Recurrent de novo variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific variants resulting in sphingolipid overproduction as a cause for juvenile ALS.

Newborn screening for Pompe disease: Parental experiences and follow-up care for a late-onset diagnosis.

Newborn screening (NBS) for Pompe disease (PD) was added to the Recommended Uniform Screening Panel (RUSP) in the United States in 2015 because there was compelling evidence of health benefits for early diagnosis of Infantile-onset Pompe disease (IOPD). However, one limitation of NBS for PD is its inability to distinguish IOPD and late onset forms of Pompe disease (LOPD). Management of LOPD is challenging because of uncertainty around progression of LOPD and determining the appropriate time for treatment initiation.

Diagnosis of Classic Homocystinuria in Two Boys Presenting with Acute Cerebral Venous Thrombosis and Neurologic Dysfunction after Normal Newborn Screening.

Homocystinuria, caused by cystathionine β-synthase deficiency, is a rare inherited disorder involving metabolism of methionine. Impaired synthesis of cystathionine leads to accumulation of homocysteine that affects several organ systems leading to abnormalities in the skeletal, cardiovascular, ophthalmic and central nervous systems. We report a 14-month-old and a 7-year-old boy who presented with neurologic dysfunction and were found to have cerebral venous sinus thromboses on brain magnetic resonance imaging (MRI)/magnetic resonance venogram (MRV) and metabolic and hypercoagulable work-up were consistent with classic homocystinuria.

Arginine to ornithine ratio as a diagnostic marker in patients with positive newborn screening for hyperargininemia.

Arginase deficiency is a rare inborn error of metabolism that interrupts the final step of the urea cycle. Untreated individuals often present with episodic hyperammonemia, developmental delay, cognitive impairment, and spasticity in early childhood. The newborn screening (NBS) algorithms for arginase deficiency vary between individual states in the US but often include hyperargininemia and elevated arginine to ornithine (Arg/Orn) ratio.

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Background: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.

Heme and sensory neuropathy: insights from novel mutations in the heme exporter feline leukemia virus subgroup C receptor 1.

Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system mainly characterized by impaired nociception and autonomic dysfunction. We previously identified heme metabolism as a novel pathway contributing to sensory neurons maintenance and nociception. Indeed, we reported mutations in the feline leukemia virus subgroup C receptor 1 (FLVCR1) gene in individuals affected by HSAN.

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α-subunit of the voltage-gated Ca2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission.

Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

Background: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.

Methods: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.

Neurotransmitter abnormalities and response to supplementation in SPG11.

Objective: To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with l-dopa/carbidopa and sapropterin.

Design: Case reports.

Setting: National Institutes of Health in the Undiagnosed Disease Program; Children's National Medical Center in the Myelin Disorders Bioregistry Program.

Multiracial competence in social work: recommendations for culturally attuned work with multiracial people.

According to the 2010 U.S. census, approximately 9 million individuals report multiracial identities.

Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2.

We have identified a recurrent de novo pericentromeric deletion in 16p11.2-p12.2 in four individuals with developmental disabilities by microarray-based comparative genomic hybridization analysis.

Focal skin defect, limb anomalies and microphthalmia.

We describe two unrelated female patients with congenital single focal skin defects, unilateral microphthalmia and limb anomalies. Growth and psychomotor development were normal and no brain malformation was detected. Although eye and limb anomalies are commonly associated, clinical anophthalmia and limb defects have not been reported with single focal aplasia of the skin.

Physicians' perceived usefulness of and satisfaction with test reports for cystic fibrosis (DeltaF508) and factor V Leiden.

Purpose: We sought to determine whether variation in test-report content for cystic fibrosis (CF DeltaF508) and factor V Leiden (fVL) would impact physician-perceived usefulness of and satisfaction with test reports.

Methods: A cross-sectional survey of US physicians from specialties likely to order the tests was performed. Physicians received an introductory letter with a clinical scenario, one randomly assigned mock report, and a one-page survey.

Medical genetic test reporting for cystic fibrosis (deltaF508) and factor V Leiden in North American laboratories.

Purpose: Physicians are ordering an increasing number of genetic tests. Results and additional information provided in the test result report are vital to the physician in making appropriate patient management decisions. Because variability in test result reports can impact patient care, we sought to determine whether variations exist in test reports for cystic fibrosis (CF) and factor V Leiden (fVL) with specific comparison to professional guidelines and recommendations.