discovery of new cytogenetic and molecular genetic techniques and principles has been explosive in recent years. A secure diagnosis based on molecular evidence has become possible for many syndromes previously only clinically defined, which has helped enormously in predicting childrens developmental progress, in allowing knowledgeable surveillance for potential associated health problems, in genetic counseling, and in prenatal diagnosis. This article reviews several of the most significant recently described cytogenetic and molecular genetic principles and techniques in relation to the child who presents with developmental delay.