Anthony Luder

Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.

Nebuliser hood compared to mask in wheezy infants: aerosol therapy without tears!

Background: Small volume nebulisers (SVNs) with masks commonly provide aerosol therapy for infants with lung diseases. However, infants and toddlers are often disturbed by and thus reject masks. Aims: To compare the lung deposition efficiency of the “usual” SVN aerosol mask and a prototype hood attached to an SVN. The advantage of the hood is that no mask is needed and medication can readily be administered during sleep. Methods:99mTc salbutamol solution was administered at random by SVN plus mask or hood to 14 wheezy infants (mean age 8 (SD 5) months). The dose and distribution of salbutamol were evaluated using gamma scintigraphy. Clinical response, tolerability by the infants, and parent preference were also compared. Results: Mean total lung deposition was 2.6% with the hood and 2.4% with the mask (p > 0.05). Variability with the mask was greater than with the hood (coefficient of variation (CoV) 54% v 39%). Both treatments provided similar clinical benefit and side effects as reflected in improved oxygen saturation, reduced respiratory frequency, and increased heart rate. Infants accepted the hood better than the mask and there was a positive correlation between poor acceptance and upper airways and stomach deposition for both treatment modalities. Parents preferred the hood treatments. Conclusions: Aerosol therapy by hood is as efficient as by mask but provides a better therapeutic index. It is much better tolerated by infants and preferred by parents. Hood nebulisation is a simple and patient friendly mode of aerosol therapy in wheezy infants.

A Double-Blind, Placebo-Controlled, Randomized Trial of Montelukast for Acute Bronchiolitis

BACKGROUND. Cysteinyl leukotrienes are implicated in the inflammation of bronchiolitis. Recently, a specific cysteinyl leukotriene receptor antagonist, montelukast (Singulair [MSD, Haarlem, Netherlands]), has been approved for infants in granule sachets. OBJECTIVE. Our goal was to evaluate the effect of montelukast on clinical progress and on cytokines in acute bronchiolitis. METHODS. This was a randomized, placebo-controlled, double-blind, parallel-group study in 2 medical centers. Fifty-three infants (mean age: 3.8 ± 3.5 months) with a first episode of acute bronchiolitis were randomly assigned to receive either 4-mg montelukast sachets or placebo, every day, from hospital admission until discharge. The primary outcome was length of stay, and secondary outcomes included clinical severity score (maximum of 12) and changes in type 1 and 2 cytokine levels (including interleukin4/IFN-γ ratio as a surrogate for the T-helper 2/T-helper 1 ratio) in nasal lavage. RESULTS. Both groups were comparable at baseline, and cytokine levels correlated positively with disease severity. There were neither differences in length of stay (4.63 ± 1.88 [placebo group] vs 4.65 ± 1.97 days [montelukast group]) nor in clinical severity score and cytokine levels between the 2 groups. No differences in interleukin 4/IFN-γ ratio between the 2 groups were seen. There was a slight tendency for infants in the montelukast group to recover more slowly than those in the placebo group (clinical severity score at discharge: 6.1 ± 2.4 vs 4.8 ± 2.2, respectively). CONCLUSIONS. Montelukast did not improve the clinical course in acute bronchiolitis. No significant effect of montelukast on the T-helper 2/T-helper 1 cytokine ratio when given in the early acute phase could be demonstrated.

A new type of peroxisomal disorder with variable expression in liver and fibroblasts

We describe two siblings, presently 5 and 9 years of age, who had neurodegenerative symptoms after the first year of life. Although they lacked clinical characteristics of a peroxisomal disorder, they had elevated levels of plasma very long chain fatty acids, pipecolic and phytanic acids, and abnormal bile acid intermediates, which suggested a generalized peroxisome deficiency disorder. Immunocytochemical study and electron microscopy of the liver disclosed absence of peroxisomes in approximately 90% of hepatocytes. However, the remaining 10% of the hepatocytes had numerous normal-looking peroxisomes containing catalase activity and catalase antigen. Alanine glyoxylate aminotransferase and the peroxisomal beta-oxidation enzymes acyl-coenzyme A oxidase and 3-ketoacyl coenzyme A thiolase were also present in the organelles. Both cell types were grouped in clusters. In contrast to most of the liver cells, fibroblasts cultured from skin biopsy specimens had normal peroxisomal functions. Thus this defect in peroxisome biogenesis is characterized by variable expression in different tissues (liver vs fibroblasts), as well as within individual cells in the same tissue (liver mosaicism). Awareness of the heterogeneity in tissue expression of peroxisomal disorders could be of critical importance in prenatal diagnosis.

Lung aerosol deposition in suckling infants

Introduction Aerosol therapy in infants may be greatly compromised by face mask rejection due to squirming and crying. Lung aerosol deposition in crying infants may thereby be greatly reduced. Since ‘suckling’ on a pacifier calms infants, they should more readily accept a face mask that incorporates a pacifier. However, since infants must breathe nasally while suckling, lung aerosol deposition may be reduced due to impaction in the nose. The aim of the present pilot study was to compare lung aerosol deposition while suckling on a pacifier incorporated into a mask with that obtained while inhaling from a conventional mask. Methods Twelve infants <12 months old and who regularly used pacifiers participated as their own controls. Lung aerosol deposition was measured scintigraphically (technetium-99mDTPA-labelled normal saline aerosol, MMAD (Mass Median Aerodynamic Diameter) 3 um and GSD (Geometric Standard Deviation) of 2) via jet nebuliser using a conventional mask versus ‘suckling’ on their pacifier incorporated into a unique mask. Results Mean lung deposition (±SD) while suckling using a mask with attached pacifier (1.6±0.5% in the right lung) was similar to that with a conventional mask (1.7±0.9%, p=0.81). Conclusions Lung aerosol deposition during nasal breathing while suckling on a pacifier-equipped mask is similar to that in infants breathing quietly using a conventional mask, and results comparable with previous data in infants and in nasal breathing models of an infants upper respiratory tract. Using a pacifier during aerosol treatment in infants may be as efficient as conventional treatment without a pacifier.

Acute human parvovirus B-19 infection in hospitalized children: A serologic and molecular survey.

Background: The extent and clinical manifestations of acute human parvovirus B19 (B19) infection were assessed in previously healthy hospitalized children admitted with clinical syndromes potentially associated the virus. Patients and Methods: The study was prospective and was conducted between October 2002 and August 2004 in the pediatric departments of 3 hospitals in Israel. The survey included previously healthy children who were hospitalized with 1 or more of the following acute diseases: acute nonallergic exanthema, fever for >1 week, aplastic anemia or pancytopenia, acute nonbacterial arthropathy, immune thrombocytopenic purpura (ITP), Henoch-Schönlein purpura (HSP) and aseptic meningitis. A control group of children with a proven, non-B19 infection was also studied. Serum samples obtained from each child on admission were tested for B19 DNA by real-time PCR and B19 IgM by ELISA. Acute B19 infection was defined by the following criteria: positive serum B19-DNA and/or B19 IgM, negative serum B19 IgG, and no other proven infection. Results: Overall, 167 children were included in the study. The mean age was 5.5 ± 4.6 years (range, 0.5–17), males and females equally divided. Acute B19 infection was demonstrated in 12.6% (n = 21) of the children. Both tests were performed in 19 children and were positive in 10 (53%). In 7 and 2 children, only B19-DNA or B19 IgM, respectively, was positive. Acute B19 infection was documented in 27% (10/39) of children who presented with a variety of acute exanthema diseases; 9% (5/57) of children with acute arthropathy (all 5 had transient synovitis); 10% (2/21) of children with fever >1 week, both presented as mononucleosis syndrome; and in 44% (4/9) of children with transient pancytopenia or aplastic anemia. No acute B19 infection was demonstrated in 15 children with ITP, 9 with HSP, and 6 with aseptic meningitis and among 70 children in the control group. By logistic regression analysis, manifestations significantly associated with acute B19 infection were exanthema (OR 2.9; 95% CI = 1.1–7.5), anemia (OR 6.35; 95% CI = 2.2–18.2) and leucopenia (OR 4.14; 95% CI =1.2–14.2). Conclusions: Acute B19 infection was documented among 12.6% of children hospitalized with clinical syndrome potentially associated with the virus. Clinical and laboratory features associated with acute B19 infection were exanthema, anemia and leucopenia. Determination of both serum B19-DNA and serum B19 IgM should be performed for the accurate diagnosis of acute B19 infection.

Decriminalization of Cannabis – potential risks for children?

The legalization of cannabis for medicinal purposes is becoming increasingly widespread worldwide. The anticipated growing ease of access to cannabis may create an increased risk for passive and/or active ingestion by children. We report a case of a 1.5‐year‐old infant who presented with unexplained coma that was later proved to be associated with the ingestion of cannabis. This case highlights the importance of considering cannabis ingestion in the differential diagnosis of infantile and toddler coma and the need for public education regarding the risks of childhood exposure in the light of the legalization of cannabis for medical purposes and its greater availability.