Peter Beighton

de la Chapelle, A.

de la Chapelle dysplasia, also known as atelosteogenesis type II, is a lethal form of neonatal dwarfism in which gross limb shortening is associated with a characteristic triangular configuration of the radius and ulna. Inheritance is autosomal recessive.

LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997

Categorization of the Ehlers-Danlos syndromes began in the late 1960s and was formalized in the Berlin nosology. Over time, it became apparent that the diagnostic criteria established and published in 1988 did not discriminate adequately between the different types of Ehlers-Danlos syndromes or between Ehlers-Danlos syndromes and other phenotypically related conditions. In addition, elucidation of the molecular basis of several Ehlers-Danlos syndromes has added a new dimension to the characterization of this group of disorders. We propose a revision of the classification of the Ehlers-Danlos syndromes based primarily on the cause of each type. Major and minor diagnostic criteria have been defined for each type and complemented whenever possible with laboratory findings. This simplified classification will facilitate an accurate diagnosis of the Ehlers-Danlos syndromes and contribute to the delineation of phenotypically related disorders.

Articular mobility in an African population.

There is considerable variation in the range ofmovements which are possible in the joints of normal individuals. In general, females are more mobile than males, while joint laxity decreases with age (Ellis and Bundick, 1956; Wynne-Davies, 1971). Ethnic differences in joint mobility have also been described. For instance, Negroes and Indians have been shown to have a greater range of movements than Caucasians of the same age and sex (Harris and Joseph, 1949). Similarly, in an investigation in Cape Town, Indians were found to be more loose-jointed than indigenous Xhosa and Hlubi, who in turn had a greater degree of joint laxity than white South Africans (Schweitzer, 1970). Articular mobility is a graded trait and at one end of the spectrum a considerable degree of joint laxity may occur in normal individuals (Wood, 1971). Apart from this form of hypermobility, joint laxity is also a component of a variety of genetically determined syndromes (McKusick, 1966; Beighton, 1970). It can also occur in the absence of other stigmata as a simple inherited entity (Sturkie, 1941; Carter and Sweetnam, 1958, 1960; Beighton and Horan, 1970). It has been suggested that hypermobile individuals are prone to orthopaedic disorders, such as degenerative joint disease, dislocations, joint effusions, and muscular pains (Hass and Hass, 1958; Kirk, Ansell, and Bywaters, 1967; Grahame, 1971). Articular laxity has also been implicated as an important factor in the genesis of congenital dislocation of the hip (Wynne-Davies, 1970). For these reasons, hypermobility may well be of considerable clinical significance. An epidemiological survey has recently been completed among the Tswana people of the Western Transvaal. The main aims of this investigation were the study of various bone and joint conditions, but the survey also provided an excellent opportunity for the measurement of the range ofjoint movements in a large number of individuals and for the assessment of the influence of age, sex, and somatotype on their articular mobility. The importance of joint laxity in the production of non-specific musculo-skeletal complaints was also evaluated. The purpose of this paper is to present the results of this investigation and to discuss the clinical significance of the observations which were made.

ORTHOPAEDIC ASPECTS OF THE EHLERS. DANLOS SYNDROME

1. The orthopaedic features of 100 patients with the Ehlers-Danlos syndrome are described. 2. The significance of these findings is discussed and comment is made of their relationship to the other stigmata of the syndrome.

Huntington's chorea.

1 Historical Background.- 1.1. Chorea in the Middle Ages: The Dancing Mania.- 1.2. Thomas Sydenham and Chorea.- 1.3. From Sydenham to Huntingdon: The First Descriptions of Inherited Chorea.- 1.4. Huntingtons Chorea.- 2 Genealogy and Geographic Distribution.- 2.1. Genealogical Methods.- 2.2. Genealogical Investigations in Various Parts of the World.- 2.2.1. United States of America.- 2.2.2. South Africa.- 2.2.3. Canada.- 2.2.4. Australia.- 2.2.5. The Caribbean.- 2.2.6. The Indian Subcontinent.- 2.2.7. Venezuela.- 2.2.8. Moray Firth Area of Scotland.- 2.2.9. Japan.- 2.3. The Importance of Genealogical Investigations.- 2.4. The Original Source of the Gene for Huntingtons Chorea.- 3 Epidemiology.- 3.1. Diagnostic Critera.- 3.2. Prevalence.- 3.2.1. Problems in the Comparison of Prevalence Data.- 3.2.2. Areas of High Prevalence: Possible Contributing Factors.- 3.2.3. Areas of Low Prevalence: Possible Contributing Factors.- 3.3. The Epidemiology of Juvenile Huntingtons Chorea.- 3.4. Incidence.- 3.4.1. International Comparison.- 3.5. Mortality Data.- 3.5.1. International Comparison.- 4 Natural History.- 4.1. Age at Onset.- 4.1.1. International Comparison.- 4.1.2. The Relevance of Age at Onset to Genetic Counselling.- 4.2. Age at Death.- 4.2.1. International Comparison.- 4.3. Duration.- 4.4. Factors Modifying the Action of the Gene.- 4.4.1. Genetic Considerations.- 4.4.2. Environmental Factors.- 5 Clinical Features.- 5.1. The Presenting Symptoms and Signs.- 5.2. General Manifestations.- 5.3. Neurological Features.- 5.3.1. Chorea.- 5.3.2. Hypertonicity: Rigidity and Spasticity.- 5.3.3. Dysarthria.- 5.3.4. Dysphagia.- 5.3.5. Disturbance of Gait.- 5.3.6. Oculomotor Dysfunction.- 5.3.7. Epilepsy.- 5.3.8. Incontinence.- 5.3.9. Cerebellar Signs.- 5.3.10. Other Neurological Signs.- 5.4. Mental Disturbance.- 5.4.1. Dementia.- 5.4.2. Affective Disturbance.- 5.4.3. Change of Personality.- 5.4.4. Schizophreniform Psychosis.- 5.4.5. Other Psychiatric Symptoms.- 5.5. Staging.- 5.6. Variants.- 5.6.1. The Westphal Variant.- 5.6.2. Juvenile Huntingtons Chorea.- 5.6.3. Other Variants.- 5.7. The Clinical Features of Juvenile Huntingtons Chorea.- 5.8. Diagnostic Techniques.- 5.8.1. Electroencephalographic Studies (EEG).- 5.8.2. Pneumoencephalographic Studies (PEG).- 5.8.3. Computerised Axial Tomography (CAT).- 5.8.4. Cerebral Angiography.- 5.9. Problems of Diagnosis.- 5.9.1. Misdiagnosis.- 5.9.2. The Differential Diagnosis of Inherited Chorea.- 6 Neuropathology.- 6.1. Gross Pathology.- 6.2. Findings on Light Microscopy.- 6.2.1. Leptomeninges.- 6.2.2. Cerebral Cortex.- 6.2.3. The Caudate Nucleus and Putamen.- 6.2.4. Pathological Changes in Other Parts of the NervousSystem.- 6.3. Ultrastructural Features.- 6.3.1. Cerebral Cortex.- 6.3.2. The Striatum.- 6.4. The Importance of Post-mortem Examination.- 6.5. The Brain and Tissue Bank.- 7 Genetics.- 7.1. Mutations.- 7.2. Heterozygote Frequency.- 7.3. The Homozygous Form.- 7.4. Heterogeneity.- 7.5. Unusual Aspects of the Genetics of Juvenile Huntingtons Chorea Ill.- 7.5.1. Predominance of Paternal Descent Ill.- 7.5.2. Familial Aggregation.- 7.6. Genetic Registers.- 7.7. Genetic Counselling.- 7.8. Reproductive Fitness.- 8 Living with Huntingtons Chorea: The Social Perspective.- 8.1. Psychosocial Consequences for the Affected Person.- 8.1.1. Psychological Defence Mechanisms.- 8.1.2. Suicide.- 8.1.3. Coping: Guidelines for Management.- 8.2. The Experience of Being At Risk.- 8.2.1. Some Guidelines for Counselling Those At Risk.- 8.2.2. Marriage and Parenthood: The Options.- 8.3. The Burden on the Unaffected Spouse.- 8.4. Huntingtons Chorea: A Family Disease.- 8.5. Antisocial Behaviour: Huntingtons Chorea and the Law.- 8.6. The Economic Burden.- 9 Management.- 9.1. A Rational Approach to Pharmacotherapy.- 9.1.1. Chorea.- 9.1.2. Rigidity.- 9.1.3. Epilepsy.- 9.1.4. Dementia.- 9.1.5. Affective Disturbance.- 9.1.6. Psychosis.- 9.2. Surgery.- 9.3. Other Therapeutic Modalities.- 9.3.1. Physical Therapy.- 9.3.2. Speech Therapy.- 9.3.3. Occupational Therapy.- 9.3.4. Nutrition.- 9.3.5. Nursing Care.- 9.3.6. Social Work.- 9.3.7. Psychotherapy.- 9.3.8. Lay Groups.- 9.4. Future Prospects.- 10 Current Trends in Research.- 10.1. A Unifying Conceptual Approach.- 10.2. Investigations of the Abnormal Gene.- 10.3. The Search for the Altered Gene Product.- 10.4. The Investigation of Disturbed Cell Function/Structure.- 10.4.1. Membrane Abnormalities.- 10.4.2. Fibroblast Activity.- 10.4.3. Immunological Abnormalities.- 10.5. Viruses.- 10.6. Neurochemistry.- 10.6.1. Dopamine.- 10.6.2. Gamma-aminobutyric acid (GABA).- 10.6.3. Acetylcholine.- 10.6.4. Serotonin.- 10.6.5. Peptides.- 10.6.6. Neurotransmitter Receptor Abnormalities.- 10.7. Neuroendocrine Disturbances.- 10.8. Predictive Tests.- 10.8.1. Ethical Dilemmas.- 10.8.2. Attempts at Presymptomatice Diagnosis.- 10.9. Conclusion.- Appendixes.- 1. The Use of Conditional Probabilities in Genetic Counselling for Huntingtons Chorea.- 2. Method for Determination of the Mutation Rate in Huntingtons Chorea...- 3. Method for Determination of the Heterozygote Frequency in Huntingtons Chorea.- 4. Name of Addresses of Lay Organisations and Other Centres for Information on Huntingtons Chorea.- 5. Brain Donation Programme.

Split-Hand/Split-Foot Malformation Is Caused by Mutations in the p63 Gene on 3q27

Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.

Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia).

Schwartz-Jampel syndrome (SJS1) is a rare autosomal recessive disorder characterized by permanent myotonia (prolonged failure of muscle relaxation) and skeletal dysplasia, resulting in reduced stature, kyphoscoliosis, bowing of the diaphyses and irregular epiphyses. Electromyographic investigations reveal repetitive muscle discharges, which may originate from both neurogenic and myogenic alterations. We previously localized the SJS1 locus to chromosome 1p34–p36.1 and found no evidence of genetic heterogeneity. Here we describe mutations, including missense and splicing mutations, of the gene encoding perlecan (HSPG2) in three SJS1 families. In so doing, we have identified the first human mutations in HSPG2, which underscore the importance of perlecan not only in maintaining cartilage integrity but also in regulating muscle excitability.

The natural history of sclerosteosis

Sclerosteosis (SCL) is a severe, progressive, autosomal‐recessive craniotubular hyperostosis (MIM 269500). The determinant gene (SOST) has been isolated, and genotype–phenotype correlations, as well as the elucidation of pathogenetic mechanisms, are dependent upon the documentation of the natural history of the condition. For this reason, the course and complications in 63 affected individuals in South Africa, seen over a 38‐year period, have been analyzed. Thirty‐four of these persons died during the course of the survey, 24 from complications related to elevation of intracranial pressure as a result of calvarial overgrowth. The mean age of death in this group of individuals was 33 years, with an even gender distribution. Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) affected persons. Mandibular overgrowth was present in 46 (73%) adults and syndactyly in 48 (76%). In South Africa in 2002, 29 affected persons were alive, 10 being ≤20 years of age. It is evident that sclerosteosis is a severe disorder which places a considerable burden upon affected individuals and their families.

Autosomal Dominant Craniometaphyseal Dysplasia Is Caused by Mutations in the Transmembrane Protein ANK

Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an approximately 5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. The mutations are two in-frame deletions and one in-frame insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.