C.A. Rupar

Severe phenotypic spectrum of mevalonate kinase deficiency with minimal mevalonic aciduria

Mevalonate kinase deficiency is a rare autosomal recessively inherited organic aciduria with a complex multi-systemic phenotype. We describe two deceased patients with clinically severe mevalonate kinase (MK) deficiency confirmed by MK mutation analysis. The phenotype in our patients ranged from neonatal hydrops in the first patient to severe failure to thrive, hepatosplenomegaly, recurrent febrile episodes and lymphadenopathy in the second. Both infants excreted relatively low amounts of mevalonic acid intermittently.

The expanding phenotype of MELAS caused by the m.3291T > C mutation in the MT-TL1 gene.

m.3291T > C mutation in the MT-TL1 gene has been infrequently encountered in association with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), however remains poorly characterized from a clinical perspective. In the following report we describe in detail the phenotypic features, long term follow up (> 7 years) and management in a Caucasian family with MELAS due to the m.3291T > C mutation and review the literature on m.3291T > C mutation. The clinical phenotype in the proposita included overlapping features of MELAS, MERRF (Myoclonic epilepsy and ragged-red fiber syndrome), MNGIE (Mitochondrial neurogastrointestinal encephalopathy), KSS (Kearns-Sayre Syndrome) and CPEO (Chronic progressive external ophthalmoplegia).

Asymptomatic critical hypoglycaemia: a dangerous presentation of glycogen storage disease type Ib in infancy

We report the case of a 3‐month‐old boy who presented with a 3‐day history of respiratory tract infection and poor feeding. He was incidentally found to have profound hypoglycaemia, high‐anion‐gap lactic acidosis, ketonuria, hyperlipidemia, hepatomegaly, growth failure and neutropenia. Glycogen storage disease type Ib (GSD Ib), an autosomal recessive metabolic defect of the microsomal transporter glucose‐6‐phosphate‐translocase, was suspected and confirmed by genetic testing. Treatment consisted of initial intravenous glucose and fluids to correct his lactic acidosis, followed by a strict dietary protocol consisting of soy‐based infant formula enriched with glucose polymers from cornstarch and overnight gastrostomy feeds.

Rapid and Efficient Stable Gene Transfer to Mesenchymal Stromal Cells Using a Modified Foamy Virus Vector

Mesenchymal stromal cells (MSCs) hold great promise for regenerative medicine. Stable ex vivo gene transfer to MSCs could improve the outcome and scope of MSC therapy, but current vectors require multiple rounds of transduction, involve genotoxic viral promoters and/or the addition of cytotoxic cationic polymers in order to achieve efficient transduction. We describe a self-inactivating foamy virus vector (FVV), incorporating the simian macaque foamy virus envelope and using physiological promoters, which efficiently transduces murine MSCs (mMSCs) in a single-round. High and sustained expression of the transgene, whether GFP or the lysosomal enzyme, arylsulphatase A (ARSA), was achieved. Defining MSC characteristics (surface marker expression and differentiation potential), as well as long-term engraftment and distribution in the murine brain following intracerebroventricular delivery, are unaffected by FVV transduction. Similarly, greater than 95% of human MSCs (hMSCs) were stably transduced using the same vector, facilitating human application. This work describes the best stable gene transfer vector available for mMSCs and hMSCs.

Fumarase deficiency: a rare disorder on the crossroads of clinical and metabolic genetics, neurology and cancer.

Department of Paediatrics, Isaac Walton Killam Health Centre, Dalhousie University, Halifax, Nova Scotia, Medical Genetics Program of Southwestern Ontario, Department of Pathology & Laboratory Medicine and Biochemistry, London Health Sciences Centre, Department of Paediatrics, London Health Sciences Centre, Western University and Children’s Health Research Institute, London, Ontario, Canada Correspondence to Chitra Prasad, MD, FRCPC, FCCMG, FACMG, Department of Genetics, Metabolism and Pediatrics, 800 Commissioners Road East, London, ON N6A 5W9, Canada Tel: + 1 519 685 8140; fax: + 1 519 685 8214; e-mail: chitra.prasad@lhsc.on.ca

Magnetic resonance imaging in the diagnosis of white matter signal abnormalities

Background White matter abnormalities (WMAs) pose a diagnostic challenge when trying to establish etiologic diagnoses. During childhood and adult years, genetic disorders, metabolic disorders and acquired conditions are included in differential diagnoses. To assist clinicians and radiologists, a structured algorithm using cranial magnetic resonance imaging (MRI) has been recommended to aid in establishing working diagnoses that facilitate appropriate biochemical and genetic investigations. This retrospective pilot study investigated the validity and diagnostic utility of this algorithm when applied to white matter signal abnormalities (WMSAs) reported on imaging studies of patients seen in our clinics. Methods The MRI algorithm was applied to 31 patients selected from patients attending the neurometabolic/neurogenetic/metabolic/neurology clinics at a tertiary care hospital. These patients varied in age from 5 months to 79 years old, and were reported to have WMSAs on cranial MRI scans. Twenty-one patients had confirmed WMA diagnoses and 10 patients had non-specific WMA diagnoses (etiology unknown). Two radiologists, blinded to confirmed diagnoses, used clinical abstracts and the WMSAs present on patient MRI scans to classify possible WMA diagnoses utilizing the algorithm. Results The MRI algorithm displayed a sensitivity of 100%, a specificity of 30.0% and a positive predicted value of 74.1%. Cohen’s kappa statistic for inter-radiologist agreement was 0.733, suggesting “good” agreement between radiologists. Conclusions Although a high diagnostic utility was not observed, results suggest that this MRI algorithm has promise as a clinical tool for clinicians and radiologists. We discuss the benefits and limitations of this approach.

Psychosocial Impact on Mothers Receiving Expanded Newborn Screening Results

Expanded newborn screening (NBS) for genetic disorders has improved diagnosis of numerous treatable diseases, positively impacting children’s health outcomes. However, research about the psychological impact of expanded NBS on families, especially mothers, has been mixed. Our study examined associations between maternal experiences of expanded NBS and subsequent psychosocial functioning and parenting stress in mothers whose infants received either true negative (TN), true positive (TP) or false positive (FP) results after a 4- to 6-month period. The Parenting Stress Index and the Depression, Anxiety and Stress Scale were used to assess symptoms of anxiety, stress and depression in 3 sets of mothers, whose infants received TN (n = 31), TP (n = 8) or FP (n = 18) results. Multivariate analyses of variance (MANOVA) results revealed no significant differences among these three groups of mothers regarding overall anxiety, stress and depression. However, FP mothers experienced lower levels of stress related to their own health compared to TN group. Two potential trends were also identified; results suggested TN mothers might experience higher levels of isolation than mothers in the TP group and that FP mothers might report higher stress levels in relation to spousal relationships compared to the TN group. FP mothers seemed to report similar or better levels of psychosocial functioning than TN mothers. Our findings are encouraging with respect to impacts of NBS on maternal well-being. We also identify key areas for improvement (parental education) and research (isolation and spousal relationships).