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<ul><li><p>r 138 1 </p><p>AUTOSOMAL RECESSIVE INHERITANCE OF DUCHENNE-TYPE MUSCULAR DYSTROPHY </p><p>BY H. W. KLOEPFER, h . D . AND CAROLYNN TALLEY, M.D. Departments of Anatomy and Pediatrics, Tulane University School of Medicine </p><p>and Charity Hospital of Louisiana, New Orleanu, La. </p><p>The occurrence of the Duchenne type of muscular dystrophy in girls has been previously reported (e.g. Minkowski &amp;, Sidler, 1928), but after a careful review of the literature Stevenson (1953) claimed that all such cases were atypical and should not be so classified. He stated also that if an autosomal recessive gene should cause this type of muscular dystrophy, males and females would be expected to occur in the same sibship. In a study of 160 cases (102 families) of pelvi- femoral, pseudohypertrophic muscular dystrophy (Duchennes disease) Lamy et Grouchy ( 1954) found the trait to be a sex-linked recessive in approximately nine out of ten cases and an auto- somal recessive in one out of ten cases. These authors also reported the occurrence of an affected male and an affected female in five sibships, and at least one affected female in five additional sibships. Steinberg (1956, personal communication), and Herndon ( 1956, personal communica- tion) have also observed that muscular dystrophy of the Duchenne type is inherited as an auto- somal recessive in certain families. Although agreeing with Stevenson that Duchenne type of muscular dystrophy is always associated with a sex-linked recessive gene, Walton (1955) included two girls among his fifty-six cases and stated that they have shown no significant difference in clinical manifestations and course from several of the boys in the series. </p><p>The purpose of the present study is to show how the existence of an autosomel recessive gene may best explain the occurrence of this type of muscular dystrophy in girls. </p><p>GENETIC CONSIDERATION Seven examples of progressive muscular dystrophy occurring in one kindred (Fig. 1) and one isolated case in an apparently unrelated family (Fig. 2) have been studied. The parents of the affected individuals in sibships A , B, C and D of kindred I (Fig. 1) are third cousins once removed, third cousins once removed, third cousins, and second cousins, respectively. Individuals 111.7 and 111.8 were common ancestors to the parents of all affected individuals in this kindred, so that the effective autosomal recessive gene may have come through either one of these two. (Note : The roman figure identifies the generation and the arabic numeral the individual of that generation.) According to church records, individuals 11.1 and 11.2 came to Louisiana from the Canary Islands in or before 1772. 11.3 and 11.4 are of Spanish descent or came from Spain at about this same time. Individuals in the present generation consider themselves to be primarily of French origin since the descendants of 111.7 and 111.8 have married into families of French origin. </p><p>The parents of VII. 2 (Fig. 2) are second cousins. 111.3, the spouse of 111.3 who is not shown, II.2,II. 3, I. 1 and I. 2 are all common ancestors to the parents of VIL 2 which made it possible for the effective autosomal gene to have come through any one of several sources. Members of the present generation in this family also consider themselves to be of French descent, although according to family names the effective gene could also be of German origin. </p></li><li><p>H. W. KLOEPFER AND CAROLYNN TALLEY 139 </p><p>111 </p><p>I V </p><p>V </p><p>VI </p><p>VII </p><p>KEY </p><p>@ Number of individuals, </p><p>Number below symbol is age or age a t death (d.) </p><p>if more than 1 </p><p>1 4 I I I </p><p>I I I </p><p>IX </p><p>A B C 'D Fig. 1. Pedigree of Duchenne-type muscular dystrophy showing autosomal recessive inheritance </p><p>in a family of Spanish descent. </p><p>KEY </p><p>Duchenne-ty pe , QQ , ? muscular dystrophy I </p><p>Number below symbol is I' @ age or age at death (d.) </p><p>VII </p><p>Fig. 2. Pedigree of Duchenne-type muscular dystrophy showing autosomal recessive inheritance in a family of French descent. </p></li><li><p>140 DUCHENNE-TYPE MUSCULAR DYSTROPHY </p><p>The gene associated with muscular dystrophy in these individuals could be 100 % penetrant in the homozygous state. Since the probability is 1 : 2 that each of the forty-six siblings of the parents of affected individuals are heterozygous, there may be about twenty-three more hetero- zygous individuals in this group. Single gene effects in these heterozygous individuals (and in the heterozygous parents of all these subjects) are not apparent, but heterozygotes have never been studied to determine whether such carriers can be identified. Since many heterozygotes are unaware of their relationship to one another, it is possible that other marriages will occur between carriers in this generation and in future generations, resulting in additional patients with muscular dystrophy. </p><p>REPORT OF CASES In none of these was there any involvement of facial muscles, which should rule out the possi- bility that we were dealing with the facioscapulohumeral type of muscle dystrophy. Except for the oldest girl Fig. 1, IX. 1 who can no longer walk or stand, but who is now pregnant, motion pictures were made of all affected individuals at the ages indicated on the pedigree charts. Six (Fig. 1, IX. 1, 12, 13, 22, 2 3 and Pig. 2, VII.2) have also undergone pertinent diagnostic and confirmatory studies at the Charity Hospital of Louisiana in New Orleans. </p><p>Fig. 1, IX. 1 (9) first walked at the age of 15 months. Weakness of the legs was first noted at age 8. At age 10, the calf muscles appeared typically pseudohypertrophic; there was also weakness and wasting of shoulder-girdle and upper arm muscles, conspicuous lumbar lordosis, and scoliosis. Cowers sign was positive. She rose from a supine to standing position in the classical manner. When last seen at age 22 she had been unable to walk for several years, but was 5 months along in pregnancy. </p><p>Pig 1, IX. 12 (9) was normal until age 8, when falling and weakness in the legs were noted. When examined at age 12, calf muscles were enlarged. A biopsied specimen showed irregular loss of cross-striations, increase of sarcolemmal nuclei, and degeneration of occasional muscle bundles. Gait and performance tests yielded typical results, and wasting of both shoulder- girdle and upper arm muscles were noted along with severe lordosis and scoliosis. When last seen at 19 years she could walk only a few steps with support. </p><p>Fig. 1, IX. 13 ($2) first walked at about 1 year. Falling, apparently due to weakness of the legs, was first noted at about age 8. A waddling gait and a typical climbing up the legs had been noted by the parents. When seen at 10 years, calf muscles were large and firm, while others were atrophied. There was obvious weakness of shoulder-girdle muscles, abductors and adductors of arms ; thigh muscles and anterior tibials were also appreciably weak. Lumbar lordosis, scoliosis and winged scapulae were prominent ; a tendency of the patient to slip through when picked up under the axillae was noted. Muscle biopsy revealed irregular loss of cross-striations, increase in sarcolemmal nuclei, and degeneration of occasional muscle bundles. She became unable to walk at 15, and was last seen at age 17. </p><p>Fig. 1, IX. 16 (6) exhibited large calves and weakness in his legs when first examined at age 8. When last seen at age 10 weakness and wasting of muscles of the shoulder girdle and upper arm were also evident. Though he had a typical waddling gait, he could still rise from the floor without climbing . He tired easily and fell frequently, but could still get around fairly well and was able to attend school. </p><p>Fig. 1, IX. 18 (3) was first examined at age 5 . He had enlarged calves and slight weakness in the legs, but no important disability. There was also some weakness of the shoulder girdle, with </p></li><li><p>H. W. K L O E P F E R AND CAROLYNN TALLEY 141 </p><p>a tendency to slip through when picked up under the axillae. This case will be followed to note the progress of his condition. It is possible that his symptoms would not have been noted at this time except for the alertness of the mother owing to the presence of the disease in the older brother. </p><p>Fig. 1, IX. 22 (a) walked at 13 months. Falling due to apparent weakness in the legs was first noted at 7 years. At 13 years the calf muscles were enlarged; Gowers sign was present, and there was marked weakness about the shoulder girdle. Pectoral muscles were barely palpable. Lordosis and scoliosis were severe. At age 15 when last seen he was seriously incapacitated for any physical activity, and was confined to a wheel chair. </p><p>Fig. 1, IX. 23 (9) seemed perfectly well until weakness was first noted in the legs at age 8. At 11, the calf muscles were enlarged, and a muscle biopsy showed hypertrophy of some fibres with slight proliferation of aarcolemmal nuclei. She was unable to rise from a sitting position without climbing. There was weakness and wasting about her shoulder girdle and some weakness also in the back muscles. There was moderate thoraco-lumbar lordosis and her scapulae were winged. She was still able to walk when last seen at age 13, but her activities were extremely limited, so that she had not attended school for a full year. </p><p>Fig. 2, VII. 2 ( 9 ) began walking at age 1, but had always had a peculiar gait. The chief com- plaints when first seen at age 12 were typical. The calf muscles showed pseudohypertrophy. There was also weakness about the shoulder girdle, this was particularly evident in the deltoids, latissimi dorsi, trapezii and rhomboids. Weakness was present bilaterally in the enlarged quadriceps muscles, and the weak gastrocnemii felt firm and rubbery. She had a waddling gait and her pelvis was tilted forward, with extreme lumbar lordosis. When last seen at age 16 she could still walk with some help but could not rise from a sitting position. </p><p>DISCUSSION </p><p>A comment frequently entered in a variety of clinical records concerning these cases was typical textbook picture of pseudohypertrophic muscular dystrophy except for the fact that the patient is a girl. For all of them the clinical descriptions, age of onset, and rate of progress are strikingly similar and compatible with the Duchenne type of muscular dystrophy, as recently described by Walton &amp; Nattras (1954). Except Fig. 1, IX.16 and 18, cases discovered most recently as a direct result of our genetic studies, all initial examinations were done by different clinicians who were unaware, as were most of the parents, that the same disease had occurred in the kindred. </p><p>As a clinical descriptive term, Duchenne-type muscular dystrophy has found wide acceptance in the literature, with transmission by a sex-linked recessive gene usually stated as the mode of inheritance. Transmission in certain families by an autosomal recessive gene, as evidenced by occurrence of the disease in females, has been claimed by some authorities and questioned by others. After critically reviewing previous attempts to classify the muscular dystrophies, Stevenson (1963) found that he could best classify his patients of fifty-one families into: (1) a Duchenne type of rapidly progressive muscular dystrophy in young boys : (2) an autosomal limb-girdle muscular dystrophy with affect$ facial muscles, and (3) autosomal limb-girdle muscular dystrophy with facial mpscles unaffecked. Except -for their occurrence in girls, our cases best fit with his first group. </p></li><li><p>142 DUCHENNE-TYPE MUSCULAR DYSTROPHY </p><p>Walton &amp; Nattrass (1964) classified their patients among fifty-six families into : (1) a Duchenne- type muscular dystrophy ; (2) facio-scapuloihumeral muscular dystrophy, and (3) limb-girdle muscular dystrophy. We feel that they were justified in rejecting Stevensons title of ( * ) Duchenne type rapidly progressive muscular dystrophy in young boys , by simply calling th, ; group Duchenne-type muscular dystrophy . Their criteria for classification in this groq include muscular dystrophy that : (a) generally affects males but rarely females, ( b ) usuallj begins in the first year or two of life but occaaionally much lster, (c ) is transmitted as a sex-linked recessive character, and (d) usually progresses rapidly, giving total disablement and often death in adolescence, but is sometimes compatible with survival to adult life . We do not believe that this classification should be limited to those (e) transmitted as a sex-linked recessive character for four reasons. First, our patients fit this classification with the exception that boys and girls appear in the same family and the mode of inheritance in our families is better explained as transmission by an autosomal recessive gene. Secondly, other investigators have observed the occurrence of Duchenne-type muscular dystrophy in males and females within the same sibship and in families in which the mode of inheritance is also compatible with an autosomal recessive gene. Thirdly, Walton (1955) included two females in his series because in clinical manifestations and course they showed no significant difference from those in the boys. Fourthly, in other genetic diseases and anomalies in man, it has not been uncommon to find that more than one genetic mechanism is associated with the appearance of similar clinical entities. </p><p>A certain amount of confusion seems to be inevitable during attempts to integrate genetic and clinical studies, especially when a vast literature of clinical description accumulates prior to carefully planned genetic investigations. Further confusion results when less frequent genes and less frequent clinical entities are discovered and are found not to fit into previously accepted patterns. Not only is more than one genetic mechanism frequently found to be associated with a given entity, but a study of many patients within a large kindred shows that often more than one clinical entity is needed to describe the various ways in which a specific gene can be expressed. </p><p>With the discovery of more refined points of discrimination different genetic entities in other diseases which exhibit the same clinical manifestation have often been later differentiated. There seems to be need for further studies of the less frequent autosomal recessive Duchenne type of muscular dystrophy before this type can be distinguished clinically from the sex-linked recessive type if, indeed, such a distinction is eventually possible. The slightly earlier age of onset in sex-linked recessive cases and somewhat more rapid rate of progress, as emphasized by Steven- son (1953), may well turn out to be distinguishing criteria when used with other features, but when used alone these criteria seem insufficient to recognize the genetic type of a given individual. </p><p>SUMMARY AND CONCLUSIONS Eight cases of muscular dystrophy (seven in one kindred and one in a second family, three males and five females) have been described. All have been considered to represent an autosomal recessive Duchenne type of muscular dystrophy because they meet both genetic and clinical requi...</p></li></ul>