Clinicopathological characteristics and molecular genetics of adhalin deficiency (severe childhood autosomal recessive muscular dystrophy/SCARMD)

Dystrophin is a cytoskeletal protein complexed with a number of cell membrane glycoproteins to from the dystrophin-glycoprotein complex (DGC) in striated muscle. The dystroglycan complex, one of the functional subcomplexes composing the DGC, is a novel type of laminin receptor playing active roles in signal transduction. Another functional subcomplex composing the DGC is the sarcoglycan complex, comprised of alpha-(also called adhalin), beta-, gamma- and delta-sarcoglycans. Recent revelations indicate that genetic defects of either alpha-, beta-, gamma- or delta-sarcoglycan lead to a loss of the entire sarcoglycan complex and result in the phenotype of severe limb-girdle muscular dystrophy (collectively called sarcoglycanopathy). In this review, I discuss the molecular pathogenesis and clinical features sarcoglycanopathy.     

Congenital muscular dystrophy with merosin deficiency: MRI findings in five patients

We present the MRI findings in five patients with congenital muscular dystrophy (CMD) and merosin (laminin alpha2) deficiency, which was total in one and partial in four. In one patient with partial merosin deficiency, MRI was normal. The other four patients had supratentorial white matter abnormalities. In three, T2-weighted images revealed subcortical, deep lobar and periventricular high signal in white matter, while in the other there were only small peritrigonal areas of increased signal. On T1-weighted images, there was slightly low signal. Cortical abnormalities were absent. None of these changes were accompanied by symptoms or signs of central nervous system involvement. White matter abnormalities in a patient with CMD should prompt investigation of merosin.     

Point mutation in a Becker muscular dystrophy patient

Occupational therapy intervention in the area of seating and positioning may play a vital role in improving the quality of life for nursing home residents. This case report indicates that appropriately positioning a client may increase comfort, decrease agitation, and decrease the administration of mood-altering drugs. Research would help to delineate the effects of appropriate seating systems, both to ensure reimbursement and to ensure that all who might benefit from positioning intervention receive the appropriate services. OBRA 1987 regulations are forcing nursing homes to assess residents for the least restrictive restraints. These assessments offer a golden opportunity for occupational therapists to become involved in determining the most appropriate seating systems and to conduct research on their benefits.     

Sleeve lobectomy for lung carcinoma in a patient with muscular dystrophy

We performed a sleeve lobectomy on a patient with squamous-cell carcinoma of the lung who had poor pulmonary function and could not move his extremities or trunk, due to a muscular dystrophy. Lung cancer in a highly disabled patient can be resected even with a bronchoplastic procedure.     

Clinical heterogeneity of adhalin deficiency

STUDY DESIGN: An assessment was made of the efficacy of a combined laminoplasty and foraminotomy operation for patients with coexisting myelopathy and unilateral radiculopathy. The procedure was done in 17 patients. OBJECTIVES: The patients were followed with lateral flexion and extension radiographs, computed tomography scans, and an assessment system specially designed to qualitatively evaluate the patients' neurologic status. Follow-up period averaged 4 years (range, 2.1-9.3 years). SUMMARY OF BACKGROUND DATA: Excellent-to-good results were obtained for 76% (13 of 17) of the patients without any significant functional compromise based on the radiographs. Sixteen nerve roots were decompressed with a less than 25% foraminotomy, whereas eight were decompressed by a 25%-50% foraminotomy without serious neurologic damage, except for one patient. The neurologic results appeared unrelated to the extent of foraminotomy. METHODS: A refined procedure for combined laminoplasty and foraminotomy was reviewed retrospectively in terms of neurologic outcome and radiographic data. RESULTS: The present series is small, and results are not comparable directly with other methods. The procedure appears effective for myelopathy and radiculopathy. This procedure is applicable to patients with myelopathy and coexisting nerve root impingement anterolaterally or in the neural foramen. CONCLUSION: The combined laminoplasty and foraminotomy operation may provide greater neurologic improvement in patients with coexisting myelopathy and unilateral radiculopathy, while maintaining cervical spine stability after surgery.     

Myophosphorylase deficiency and limb-girdle muscular dystrophy in the same pedigree

We report 2 familial patients with limb-girdle muscular dystrophy (LGD). The parents of patient 1 showed a consanguineous marriage and patient 2 was a paternal cousin of patient 1. Slowly progressive muscular weakness/wasting and dystrophic changes in the biopsied muscles were observed in both patients. However, a quantitative assay revealed a severely reduced myophosphorylase activity in patient 1 with normal activity in patient 2. A semi-ischemic exercise test disclosed no elevation of venous lactate in patient 1 with a normal increase in patient 2. A leukocytes DNA analysis in patient 1 did not show the gene deficits previously recognized in patients with McArdle's disease (McD). Patient 1 may only have abnormal myophosphorylase activity with dystrophic changes secondary to the myophosphorylase deficiency or coincidentally two genomic abnormalities for McD and LGD. LGD still has heterogenous etiologies and the responsible genes for these two disorders may be closely mapped.     

Anesthetic management of a patient with Duchenne's muscular dystrophy undergoing radical repair for tetralogy of Fallot

This report describes a 13-month-old-girl with Duchenne's muscular dystrophy (DMD) who had radical repair for tetralogy of Fallot safely. Patients with DMD are considered to be at risk of malignant hyperthermia (MH). Drugs for induction and maintenance were chosen from a list of agents rarely associated with MH. To wash out the inhalation anesthetics from the equipment, oxygen was circulated continuously for 24 hours. Dantrolene sodium was kept readily available in case of MH occurrence. Differential diagnosis during surgery is difficult in term of the episodes of MH and complications of cardiac surgery, as cardiac surgery is also associated with tachycardia, tachyarrhythmias, metabolic asidosis and red colored urine, which are frequently accompanied by MH. Although increased levels of CK, GOT, LDH and myoglobin strongly support the diagnosis of MH, such evidence can only be confirmed after operation. Fortunately, these factors recovered to the normal range without treatment by dantrolene sodium. During the cardiac surgery, treatment of MH may be delayed due to its late confirmation.     

The sarcoglycan complex in limb-girdle muscular dystrophy

The involvement of the sarcoglycan complex in the pathogenesis of muscular dystrophy is becoming increasingly clear. Sarcoglycan gene mutations lead to four forms of autosomal recessive limb-girdle muscular dystrophy. Recent progress has been made with the identification of novel mutations and their correlations with disease. Through this research, a better understanding the molecular pathogenesis of limb-girdle muscular dystrophy has been gained. Finally, animal models are now being used to study viral-mediated gene transfer for the future treatment of this disease.     

Absence of a calmitine-specific protease inhibitor in skeletal muscle mitochondria of patients with Duchenne's muscular dystrophy

We studied the effect of mitochondrial extracts from skeletal muscle of patients with Duchenne's muscular dystrophy (DMD) on calmitine from the skeletal muscle of normal mice and control subjects. Our results clearly show the existence of an abnormal proteolytic activity of mitochondria from patients with DMD on calmitine from the normal mouse. This proteolytic activity was not found on calmitine from the control subject. Overall, our observations suggest that calmitine concentration in the muscle of the control subject remains elevated because of the presence of a calmitine-specific protease and an inhibitor of this protease which regulates and/or suppresses the activity of the enzyme according to the requirements of the muscle cell. Conversely, the calmitine deficiency observed in the muscle of patients with DMD would be due to the absence of this inhibitor. This would account for the continual activity of the enzyme in degrading calmitine as soon as it is synthesized. The identification of this inhibitor is currently being investigated in our laboratory.     

Abnormalities in alpha-, beta- and gamma-sarcoglycan in patients with limb-girdle muscular dystrophy

We have identified 12 cases from a group of 45 patients with early onset limb-girdle muscular dystrophy (LGMD), who have a deficiency of the 50 kDa dystrophin-associated glycoprotein, alpha-sarcoglycan. An additional male sibling of one case was also studied clinically. All 12 patients showed a concomitant, but variable, deficiency of alpha-, beta- and gamma-sarcoglycan. None of our patients had a defect in only one component of the sarcoglycan complex. Molecular analysis confirmed that a total absence of one sarcoglycan, associated with reduced expression of the other two, indicates a primary defect. Immunocytochemistry is thus useful for directing molecular studies. Morphological features not usually observed in Xp21 dystrophies were peripheral accumulations of mitochondria, discrete core-like areas, and nemaline rods in one case. Clinical severity and progression was variable between and within families but early loss of ambulation, at or before the age of 12 years, was associated with a total absence of gamma-sarcoglycan. Common clinical features were calf hypertrophy, contractures of the tendo achilles, lumbar lordosis, winging of the scapulae, weak hamstrings and weak neck muscles. All cases had grossly elevated serum creatine kinase. In contrast to patients with Duchenne muscular dystrophy (DMD), our patients with sarcoglycan deficiencies had normal early motor milestones, normal intellect, and good respiratory and cardiac function. Our data confirm that the sarcoglycan complex acts as a unit and that morphological and clinical features can distinguish patients with defects in the sarcoglycans from those with Xp21 dystrophy. In our group of patients prognosis is better than in DMD, but clinical variability makes this difficult to predict in isolated cases.     

Body composition determined with MR in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and normal subjects

OBJECTIVE: To examine the feasibility of using spectral analysis techniques to identify potential biomarkers of diminished postural control in elderly individuals. DESIGN: Data from spectral signatures (derived from postural sway) of 21 young adults and 42 elderly individuals classified as "high" or "low" risk with regard to functional balance capacity were analyzed using Risk Category (3) x Sensory Condition (3) multivariate analyses of variance. Postural control was challenged by varying the visual conditions under which individuals stood on a measurement platform. RESULTS: Results indicated that measures of central tendency and dispersion of the spectral frequency distribution from medial-lateral components of sway (but not antero-posterior sway) clearly differentiated between "high" and "low" risk elderly. Low risk elderly were not different from young adults. High risk elderly exhibited greater dispersion and lower mean frequency than other groups. CONCLUSIONS: Differences in spectral characteristics of medial-lateral components of sway were more related to risk category than to age. Elderly persons with high functional balance capacity displayed characteristics similar to those of young adults. Thus, spectral frequency analysis techniques may be a clinically useful tool for identifying individuals potentially at risk of falling.     

Western type cerebro-muscular dystrophy and congenital merosin deficiency muscular dystrophy: two terms for the same disorder

INTRODUCTION: Congenital muscular dystrophies (CMD) are a clinically heterogeneous group of muscular disorders characterized by hypotonia, muscle weakness and early or congenital joint contractures. Electromyography reveals a myopathic pattern, creatine-kinase (CK) may be moderately elevated and muscle biopsy shows pathological changes consistent with a dystrophic process. OBJECTIVE: Report the cases of two brothers with 'Occidental type cerebro-muscular dystrophy' versus 'merosin-deficient CMD'. PATIENTS AND METHODS: Two children, a boy and a girl, of a first consanguineous parents. In the first case, the diagnosis of Occidental type cerebro-muscular dystrophy was made in 1983, at the age of 4 years, according to clinical, biochemical, electromyographic, pathological and neuroradiological data. In the second case, the diagnosis of merosindeficient form of CMD was made with the same criteria and with immunohistochemistry and Western blot techniques in 1997, when she was 6 months old. CONCLUSION: Occidental type cerebro-muscular dystrophy, described 13 years ago by one member of our group, corresponds with merosin-deficient form of CMD.     

Treatment of nocturnal periodic hypoxemia with safrazine hydrochloride in a patient with Duchenne muscular dystrophy under nasal intermittent positive pressure ventilation

Nocturnal periodic hypoxemia occurring in a 25-year-old Duchenne muscular dystrophy patient under NIPPV control was successfully treated with monoamine oxydase inhibitor (MAOI), safrazine hydrochloride. Five mg of safrazine hydrochloride was administered before sleep, and the periodic hypoxemia disappeared within 14 days. The effect lasted almost seven months without notable side effect. MAOI may be effective for nocturnal hypoventilation through suppression of REM sleep as in the case of tricyclic antidepressants. The effect of tricyclic antidepressants appears immediately. However, it usually fades away within forty days. Safrazine hydrochloride was effective obviously longer than tricyclic antidepressants. Consequently MAOI may be a hopeful candidate of medication for a treatment of nocturnal periodic hypoxemia in Duchenne muscular dystrophy.     

The frequency and development of tissue iron deficiency in 6 iron deficiency anemia patients with plummer-vinson syndrome

The physical signs of tissue iron deficiency include smooth and red tongue, angular stomatitis, koilonychia, and pica. The incidence of these conditions is unknown in Japan. We evaluated the frequency and development of tissue iron deficiency in 353 patients with iron deficiency anemia. The frequency of tissue iron deficiency was 6.8%; papillary atrophy of the tongue, 5.4%; abnormal nails, 5.4%; angular stomatitis, 1.1%; Plummer-Vinson syndrome, 1.7%; and pica, 0.06%. These findings were compared with the date collected by Wintrobe and Beveridge. The development and incidence of tissue iron deficiency correlated significantly with the severity of iron deficiency anemia.     

Challenges in Duchenne muscular dystrophy

The last seven years has witnessed an explosion in our understanding of the muscular dystrophies. In the early 1980s, prenatal diagnosis of Duchenne muscular dystrophy was developed. The cloning of the gene, in 1996, resulted in a better understanding of the disease process and led to the identification of a novel complex at the membrane. This information led to the cloning of other genes responsible for the autosomally inherited dystrophies. As we approach the millenium, the challenge is shifting to the development of therapy of these diseases. This review, in honour of Professor Alan Emery, explains how these advances have an impact in the clinical management of patients and head the promise the progress holds for the future.     

Congenital muscular dystrophy with distinct CNS involvement

The medical imaging and clinical histories of three cases of haematoma of the urinary bladder in paediatrics were reviewed retrospectively. The sonographic findings are unique and diagnostic. Three distinctive sonographic features were observed. The haematomas were large, occupying most of the bladder lumen. They showed an echogenic thick, smooth rim and, in two cases, a laminated appearance with concentric layers of alternating hyperechogenicity and hypo-echogenicity.     

Cardiomyopathy of limb-girdle muscular dystrophy

OBJECTIVES: This study sought to find an association between dilated cardiomyopathy and limb-girdle muscular dystrophy. BACKGROUND: Cardiomyopathy has been seen in various neuromuscular disorders, but it has not been recognized to be associated with limb-girdle muscular dystrophy. METHODS: We investigated three sisters with well documented limb-girdle dystrophy and congestive heart failure by the 3rd decade of life. All underwent noninvasive evaluation of left ventricular systolic function by both echocardiography and radionuclide scanning, and one also had cardiac catheterization. Deoxyribonucleic acid (DNA) linkage analysis was performed in these affected subjects and in the unaffected family members, and DNA was extracted from mononuclear cells with primer sequences for three chromosome 13q microsatellite markers. RESULTS: The parents had no evidence of clinical disease, but all three sisters had echocardiographic evidence of dilated cardiomyopathy. The sister with additional evidence of left ventricular dysfunction of cardiac catheterization had no coronary artery disease. The affected subjects had the same paternal allele for three potential markers of limb-girdle muscular dystrophy but different maternal alleles. The very small family size did not permit statistical confirmation or refutation of linkage for chromosome 13q markers. CONCLUSIONS: Demonstrable cardiomyopathy accompanying limb-girdle muscular dystrophy and its probable genetic associations require continued investigation by anticipating the cardiomyopathy in limb-girdle muscular dystrophy.