A 37-year-old Menkes disease patient-Residual ATP7A activity and early copper administration as key factors in beneficial treatment.

Menkes disease (MD) is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving MD patient (37 years) receiving early-onset and long-term copper treatment. He has few neurological symptoms without connective tissue disturbances; and a missense ATP7A variant, p.(Pro852Leu), which results in impaired protein trafficking while the copper transport function is spared. These findings suggest that some cuproenzymes maintain their function when sufficient copper is provided to the cells; and underline the importance of early initiated copper treatment, efficiency of which is likely to be dependent on the mutant ATP7A function.

Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients.

We report on the long-term clinical course of 4 boys with Menkes disease, treated from early infancy with parenteral copper-histidine, with follow-up over 10-20 years. Three of the 4 had male relatives with a severe clinical course compatible with classical Menkes disease. As a consequence of early treatment, our patients have normal or near-normal intellectual development, but have developed many of the more severe somatic abnormalities of the related disorder, occipital horn syndrome, including severe orthostatic hypotension in 2. In addition, 1 boy developed a previously unreported anomaly, namely, massive splenomegaly and hypersplenism as a consequence of a splenic artery aneurysm. Previously reported molecular studies in 2 of these patients had shown gene defects which would have predicted a truncated and probably nonfunctional gene product. Despite the favorable effects on the neurological symptoms, parenteral copper treatment for Menkes disease should still be regarded as experimental. The development of more effective treatments must await a more precise delineation of the role which the Menkes protein plays in intracellular copper trafficking.

[Current aspects of infant nutrition]. / Aktuelle Aspekte der Säuglingsernährung.

It is still an important duty for pediatricians to inform parents about infant nutrition. An effort to insure successful breastfeeding in newborns is particularly necessary in order to avoid the introduction of foreign proteins, especially in high risk children. Allergy prevention is thus instigated early on. If necessary, a hypoallergenic milk may be used. Recently, there has been great concern that a high content of dioxine in breast milk exists, higher than in infant formulas. However, no evidence of toxicity has been noticed to date in breast fed children due to dioxine. Therefore, because of the many advantages, breast feeding should still be recommended for the first 4-6 months. In the last few years infant formulas have been adapted to simulate breastmilk by supplementation with taurine, carnitine and nucleotides. Most recently, Omega-3-fatty acids, which are important constituents of membrane phospholipids in the nervous system and the retina, have been added. In infant nutrition there is a trend nowadays toward unconventional forms of nutrition. An exclusive "lactoovo-vegetable" diet is able to meet all the requirements of a growing child. The critical components of a vegetarian diet are iron, calcium, vitamin B12 and vitamin D. These few examples demonstrate how important a nutrition-committee could be in elaborating basic information for the pediatrician, which would be useful in his daily work.

[Hypoglycemias in childhood. Pathophysiologic reflections and examples of hypoglycemias in hereditary disorders of carbohydrate metabolism]. / Hypoglykämien im Kindesalter. Pathophysiologische Uberlegungen und Beispiele von Hypoglykämien bei hereditären Störungen des Kohlenhydratstoffwechsels.

For the understanding and interpretation of hypoglycemia it is important to know the many complex endocrine and metabolic regulations in the homoeostasis of blood glucose. Glucose-absorption, distribution and availability, glycolysis, production and utilization of glycogen as well as gluconeogenesis are important steps of this homoeostasis, and hypoglycemia always reflects a disturbance in it. When blood glucose is low the availability of energy for the brain is decreased if no alternative energy sources like lactate or ketones are provided. Hypoglycemia is more often in the neonatal period than in later childhood. The causes can be divided into different groups according to pathogenetic mechanisms. Within each group again many singular defects are known. Fructose-1,6-diphosphatase deficiency, hereditary fructose intolerance, glycogenosis type I and so called "ketotic hypoglycemia" are given as examples to elucidate special clinical and biochemical aspects of inborn errors of carbohydrate metabolism.

[Amino acids in plasma of patients with cerebral gigantism (Sotos syndrome) (author's transl)]. / Zur Frage von Aminosäurenveränderungen im Plasma beim zerbralen Gigantismus (Sotos-Syndrom).

Bejar et al. described increased concentrations of valine, leucine and isoleucine in the plasma of 2 patients with cerebral gigantism (Sotos-syndrome). We have recently investigated a group of 14 children with Sotos-syndrome. The data of the plasma amino-acid determinations were compared with those of aged-matched healthy controls, 9 children with benign muscular hypotonia, 10 children with Down's syndrome and finally with those of 13 children with familial tall stature. The mean concentration of serine, glutamic acid, valine, isoleucine, leucine and phenylalanine was lower in the patients with Sotos-syndrome when compared to the healthy control group. However, all patients with benign muscular hypotonia and Down's syndrome showed increased concentrations of proline, glycine, alanine, ornithine and lysine in the plasma whereas the mean values of the children with familial tall stature differed only slightly from those of the controls. The levels of the plasma-aminoacids in patients with Sotos-syndrome were only slightly different from those in patients with muscular hypotonia, but generally lower than in tall children. We conclude that the determination of plasma-aminoacids is of no value in the diagnosis of Sotos-syndrome.

Menkes' disease: long-term treatment with copper and D-penicillamine.

Menkes' disease is a rare X-linked recessive inherited disorder of copper metabolism characterized by neurodegeneration, peculiar hair, and early death. The symptoms can be attributed to decreased activity of copper-dependent enzymes, but treatment with copper has so far failed to influence the course of the disease. We present the case of an 8.5-year-old boy, whom we treated alternately with intramuscular copper-histidine and oral D-penicillamine and who showed an extraordinary mild form of Menkes' disease. In contrast to his untreated maternal uncle, this patient had normal growth and intellectual development, but showed marked ataxia and slight speech difficulties. We suggest that parenteral copper-histidine supplemented by oral D-penicillamine may be of benefit to early-treated patients with Menkes' disease.

[Dubowitz syndrome: a dysmorphism syndrome with developmental delay, transitory short stature, hyperactive behavior and atopic dermatitis]. / Das Dubowitz-Syndrom: ein Dysmorphiesyndrom mit Entwicklungsrückstand, transitorischem Kleinwuchs, hyperaktivem Verhalten und atopischer Dermatitis.

The Dubowitz-syndrome, a rare, autosomal-recessive condition, was seen in a 6-year-old female patient. Verbal, fine motor, and social development were severely retarded. Behavioral disturbances, predominantly hyperactivity were apparent. Short stature of unknown origin became evident during infancy and early childhood. Atopic dermatitis and specific sensitivity to inhalant and nutritive allergens was found. A pattern of minor anomalies included inner epicanthic folds, hypertelorism, flat nasal bridge, globular nasal tip, coarse lips, and retrogenia as well as pes planovalgus, and a sacral dimple.

Open study of the clinical effect of suprofen drops in children.

Antipyretic effect, tolerability, and acceptance of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) drops were tested within the scope of an open study including a total of 111 children with fever of various etiology; two investigational centers participated in this study. The initial mean rectal temperature averaged 39.3 degrees C. The dosage of suprofen drops depended upon the patient's body weight and age; the drug was administered up to q.i.d., for 4 days at the longest. Body temperature, pulse rate, and respiratory rate were recorded prior to administration and 1/2, 1, 1 1/2, 2, 3, 4, 5 and 6 h after first administration of the drug. The antipyretic effect of the treatment was appreciated good in 89% of the cases. Reduction in temperature was statistically significant at all rating times after first administration of the drops as compared with the initial values. Adverse drug experiences such as vomiting and loose stools were seen in only 5 cases. The tolerability was considered good in 96% and the acceptance in 94% of the cases.

Hereditary fructose intolerance in early childhood: a major diagnostic challenge. Survey of 20 symptomatic cases.

Twenty infants and young children with hereditary fructose intolerance (HFI) were admitted to hospital. None was diagnosed at admission. Referals were for vomiting of unknown aetiology (16X), pyloric stenosis or hiatus hernia (5X), toxic condition (3X), and hepatomegaly of unknown origin (5X). Feeding difficulties (20X), vomiting (18X), and failure to thrive (16X) were leading symptoms. The most frequent clinical findings were hepatomegaly (18X), pallor (14X), haemorrhages (13X). Ascites, oliguria, tachypnoea, fever, splenomegaly and rickets were less frequent. Laboratory findings were indicative of disturbed hepatic and renal tubular function and also of disturbed intermediary metabolism (hypokaliaemia, hypophosphataemia). However, hypoglycaemia was found in only 4 out of 15 patients tested. Differential diagnosis after hospital admission centered on metabolic disorders such as glycogenoses, galactosaemia, tyrosinosis, or Wilson's disease. Hepatitis, toxic hepatosis, liver tumour, intrauterine infection and sepsis were also considered. Eleven children had first ingested fructose within the first 6 weeks of life. The diagnosis was usually established only many weeks or months after first fructose intake and appearance of symptoms. This documents how difficult the diagnosis of this disease can be both in practice and in hospital. The course was severe in 11 children and lethal in 4. In only 5 patients was the course mild. The 16 survivors are doing well under fructose-exclusion diet. Irreversible visual impairment after intraocular haemorrhage occurred once. In each case HFI could have been suspected immediately, had a detailed nutritional history been taken. Practising paediatricians should know the composition of commonly used infant formulae. They should never prescribe sugared condensed milk for intractable vomiting prior to excluding HFI. Solution for intravenous infusion containing fructose and sorbitol are life-threatening for undiagnosed HFI patients.

[Carbamyl phosphate synthase deficiency: clinical symptoms, diagnosis and dietary-medicamentous treatment in the neonatal period and infancy]. / Carbamyl-Phosphat-Synthetase-Mangel: klinische Symptomatik, Diagnostik und diätetisch-medikamentöse Behandlung im Neugeborenen- und Säuglingsalter.

Carbamyl phosphate synthetase (CPS) catalyses the synthesis of carbamyl-phosphate from ammonia and bicarbonate and is the first step in ureagenesis. The infant described in this report suffered from deficiency of this enzyme. The symptoms started on the 2nd day of life with tachycardia, apathy, irritability and metabolic alcalosis, on the 4th day coma and fits occurred due to hyperammonia (ammonia in the blood max 496 mumol/l, normally up to 150 in newborns). In hepatic tissue no activity of carbamyl phosphate synthetase could be measured (normal range 0.66-2.1 mumol/h/mg protein). Peritoneal dialysis was instituted, but the metabolic crisis could only be overcome by the following therapeutic measures: restriction of protein intake to 1.5 g/kg/d in part as a special aminoacid mixture, in part as breast milk; sufficient caloric supply (600-500 kJ/kg/d); sodium benzoate 350 mg/kg/d: arginine 2 mmol/kg/d respectively citrulline 350 mg/kg/d, and carnitine 150 mg/kg/d. By these procedures the exogenous and endogenous load of ammonia could be minimized. Electroencephalogram and mental development were normal. Acute metabolic crises with hyperammonia during catabolic states (infections) could be treated several times. At the age of 8 months, however, the patient died during such a crisis. This case shows that it is possible to achieve a normal psychomotor development in complete CPS-deficiency by adequate therapy. Catabolic states are difficult to manage.

Ontogeny of iminoglycine transport in mammalian kidney.

Renal tubular absorption of proline, hydroxyproline, and glycine by the newborn of most mammals is inefficient compared to that of the adult. Cortex slices from seven-day-old rat kidney also transport proline and glycine at reduced initial rates compared to mature kidney. Nonetheless, newborn slices achieve higher intracellular concentrations during prolonged incubation; the latter reflects a reduced rate of efflux, a characteristic peculiar to the membrane of postnatal kidney. The postnatal reduction of initial uptake rates is observed clearly only at substrate concentrations in or below the physiological range; it correlates with the absence of two high-affinity systems which normally serve proline and glycine transport independently at these concentrations in mature kidney, in conjunction with a "common" low-affinity system. The low-affinity system alone performs the observed uptake in the newborn kidney. Specific activity of the high-affinity systems for proline and glycine increases asynchronously after birth, suggesting independent genetic control of the three systems for iminoglycine transport in mammalian kidney.