De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Proximal 6q interstitial deletion without severe mental retardation.

Deletions of the proximal portion of the long arm of chromosome 6 are rare, and the patients reported in the literature have been described as having significant mental retardation, often in the severe to profound range. We report on a young girl with a proximal 6q interstitial deletion [46, XX, del (6) (q1 3q15)] who exhibits the typical morphological and neurological manifestations except that the degree of language and non-language cognitive delay is mild. Cognitive development has been assessed using the Capute Scales. Gross motor development has been assessed clinically using standard milestones. At 34 months of age, she was found to have severe gross motor delay, with mildly delayed non-language cognitive abilities and expressive language abilities. Her receptive language skills tested in the average range. In recent years. several forms of autosomal dominant drusen and macular degeneration have been mapped to 6q14, and substantial variability in clinical expression has been described. Serial ophthalmologic examinations have not detected any drusen or atrophic macular changes in our patient. To our knowledge, this is the first description of a child with proximal 6q interstitial deletion in the documented absence of severe cognitive deficiency. This information may be important to clinicians who counsel families of infants determined to have proximal 6q interstitial deletions. Because the deleted region contains the area to which autosomal dominant drusen and macular degeneration has been mapped, we believe that this child is at risk for visual loss, and she will continue to be monitored closely.

Methylphenidate: its pharmacology and uses.

Methylphenidate is a commonly used medication in the United States. This central nervous system stimulant has a mechanism of action distinct from that of amphetamine. The Food and Drug Administration has approved methylphenidate for the treatment of attention-deficit/hyperactivity disorder and narcolepsy. Treatment with methylphenidate has been advocated in patients with traumatic brain injury and stroke, cancer patients, and those with human immunodeficiency virus infection. Placebo-controlled trials have documented its efficacy as an adjunctive agent in the treatment of depression and pain. This article reviews the current understanding of the mechanism of action and efficacy of methylphenidate in various clinical conditions.