Jim McGill

Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age–a sibling control study

McGill JJ, Inwood AC, Coman DJ, Lipke ML, de Lore D, Swiedler SJ, Hopwood JJ. Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age–a sibling control study

Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study

BACKGROUND Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the disorder thought most to justify neonatal screening by tandem-mass spectrometry because, without screening, there seems to be substantial morbidity and mortality. Our aim was to assess the overall effectiveness of neonatal screening for MCAD deficiency in Australia. METHODS We identified MCAD-deficient patients from a total population of 2,495,000 Australian neonates (810,000 screened) born between April 1, 1994, and March 31, 2004. Those from a cohort of 1,995,000 (460,000 screened) were followed up for at least 4 years, and we recorded number of deaths and severe episodes, medical and neuropsychological outcome, and hospital admissions within the screened and unscreened groups. FINDINGS In cohorts aged at least 4 years there were 35 MCAD-deficient patients in those not screened (2.28 per 100,000 total population) and 24 in the screened population (5.2 per 100,000). We estimated that patients with this disorder in the unscreened cohort remained undiagnosed. Before 4 years of age, three screened patients had an episode of severe decompensation (including one neonatal death) versus 23 unscreened patients (including five deaths). At the most conservative estimate, relative risk of an adverse event was 0.44 (95% CI 0.13-1.45). In the larger cohort the relative risk (screened vs unscreened) of an adverse event by age 2 years was 0.26 (95% CI 0.07-0.97), also a conservative estimate. 38 of 52 living patients had neuropsychological testing, with no suggestions of significant differences in general cognitive outcome between the groups. INTERPRETATION Screening is effective in patients with MCAD deficiency since early diagnosis reduces deaths and severe adverse events in children up to the age of 4 years.

Expanded newborn screening: Outcome in screened and unscreened patients at age 6 years

OBJECTIVE: Tandem mass spectrometry is widely applied to routine newborn screening but there are no long-term studies of outcome. We studied the clinical outcome at six years of age in Australia. METHODS: In a cohort study, we analyzed the outcome at 6 years for patients detected by screening or by clinical diagnosis among >2 million infants born from 1994 to 1998 (1 017 800, all unscreened) and 1998 to 2002 (461 500 screened, 533 400 unscreened) recording intellectual and physical condition, school placement, other medical problems, growth, treatment, diet, and hospital admissions. Results were analyzed separately for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and other disorders, and grouped patients as those who presented clinically or died in the first 5 days of life; patients presented later or diagnosed by screening, and those with substantially benign disorders. RESULTS: Inborn errors, excluding phenylketonuria, were diagnosed in 116 of 1 551 200 unscreened infants (7.5/100 000 births) and 70 of 461 500 screened infants (15.2/100 000 births). Excluding MCADD, 21 unscreened patients with metabolic disorders diagnosed after 5 days of life died or had a significant intellectual or physical handicap (1.35/100 000 population) compared with 2 of the screened cohort (0.43/100 000; odds ratio: 3.1 [95% CI: 0.73–13.32]). Considering the likely morbidity or mortality among the expected number of never-diagnosed unscreened patients, there would be a significant difference. Growth distribution was normal in all cohorts. CONCLUSION: Screening by tandem mass spectrometry provides a better outcome for patients at 6 years of age, with fewer deaths and fewer clinically significant disabilities.

Multicentric Carpotarsal Osteolysis Is Caused by Mutations Clustering in the Amino-Terminal Transcriptional Activation Domain of MAFB

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.

Seizures, ataxia, developmental delay and the general paediatrician : Glucose transporter 1 deficiency syndrome

Aim  Glucose transporter 1 deficiency syndrome (GLUT1‐DS) is an important condition for the general paediatrician’s differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1‐DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4).

A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases

BackgroundMorquio A (MPS IVA) is a rare disease characterised by a deficiency of N-acetylgalactosamine-6 sulfatase (GALNS) and presenting with short stature, abnormal gait, cervical spine instability and shortened lifespan.PurposeTo prepare a systematic review of the prevalence of Morquio A in multiple countries and suggest recommendations for reporting rare diseases.MethodsMedline, Medline In-Process, Medline Daily Update, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database and PROSPERO were searched from inception to October 2013 to identify relevant information on the epidemiology of Morquio A. Forty Patient Organisation Representatives (POR) and Key Opinion Leaders (KOL) across 24 countries were contacted for data. Observational studies were included and case reports were excluded. Searches were performed without date or language restriction. Two researchers independently screened and extracted data. Quality of study reporting was assessed using a checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology). Point or birth prevalence was stratified according to diagnostic method and discussed narratively.ResultsIn total 9,074 records were retrieved from searching and 25 studies were included for data extraction. Twenty out of 40 KOL and POR responded (50%) and 9 provided data (23%). Point prevalence of Morquio A was 1 per 926,000 in Australia, 1 per 1,872,000 in Malaysia and 1 per 599,000 in UK and Morquio (unclassified) was 1 per 323, 000 in Denmark. Birth prevalence of Morquio A (using recommended diagnostic methods) ranged from 1 per 71,000 in UAE to 1 per 500,000 in Japan. All results were compromised by poor study reporting and internal validity.ConclusionsThe review highlighted that there is a misunderstanding of the definitions for prevalence and incidence in the field; that studies were poorly reported (diagnostic methods and patient characteristics) and that no suitable quality assessment tool exists. Overestimation and underestimation of prevalence data can occur. Bespoke reporting guidelines and a quality assessment tool specifically for prevalence of rare diseases are recommended.

A Preliminary Investigation of the Role of the Phenylalynine:Tyrosine Ratio in Children With Early and Continuously Treated Phenylketonuria: Toward Identification of Safe Levels

Children with early and continuously treated phenylketonuria (ECT-PKU) remain at risk of developing executive function (EF) deficits. There is some evidence that a high phenylalanine to tyrosine ratio (phe:tyr) is more strongly associated with impaired EF development than high phenylalanine alone. This study examined EF in a sample of 11 adolescents against concurrent and historical levels of phenylalanine, phe:tyr, and tyrosine. Lifetime measures of phe:tyr were more strongly associated with EF than phenylalanine-only measures. Children with a lifetime phe:tyr less than 6 demonstrated normal EF, whereas children who had a lifetime phe:tyr above 6, on average, demonstrated clinically impaired EF.

Biochemical markers associated with executive function in adolescents with early and continuously treated phenylketonuria.

Debate continues as to why executive function (EF) continues to show impairments in children with early and continuously treated phenylketonuria (ECT‐PKU). Using a mixed model, we measured EF in 10 adolescent children with ECT‐PKU and 6 sibling controls, and examined associations between EF and (1) phenylalanine (phe) and (2) the phenylalanine : tyrosine ratio (phe : tyr). Measurements were taken on two occasions anticipated to yield variation in concurrent biochemistry resulting from changes in dietary compliance (i.e. holiday vs non‐holiday period). A repeated measures anova using the Behaviour Rating Inventory of Executive Function yielded the following results: no significant interactions; two significant group effects of substantially impaired working memory and initiation skills in children with ECT‐PKU compared with controls, irrespective of occasion and two significant time effects, suggestive of slightly poorer non‐holiday planning and organization scores in both groups. Further analyses revealed that phe levels were not significantly different on these occasions, suggesting that holiday dietary compliance may be better than expected. Correlations between EF and biochemistry in children with PKU showed that participant’s lifetime phe : tyr ratio was positively and significantly associated with EF impairment, more so than phe‐only measures.

Acute hyperammonemic encephalopathy in adult onset ornithine transcarbamylase deficiency

ObjectivesTo report the clinical manifestations of acute hyperammonemic encephalopathy in adult onset ornithine transcarbamylase deficiency (OTCD).DesignCase report.SettingIntensive care unit of a tertiary medical centre.PatientA 48-year-old Caucasian male body builder who developed acute loss of consciousness after a febrile illness.InterventionsThe patient was immediately started on hemodia-filtration, protein elimination and ammonia scavenging medications.Measurements and resultsSerum ammonium was elevated and plasma and urine amino acids had a pattern indicative of a urea cycle defect. DNA studies revealed a mutation of the urea cycle enzyme, ornithine transcarbamylase. The encephalopathy resolved and the patient slowly recovered though with some cognitive impairment.ConclusionsAdult presentation of OTCD is rare and the mortality and morbidity rates are high. However, survival is possible with rapid correction of hyperammonemia. As the clinical manifestations are non-specific, a high index of suspicion is necessary for the correct diagnosis and management.

The natural history and osteodystrophy of mucolipidosis types II and III

Aim:  To assess the natural history and impact of the secondary bone disease observed in patients with mucolipidosis (ML) II and III.