Chapter 148 - Metabolic neuropathies and myopathies

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Abstract

Inborn errors of metabolism may impact on muscle and peripheral nerve. Abnormalities involve mitochondria and other subcellular organelles such as peroxisomes and lysosomes related to the turnover and recycling of cellular compartments. Treatable causes are β-oxidation defects producing progressive neuropathy; pyruvate dehydrogenase deficiency, porphyria, or vitamin B12 deficiency causing recurrent episodes of neuropathy or acute motor deficit mimicking Guillain–Barré syndrome. On the other hand, lysosomal (mucopolysaccharidosis, Gaucher and Fabry diseases), mitochondriopathic (mitochondrial or nuclear mutations or mDNA depletion), peroxisomal (adrenomyeloneuropathy, Refsum disease, sterol carrier protein-2 deficiency, cerebrotendinous xanthomatosis, α-methylacyl racemase deficiency) diseases are multisystemic disorders involving also the heart, liver, brain, retina, and kidney.

Pathophysiology of most metabolic myopathies is related to the impairment of energy production or to abnormal production of reactive oxygen species (ROS). Main symptoms are excercise intolerance with myalgias, cramps and recurrent myoglobinuria or limb weakness associated with elevation of serum creatine kinase. Carnitine palmitoyl transferase deficiency, followed by acid maltase deficiency, and lipin deficiency, are the most common cause of isolated rhabdomyolysis. Metabolic myopathies are frequently associated to extra-neuromuscular disorders particularly involving the heart, liver, brain, retina, skin, and kidney.

Introduction

Among the heterogeneous group of disorders that involve the peripheral nerve, the concept of metabolic peripheral neuropathies is linked in most conditions to the association of a peripheral neuropathy with a more complex sequence of symptoms and signs that go with a metabolic disorder. By metabolic disorder, we currently wish to indicate a disorder in which a metabolic marker is available to clarify physiological and pathogenic mechanisms and is useful for proper definition. Moreover the presence or absence of a peripheral neuropathy in a given disorder can help to better address the correct diagnosis. For example, when faced with a neuroimaging diagnosis of a leukodystrophy, the presence of a peripheral neuropathy together with the neuroimaging distribution and quality of white matter anomalies is useful to restrict the number of conditions to take into consideration for further evaluation and genetic confirmation. Conversely, isolated neuropathy may be the first symptom of an inborn error of metabolism which needs to be identified.

In contrast, metabolic myopathies can generally be distinguished by characteristic clinical signs that help to tackle the proper diagnostic algorithm, such as muscle weakness with myalgia, exercise intolerance, rhabdomyolysis, or ptosis with limitation of eye movements. Additionally, while the morphology of the sural nerve biopsy is not particularly useful in the assessment of a metabolic disorder, muscle biopsy is frequently of paramount importance for evaluating and defining a metabolic myopathy.

Section snippets

Metabolic peripheral neuropathies

A neuropathy is suspected in the presence of distal motor deficit, proprioceptive ataxia, associated with orthopedic deformities. Where there are familial antecedents of Charcot–Marie–Tooth disease, genetic investigations after nerve conduction velocity studies should be the first line. If the neuropathy has an early onset and there is no family history, metabolic investigations are required. Nerve conduction velocity studies contribute to characterize the type of neuropathy: axonal or

Metabolic myopathies

Metabolic myopathies are a heterogeneous group of hereditary muscle disorders caused by specific enzymatic defects of muscle energy metabolism resulting in skeletal muscle dysfunction. Traditionally, these diseases are grouped into abnormalities of glycogen, lipid, purine, or mitochondrial biochemistry. The exact incidence and prevalence of metabolic myopathies is uncertain. Carnitine palmitoyl transferase deficiency is the most commonly identified metabolic cause of recurrent myoglobulinemia

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