A NEONATE PRESENTING WITH GRACILE SYNDROME AND BJORNSTAD PHENOTYPE ASSOCIATED WITH BCS1L MUTATION.

GRACILE Syndrome, is an autosomal recessive disease presenting with growth retardation, severe lactic acidosis, Fanconi type tubulopathy, cholestasis, iron overload and early death without any dysmorphological or neurological features. The BCSIL gene mutation is responsible for GRACILE syndrome, Bjornstad syndrome and complex III deficiency. Bjomstad syndrome is characterized by sensorineural hearing loss and abnormal flat twisted hair shafts. The case is GRACILE syndrome with Bjomstad phenotype in neonatal period due to BCSL1 gene mutation.

[GRACILE syndrome--a severe neonatal mitochondrial disorder]. / SGRACILE-oireyhtymä--vastasyntyneen vakava mitokondriotauti.

GRACILE syndrome belongs to the Finnish disease heritage, and is caused by a point mutation in the BCS1L-gene encoding a mitochondrial protein. This leads to dysfunction of the complex III in the respiratory chain. Significant fetal growth disturbance is the primary manifestation. Within the first day the newborn infant develops severe lactic acidosis. Hypoglycemia, elevated serum ferritin and conjugated bilirubin values and aminoaciduria imply mitochondrial liver disease and renal tubulopathy. In Finland, the diagnosis is based on the 232A>G mutation in the BCS1L-gene. No specific treatment is available. GRACILE syndrome leads to early death.

Lysinuric protein intolerance: reviewing concepts on a multisystem disease.

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI was initially described in Finland, but has worldwide distribution. Typically, symptoms begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features. Two major complications, pulmonary alveolar proteinosis and renal disease are increasingly observed in LPI patients. There is extreme variability in the clinical presentation even within individual families, frequently leading to misdiagnosis or delayed diagnosis. This condition is diagnosed by urine amino acids, showing markedly elevated excretion of lysine and other dibasic amino acids despite low plasma levels of lysine, ornithine, and arginine. The biochemical diagnosis can be uncertain, requiring confirmation by DNA testing. So far, approximately 50 different mutations have been identified in the SLC7A7 gene in a group of 142 patients from 110 independent families. No genotype-phenotype correlation could be established. Therapy requires a low protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements. Supportive therapy is available for most complications with bronchoalveolar lavage being necessary for alveolar proteinosis.

Multiple bone fracture due to Fanconi's syndrome in primary Sjögren's syndrome complicated with organizing pneumonia.

Abstract A 66-year-old woman showing renal dysfunction with elevated serum alkaline phosphatase and anti-SS-A antibody was admitted. A labial salivary gland biopsy showing infiltration of mononuclear cells and positive anti-SS-A antibody with sicca symptoms led to a diagnosis of primary Sjögren's syndrome (SS). Fanconi's syndrome was diagnosed by renal tubular acidosis along with renal glucosuria or aminoaciduria and multiple bone fractures on bone scintigraphy. Typical bilateral pulmonary shadows were confirmed as organizing pneumonia (OP) determined by the analysis of bronchoalveolar lavage fluid and transbronchial lung biopsy. A rare complication of Fanconi's syndrome with OP in SS is described.

Aminoacidurias: Clinical and molecular aspects.

Inherited aminoacidurias are caused by defective amino-acid transport through renal (reabsorption) and in many cases also small intestinal epithelia (absorption). Recently, many of the genes causing this abnormal transport have been molecularly identified. In this review, we summarize the latest findings in the clinical and molecular aspects concerning the principal aminoacidurias, cystinuria, lysinuric protein intolerance, Hartnup disorder, iminoglycinuria, and dicarboxylic aminoaciduria. Signs, symptoms, diagnosis, treatment, causative or candidate genes, functional characterization of the encoded transporters, and animal models are discussed.

VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype.

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare multisystem disorder first described in 1979 and recently ascribed to mutation in VPS33B, whose product acts in intracellular trafficking. Arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia define an ARC core phenotype, in some patients associated with ichthyosis, central nervous system malformation, deafness, and platelet abnormalities. We describe a patient with cholestasis, aminoaciduria, ichthyosis, partial callosal agenesis, and sensorineural deafness who, although homozygous for the novel VPS33B mutation 971delA/K324fs, predicted to abolish VPS33B function, did not exhibit arthrogryposis. The phenotypes associated with VPS33B mutation may include incomplete ARC.

Tyrosinemia type I: a clinico-laboratory case report.

Progressive hepatocellular dysfunction in a neonate, resulting in elevated serum alpha-fetoprotein together with raised blood levels of tyrosine and methionine, a generalized amino aciduria and the absence of urinary delta-aminolevulinic acid and succinylacetone, suggests a diagnosis of tyrosinemia type Ib. Classical tyrosinemia type I arises from a deficiency of fumarylacetoacetate hydrolase while the variant tyrosinemia type Ib results from a deficiency of maleylacetoacetate isomerase.

[Hyperaminoaciduria in children]. / Les hyperaminoaciduries chez l'enfant.

Hyperaminoaciduria is a major disorder to be considered in the event of growth and mental retardation, convulsion and other unexplained clinical symptoms. This review should enable the general practitioner to determine the conditions necessitating urinary and blood amino acid analyses in order to improve the treatment of children presenting rare pathologies, the prognosis of whom depends on the rapidity of the intervention. The diagnosis and treatment of hereditary and renal hyperaminoaciduria are discussed and a physiological and physiopathological synthesis of the tubular reabsorption of amino acids is presented. The different clinical entities associated with hyperaminoaciduria are then briefly described according to their origin (renal or prerenal).

2-Hydroxyglutaric aciduria: a case report on an infant with the D-isomeric form with review of the literature.

We report on an infant with D-2-hydroxyglutaric aciduria, who presented with severe seizures and developmental delay. We reviewed the literature for 2-hydroxyglutaric aciduria and found six other patients with the D-isomer and 24 patients with the L-isomer. Although the clinical spectrum of this inborn error of metabolism is variable, the clinical course of the D-form seems to be more severe than this of the L-form.

Use of amniotic fluid amino acids in prenatal testing for argininosuccinic aciduria and citrullinaemia.

Prenatal testing of 12 pregnancies at risk for argininosuccinic aciduria due to argininosuccinate lyase (ASAL) deficiency and three pregnancies at risk for citrullinaemia due to argininosuccinate synthatase (ASAS) deficiency was performed by metabolite detection in amniotic fluid and measurement of enzyme activity in uncultured and cultured chorionic tissue and in cultured amniocytes. From our data and those of previous studies, amniotic fluid argininosuccinate measurement alone is clearly a reliable and rapid diagnostic test for both severe and mild ASAL deficiency if maternal ASAL deficiency can be excluded. For prenatal diagnosis of ASAS deficiency, however, both measurement of the amniotic fluid citrulline level and enzyme assay should be employed.

Identification of the D-enantiomer of 2-hydroxyglutaric acid in glutaric aciduria type II.

We determined the optical isomer of the 2-hydroxyglutaric acid (2HG) that was elevated in the urine of five Japanese children with a mild form of glutaric aciduria type II (GA2), caused by a deficiency of electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO). The D- and L-enantiomers of 2HG were separated by capillary gas chromatography with a combination of (S)-(+)-2-octanol derivatization and chromatography on a DB-1 column. The isomer that was elevated in GA2 patients was predominantly the D-enantiomer, an observation that may serve as an additional marker for the biochemical diagnosis of GA2. D-2HG dehydrogenation, but not L-2HG dehydrogenation is apparently blocked in GA2. A specific D-2HG dehydrogenase or D-2HG-CoA dehydrogenase may be metabolically linked to ETF and ETF-QO in the mitochondria.

Iminoglycinuria: a benign type of inherited aminoaciduria.

The diagnosis of iminoglycinuria was established in two patients on the basis of increased urinary excretion of proline, hydroxyproline and glycine in the presence of normal plasma concentrations of these respective compounds. Routine metabolic screening was performed in these infants in order to find the cause for the developmental delay observed in one infant and the siblings deaths noted in the family of the other. These two patients gave further support to the previous suggestion that renal iminoglycinuria is a benign disorder with no recognizable clinical pattern. Its detection, therefore, requires screening programs or amino acid studies.

Organic acidurias: a review. Part 2.

Laboratory findings are an essential part of the diagnostic approach to organic acidemias. In most organic acidemias, metabolism of glucose, ketone bodies, and ammonia is deranged primarily or secondarily, in addition to derangement of the acid-base balance. Hypoglycemia, lactic and/or ketoacidosis, and hyperammonemia of varying severity accompany the overt or compensated acidosis. In most instances, a definite diagnosis will be achieved by gas chromatography/mass spectrometry (GC/MS) studies of the urine. We detail the pattern of excreted organic acids in the major disorders. When the diagnosis reached by clinical and laboratory assessments is not conclusive, it must be supported by loading tests. We list the available methods of demonstrating the putative enzyme deficiency in the patient's cells and tissues. The majority of organic acidemias may be treated by limiting the source of or removing the toxic intermediary metabolite. We provide lists of available diets, supplements, and medications. In some instances, residual defective enzyme activity may be stimulated. We describe symptomatic management of the disturbed acid-base and electrolyte balance.

Aminoacidos urinarios: electroforesis por alto voltaje y acetato de celulosa gelatinizado / Urinary amino acids: electrophoresis for high voltage and in gelatinized cellulose acetate

El estudio de las alteraciones del metabolismo de los aminoacidos urinarios ha motivado el desarrollo de dos tecnicas simples, rapidas y economicas, para el uso en Quimica clinica. Se describe la celda electroforetica disenada, asi como todas las operaciones requeridas para lograr dicho objetivo (tratamiento de los soportes usados y de las muestras, buffers, condiciones de corrida, distintos metodos y reactivos de revelado, desintometria). Se comparan los resultados obtenidos para los soportes empleados, papel y acetato de celulosa gelatinizado, usando para ambos igual sistema de refrigeracion y los resultados obtenidos en comparacion con otra forma de enfriamiento del sistema, utilizada previamente. Tambien se discute la aplicacion de mayores voltajes y la importancia de la estandarizacion en la coloracion. Trabajando con acetato de celulosa gelatinizado se pueden valorar por densitometria las corridas, lo cual brinda una util herramienta a los laboratorios clinicos

Aminoacidos urinarios: electroforesis por alto voltaje y acetato de celulosa gelatinizado / Urinary amino acids: electrophoresis for high voltage and in gelatinized cellulose acetate

El estudio de las alteraciones del metabolismo de los aminoacidos urinarios ha motivado el desarrollo de dos tecnicas simples, rapidas y economicas, para el uso en Quimica clinica. Se describe la celda electroforetica disenada, asi como todas las operaciones requeridas para lograr dicho objetivo (tratamiento de los soportes usados y de las muestras, buffers, condiciones de corrida, distintos metodos y reactivos de revelado, desintometria). Se comparan los resultados obtenidos para los soportes empleados, papel y acetato de celulosa gelatinizado, usando para ambos igual sistema de refrigeracion y los resultados obtenidos en comparacion con otra forma de enfriamiento del sistema, utilizada previamente. Tambien se discute la aplicacion de mayores voltajes y la importancia de la estandarizacion en la coloracion. Trabajando con acetato de celulosa gelatinizado se pueden valorar por densitometria las corridas, lo cual brinda una util herramienta a los laboratorios clinicos

Glutaric aciduria Type II.

Two infants have been studied with glutaric aciduria Type II. The clinical presentation was of an overwhelming illness very early in life; both infants died in the neonatal period. One had dysmorphic features. An acrid odor may be a clue to the diagnosis. Neonatal acidosis, hypoglycemia, and hyperammonemia are characteristic. Organic acid analysis revealed massive lactic aciduria and glutaric aciduria. A variety of other dicarboxylic acids and hydroxy acids and amino acids were found in elevated amounts in body fluids, along with elevated concentrations of butyric, isobutyric, 2-methylbutyric, and isovaleric acids. The pattern of metabolites accumulated is consistent with deficient activity of a number of acyl-CoA dehydrogenases.