Lucien Corbeel

Chronic Granulomatous Disease: The European Experience

CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a “respiratory burst”, essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (∼1∶250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91phox deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with γ-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.

Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG-deficiency, increased serum arylsulphatase A and increased CSF protein: a new syndrome?: 90

Identical twin-sisters (born at 36 wks; birthweight 2.2 and 3.0 kg) presented at 2 years of age with marked psychomotor retardation and bone-age of 1 year. Physical growth and phenotype were normal. Repeated investigations revealed: markedly fluctuating basal serum prolactin (778-5652 μU/ml; nl < 800), FSH (17-55 mIU/ml; nl < 10) and GH (2-144 ng/ml; nl < 10), but normal LH; low TBG (1.1 and 1.2 mg/dl; nl 1.6-2.4) also present in the father, with otherwise normal thyroid function including TRH test, arylsulphatase A moderately increased in serum (mean 293 and 272 nmol/ml; nl 30-130) but not in leukocytes, without increase of other lysosomal enzymes, and increasing CSF protein. Normal results were found for GH response to i.m. glucagon, urinary excretion of 17-keto and 17-hydroxysteroids, at funduscopy and for lymphocyte karyotype (Giemsa banding), buffy coat of blood leukocytes and electronmicroscopy of conjunctiva. Sella tursica was normal on x-ray. Cortical and cerebellar hypotrophy was evident on CAT-scan. Electromyography was normal but nerve conduction velocity was delayed (30-31 m/sec; nl 50 ± 1). A nerve and muscle biopsy is planned. At this stage we have no satisfactory explanation for these unusual findings.

Respiratory syncytial virus bronchiolitis: A double-blind dexamethasone efficacy study

The efficacy of dexamethasone therapy for primary respiratory syncytial virus bronchiolitis was studied in a double-blind placebo design in 29 previously healthy infants (median age, 194 days). No significant differences were found between the groups in evolution of respiratory rate, oxygen saturation, clinical score, or pulmonary function tests on day 3.

Congenital folate malabsorption

A Turkish girl presented with a history of fever, diarrhoea, convulsions, recurrent infections and failure to thrive from the age of 5 months. Megaloblastic anaemia was present and profound folate deficiency was evidenced in plasma and in CSF. Treatment with oral folic acid cured the anaemia, diarrhoea and infections but failed to prevent convulsions and the appearance of mental retardation and cerebral calcifications. Loading tests with folic acid and its derivatives led to the conclusion that the folate deficiency was caused by a defect in folate transport both across the gut and the blood-brain barrier. Low plasma concentrations of methionine prompted a therapeutic trial with methionine associated with vitamin B12 and folic acid that spectacularly improved the convulsions.

Rab proteins and Rab-associated proteins: major actors in the mechanism of protein-trafficking disorders.

Ras-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot–Marie–Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot–Marie–Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be ‘prenylated’—i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity. Conclusion: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.

A Block in Glycine Cleavage Reaction as a Common Mechanism in Ketotic and Nonketotic Hyperglycinemia

Extract: Our previous study demonstrated a block in glycine cleavage reaction in the liver from two patients with hyperglycinemia of the nonketotic type. The present study extended this work to two other patients with nonketotic hyperglycinemia and a patient with ketotic hyperglycinemia. The liver specimens obtained from these patients by autopsy or biopsy were studied for the activities of glycine cleavage reaction and of serine hydroxymethylase.A low activity of glycine cleavage reaction was found in all three patients with nonketotic or ketotic hyperglycinemia, whereas the activity of serine hydroxymethylase remained within normal limits.Speculation: The present study suggests that a block in the glycine cleavage reaction, either primarily or secondarily, plays an important role in glycine accumulation in both types of hyperglycinemias.

Ultrastructural abnormalities of bronchial cilia in children with recurrent airway infections and bronchiectasis.

Anomalies of the bronchial cilia were studied in 5 children with recurrent pulmonary infections. Case 1 had Kartageners syndrome and an absence of the inner and outer dynein arms in most cilia, although a few shortened and even some normal arms could be seen. Cases 2 and 3 had unilateral bronchiectasis without family history of Kartageners syndrome. Serial studies of the bronchial epithelium at times showed a bilateral lack of the inner dynein arms and a partial lack of outer arms. These abnormalities persisted in these 2 children after they had recovered from the acute pulmonary infection but disappeared after 6-8 months of antibiotic treatment. Cases 4 and 5 had recurrent pulmonary infections without bronchiectasis and many shortened outer dynein arms could be seen, but these anomalies disappeared after recovery. In all 5 children such architectural ciliary anomalies were present as megacilia, fused cilia, naked cilia, and completely disorganised axonemas. These architectural defects were particularly numerous in the children without bronchiectasis. Our observations suggest that anomalies of the bronchial ciliary microtubular system may not only be congenital but may also be acquired; this might well help to explain some cases of repeated respiratory tract infection and bronchiectasis.

Spontaneous healing of Langerhans cell histiocytosis (histiocytosis X)

A 3-month-old male infant presented with pallor, hepatomegaly (4.5 cm), splenomegaly (1.5 cm), anaemia (Hb 6 g/dl) and thrombocytopenia (16×109/l). A liver biopsy was diagnostic for Langerhans cell histiocytosis (histiocytosis X). The patients lymphocytes, co-cultured with neonatal lymphocytes, were positive for virus-like particles without reverse transcriptase activity. The hepatomegaly diminished after 6 months and a second liver biopsy showed decreased histiocytic infiltration. A second viral blood culture remained negative. After 14 months, the hepatomegaly had disappeared completely and there were no more abnormal haematological or clinical findings.

Clinical and biochemical findings before and after portacaval shunt in a girl with type Ib glycogen storage disease.

Summary: A girl presented with an important growth retardation, hepatomegaly, fasting hypoglycemia, lactic acidosis, increased serum cholesterol, triglycerides and uric acid, and increased liver glycogen (7.5%). There was no rise in blood glucose after IV galactose or fructose, but glucagon gave a delayed response. Type Ib glycogen storage disease was suggested by the low normal activity of glucose-6-phosphatase (G-6-Pase) which reached 1.8 units/g (normal, 2 to 10 units/g) and the normal activity of other glycogenolytic enzymes, measured in homogenates prepared in H2O from previously frozen liver tissue. After portacaval shunt (PCS), height increased by 29 cm in 3 years. Serum cholesterol decreased from 618 to 216 mg/dl, and triglycerides decreased from 890 to 116 mg/dl. During an oral glucose tolerance test, peak values for glucose (mg/dl) and insulin (μunits/ml) were, respectively, 210 and 50 before and 280 and 90 after PCS. Sixty min after the IV administration of a tracer dose of [2-3H; U-14C]glucose, the 3H/14C ratio in blood glucose decreased to 24% of its initial value indicating a functional G-6-Pase (mean ± S.E. in control subjects: 59% ± 7; in type la CSD: 92% ± 3). The activity of G-6-Pase measured as described above increased to 3.8 units/g of liver 1 year after PCS and 7.85 units/g of liver after 3 years. At that time, a simultaneous assay of the enzyme in a fresh, previously not frozen liver biopsy, homogenized in 0.25 M sucrose, revealed only about 29% of the activity of the same sample prepared in H2O (mean ± S.E. in three controls: 95.8% ± 8.9).Speculation: The higher than normal utilization of [2-3H; U-14C]glucose observed after portacaval shunt hi this patient suggests that besides the postulated defect of the microsomal glucose-6-phos-phate transport system (19), other hitherto unexplored pathogenetic mechanisms should be investigated, including the regulation of the synthesis of glucose-6-phosphatase, to explain the unpaired degradation of glycogen hi type Ib glycogen storage disease.

Haematological findings in type Ib glycogen storage disease before and after portacaval shunt.

Persistent neutropenia and repeated respiratory infections were documented in a girl with glycogen storage disease type Ib. A termino-lateral portacaval shunt resulted in normalisation of the granulocyte counts and disappearance of the recurrent infections. The platelet dysfunction that was apparent before surgery, was also corrected by the shunting procedure. A marked hypochromic anaemia, however, probably caused by a sequestration of iron in the spleen and resistant to therapy, remains a persistent feature in this patient.