Jennifer MacKenzie

Microduplication and triplication of 22q11.2: a highly variable syndrome.

22q11.2 microduplications of a 3-Mb region surrounded by low-copy repeats should be, theoretically, as frequent as the deletions of this region; however, few microduplications have been reported. We show that the phenotype of these patients with microduplications is extremely diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. This diversity will make ascertainment difficult and will necessitate a rapid-screening method. We demonstrate the utility of four different screening methods. Although all the screening techniques give unique information, the efficiency of real-time polymerase chain reaction allowed the discovery of two 22q11.2 microduplications in a series of 275 females who tested negative for fragile X syndrome, thus widening the phenotypic diversity. Ascertainment of the fragile X-negative cohort was twice that of the cohort screened for the 22q11.2 deletion. We also report the first patient with a 22q11.2 triplication and show that this patients mother carries a 22q11.2 microduplication. We strongly recommend that other family members of patients with 22q11.2 microduplications also be tested, since we found several phenotypically normal parents who were carriers of the chromosomal abnormality.

Gaucher disease associated with parkinsonism: four further case reports.

Type 1 Gaucher disease is considered the non‐neuronopathic form of this autosomal recessively inherited lysosomal storage disease. We report the simultaneous occurrence of Gaucher disease with parkinsonian in four adult patients. The patients had a relatively early onset of parkinsonian manifestations, and their disease was rapidly progressive and refractory to therapy. Each had a different Gaucher genotype, although four alleles carried the common N370S mutation. No mutations were identified in the genes for parkin or α‐synuclein. The concurrence of these two phenotypes, both in this series of patients and in others in the literature, suggests a shared pathway, modifier, or other genetic etiology. Published 2003 Wiley‐Liss, Inc.

Guanidinoacetate methyltransferase (GAMT) deficiency : Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring

We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes.

Fat-Soluble Vitamin Deficiency in Pregnancy: A Case Report and Review of Abetalipoproteinemia

BACKGROUND Abetalipoproteinemia (ABL) is a metabolic disorder resulting in poor absorption of fat-soluble vitamins. CASE Two pregnancies in a woman with ABL are reported, contrasting outcomes with subtherapeutic and normal vitamin levels. CONCLUSION Fat-soluble vitamin levels in pregnancy are critical for many aspects of fetal development. This report details a congenital ophthalmologic finding that may be associated with vitamin A deficiency.

Congenital myopathy with cap-like structures and nemaline rods: case report and literature review.

BACKGROUND Cap myopathy is a rare congenital myopathy characterized by cap structures located at the periphery of the muscle fiber. Cap structures consist of disarranged thin filaments with enlarged Z discs. The clinical presentation and natural history of cap myopathy is variable and overlaps with other congenital myopathies. METHODS We describe a 10-year-old boy with cap myopathy and contrast him with 20 other individuals reported in the literature. RESULTS Our patient presented at birth with hypotonia and weakness and subsequently developed respiratory failure in infancy. He is ambulatory but has increasing fatigue and requires a wheelchair by midafternoon. His muscle biopsy at 3 months revealed a nemaline myopathy and secondary fiber-type disproportion with type 1 hypotrophy and predominance. A repeat muscle biopsy at age 6 years revealed numerous peripherally located cap-like structures containing nemaline rods and exhibited a spectrum of Z-disk and myofibrillar abnormalities. Molecular genetic testing was performed for NEB, TPM2, TPM3, ACTA1, TNNT1, SEPN1, SMN1, DMPK, FSHMD1A, and mtDNA. A known pathogenic mutation, c.1152+1G>A, and a previously unreported variant, c.1782+4_1782+5delAG, were detected in NEB. CONCLUSION Our patient has a more severe phenotype than most reported patients and is the first patient with cap myopathy to have a mutation in NEB. Our case supports the identification of cap myopathy as a congenital myopathy with significant overlapping features with nemaline myopathies and further elucidates the phenotype of this disease.

Biotinidase deficiency: Spectrum of molecular, enzymatic and clinical information from newborn screening Ontario, Canada (2007–2014)

Untreated profound biotinidase deficiency results in a wide range of clinical features, including optic atrophy, cutaneous abnormalities, hearing loss and developmental delay. Ontario, Canada incorporated this treatable deficiency in newborn screening over the past 8years. This study elucidates the molecular, biochemical, and clinical findings from the pilot project. Information from initial screens, serum biotinidase activity level assays, molecular testing, and family history for 246 positive newborns screens were analyzed. A mutation spectrum was created for the province of Ontario, including common mutations such as D444H, D444H/A171T, Q456H, C33fs, and R157H. Individuals with partial deficiency were separated into 3 groups: D444H homozygotes (Group 1); compound heterozygotes for D444H with another profound allele (Group 2); compound heterozygotes with two non-D444H alleles (Group 3). Biochemical phenotype-genotype associations in partial deficiency showed a significant difference in serum biotinidase activity in between any given two groups. Three children with partial deficiency discontinued biotin for varied lengths of time. Two of whom became symptomatic with abnormal gait, alopecia, skin rashes and developmental delay. A need for more congruency in diagnostic, treatment and educational practices was highlighted across the province. Heterogeneity and variation in clinical presentations and management was observed in patients with the partial deficiency.

Spontaneous Recovery of Ovarian Function in an Adolescent with Galactosemia and Apparent Premature Ovarian Insufficiency

BACKGROUND Galactosemia is an inborn error of metabolism resulting in premature ovarian insufficiency in 80-90% of females. There have been no reported cases of biochemical ovarian failure followed by normal menses. CASE A 12-year-old girl with galactosemia presented for gynecologic consultation. Her follicle-stimulating hormone (FSH) and estradiol levels were 52.9 U/L and less than 100 pmol/L, respectively. She started exogenous estrogen to stimulate puberty. At 16, she had spontaneous regular menstrual cycles. FSH and luteinizing hormone (LH) levels reflected normal ovarian function. Hormonal contraception was provided. One year later, she was found to be in ovarian failure (FSH 86.6 U/L, LH 33.3 U/L), and both estradiol and anti-Müllerian hormone were undetectable. SUMMARY AND CONCLUSIONS This case documents spontaneous resumption of ovarian function after galactosemia-related ovarian failure. The use of FSH and LH is potentially limited in predicting ovarian function in this population.

Melanocortin-4 Receptor Deficiency Phenotype with an Interstitial 18q Deletion: A Case Report of Severe Childhood Obesity and Tall Stature

Childhood obesity is a growing health concern, associated with significant physical and psychological morbidity. Childhood obesity is known to have a strong genetic component, with mutations in the melanocortin-4 receptor (MC4R) gene being the most common monogenetic cause of obesity. Over 166 different MC4R mutations have been identified in persons with hyperphagia, severe childhood obesity, and increased linear growth. However, it is unclear whether the MC4-R deficiency phenotype is due to haploinsufficiency or dominant-negative effects by the mutant receptor. We report the case of a four-and-a-half-year-old boy with an interstitial deletion involving the long arm of chromosome 18 (46,XY,del(18)(q21.32q22.1)) encompassing the MC4R gene. This patient presented with tall stature and hyperphagia within his first 18 months of life leading to significant obesity. This case supports haploinsufficiency of MC4-R as it describes a MC4-R deficiency phenotype in a patient heterozygous for a full MC4R gene deletion. The intact functional allele with MC4-R haploinsufficiency has the potential to favor a therapeutic response to gastric surgery. Currently, small molecule MC4-R agonists are under development for pharmacologic therapy.

MG-111 Clinical genetics education: Building foundations using e-modules for paediatric residents

Objectives Clinical Genetics is rapidly evolving so it is essential that future physicians are equipped to practice in a genetics literate world. The goal of this project is to provide non-genetics trainees with an accessible resource to enhance their genetics education and to complement traditional teaching modalities. We are undertaking a pilot study of Paediatric residents’ genetics knowledge and perceptions before and after completing the e-modules. Design/methods We have created two e-modules highlighting common situations encountered in practice, a positive newborn screen and developmental disability/autism. The e-modules lead students through gathering information, interpreting findings, and management strategies. Basic genetic concepts, indications and limitations of testing are highlighted. The modules are designed for trainees prior to exposure to Clinical Genetics, to provide a foundation to build upon with clinical experience. The modules are available through the Queen’s School of Medicine technology platform. A questionnaire assessing knowledge and comfort with genetics will be administered before, immediately after, and 6 months after the modules. Focus groups will be conducted to determine residents’ perception of the modules and thematically analysed through a lens of constructivist grounded theory. Results/conclusions The e-modules have been designed and are in the process of being implemented. By sharing our preliminary experience we hope to expand genetics education opportunities for non-genetics residents.

Metabolic Clinic Atlas: Organization of Care for Children with Inherited Metabolic Disease in Canada

INTRODUCTION Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the countrys Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities. METHODS Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively. RESULTS We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research. CONCLUSIONS The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial.