Two novel mutations identified in familial cases with Donohue syndrome.

Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype-phenotype issues playing a role in the pathophysiology of DS. A female infant born to first-degree cousins Muslim Arab parents and two brothers born to first-degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post-translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease.

Intestinal protein loss and hypoalbuminemia in children with pneumonia.

BACKGROUND: Intestinal protein loss has been reported mainly in diseases affecting the gastrointestinal tract. Intestinal protein loss during pneumonia with effusion has not been reported to date. The authors attempted to assess the associations between pneumonia with effusion and intestinal protein loss and hypoalbuminemia in children. METHODS: This was a prospective consecutive case series study of in children hospitalized with pneumonia and effusion during a period of 4(1/2) years. Serum albumin, C-reactive protein (CRP), and fecal alpha-1 antitrypsin (alpha-1-AT) were measured in the first 72 hours of hospitalization. Two control groups were studied: one consisted of 50 febrile children hospitalized because of viral or mild bacterial infections, and the other consisted of 20 afebrile children hospitalized because of convulsive disorders. RESULTS: Sixty-seven children ages 4 months to 14 years hospitalized with pneumonia and effusion were enrolled in the study. Fifty-nine percent (40 children) were found to have elevated fecal alpha-1-AT excretion (range, 2-10 mg/g) compared with none in the two control groups (P < 0.000).Fifty-two percent (35 children) of the children with pneumonia and effusion had mild to moderate hypoalbuminemia (range, 22-34 g/L). Only one child (2%) in the febrile control group had a low albumin of 34 g/L; none were found in the afebrile control group. The level of fecal alpha-1-AT was inversely correlated with serum albumin level. CONCLUSIONS: Pneumonia with effusion in children is often associated with an intestinal protein loss that can be monitored by measuring gastrointestinal loss of protein, namely fecal alpha-1-AT. In most cases the development of hypoalbuminemia correlates with the development of intestinal protein loss.

Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A.

Griscelli syndrome (GS), a rare autosomal recessive disorder, is characterized by partial albinism, along with immunologic abnormalities or severe neurological impairment or both. Mutations in one of two different genes on chromosome 15q can cause the different subtypes of GS. Most patients with GS display the hemophagocytic syndrome and have mutations in RAB27A, which codes for a small GTPase. Two patients with neurological involvement have mutations in MYO5A, which codes for an actin-based molecular motor. The RAB27A and MYO5A gene products interact with each other and function in vesicle trafficking. We report the molecular basis of GS in a Muslim Arab kindred whose members have extremely variable neurological involvement, along with the hemophagocytic syndrome and immunologic abnormalities. The patients have normal MYO5A genes but exhibit a homozygous 67.5-kb deletion that eliminates RAB27A mRNA and immunocytofluorescence-detectable protein. We also describe the molecular organization of RAB27A and a multiplex polymerase chain reaction assay for the founder deletion in this kindred. Finally, we propose that all patients with GS have RAB27A mutations and immunologic abnormalities that sometimes result in secondary neurological involvement. The two patients described elsewhere who have MYO5A mutations and neurological complications but no immunologic defects may not have GS but instead may have Elejalde syndrome, a condition characterized by mild hypopigmentation and severe, primary neurological abnormalities.