Recent advances in liver transplantation for metabolic disease.

The indications and outcomes of liver transplantation for metabolic disease have been reviewed recently and this short review concentrates on recent developments and advances. Recently recognized metabolic causes of acute liver failure are reviewed and their implications for transplantation discussed. Newly described indications for liver transplantation in systemic metabolic diseases are described and an update is given on the role of auxiliary and domino liver transplantation.

Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease.

Ethylmalonic encephalopathy is a fatal, rapidly progressive mitochondrial disorder caused by ETHE1 mutations, whose peculiar clinical and biochemical features are due to the toxic accumulation of hydrogen sulphide and of its metabolites, including thiosulphate. In mice with ethylmalonic encephalopathy, liver-targeted adeno-associated virus-mediated ETHE1 gene transfer dramatically improved both clinical course and metabolic abnormalities. Reasoning that the same achievement could be accomplished by liver transplantation, we performed living donor-liver transplantation in an infant with ethylmalonic encephalopathy. Unlike the invariably progressive deterioration of the disease, 8 months after liver transplantation, we observed striking neurological improvement with remarkable achievements in psychomotor development, along with dramatic reversion of biochemical abnormalities. These results clearly indicate that liver transplantation is a viable therapeutic option for ETHE1 disease.

Pharmacokinetics of clofarabine in patients with high-risk inherited metabolic disorders undergoing brain-sparing hematopoietic cell transplantation.

Clofarabine, a newer purine analog with reduced central nervous system toxicity, may prove advantageous in hematopoietic cell transplantation in patients for whom neurotoxicity is a natural part of disease progression. This study evaluated clofarabine pharmacokinetics in adult and pediatric patients undergoing hematopoietic cell transplantation for the treatment of high-risk, inherited metabolic disorders. Clofarabine (40 mg/m(2)/d) was administered intravenously on days -7 to -3. Kinetic sampling occurred with doses 1 and 5, along with a single level collected on day of transplant (day(0)). Sixteen patients were studied with a median (range) age and body surface area (BSA) of 7.5 years (0.5-43) and 0.94 m(2) (0.31-2.3), respectively. Clofarabine area under the concentration-time curve from time 0 to infinity was 931 ng·h/mL (685-1876), maximum concentration was 226 ng/mL (162-600), and minimum concentration was 3.2 ng/mL (1.7-5.6). Clofarabine clearance was 1.6 L/h/kg (0.7-2.4) and weakly correlated with weight (r(2) = 0.33) and BSA (r(2) = 0.26). No difference in plasma concentrations was found between dose 1 and dose 5 (all P > .05). All concentrations were below the limit of quantification (1 ng/mL) on day(0) in patients with normal renal function. Variability in clofarabine clearance was approximately 3-fold and was not adequately explained by covariates describing renal function and body size. In patients with adequate renal function, no drug accumulation occurs with consecutive daily dosing.

Glutaric acidemia type I: a neurosurgical perspective. Report of two cases.

Glutaric acidemia type I (GA-I) is a rare, autosomal recessive metabolic disorder that leads to severe dystonia, basal ganglia degeneration, and bilaterally enlarged anterior middle cranial fossae. The current management of this disease includes early diagnosis with newborn screening, prevention of catabolism, carnitine supplementation, and a strict dietary protein restriction. Neurosurgical evaluation and intervention may be necessary in patients with structural lesions associated with this disease. In this report, the authors present two pediatric patients with GA-I and discuss the neurosurgical aspects of this rare medical disorder.

Stem cell therapy in utero.

In utero stem cell transplantation represents a new and still experimental therapeutic strategy for diseases related to the hematopoietic system, i.e. hemoglobinopathies, immunodeficiency diseases and metabolic disorders. To date, a total of 21 cases of transplantations using stem cells either of fetal liver or adult bone marrow origin have been reported in the literature. Success has been limited--with the exception of one case of beta-thalassemia--to four cases with immunodeficiency diseases. In this review the broad therapeutic implications as well as potentials and limitations of this technique are summarized. Furthermore, ethical considerations based on the use of fetal cells are pointed out and a prospective view concerning experimental and clinical future perspectives including the possibility for gene therapy is presented.

Extensive intracranial xanthoma associated with type II hyperlipidemia.

Xanthomas are associated with a spectrum of medical conditions, most commonly disorders of lipid storage and lipid metabolism. They occur primarily in the subcutaneous tissues, especially along the Achilles tendon and the extensor tendons of the hands. Intracranial xanthomas are extremely rare. We present a case of an extensive xanthoma of the temporal bone in a patient with hyperlipidemia.