Hepatocyte transplantation using the domino concept in a child with Tetrabiopterin non-responsive phenylketonuria.

in Cell Transplantation (2012), 21(12), 2765-70

Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and ... [more ▼]

Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and severe psychosocial burden. Oral administration of tetrahydrobiopterin can increase residual enzyme activity, but most patients with severe clinical phenotypes are non-responders. We performed liver cell transplantation in 6 years-old boy with severe tetrahydrobiopterin non-responsive phenylketonuria, who failed to comply with diet prescriptions. The transplanted hepatocytes were obtained in part from an explanted glycogen storage type 1b liver. Following two infusions, blood phenylalanine levels returned within the therapeutic target while the phenylalanine half-life assessed by loading tests decreased from 43 h to 19 h. However, three months later, blood phenylalanine concentrations increased and the phenylalanine intake had to be reduced. Cell based therapy is a promising therapeutic option in phenylketonuria and the domino concept may solve the issue of cell sources for hepatocyte transplantation. [less ▲]

LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency.

in Journal of Medical Genetics (2011)

Background The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients ... [more ▼]

Background The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied. Results 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to >30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p<0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1-deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001). Conclusion SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome. [less ▲]

Left ventricular assist device as bridge to liver transplantation in a patient with propionic acidemia and cardiogenic shock.

in Journal of Pediatrics (2011)

Low citrulline in Leigh disease: still a biomarker of maternally inherited Leigh syndrome.

in Journal of Child Neurology (2010), 25(8), 1000-2

Two siblings presented with encephalopathy, lactic acidosis, and hypocitrullinemia. Muscle and liver biopsies were considered for respiratory chain studies, but because of hypocitrullinemia, molecular ... [more ▼]

Two siblings presented with encephalopathy, lactic acidosis, and hypocitrullinemia. Muscle and liver biopsies were considered for respiratory chain studies, but because of hypocitrullinemia, molecular analysis for maternally inherited Leigh syndrome was first performed, revealing in both siblings the mitochondrial DNA T8993G mutation (95% heteroplasmy), allowing to avoid tissue biopsies. Hypocitrullinemia, an occasional finding in mitochondrial diseases, has been specifically associated with T8993G mutation. However, only few patients have been reported, and the prevalence of hypocitrullinemia in 8993 mitochondrial DNA mutations is unknown. In a small series of 16 Leigh syndrome patients, sensitivity and specificity of hypocitrullinemia (< or = 12 micromol/L) for 8993 mitochondrial DNA mutations were 66% and 85%, respectively. Although studies in larger cohorts are necessary, we suggest considering T8993G mutation early in the diagnostic evaluation of infantile mitochondrial diseases with hypocitrullinemia, which minimizes the need for invasive procedures associated with a small but nonnegligible risk of complications and incorrect diagnosis. [less ▲]

Temple-Baraitser syndrome: a rare and possibly unrecognized condition.

in American Journal of Medical Genetics. Part A (2010), 152A(9), 2322-6

Temple-Baraitser syndrome, previously described in two unrelated patients, is the association of severe mental retardation and abnormal thumbs and great toes. We report two additional unrelated patients ... [more ▼]

Temple-Baraitser syndrome, previously described in two unrelated patients, is the association of severe mental retardation and abnormal thumbs and great toes. We report two additional unrelated patients with Temple-Baraitser syndrome, review clinical and radiological features of previously reported cases and discuss mode of inheritance. Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. All patients were born to unrelated parents and occurred as a single occurrence in multiple sibships, suggesting sporadic inheritance from a de novo mutation mechanism. Comparative genomic hybridization in Patients 1, 2 and 3 did not reveal any copy number variations. We confirm that Temple-Baraitser syndrome represents a distinct syndrome, probably unrecognized, possibly caused by a de novo mutation in a not yet identified gene. [less ▲]

Le cas clinique du mois. Osteogenesis imperfecta

in Revue Médicale de Liège (2009)

We report the case of a young boy who had had multiple bone fractures (more than 10) since the age of 19 months. The father had the same clinical history. The clinical examination was normal for his age ... [more ▼]

We report the case of a young boy who had had multiple bone fractures (more than 10) since the age of 19 months. The father had the same clinical history. The clinical examination was normal for his age except blue sclera. The bone densitometry showed a severe osteoporosis for his age. Biological exam swere correct. The genetic exploration revealed mutation of COL1A2 gene. With this clinical history, the diagnosis of Osteogenesis imperfecta (OI) was retained. OI is a hereditary dystrophy with abnormal synthesis or metabolism of collagen with, often, mutation of COL1A1 or COL1A2 genes. There are 7 different forms. We consider the possible differential diagnoses. The goal of any treatment is to promote bone remineralisation and to decrease the fracture frequency. The treatment includes calcium and vitamin D, and in the presence of some precise criteria, biphosphonate therapy. [less ▲]

Acute tubular dysfunction wtih Fanconi syndrome : a new manifestation of mitochondrial cytopathies

in American Journal of Kidney Diseases (2008), 51(4), 691-696

Reduced brain choline in homocystinuria due to remethylation defects

in Neurology (2008), 71(1), 44-49

Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15

in Journal of Medical Genetics (2008), 45(11), 759-764

Long-term outcome of Leigh syndrome caused by the NARP-T8993C mtDNA mutation.

in American Journal of Medical Genetics. Part A (2007), 143A(17), 2046-51

Mutations at mitochondrial DNA (mtDNA) nucleotide 8993 can cause neurogenic weakness, ataxia and retinitis pigmentosa (NARP syndrome), or maternally inherited Leigh syndrome (LS), with a correlation ... [more ▼]

Mutations at mitochondrial DNA (mtDNA) nucleotide 8993 can cause neurogenic weakness, ataxia and retinitis pigmentosa (NARP syndrome), or maternally inherited Leigh syndrome (LS), with a correlation between the amount of mutant mtDNA and the severity of the neurological disease. The T8993C mutation is generally considered to be clinically milder than the T8993G mutation but when the level of heteroplasmy exceeds 90%, progressive neurodegeneration has been found. We report on a long-term follow-up of a patient who presented at 4 years of age with typical LS but showed an unexpected resolution of his symptoms and a favorable outcome. At 18 years of age, his neurological examination was near normal, with neither peripheral neuropathy nor retinopathy. mtDNA analysis identified the presence of T8993C mutation at high level (>95%) in the patient's blood leukocytes. This case report and literature review emphasizes the variability of the phenotypic expression of the T8993C mutation and the need for caution in predictive counseling in such patients. (c) 2007 Wiley-Liss, Inc. [less ▲]