MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals.

Neuropsychiatric comorbidities in adults with phenylketonuria: A retrospective cohort study.

Adults with phenylketonuria (PKU) may experience neurologic and psychiatric disorders, including intellectual disability, anxiety, depression, and neurocognitive dysfunction. Identifying the prevalence and prevalence ratios of these conditions will inform clinical treatment. This nested, case-controlled study used International Classification of Diseases, Ninth Revision (ICD-9) codes from the MarketScan® insurance claims databases from 2006 to 2012 and healthcare claims data for US-based employer and government-sponsored health plans.

Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses.

Background: Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response.

Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1 c.772G>A; R258G): A report of two patients.

Severe variants of fibrodysplasia ossificans progressiva (FOP) affect <2% of all FOP patients worldwide, but provide an unprecedented opportunity to probe the phenotype-genotype relationships that propel the pathology of this disabling disease. We evaluated two unrelated children who had severe reduction deficits of the hands and feet with absence of nails, progressive heterotopic ossification, hypoplasia of the brain stem, motor and cognitive developmental delays, facial dysmorphology, small malformed teeth, and abnormal hair development. One child had sensorineural hearing loss, microcytic anemia, and a tethered spinal cord and the other had a patent ductus arteriosus and gonadal dysgenesis with sex reversal (karyotype 46, XY female).

Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease.

Purpose: High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role.

The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease.

Purpose: Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers.

Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects.

Background: Systemic primary carnitine deficiency is an autosomal recessive disorder of the carnitine cycle caused by mutations in the SLC22A5 gene that encodes the carnitine transporter, organic cation transporter. Systemic primary carnitine deficiency typically presents in childhood with either metabolic decompensation or cardiomyopathy. We report five families in which low free carnitine levels in the infants' newborn screening have led to the diagnosis of maternal systemic primary carnitine deficiency.

Progressive and symmetric supraorbital hyperostosis with bony and soft tissue overgrowth in an Ethiopian female: a newly recognized overgrowth syndrome?

We report on an Ethiopian female with generalized overgrowth of postnatal onset accompanied by progressive and symmetric overgrowth of skeletal and soft tissues. Her phenotype consisted of progressive and symmetric overgrowth of the supraorbital ridges, glabella, occiput, cervical spine, and distal phalanges of all extremities, but particularly the 3rd and 4th digits. She also has overgrowth of soft tissues of the posterior neck (thought to be fatty in origin), alveolar hyperplasia, and overgrowth of the skin comprising the areola and umbilicus.

Early neonatal diagnosis of long-chain 3-hydroxyacyl coenzyme a dehydrogenase and mitochondrial trifunctional protein deficiencies.

Tandem mass spectrometry (MS/MS) has been introduced in several newborn screening programs for the detection of a large number of inborn errors of metabolism, including fatty acid oxidation disorders (FAOD). Early identification and treatment of FAOD have the potential to improve outcome and may be life-saving in some cases; an estimated 5% of sudden infant deaths are attributable to undiagnosed disorders of fatty acid oxidation. We report very early neonatal presentations of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (TFP) deficiencies confirmed by molecular analysis.