EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy.

Heterozygous mutations in the early growth response gene 2 (EGR2), which encodes a zinc-finger transcription factor that regulates the late stages of myelination, cause myelinopathies including congenital hypomyelinating neuropathy, Dejerine-Sottas neuropathy (DSN), and Charcot-Marie-Tooth disease type 1. We screened 170 unrelated neuropathy patients without mutations involving the peripheral myelin protein 22 gene (PMP22), the myelin protein zero gene (MPZ), or the gap junction protein beta1 gene (GJB1) and identified two DSN patients with the heterozygous mutation R359W in the alpha-helix domain of the first zinc-finger of EGR2. We now report that this mutation is a recurrent cause of DSN, and that expressivity ranges from that typical for DSN to a more rapidly progressive neuropathy that can cause death by age 6 years. Furthermore, in contrast to patients with typical DSN, patients with the EGR2 R359W mutation have more respiratory compromise and cranial nerve involvement.

Calpain III mutation analysis of a heterogeneous limb-girdle muscular dystrophy population.

OBJECTIVE: To determine the frequency of calpain III mutations in a heterogeneous limb-girdle muscular dystrophy (LGMD) population. BACKGROUND: Mutations of the calpain III gene have been shown to cause a subset of autosomal recessive LGMDs. Patient populations studied to date have been primarily of French and Spanish origin, in which calpain III may cause 30% of autosomal recessive MDs. The incidence of calpain III mutations in non-French/Spanish MD patients has not been studied thoroughly. No sensitive and specific biopsy screening methods for detecting patients with abnormal calpain III protein are available. Thus, detection of patients relies on direct detection of gene mutations. METHODS: The authors studied the calpain III gene in 107 MD patient muscle biopsies exhibiting normal dystrophin. Muscle biopsy RNA was produced for each patient, and the entire calpain III complementary DNA was screened for mutations by reverse-transcriptase PCR/single-strand conformation polymorphism using three different conditions. RESULTS: The authors identified nine patients (eight unrelated) with causative mutations. Six of the seven distinct mutations identified are novel mutations and have not been described previously. CONCLUSION: The results suggest that approximately 9.2% of patients in the heterogeneous population with an LGMD diagnosis will show mutations of the calpain III gene. Interestingly, two patients were heterozygous for a single mutation at the DNA level, whereas only the mutant allele was observed at the RNA level. This suggests that there are undetectable, nondeletion mutations that ablate expression of the calpain III gene.

FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing.

Fibroblast growth factor receptor 2 (FGFR2) mutations have been associated with the craniosynostotic conditions Crouzon, Jackson-Weiss, and Pfeiffer syndromes. Previously, mutations were described in the exons IIIa and IIIc, which form the extracellular, third immunoglobulin-like domain (IgIII) and adjacent linker regions, both of which are normally involved in ligand binding. For all three conditions, mutations were found in exon IIIc. Only in Crouzon syndrome were mutations identified in exon IIIa. In this study, 39 cases with one of these three conditions were screened for exon IIIa or IIIc mutations. Eleven mutations are reported in 17 unrelated cases. Mutations in exon IIIa are identified for not only Crouzon but also Jackson-Weiss and Pfeiffer syndromes. Four mutations in either exon IIIa or exon IIIc reported only in Crouzon syndrome are present also in one of the other two syndromes. Two insertions, one in exon IIIa in a Crouzon syndrome patient and the other in exon IIIc in a Pfeiffer syndrome patient, were observed. The latter mutation has the same alternative RNA splicing effect as a reported synonymous mutation for Crouzon syndrome. A missense mutation was detected in one Pfeiffer syndrome family in which two members had craniosynostosis without limb anomalies. The inter- and intrafamilial variability in expression of FGFR2 mutations suggests that these three syndromes, presumed to be clinically distinct, are instead representative of a spectrum of related craniosynostotic and digital disorders.

The Johanson-Blizzard syndrome: case report and autopsy findings.

We report the case of a boy with the Johanson-Blizzard syndrome who died at the age of 8 years with complications of pancreatic exocrine insufficiency, and at autopsy was found to have a small thyroid filled with colloid, virtually complete replacement of the pancreas with adipose tissue, and a brain of normal size but with evidence of a cortical developmental defect consisting of abnormalities of gyral formation and of cortical neuronal organization. In addition the boy had postnatal growth failure, apparent severe mental retardation, congenital scalp defects and scalp hair patterning abnormalities, aplasia of the nasal alae, nasolacrimo-cutaneous fistulae, hypotonia, severe congenital sensorineural deafness, and small conical and widely spaced teeth. Evidence is accumulating that this syndrome is likely to be inherited as an autosomal recessive disorder. Our case represents the first report of autopsy findings in the syndrome.

Hyaline cartilage changes in diastrophic dwarfism.

Hyaline cartilage of the talus of a diastrophic dwarf was studied by light and transmission electron microscopy before and after proteoglycan extraction or digestion, glycogen digestion, and enzyme marking. The nuclei of the chondrocytes were as a rule large and round and the cytoplasm contained large vacuoles. Best's carmine stained the cytoplasm of most cells red; after diastase digestion the cytoplasm remained unstained. This suggested that the cells contained glycogen. This observation was complimented by the ultrastructural demonstration of large amounts of glycogen. Cell scars were frequent. The shape and state of activity of the cells as well as the development of intracytoplasmic organelles showed great variability. The matrix showed many areas of degeneration and a general dearth of sulphated acid mucopolysaccharides. A lacey pattern of unmasked collagen fibers was frequently seen. Collagen fibers showed a great variability in diameter and often appeared frayed when examined by electron microscopy. These observations suggest an enzymatic deficiency in chondrocyte mucopolysaccharide and glucose metabolism. The techniques we used when added to biochemical studies should prove useful in the investigation of human dwarfism.

DNA synthetic capabilities of differentiating sperm cells.

Spermatogenic cells separated by velocity sedimentation were analysed by a micro-procedure for differentiation-associated changes in DNA synthetic capabilities. DNA-dependent DNA polymerase activity is maximal in premeiotic and meiotic cells, sequentially declines in progressively more differentiated spermiogenic cells to a minimum value in testicular spermatozoa which is 1/14 of the maximum. No further decrease of activity is observed during the subsequent process of sperm cell maturation and, at the end-differentiated state, the potential of sperm cells for DNA synthesis is demonstrated by the presence of substantial activities of thymidine and thymidylate kinases as well as DNA polymerase activity, as determined by in vitro assay, are polymerase. Although levels of DNA polymerase activity, as determined by in vitro assay, are negatively correlated with the state of differentiation, the findings support the hypothesis that, in this cell system, DNA synthetic enzymes may not be limiting factors in the control of DNA synthesis.

Hypochondroplasia.

Hypochondroplasia is a hereditary form of short-limbed dwarfism which somewhat resembles achondroplasia, but which is clinically, roentgenographically, and genetically distinct. The pertinent findings in 6 new cases are: moderate rhizomelic shortness of stature; normal craniofacial appearance and hand configuration; and later recognition of the presence of the abnormality than in achondroplasia (which can be recognized at birth). A review of the 35 previously described cases in the literature reveals a preponderance of affected females and a high incidence of spontaneous mutation, although when once evident the trait is passed as an autosomal dominant. Two of our patients had seizures, and mental deficiency may be an associated finding although it is by no means usually present. Orthopedists should be aware of this entity, which may be somewhat more common than has been thought, because of the different implications for ultimate height, which is greater in hypochondroplasia than in achondroplasia, the lack of cauda equina compression findings, and the need for genetic counseling.