Biomedical subjects

Fernando Scaglia

Publications and source records attributed to Fernando Scaglia.

24 records · Page 2Linked to original sources

PubMed2003

Novel homoplasmic mutation in the mitochondrial tRNATyr gene associated with atypical mitochondrial cytopathy presenting with focal segmental glomerulosclerosis.

We report a 9-year-old girl with a mitochondrial cytopathy preceded by steroid-resistant focal segmental glomerulosclerosis (FSGS). The proband presented at the age of 2 years with steroid-resistant nephrotic syndrome caused by FSGS. Her renal function progressively deteriorated and a dilated cardiomyopathy developed at the age of 7 years. A skeletal muscle biopsy showed a combined respiratory chain (RC) defect and a partial deficiency of coenzyme Q(10). A novel mutation in the evolutionary highly conserved region of the mitochondrial tRNA(Tyr) gene was found in homoplasmic state in skeletal muscle, blood, and renal tissue. The mutation was also found in homoplasmic state in her mildly symptomatic mother. No other maternal family members were available for testing. The present case of mitochondrial cytopathy initially presenting with steroid-resistant nephrotic syndrome, unusual biochemical and renal findings associated with a novel tRNA point mutation suggests that steroid-resistant FSGS can predate other features of mitochondrial disease for a prolonged period of time and that the progressive glomerulopathy associated with combined mitochondrial RC defects is genetically heterogeneous.

Abnormalities, Multiple↗

PubMed2003

Differential utilization of systemic and enteral ammonia for urea synthesis in control subjects and ornithine transcarbamylase deficiency carriers.

BACKGROUND: Female carriers of ornithine transcarbamylase deficiency (OTCD) have nearly normal rates of total urea synthesis, but they derive less urea from systemic glutamine amide nitrogen than do healthy persons. OBJECTIVE: The objective of the study was to investigate whether females with symptomatic OTCD rely on alternative pathways to compensate for the reduced urea synthesis activity observed in this disorder. DESIGN: The 5-d study involved 6 control subjects (3 males, 3 females) and 6 female OTCD carriers who had a fixed energy intake of 133 kJ. kg(-)(1). d(-)(1) and a protein intake of 0.8 g. kg(-)(1). d(-)(1). They underwent two 12-h periods of isotopic tracer administration, separated by 2 d. On both occasions, [(18)O] or [(13)C]urea was infused intravenously, and the subjects consumed hourly meals. During the first period, [(15)N]NH(4)Cl was given intravenously; during the second period, the tracer was given as hourly oral doses. RESULTS: OTCD carriers produced less urea (P < 0.05) but had a higher (P < 0.05) mean ammonia appearance rate and plasma ammonia concentration than did control subjects. OTCD carriers incorporated a lower (P < 0.001) mean (+/- SE) proportion of the intravenous [(15)N]NH(4)Cl dose into circulating urea than did control subjects (16 +/- 1% compared with 36 +/- 2%), but there was no genotypic difference in the incorporation of orally administered tracer (81 +/- 4% compared with 72 +/- 4%, respectively). CONCLUSION: A good degree of dietary protein tolerance seemed to be retained in OTCD carriers by the maintenance of higher ammonia appearance rates, expansion of the plasma ammonia pool, and reliance on the ability of the perivenous hepatocytes to clear excess ammonia via glutamine synthesis.

Administration, Oral↗

PubMed2002

Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism.

BACKGROUND: Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian Inheritance in Man database: *212138), a mitochondrial fatty acid oxidation disorder with a lethal prognosis. These features have not been identified as the presenting features of mitochondrial cytopathy in the neonatal period. CASE PRESENTATION: We describe an atypical presentation of mitochondrial cytopathy in a 2 day-old neonate. She presented with a Reye-like syndrome episode, premature ventricular contractions and ventricular tachycardia. Initial laboratory evaluation exhibited a large amount of 3-methylglutaconic acid on urine organic acid analysis, mild orotic aciduria and a nonspecific abnormal acylcarnitine profile. The evaluation for carnitine-acylcarnitine translocase deficiency and other fatty acid oxidation disorders was negative. The patient later developed a hypertrophic cardiomyopathy and continued to be affected by recurrent Reye-like syndrome episodes triggered by infections. A muscle biopsy exhibited signs of a mitochondrial cytopathy. During the course of her disease, her Reye-like syndrome episodes have subsided; however, cardiomyopathy has persisted along with fatigue and exercise intolerance. CONCLUSIONS: This case illustrates that, in the neonatal period, hyperammonemia and ventricular tachycardia may be the presenting features of a lethal carnitine-acylcarnitine translocase deficiency or of a mitochondrial cytopathy, associated with a milder clinical course. This association broadens the spectrum of presenting phenotypes observed in patients with disturbed mitochondrial energy metabolism. Also, the presence of 3-methylglutaconic aciduria suggests mitochondrial dysfunction and mild orotic aciduria could potentially be used as a marker of mitochondrial disease.

Biomarkers↗

PubMed2002

Variant Gaucher disease characterized by dysmorphic features, absence of cardiovascular involvement, laryngospasm, and compound heterozygosity for a novel mutation (D409H/C16S).

A 20-month-old girl with developmental delay, dysmorphic features, horizontal supranuclear gaze palsy, retrocollis, and episodes of laryngospasm was diagnosed with variant neuronopathic Gaucher disease. The diagnosis was made enzymatically. Mutation analysis showed compound heterozygosity for D409H and a previously unreported mutation C16S. The presence of dysmorphic features, laryngospasm, absent cardiac findings, and the severe clinical phenotype distinguishes our case from other cases of variant neuronopathic Gaucher disease. We therefore propose to extend the spectrum of variant Gaucher disease.

Amino Acid Substitution↗

PubMed2002

Tyrosinemia.

Explore the source record for details and available documents.

Biopsy↗

PubMed2002

An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited urea cycle disorder, and is transmitted as an X-linked trait. Female OTCD heterozygotes exhibit wide clinical severities, ranging from being apparently asymptomatic to having the profound neurologic impairment observed in affected males. However, clinical and laboratory diagnosis of partial OTCD during asymptomatic periods is difficult, and correlation of phenotypic severity with either DNA mutation and/or in vitro enzyme activity is imprecise. Provocative testing, including protein load and allopurinol challenge used in the diagnosis of OTCD females, is not without risk and subject to both false positives and negatives. Although definitive when successful, DNA-based diagnosis is unable to detect mutations in all cases. We have previously used the ratio of isotopic enrichments of [(15)N]urea/[(15)N]glutamine ((15)N-U/G) derived from physiologic measurements of ureagenesis by stable isotope infusion as a sensitive index of in vivo urea cycle activity. We have now applied this method in combination with traditional biochemical testing to aid in the diagnosis of a symptomatic OTCD female in whom mutation in the ornithine transcarbamylase (OTC) gene was not found. The (15)N-U/G ratio in this patient showed that she had severe reduction of in vivo urea cycle activity on par with affected male subjects. This was correlated with partially deficient OTC activity in her liver, degree of orotic aciduria, and history of suspected recurrent hyperammonemic episodes before age 3. The measurement of in vivo urea cycle activity in combination with traditional biochemical indices optimizes a diagnostic approach to the at-risk partial OTCD patient, especially in those in whom molecular testing is unproductive. Together they contribute to the risk versus benefit considerations regarding the pursuit of medical therapy versus surgical, ie, orthotopic liver transplantation (OLT) therapy. The decision to resort to OLT in females with partial OTC activity is controversial, requiring consideration of phenotypic severity, failure of medical therapy, access to tertiary care centers experienced in the management of acute hyperammonemia, and social factors. In this patient, the use of in vivo and in vitro measures of urea cycle activity in conjunction with a consideration of her clinical history and medical-social situation led to a decision for OLT.

Child, Preschool↗