Francesca Furlan

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

BackgroundThe disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood.AimsTo evaluate the complex clinical phenotype of OAD and UCD patients at different ages.ResultsAcquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut0 patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population.ConclusionsNeurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

IDUA mutational profiling of a cohort of 102 European patients with mucopolysaccharidosis type I: identification and characterization of 35 novel α-L-iduronidase (IDUA) alleles

Mutational analysis of the IDUA gene was performed in a cohort of 102 European patients with mucopolysaccharidosis type I. A total of 54 distinct mutant IDUA alleles were identified, 34 of which were novel including 12 missense mutations, 2 nonsense mutations, 12 splicing mutations, 5 micro‐deletions, 1 micro‐duplication 1 translational initiation site mutation, and 1 ‘no‐stop’ change (p.X654RextX62). Evidence for the pathological significance of all novel mutations identified was sought by means of a range of methodological approaches, including the assessment of evolutionary conservation, RT‐PCR/in vitro splicing analysis, MutPred analysis and visual inspection of the 3D‐model of the IDUA protein. Taken together, these data not only demonstrate the remarkable mutational heterogeneity characterizing type 1 mucopolysaccharidosis but also illustrate our increasing ability to make deductions pertaining to the genotype‐phenotype relationship in disorders manifesting a high degree of allelic heterogeneity.

Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia

BACKGROUND & AIMS Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities. METHODS We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands. RESULTS ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations. CONCLUSIONS Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.

Glucose metabolism and diet-based prevention of liver dysfunction in MPV17 mutant patients

BACKGROUND/AIMS To describe in detail the specific clinical and biological characteristics of three patients with MPV17 gene mutations, a rare hepatocerebral mitochondrial DNA depletion syndrome (MDS) and the positive effects of a novel dietetic treatment based on avoidance of fasting. METHODS We describe the case histories of three members of the same family with MPV17 mutations. RESULTS Two patients had a very severe and progressive liver disease: 1 died in the first year of life and the other underwent liver transplantation. The third patient, now 13 years of age, had a milder form of liver disease and developed progressive ataxia. Psychomotor involvement at onset of disease was mild or absent. No patient had severe hyperlactataemia. In vivo functional studies on two patients showed no hyperlactataemia even after intravenous and oral glucose loading, regular fasting hypoglycemia 3-4h after meals and no response to glucagon. Liver function tests improved when patients received continuous iv glucose infusion or were regularly fed every 3h. CONCLUSIONS These clinical and biochemical features allow us to differentiate patients with MPV17 mutations from other liver MDS and suggest that regular glucose intake at short intervals may be beneficial in slowing the progression of the disease.

Efficacy of ACE‐inhibitor therapy on renal disease in glycogen storage disease type 1: a multicentre retrospective study

Background  The efficacy of ACE‐inhibitors in decreasing microalbuminuria and proteinuria has been reported in a few patients with glycogen storage disease type 1 (GSD1); however, no case‐control study has ever been published.

Multiple cryptic splice sites can be activated by IDS point mutations generating misspliced transcripts

Mutations in the gene encoding the enzyme iduronate-2-sulfatase (IDS) were reported as the cause of the X-linked recessive lysosomal disease, mucopolysaccharidosis II (MPS II). Amongst the different mutations, it emerges that nearly 10% are nucleotide substitutions causing splicing mutations. We now report the molecular characterisation of three MPS II patients with multiple aberrant transcripts due to three different point mutations. The c.418+1G>C that occurred in the invariant splice-site motif, produced only aberrantly spliced transcripts. Whilst the mutations affecting variant motifs (c.419G>T) or coding regions (c.245C>T) led to aberrantly spliced transcripts in addition to correctly spliced transcripts with the respective predicted missense mutation, p.G140V or p.A82V. A combination of experimental tests and computational approaches were used to understand the molecular basis underlying the altered transcription patterns. In addition, by using real-time reverse transcriptase polymerase chain reaction, the reduction of mRNA amount in two patients observed was likely due to nonsense-mediated mRNA decay pathway. Overall, our results further emphasised the importance of cloning and sequencing independent transcripts to reveal less abundant, aberrant products, which often could not be detected by direct sequencing. Moreover, the different splicing patterns observed in the three patients as a consequence of point mutations show how sensitive the balance is between constitutive and cryptic splice sites in the IDS gene. The generation of such diverse transcripts, together with their level of expression, could contribute to the profound phenotypic variability reported in MPS II.

The Fanconi–Bickel Syndrome: a Case of Neonatal Onset

A male newborn infant was recognized having Fanconi–Bickel syndrome (FBS) in the neonatal period. The presenting clinical findings were hyperglycemia and polyuria detected during an episode of acute enteritis. Physical examination was normal, biochemical analyses were suggestive of FBS: glycosuria, proteinuria, phosphaturia, generalized aminoaciduria, and increased levels of urinary β2-microglobulin, serum glucose and serum alkaline phosphatase. The molecular genetic analysis showed homozygosity for mutations within the gene of the glucose transporter 2 (Glut 2), 1213 C>T. The patient demonstrated improved clinical and metabolic status following institution of diet with frequent small meals and galactose-free-milk as well as pharmacological treatment with phosphate and vitamin α-OH-D3. In conclusion, infants showing hyperglycemia and polyuria may be considered having FBS also in the neonatal period. Early institution of adequate caloric intake and replacement of electrolytes and vitamin D may avoid or reduce metabolic complications.

Muscle MRI of classic infantile pompe patients: Fatty substitution and edema-like changes

The aim of this study was to evaluate the muscle MRI pattern of 9 patients (median age: 6.5 ± 2.74 years) affected by classic infantile‐onset Pompe disease who were treated with enzyme replacement therapy.

Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation (J Inherit Metab Dis, 10.1007/s10545-015-9839-3)

Stefan Kölker & Angeles Garcia Cazorla & Vassili Valayannopoulos & Allan M. Lund & Alberto B. Burlina & Jolanta Sykut-Cegielska & Frits A. Wijburg & Elisa Leão Teles & Jiri Zeman & Carlo Dionisi-Vici & Ivo Barić & Daniela Karall & Persephone Augoustides-Savvopoulou & Lise Aksglaede & Jean-Baptiste Arnoux & Paula Avram & Matthias R. Baumgartner & Javier Blasco-Alonso & Brigitte Chabrol & Anupam Chakrapani & Kimberly Chapman & Elisenda Cortès i Saladelafont & Maria L. Couce & Linda de Meirleir & Dries Dobbelaere & Veronika Dvorakova & Francesca Furlan & Florian Gleich & Wanda Gradowska & Stephanie Grünewald & Anil Jalan & Johannes Häberle & Gisela Haege & Robin Lachmann & Alexander Laemmle & Eveline Langereis & Pascale de Lonlay & Diego Martinelli & Shirou Matsumoto & Chris Mühlhausen & Hélène Ogier de Baulny & Carlos Ortez & Luis Peña-Quintana & Danijela Petković Ramadža & Esmeralda Rodrigues & Sabine Scholl-Bürgi & Etienne Sokal & Christian Staufner & Marshall L. Summar & Nicholas Thompson & Roshni Vara & Inmaculada Vives Pinera & John H. Walter & Monique Williams & Peter Burgard

Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype (J Inherit Metab Dis, 10.1007/s10545-015-9840-x)

Stefan Kölker & Vassili Valayannopoulos & Alberto B. Burlina & Jolanta Sykut-Cegielska & Frits A. Wijburg & Elisa Leão Teles & Jiri Zeman & Carlo Dionisi-Vici & Ivo Barić & Daniela Karall & Jean-Baptiste Arnoux & Paula Avram & Matthias R. Baumgartner & Javier Blasco-Alonso & S. P. Nikolas Boy & Marlene Bøgehus Rasmussen & Peter Burgard & Brigitte Chabrol & AnupamChakrapani &Kimberly Chapman & Elisenda Cortès i Saladelafont & Maria L. Couce & Linda de Meirleir & Dries Dobbelaere & Francesca Furlan & Florian Gleich & Maria Julieta González & Wanda Gradowska & Stephanie Grünewald & Tomas Honzik & Friederike Hörster & Hariklea Ioannou & Anil Jalan & Johannes Häberle & Gisela Haege & Eveline Langereis & Pascale de Lonlay &DiegoMartinelli & ShirouMatsumoto &ChrisMühlhausen &ElaineMurphy &HélèneOgier de Baulny & Carlos Ortez & Consuelo C. Pedrón & Guillem Pintos-Morell & Luis Pena-Quintana & Danijela Petković Ramadža & Esmeralda Rodrigues & Sabine Scholl-Bürgi & Etienne Sokal & Marshall L. Summar & Nicholas Thompson & Roshni Vara & Inmaculada Vives Pinera & John H. Walter & Monique Williams & Allan M. Lund & Angeles Garcia Cazorla