Recognition and management of fatty acid oxidation defects: a series of 107 patients.

In a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty-eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long-chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long-term dietary therapy aims to prevent periods of fasting and restrict long-chain fatty acid intake with supplementation of medium-chain triglycerides. Despite these therapeutic measures, the long-term prognosis remains uncertain.

Clinical features of 52 neonates with hyperinsulinism.

BACKGROUND: Neonatal hyperinsulinemic hypoglycemia is often resistant to medical therapy and is often treated with near-total pancreatectomy. However, the pancreatic lesions may be focal and treatable by partial pancreatic resection. METHODS: We studied 52 neonates with hyperinsulinism who were treated surgically. The type and location of the pancreatic lesions were determined by preoperative pancreatic catheterization and intraoperative histologic studies. Partial pancreatectomy was performed in infants with focal lesions, and near-total pancreatectomy was performed in those with diffuse lesions. The postoperative outcome was determined by measurements of plasma glucose and glycosylated hemoglobin and by oral glucose-tolerance tests. RESULTS: Thirty neonates had diffuse beta-cell hyperfunction, and 22 had focal adenomatous islet-cell hyperplasia. Among the latter, the lesions were in the head of the pancreas in nine, the isthmus in three, the body in eight, and the tail in two. The clinical manifestations were similar in both groups. The infants with focal lesions had no symptoms of hypoglycemia and had normal preprandial and postprandial plasma glucose and glycosylated hemoglobin values and normal results on oral glucose-tolerance tests after partial pancreatectomy (performed in 19 of 22 neonates). By contrast, after near-total pancreatectomy, 13 of the patients with diffuse lesions had persistent hypoglycemia, type 1 diabetes mellitus developed in 8, and hyperglycemia developed in another 7; overall, only 2 patients with diffuse lesions had normal plasma glucose concentrations in the first year after surgery. CONCLUSIONS: Among neonates with hyperinsulinism, about half may have focal islet-cell hyperplasia that can be treated with partial pancreatectomy. These neonates can be identified through pancreatic catheterization and intraoperative histologic studies.

Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria.

UNLABELLED: Primary persistent hyperinsulinaemic hypoglycaemia of infancy is rare. Diazoxide treatment remains the mainstay of medical therapy in long-term management. We reviewed 77 cases of primary persistent hyperinsulinism in neonates and infants who were treated with diazoxide and studied criteria predictive of therapeutic efficacy. The only criterion identified was age at manifestation. All but 1 of the 31 neonatal cases were unresponsive to diazoxide. Responsiveness increased with age: 12 of 39 early-infantile cases, and all seven late-infantile cases were diazoxide-responsive. In responders, a diazoxide dose of 10-15 mg/kg per day was always effective, suggesting an "all or none" response. Diazoxide-resistant hyperinsulinism is characterized by its severity with higher plasma insulin levels. The analysis of 46 surgically treated patients showed that the efficacy of diazoxide is not related to the aetiology of the pancreatic lesions. In six cases, after many years of management, diazoxide treatment was stopped without recurrence of hypoglycaemia. CONCLUSION: Diazoxide is an efficient treatment in the long-term management of most persistent hyperinsulinaemic hypoglycaemia of infancy revealed in infants and children but is usually ineffective in neonatal forms. Drug efficacy does not correlate with anatomical lesions. Medical treatment can sometimes be stopped after many years of management without recurrence of disease manifestations.

Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy.

Sporadic persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or nesidioblastosis is a heterogeneous disorder characterized by profound hypoglycemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI) because management strategies differ significantly. 16 infants with sporadic PHHI resistant to diazoxide and who underwent pancreatectomy were investigated. Selective pancreatic venous sampling coupled with peroperative surgical examination and analysis of extemporaneous frozen sections allowed us to identify 10 cases with FoPHHI and 6 cases with DiPHHI. We show here that in cases of FoPHHI, but not those of DiPHHI, there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event is consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, we provide the first molecular explanation of the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia.

Metabolic intermediates in lactic acidosis: compounds, samples and interpretation.

A number of acquired conditions including infections, severe catabolic states, tissue anoxia, severe dehydration and poisoning can give rise to hyperlactacidaemia. All these causes should be ruled out before considering inborn errors of metabolism. Carefully collected samples are necessary if artefacts that result in spuriously increased lactate/pyruvate (L/P) and 3-hydroxybutyrate/acetoacetate (B/A) ratios are to be avoided. When properly performed, 24-h studies of L/P and B/A ratios provide a useful tool in making a diagnosis. A few metabolic profiles when present are specific or highly suggestive of a given disorder. When the L/P ratio is normal or low, pyruvate dehydrogenase (PDH) deficiency is highly probable whatever the lactate concentration, which is often only moderately elevated after meal, may be. When the L/P ratio is very high in association with post-prandial hyperketonaemia and in contrast to a normal or low B/A ratio, pyruvate carboxylase (PC) deficiency and alpha-ketoglutarate dehydrogenase (KGDH) deficiency are the most likely diagnoses. The distinction between the two disorders relies upon amino acid and organic acid profiles (glutamate and alpha-ketoglutarate accumulations in KGDH deficiency and hyperammonaemia and hypercitrullinaemia in PC deficiency). When both L/P and B/A ratios are elevated and associated with significant post-prandial hyperketonaemia, respiratory-chain disorders should first be suspected. All other profiles, especially a high L/P ratio without hyperketonaemia, are compatible with respiratory-chain disorders but are not specific; all acquired anoxic conditions should also be ruled out. Clearly, the clinical utility of these profiles needs to be interpreted cautiously in very ill patients in relation to the cardiocirculatory condition and to therapy. Finally, a normal profile, even after stress and loading, does not rule out an inborn error of lactate/pyruvate oxidation.

Clinical approach to inherited peroxisomal disorders.

At least 21 genetic disorders have now been found that are linked to peroxisomal dysfunction. Whatever the genetic defect might be, peroxisomal disorders should be considered in various clinical conditions, dependent on the age of onset. The prototype of peroxisomal disorders is represented by 'classical' Zellweger syndrome (ZS) which is the most severe disorder combining all the characteristic symptoms. ZS is characterized by the association of errors of morphogenesis, severe neurological dysfunction, neurosensory defects, regressive changes, hepatodigestive involvement with failure to thrive, usually early death, and absence of recognizable liver peroxisomes. Other peroxisomal disorders (pseudo-Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), pseudo-neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata (RCDP), and hyperpipecolic acidaemia) share some of these symptoms, but with varying organ involvement, severity of dysfunction, and duration of survival. The diagnosis should not cause difficulty when all the characteristic manifestations are present. Depending on the main presenting sign, peroxisomal disorders in neonates should be suspected in two categories of circumstances: polymalformative syndrome with craniofacial dysmorphism, and severe neurological dysfunction. During the first 6 months of life, the predominant symptoms may be hepatomegaly, prolonged jaundice, liver failure, anorexia, vomiting and diarrhoea leading to failure to thrive resembling a malabsorption syndrome; severe psychomotor retardation, hearing loss and ocular abnormalities become evident. Beyond 4 years of age, behavioural changes, intellectual deterioration, visual impairment and gait abnormalities may be the presenting symptoms. Independently of the clinical symptoms and age of onset, most peroxisomal disorders described so far can be clinically screened by recordings of electroretinogram, visual-evoked responses, and brain auditory-evoked responses, which are almost always abnormal. Nine of the 17 peroxisomal disorders with neurological involvement are associated with an accumulation of very long-chain fatty acids (VLCFA), which suggests that assay of plasma VLCFA should be used as a primary test. However, assays of plasma phytanic acid and plasma/urine bile acid intermediates should also be performed in view of the recent reports of atypical chondrodysplasia variants (without rhizomelic shortening) and isolated trihydroxycholestanoic aciduria. The differential diagnoses in various clinical conditions and age periods are discussed.

Liver transplantation in two cases of propionic acidaemia.

Orthotopic liver transplantation (OLT) was performed in two patients with propionic acidaemia, a 7-year-old boy and a 9-year-old girl, diagnosed with a severe neonatal form with high risk of metabolic decompensation. In both cases the metabolic liver functions recovered within the 12 postoperative hours; no clinical symptoms of propionic acid toxicity, metabolic acidosis, severe hyperammonaemia, hyperglycinaemia or haematological abnormalities were observed. In both cases insulin-dependent diabetes mellitus occurred early after OLT (persisting in the boy's case). Severe post-transplantation complications were observed (acute rejection and CMV infection in both patients) which did not trigger metabolic decompensation. The boy developed chronic rejection and vanishing bile duct syndrome due to incomplete hepatic arterial thrombosis. He required permanent in-patient care with chronic hyperammonaemia and neurological sequelae involving the basal ganglia and died 15 months after OLT. The girl left hospital after 2 months and is presently leading a normal life with almost no dietary protein restriction (40 g protein per day). Urinary urea excretion and daily protein intake increased after liver transplantation. Propionyl- and tiglylglycine disappeared immediately after OLT. Urinary methylcitrate and 3-hydroxypropionate remained at concentrations corresponding to those before OLT. However, the total of all characteristic metabolites of organic acid analysis was reduced to 50-60% of the values before OLT in both patients. Propionylcarnitine was still detected at significant concentrations. Plasma odd-chain fatty acid concentrations decreased continuously after OLT only in the girl's case. Tissue of both transplanted livers showed increased odd-chain fatty acid concentrations 9 and 15 months after OLT, respectively, in both patients. We consider that at present OLT should only be performed in severe forms of propionic acidaemia.

[Diagnosis of metabolic coma in children]. / Diagnostic des comas métaboliques chez l'enfant.

This article describes the metabolic investigations to be applied in any clinical situation consistent with a late acute form of inborn error of metabolism: unexplained coma with or without focal neurological manifestations, recurrent vomiting with lethargy, episodes of ataxia with or without behaviour disorder, fits of psychiatric troubles. In each of these situations, careful medical history is of major importance searching for previous clinical manifestations such as episodes of coma, ataxia or vomiting, anorexia, failure to thrive, developmental delay, all very suggestive of metabolic disorder. The association of neurological symptoms and abnormal hepatic tests is also of great value and must not lead to the diagnosis of Reye's syndrome without considering a metabolic defect of fatty acid oxidation, urea cycle, respiratory chain, or Wilson's disease. When looking for an etiological origin, it is mandatory to collect all the biological information at the same time, also knowing that metabolic abnormalities may be mild and transitory, and that many of them are non specific (metabolic acidosis, hyperlactacidemia, hyperammonemia, hepatic tests disturbances) being encountered in collapsus, shock and multiple organ failure syndrome.