David Arnold, Department of Neurology, Division of Neuromuscular Medicine, The Ohio State University Medical Center, Columbus, OH, USA. Amy Chen, Department of Neurology, University of Rochester, Rochester, NY, USA Emma Ciafaloni, Department of Neurology,. Dimachkie, Neuromuscular Section, Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA Annie Dionne, Department of Neurology.
Nicholas Johnson, Department of Neurology, University of Rochester Medical Center, NY, USA Petra Kaufmann, National Institute of Neurological. Jacqueline Montes, SMA Clinical Research Center, Department of Neurology, Columbia University, New York, NY, USA.
Muscular disorders are almost always associated with weakness, much less often with myalgia, contractures or myoglobinuria, and rarely with chronic respiratory failure or cardiac dysfunction. History and research provide the best clues in delineating the basic characteristics of individual muscle disorders.
What i s the p attern of w eakness?
What i s the t emporal c ourse?
Is t here a f amily h istory?
Are t here p rovocative f actors?
Are o ther o rgan s ystems a ffected?
The most pronounced weakness in some patients may be of the neck (isolated extensor neck myopathy) or of the paraspinous muscles (camptocormia). It is important to recognize that the EMG may be normal in some of them. Muscle biopsy and pathological examination of the obtained specimen are important diagnostic procedures for patients with suspected inflammatory myopathy.
A normal serum CK may be present in patients with progressive disease and does not exclude the diagnosis. Methotrexate should be avoided in patients with inflammatory myopathies and interstitial lung disease due to its potential pulmonary toxicity.
Fatty acid oxidation
Triglyceride and membrane phospholipid biosynthesis
Phosphorylase deficiency or McArdle's disease is the most common glycogenosis resulting in recurrent myoglobinuria. Acid maltase deficiency (AMD) can present with three very different clinical presentations including: (1) severe generalized disease of infancy described by Pompe, which is fatal before the age of 2 years and includes diffuse infantile hypotonia, macroglossia , respiratory weakness, cardiomyopathy, myopathy, hepatomegaly and anterior horn cell disease; (2) a juvenile variant that affects exclusively the muscles with onset in childhood and death in the second or third decade; and (3) a milder, adult-onset variant simulating limb-girdle myopathy. The most common defect is medium-chain acyl-CoA dehydrogenase (MCAD) deficiency with an incidence of up to 1 in 8930 live births in the Pennsylvania Newborn Screening Program.
Dietary supplementation with essential fatty acids (at 1 – 2% of total energy intake) is often used to reduce the risk of essential fatty acid deficiencies. Specific measures include riboflavin replacement in certain cases of multiple acyl-CoA dehydrogenase deficiencies, medium-chain triglyceride (MCT) oil in long-chain FAO disorders, and oral prednisone and docosahexaenoic acid (essential polyunsaturated fatty acid or PUFA) in myoneuropathic long chain 3 - hydroxysyl - coenzyme A dehydrogenase (LCHAD) deficiency.
Mutations in mitochondrial protein synthesis
Defects of the respiratory chain subunit genes – complex I, II, III
Defects in respiratory chain assembly ancillary proteins – complex I e.g
Defects of intergenomic signaling required for mtDNA integrity and
Alternatively, a variety of techniques can be used to screen for deletions and duplications in the dystrophin gene (multiplex polymerase chain reaction [PCR] and multiplex ligation-dependent probe amplification are two of the most common). Gene therapies in dystrophinopathies are directed at gene replacement (viral vectors or plasmid delivery of dystrophin gene constructs, stem cell or myoblast transplantation) or gene modification (using small molecules or antisense oligonucleotides to target specific mutations). However, dystrophinopathies (including carrier status) should also be suspected in the presence of marked calf hypertrophy.
Muscle immunohistochemistry and immunoblotting are crucial in diagnosing the various forms of LGMD and in directing further genetic testing in most cases. Considering the complexity of muscle biopsy analysis in the diagnosis of various forms of LGMD, it should be undertaken in a laboratory with expertise in performing and interpreting these techniques. Identification of the causative mutation by molecular analysis remains the gold standard in the diagnosis of the various forms of LGMD.
Effective treatment and early diagnosis are key in the management of patients with LGMD. In another model, the contraction of the repeats affected the expression of genes proximal to the deletion. A large percentage of patients will use a cane or walker late in the course of the disease.
The family history should be negative except in the rare cases of congenital myasthenia gravis. Patients with the distal myopathy of the type described in the Australian family from Victoria with pathology ranging from normal to terminal. Myotonic dystrophy type 1 (DM1) typically causes distal weakness in the hands and ankles, without major proximal muscle weakness in the early stages of the disease.
Symptomatic onset is typically with episodic weakness in the first or second decade. The first task in the diagnosis of a congenital myopathy is to rule out other causes of muscle.
Tests to exclude other causes of muscle weakness
Defining the gene that causes a congenital myopathy should be a goal for all families, because it informs genetic counseling, provides important information about prognosis, often guides management, and in the future will be essential to prescribe specific therapies. Patients with mild generalized weakness may develop Achilles tendon contractures, but other joint contractures are uncommon if patients remain ambulatory. Scoliosis is a common complication and is often seen in myopathies due to RYR1 and SEPN1.
Intellectual function is generally normal and, unlike some muscular dystrophies, primary cardiac involvement is rare.
A few CCD patients have severe weakness and resemble MmD patients due to RYR1 (see below). However, MG was included in the differential by the primary evaluating physician in less than half of MG patients ultimately referred to the author's clinic (Table 15.1. Initial symptoms in 919 patients with myasthenia gravis seen at the Duke University myasthenia gravis clinic (Sanders DB and Massey JM, unpublished data).
Patients with MG associated with MuSK antibodies may have clinical findings suggestive of motor neuron disease or a myopathy, rather than of MG. With moderate weakness of these muscles, the patient cannot "bury" the eyelashes during forced eye closure. The weakness in LES is often attributed to cachexia, polymyositis, or, in patients with known cancer, a paraneoplastic neuromuscular syndrome.
This confirms the diagnosis of MG in most patients – 80% of patients with generalized MG and 50% with ocular MG have serum antibodies against the acetylcholine receptor (AChR). In patients with limited ocular symptoms at 2 years, there is a 90% probability that they will not generalize. Eye weakness (eg, the inability to fully bury the eyelashes) is also frequently observed.
Occasional false-positive results are reported in patients with asymptomatic thymomas and other autoimmune diseases. In patients with typical symptoms of ocular or generalized MG, positive ACh receptor antibodies should be considered diagnostic. Literature review of the utility of repetitive nerve stimulation and single fiber EMD in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert Eaton myasthenic syndrome.
Botulinum toxin B,
The diagnosis is established by the discovery of the organism in the wound or the toxin from the circulation. Top: Repetitive nerve stimulation at 3 Hz of left abductor pollicis brevis (Abd Dig Min) and left abductor pollicis brevis (Abd Poll Brevis). The high concentration of AChRs at the terminal extensions of junctional folds and Na v 1.4 at the depth of the folds ensures that excitation propagates across the endplate.
This reduces the rate of ACh resynthesis and the ACh content of synaptic vesicles during physiological activity. The margin of safety is compromised by AChR deficiency and postsynaptic simplification, which reduces the input resistance of the postsynaptic region. Deficiency of endplate AChRs results from mutations in the α, β, δ, or ε subunits of the receptor.
Congenital Lambert-Eaton-like syndrome A CMS in which the EMG characteristics resembled those of the acquired autoimmune form of the disease was reported in a single patient. The morphologic features of the endplate and the factors that impair the margin of safety are like those of primary AChR deficiency. Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme.
Motor axons arise from anterior horn cells in the ventral horn of the spinal cord and exit through ventral roots. Although diagnostic confusion is unlikely in this case, diagnosis may be delayed, especially in patients who exhibit more subtle features early in the course of the disease. Hereditary motor and sensory neuropathies (HMSN) are the most common inherited neuropathy (IN) with a prevalence of about 1 in 2500 (Table 21.1 .) The term "HMSN" is used interchangeably with Charcot-Marie-Tooth (CMT) . ) disease, although HMSNs are increasingly being described in terms of genetically specified CMT disease subtypes.
As a result, sensory symptoms and signs first appear at the ends of the toes. Sensory abnormalities may start in the fingertips somewhat later than in the lower extremities. Surgical decompression of the median nerve at the wrist benefits CTS patients with or without diabetes.
The role of ulnar nerve decompression at the elbow, although widely used, remains controversial. Symptoms are tingling, numbness, and pain along the lateral thigh in the distribution of the lateral femoral cutaneous nerve. The duration and degree of exposure to an offending agent corresponds to the severity of the neuropathy.
However, in most cases these factors will only influence the severity, but not the pattern, of the neuropathy (i.e. length-dependent neuropathy, sensory neuronopathy, etc.). The most important principle in the treatment of toxic neuropathies is, of course, the immediate withdrawal of the offending agent. The prognosis depends on both the specific agent and the severity of the neuropathy and is discussed below.
Treatment is based on reversing any causative factors and replacing the underlying nutritional deficiency. In most cases, objective sensory loss is only demonstrated later in the course of the disease. Most of the patients with MFS present with two of three features and have an elevated cerebrospinal fluid (CSF) protein.
