Michel Tchan

Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis

Abnormalities in WNT signaling are implicated in a broad range of developmental anomalies and also in tumorigenesis. Here we demonstrate that germline mutations in WTX (FAM123B), a gene that encodes a repressor of canonical WNT signaling, cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS; MIM300373). This condition is typically characterized by increased bone density and craniofacial malformations in females and lethality in males. The mouse homolog of WTX is expressed in the fetal skeleton, and alternative splicing implicates plasma membrane localization of WTX as a factor associated with survival in males with OSCS. WTX has also been shown to be somatically inactivated in 11–29% of cases of Wilms tumor. Despite being germline for such mutations, individuals with OSCS are not predisposed to tumor development. The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis.

Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia.

BackgroundMutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2.MethodsTwelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects.ResultsPathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism.ConclusionIn this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.

Cardiac involvement in genotype-positive Fabry disease patients assessed by cardiovascular MR

Objective Cardiac magnetic resonance (CMR) has the potential to provide early detection of cardiac involvement in Fabry disease. We aimed to gain further insight into this by assessing a cohort of Fabry patients using CMR. Methods/results Fifty genotype-positive Fabry subjects (age 45±2 years; 50% male) referred for CMR and 39 matched controls (age 40±2 years; 59% male) were recruited. Patients had a mean Mainz severity score index of 15±2 (range 0–46), reflecting an overall mild degree of disease severity. Compared with controls, Fabry subjects had a 34% greater left ventricular mass (LVM) index (82±5 vs 61±2 g/m2, p=0.001) and had a significantly greater papillary muscle contribution to total LVM (13±1 vs 6±0.5%, p<0.001), even in the absence of left ventricular hypertrophy (LVH). Late gadolinium enhancement (LGE) was present in 15 Fabry subjects (9/21 males and 6/23 females). The most common site for LGE was the basal inferolateral wall (93%, 14/15). There was a positive association between LVM index and LGE. Despite this, there were two males and three females with no LVH that displayed LGE. Of Fabry subjects who were not on enzyme replacement therapy at enrolment (n=28), six were reclassified as having cardiac involvement (four LVH-negative/LGE-positive, one LVH-positive/LGE-positive and one LVH-positive/LGE-negative). Conclusions CMR was able to detect cardiac involvement in 48% of this Fabry cohort, despite the overall mild disease phenotype of the cohort. Of those not on ERT, 21% were reclassified as having cardiac involvement allowing improved risk stratification and targeting of therapy.

Autosomal Dominant Polycystic Kidney Disease: A Path Forward

Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited cause of renal failure in adults, and is due to loss-of-function mutations in either the PKD1 or PKD2 genes, which encode polycystin-1 and polycystin-2, respectively. These proteins have an essential role in maintaining the geometric structure of the distal collecting duct in the kidney in adult life, and their dysfunction predisposes to renal cyst formation. The typical renal phenotype of ADPKD is the insidious development of hundreds of renal cysts, which form in childhood and grow progressively through life, causing end-stage kidney failure in the fifth decade in about half affected by the mutation. Over the past 2 decades, major advances in genetics and disease pathogenesis have led to well-conducted randomized controlled trials, and observational studies that have resulted in an accumulation of evidence-based data, and raise hope that the lifetime risk of kidney failure due to ADPKD will be progressively curtailed during this century. This review will provide a contemporary summary of the current state of the field in disease pathogenesis and therapeutics, and also briefly highlights the importance of clinical practice guidelines, patient perspectives, patient-reported outcomes, uniform trial reporting, and health-economics in ADPKD.

The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: Report from the SSIEM Adult Metabolic Physicians Group

BACKGROUND There are few centres which specialise in the care of adults with inborn errors of metabolism (IEM). To anticipate facilities and staffing needed at these centres, it is of interest to know the distribution of the different disorders. METHODS A survey was distributed through the list-serve of the SSIEM Adult Metabolic Physicians group asking clinicians for number of patients with confirmed diagnoses, types of diagnoses and age at diagnosis. RESULTS Twenty-four adult centres responded to our survey with information on 6,692 patients. Of those 6,692 patients, 510 were excluded for diagnoses not within the IEM spectrum (e.g. bone dysplasias, hemochromatosis) or for age less than 16 years, leaving 6,182 patients for final analysis. The most common diseases followed by the adult centres were phenylketonuria (20.6%), mitochondrial disorders (14%) and lysosomal storage disorders (Fabry disease (8.8%), Gaucher disease (4.2%)). Amongst the disorders that can present with acute metabolic decompensation, the urea cycle disorders, specifically ornithine transcarbamylase deficiency, were most common (2.2%), followed by glycogen storage disease type I (1.5%) and maple syrup urine disease (1.1%). Patients were frequently diagnosed as adults, particularly those with mitochondrial disease and lysosomal storage disorders. CONCLUSIONS A wide spectrum of IEM are followed at adult centres. Specific knowledge of these disorders is needed to provide optimal care including up-to-date knowledge of treatments and ability to manage acute decompensation.

Upregulation of inward rectifying currents and Fabry disease neuropathy

Peripheral neuropathy and neuropathic pain are common clinical manifestations of Fabry disease (FD). Although the mechanisms underlying the development of sensory neuropathy remain to be fully elucidated, a chronic ischemic process was proposed. Consequently, this study utilized axonal excitability techniques to gain further insights into the pathophysiological mechanisms underlying the development of FD neuropathy. Median motor and sensory axonal excitability studies were undertaken in 13 FD patients and results were compared to 19 healthy subjects. A “fanning‐in” of threshold electrotonus, suggestive of membrane depolarization, was evident only in motor axons in FD patients. In contrast, the sensory axons exhibited a lower threshold in FD (p < 0.05) and a significantly increased hyperpolarizing current/threshold (I/V) gradient (FD 0.48 ± 0.03; controls, 0.31 ± 0.02, p < 0.001), which correlated with clinical scores of disease severity (Rho = 0.65, p < 0.05), neuropathy (Rho = 0.54, p < 0.05) and neuropathic pain (Rho = 0.56, p < 0.05). These findings indicate that upregulation of Ih, rather than ischemia, may underlie the sensory symptoms and possibly development of neuropathy in FD. Modulation of sensory Ih may prove therapeutically useful in Fabry disease.

Identifying and integrating consumer perspectives in clinical practice guidelines on autosomal-dominant polycystic kidney disease

This study aimed to identify consumer perspectives on topics and outcomes to integrate in the Kidney Health Australia Caring for Australasians with Renal Impairment (KHA‐CARI) clinical practice guidelines on autosomal‐dominant polycystic kidney disease (ADPKD).

Hyperammonemic encephalopathy complicating bariatric surgery: A case study and review of the literature

Hyperammonemic encephalopathy complicating bariatric surgery: A case study and review of the literature Jane Estrella, M.D., M.Med., Gary Yee, M.B.B.S., F.R.A.C.S.*, Bridget Wilcken, M.B.Ch.B., M.D., Michel Tchan, B.Med.Sc., M.B.B.S., Ph.D., Michael Talbot, M.B.Ch.B., F.R.A.C.S. Department of Genetic Medicine, Westmead Hospital, Sydney, Australia Sydney Medical School, University of Sydney, Australia Department of Endocrinology, Blacktown Hospital, Sydney, Australia St. George Hospital, Sydney, Australia Received October 24, 2013; accepted October 29, 2013

Cognitive and psychological functioning in fabry disease

Fabry disease is an X-linked lysosomal storage disorder which can result in renal, cardiac, and cerebrovascular disease. Patients are at increased risk of stroke and neuroimaging studies note cerebrovascular pathology. This study provides a cognitive profile of a cohort of individuals with Fabry disease and investigates the impact of pain, age, renal, cardiac, and cerebrovascular functioning on cognition and psychological functioning. Seventeen Fabry patients (12 males) with ages ranging 25 to 60 years (M = 46.6+11.8), and 15 age-matched healthy controls (M = 46.2+12.7) were administered a comprehensive neuropsychological battery. Fabry males demonstrated slower speed of information processing, reduced performance on measures of executive functions (verbal generation, reasoning, problem solving, perseveration), were more likely to show clinically significant reductions, and were more likely to report symptoms of anxiety and depression. Conversely, Fabry females performed at a similar level to controls. Correlational analyses indicated a link between cognitive and clinical measures of disease severity.

The Management of Pregnancy in Maple Syrup Urine Disease: Experience with Two Patients

We describe the management and outcomes of pregnancy in two women affected with Maple syrup urine disease (MSUD). Both patients had classical disease diagnosed in the newborn period and were managed with low-protein diets and supplements, although compliance was moderately poor throughout life. Both pregnancies were complicated by poor compliance and one patient had a metabolic decompensation, which included seizures and profound encephalopathy, at the end of the first trimester. Peri-partum management required a coordinated team approach including a high-calorie and low-protein diet. Both patients had elevated leucine levels in the post-partum period - one due to mastitis and the other due to poor dietary and supplement compliance combined with uterine involution. On later review, leucine had returned to pre-pregnancy levels. Both infants were unaffected and have made normal developmental progress in the subsequent 1 to 2 years.