[13C]-galactose breath test in a patient with galactokinase deficiency and spastic diparesis.

Galactokinase deficiency is an inborn error of carbohydrate metabolism due to a block in the formation of galactose-1-phosphate from galactose. Although the association of galactokinase deficiency with formation of cataracts is well established, the extent of the clinical phenotype is still under investigation. We describe a 6-year-old female who was diagnosed with galactokinase deficiency due to cataract formation when she was 10 months of age and initially started on galactose-restricted diet at that time for 5 months. She developed gait abnormality at 4 years of age. Breath tests via measurement of 13C isotope in exhaled carbon dioxide following 13C-labeled galactose administration at carbon-1 and carbon-2 positions revealed oxidation rates within the normal range. The results in this patient strikingly contrast with the results of another patient with GALK1 deficiency that underwent breath testing with [1-14C]-galactose and [2-14C]-galactose. Extension of in vivo breath tests to other galactokinase patients is needed to better understand the pathophysiology of this disease.

Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature.

PURPOSE: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients. METHODS: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information. RESULTS: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports. CONCLUSION: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

Developmental delay timely identification and assessment.

This paper outlines the prevalence of developmental delay in children and discusses the recent literature regarding the benefits of early identification and evidence based strategies for developmental surveillance and screening. We describe a systematic approach to the child with developmental delay and the optimal methodology for arriving at the etiologic basis for the delay. A review of the most upto date and relevant literature was completed using Pub Med, online databases, and texts. The medical evaluation with specific emphasis on the most recent recommendations for genetic, laboratory and imaging studies is described. The American Academy of Pediatrics algorithm for developmental surveillance and screening is discussed with consideration for the importance of culturally relevant screening tools across populations. In addition, specific screening tools are briefly discussed that may prove beneficial to the primary care provider as he/she implements routine surveillance and screening.

Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management.

PURPOSE: To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. EXPERIMENTAL DESIGN: We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. RESULTS: We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. CONCLUSIONS: In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

Mosaic duplication 1(q11q44) in an infant with nephroblastomatosis and mineralization of extraplacental membranes.

Partial trisomy of 1q is rare. Only 32 cases of isolated partial trisomy 1q have been previously reported. From these cases, a characteristic phenotype is beginning to emerge. We present a case of mosaic duplication of 1q [46,XX,dup (1)(q11q44)/46,XX]. Many features of our patient have been described in previous patients, thus supporting the emerging phenotype. Two particular features, however, have not been previously described. The present case demonstrated extensive mineralization of the extraplacental membranes and bilateral nephromegaly, with an extreme form of diffusely hyperplastic perilobar nephroblastomatosis. Clinical comparison is made between our case and previously reported cases, and the clinical significance of the unique findings are reviewed and discussed.

Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o-mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran-Valero de Bernabe et al., 2002], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non-consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran-Valero de Bernabe et al. [2002] and it can be as low as approximately 7%, as reported here.