Methylmalonic and propionic acidurias: management without or with a few supplements of specific amino acid mixture.

In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4-0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24-hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.

Breast feeding in IMD.

Breast feeding has proven benefits for many infants with inherited metabolic disorders (IMDs) but, with the exception of phenylketonuria, there are few reports in other conditions. A questionnaire, completed by dietitians and clinicians from 27 IMD centres from 15 countries (caring for a total of over 8000 patients with IMDs on diet) identified breast feeding experience in IMD. Successful, demand breast feeding (in combination with an infant amino acid formula free of precursor amino acids) was reported in 17 infants with MSUD, 14 with tyrosinaemia type I, and 5 with homocystinuria. Eighty-nine per cent were still breast fed at 16 weeks. Fewer infants with organic acidaemias were demand breast fed (7 with propionic acidaemia; 6 with methylmalonic acidaemia and 13 with isovaleric acidaemia) (usually preceded by complementary feeds of a protein-free infant formula or infant amino acid formula free of precursor amino acids). Only 12 infants with urea cycle disorders were given demand breast feeds, but this was unsuccessful beyond 8 days in CPS deficiency. Further work is needed in developing guidelines for feeding and for clinical and biochemical monitoring for breast-fed infants with IMDs.

[Dietary recommendations for pregnant women affected with phenylketonuria]. / Recommandations diététiques pour les femmes enceintes atteintes de phénylcétonurie.

Prevention of embryopathy due to maternal phenylketonuria is possible thanks to a maternal-specific low-phenylalanine diet, which has to be started before conception and followed during the whole gestation. The setup of this diet implies knowing the recommended dietary allowances for normal pregnant women as well as for women with nutritional deficiencies. Women with phenylketonuria must be considered at risk for nutritional imbalance for two main reasons. First, most adult women with phenylketonuria have been on a vegetarian diet for many years without protein substitutes or medical control. Secondly, the strict diet for pregnant women with phenylketonuria may induce anorexia or nutritional deficits if it is not well tolerated or understood. Protein, iron, calcium, selenium, vitamin B 12 and caloric intakes are the most sensitive parameters. Close cooperation with an experienced medical and dietician team is required.

Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. Evidence for clinical and biological improvement.

We report an attempt at dietetic therapy in two unrelated patients with isolated sulphite oxidase deficiency, with a mild clinical course and late onset of symptoms. In case 1, disease started at 15 months with an acute crisis of agitation, unexplained crying and restlessness following otitis. Case 2 was diagnosed at 10 months when she presented with slight motor delay and dislocation of lenses. In both cases, sulphite oxidase activity measured in fibroblasts was undetectable. Therapy consisted of a diet low in protein from natural foods (daily methionine intake 130-150 mg) and a synthetic amino acid mixture (50 g per day) without cystine and methionine (Xmet, Cys Maxamaid, SHS International Ltd). A comparison of clinical and biochemical parameters was made between the period before treatment and after 2 years of treatment. Restriction in protein and sulphur amino acids brought about a dramatic decrease of urinary thiosulphate and S-sulphocysteine. It also brought about a generalized hypoaminoacidaemia with a low plasma methionine and cystine in both patients. Furthermore, both patients grew normally with no signs of neurological deterioration, and there was evidence of progress in psychomotor development.

[Pregnancy and the child of a mother with phenylketonuria]. / La grossesse et l'enfant de mère phénylcétonurique.

Pregnant women with hyperphenylalaninemia are at high risk of spontaneous abortion and of giving birth to infants with congenital malformations, microcephaly and mental defect. Among mothers whose phenylalaninemia is greater than 1200 mumol/L (20 mg/100 mL), 95% have at least one child with mental retardation. A low phenylalanine diet with a good control of phenylalaninemia, started before conception, reduces this risk, better results being obtained when plasma phenylalanine levels are maintained below 360 mumol/L (6 mg/100 mL) as compared with levels maintained between 360 to 600 mumol/L (6-10 mg/100 mL). Thus, systematic contraception and planned pregnancies must be recommended in all hyperphenylalanemic young women. This implies early information of phenylketonuric teenage girls and their parents. In addition, efforts must be made to join and inform all women having had hyperphenylalaninemia at birth, whether they received a dietary treatment or not. It is also important that general practitioners, pediatricians and obstetricians be aware of the high recurrence risk in hyperphenylalanemic women who gave birth to a microcephalic or malformed infant.

Clinical outcome and long-term management of 17 patients with propionic acidaemia.

UNLABELLED: A retrospective study was performed on the clinical outcome and long-term treatment of 17 patients with propionic acidaemia diagnosed during the last 20 years in our hospital. The study group consisted of 12 patients with early onset type of disease and 5 patients with late onset. Seven (41%) patients died, five with early onset and two with late onset. The deceased early onset patients had a median survival of 0.4 years while the deceased late onset patients died at the age of 2.8 and 4 years respectively. Median age of the living early onset patients was 5.2 (1-9.25) years, the late onset patients were 4, 7 and 23 years old. Patients were all treated with natural protein restriction and in most cases carnitine and metronidazole were added. The early onset patients were almost all treated with daily home tube feeding. The mean natural protein intake of early onset patients (6.3 +/- 1.5 g/day) was significantly lower than the natural protein intake of late onset patients (17.6 +/- 5.3 g/day). Supplemental protein intake was higher in early onset patients. The general neurological outcome of our study group was satisfactory with a better outcome for early onset patients. As to growth, many patients showed a failure to thrive, this was particularly for height. The strong protein restriction during the first years of life probably contributed to this. CONCLUSION: The prognosis for patients with propionic acidaemia appeared to be satisfactory in terms of survival and outcome characteristics such as neurological and mental development. Despite these results the authors feel that the prognosis and quality of life of these patients might be improved with liver transplantation or possibly somatic gene therapy in the future.

Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia.

We performed a retrospective study of all patients with methylmalonic acidemia diagnosed during the past 20 years. Only those patients who were nonresponsive to vitamin B12 in vivo and in vitro were included. The final study group consisted of 26 patients, of whom 16 had a neonatal (early) onset; in 10 patients the diagnosis was made after 2 months to 2.2 years (late onset). Of the early-onset patients, 14 (87%) died, with a mean survival time of 1.5 years (range, 10 days to 2.5 years), whereas four of the late-onset patients (40%) died (range, 1.2 to 15 years). At present, eight patients are alive; their mean age is 4.6 years (range, 1 to 10 years). In the early 1970s, treatment was based on the principles of treating patients with phenylketonuria: restricting natural protein intake and supplementing essential amino acids, vitamins, and trace elements. After about 1980, nasogastric tube feeding became a mainstay of the therapy, natural protein restriction became stricter, and the use of essential amino acid mixtures diminished. Carnitine was added to the therapy and, in later years, metronidazole. Since these changes were implemented, the number of episodes of metabolic decompensation and hospitalizations has decreased. Mean survival time of the patients, in particular those with early onset, has only slightly improved, partly because of psychosocial problems in many of these families. Almost all the patients, especially those with early onset, had some degree of neurologic impairment and mental retardation, and many patients were at less than 2 SD for weight or height or both. In contrast, the neurologic and mental status of the late-onset patients was frequently normal, and their weight and height were more often within normal limits. Our results show that the treatment of methylmalonic acidemia still poses considerable problems; despite intense medical efforts and familial stress, the prognosis for the early-onset patients is disappointing. The patients with late-onset disease, however, appear to have a fairly good prognosis with the present therapeutic approach. Liver transplantation or possibly genetic therapy might improve our results in the future.

Hudson memorial lecture. Neonatal management of organic acidurias. Clinical update.

Therapeutic guidelines have been obtained from a retrospective review of 41 patients affected with organic acidaemias, 16 patients with neonatal maple syrup urine disease (MSUD), 11 methylmalonic acidaemia, (MMA) seven propionic acidaemias (PA) and seven isovaleric acidaemias (IVA), and by comparing this personal series with similar reported cases. The emergency treatment of these organic acidurias in the neonate has to main goals: toxin removal and anabolism. Anabolism is always promoted by early diet therapy. The best method of toxin removal depends on the nature of the defect; peritoneal dialysis with exchange transfusions or multiple or prolonged exchange transfusions in MSUD and in PA, diuresis and exchange transfusions in MMA and glycine supplementation in IVA. Vitamin supplementation (thiamine 20 mg, biotin 10 mg, B12 2 mg and riboflavin 100 mg) should be tried in all cases although the neonatal forms of these defects are very rarely vitamin responsive. Additional treatments such as carnitine or insulin may prove to be useful.

[Heterogeneity of leucinosis. Correlations between clinical manifestations, protein tolerance and enzyme deficiency]. / Hétérogénéité de la leucinose. Corrélations entre l'aspect clinique, la tolérance protéique et le déficit enzymatique.

Maple syrup urine disease (MSUD) is an inborn error of branched-chain aminoacid (BCAA) catabolism due to a defect of BC ketoacid decarboxylation. Beside the classical form of the disease, general variant forms have been recently reported. From our personal experience in 21 patients consisting of 14 patients with classical MSUD and 7 patients with "variant" forms (1 intermittent, 2 subacute forms, 1 lipoamide dehydrogenase deficiency and 3 composite heterozygotes), we tried to correlate clinical features with protein tolerance and enzyme activity. All classical forms share an acute neonatal presentation, with a low leucine tolerance (m +/- SD = 465 +/- 88 mg per day), and a very low enzyme activity (m +/- SD = 2.5 +/- 1.5% of controls), mild variations being consistent with a possible polyallelism within this group. All "variant" forms share a late onset with a reasonable leucine tolerance (2-3 grams per day) and a fair enzyme activity, ranging from 7 to 20% of controls. However, no strict correlation could be found between the severity of the outcome and the extent of the residual enzyme activity, since acute episodes or chronic deterioration occurred even in "variants", irrespective of the level of their enzyme activity. Finally, our data suggest that variant forms could result from a composite heterozygotism, combining heterozygotism for the gene of classical MSUD and heterozygotism for a "petite" mutation, undetectable when isolated. The occurrence of classical MSUD and "variant" forms of the disease within a single family of our series further supports this hypothesis.

[Isovaleric acidemia. Study and treatment in 3 brothers]. / Acidémie isovalérique. Etude et traitement chez trois freres

The cases of 3 sibs presenting with isovaleric acidemia are reported. The first infant died when he was 9 day-old. The two others appear to have benefited from a controlled leucine diet which was introduced from the first days on of life. The clinical symptomatology, highly typical of the disease, is described. Diagnosis was not assessed on amino-acids chromatography but on the chromatography of volatile fatty acids. The mode of treatment is described: peritoneal dialysis, with the object of rounding a crucial cape, and overall controlled leucine diet, but supplemented by essential amino-acids.