ABSTRACT
In a new family with X-linked congenital autophagic vacuolar myopathy (AVM), seven affected boys presented with congenital hypotonia, dyspnea, and dysphagia with delayed motor milestones. Muscle pathology revealed autophagic vacuoles with sarcolemmal features, multilayered basal lamina with marked sarcolemmal deposition of C5-9 membrane attack complex and calcium, histologically indistinguishable from childhood-onset X-linked myopathy with excessive autophagy (XMEA). Haplotype analysis suggests that this new AVM and XMEA may be allelic despite different clinical presentations.
Subject(s)
Autophagy/genetics , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Muscle, Skeletal/pathology , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Antigens, Protozoan/genetics , Antigens, Surface/genetics , Bone and Bones/abnormalities , Child , DNA Mutational Analysis , Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Genetic Diseases, X-Linked/physiopathology , Genetic Linkage , Genetic Testing , Haplotypes/genetics , Humans , Infant , Infant, Newborn , Lod Score , Male , Muscle Weakness/diagnosis , Muscle Weakness/genetics , Muscle Weakness/physiopathology , Muscle, Skeletal/metabolism , Muscle, Skeletal/physiopathology , Muscular Atrophy/diagnosis , Muscular Atrophy/genetics , Muscular Atrophy/physiopathology , Muscular Diseases/congenital , Pedigree , Phenotype , Sarcolemma/metabolism , Sarcolemma/pathology , Vacuoles/genetics , Vacuoles/metabolism , Vacuoles/pathologySubject(s)
Encephalomyelitis, Acute Disseminated/diagnosis , Peptide Hydrolases/blood , Antithrombin III , Biomarkers/blood , Child , Encephalomyelitis, Acute Disseminated/blood , Encephalomyelitis, Acute Disseminated/drug therapy , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Humans , Magnetic Resonance Imaging , Male , Methylprednisolone/administration & dosage , Methylprednisolone/therapeutic useABSTRACT
Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl CoA lyase (HL, EC4.1.3.4.) is an autosomal recessive genetic disorder characterized by acute episodes of vomiting, hypotonia, and lethargy in the neonatal period or in infancy. Except in Saudi Arabia, where HL deficiency is the most common organic acidemia, the disorder is quite rare with only 41 cases being reported in the English literature, and only five known cases among Japanese. In this study, we present the results of a molecular analysis of all five Japanese patients together with their clinical phenotypes. Five different mutations in the HL gene were identified: one large deletion, one nonsense mutation, one missense mutation, and two splice mutations. Except for G835A (E279K) with its relatively common occurrence among Japanese, these mutations were unique to each family. The results of expression studies with mutated HL cDNAs confirmed the pathogenicity of these mutations and supported the importance of previously identified functional domains of the HL molecule, i.e., the putative catalytic site or dimerization site. In addition, we identified an alternative splicing event that resulted in the skipping of exons 5 and 6. This alternatively spliced product did not show HL activity and was present in various tissues of normal subjects. Clinically, all patients presented with similar symptoms, except that the timing of the initial presentation varied considerably, from 1 day to 1 year 3 months. In general, patients with null-activity mutations presented earlier in life, whereas those with residual activities presented later.
Subject(s)
Mutation , Oxo-Acid-Lyases/deficiency , Oxo-Acid-Lyases/genetics , Age of Onset , Alternative Splicing , Base Sequence , DNA Mutational Analysis , DNA Primers/genetics , Female , Gene Expression , Genetic Vectors , Humans , Infant , Infant, Newborn , Male , Molecular Biology , Phenotype , Point Mutation , Reverse Transcriptase Polymerase Chain Reaction , Sequence Deletion , TransfectionABSTRACT
The current paper reports an 8 year old girl with arthralgia and polyclonal B cell activation induced by human parvovirus B19 infection (HPV B19). The infection was diagnosed by the presence of the virus genome in sera. The patient presented with transient arthritis in the wrist, ankle joint and neck and elevation of immunoglobulin IgM antibodies to HPV B19 and rubella, antibodies to Mycoplasma and antistreptolysin O but without the typical clinical features of erythema infectiosum. The polyclonal B cell activation was paralleled by the presence of the virus genome of HPV B19 in sera. In some children with arthralgia, it is important to examine the genomes of viruses that may cause arthritis as well as the antibody titers to the viruses.
