Pediatric Neurology, Part III

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• Publisher: Elsevier
• Year: 2013
• Print ISBN:
  9780444595652
• eBook ISBN:
  9780444595775
• Topic: Medicine
• Subtopic: Neurology

The child is neither an adult miniature nor an immature human being: at each age, it expresses specific abilities that optimize adaptation to its environment and development of new acquisitions. Diseases in children cover all specialties encountered in adulthood, and neurology involves a particularly large area, ranging from the brain to the striated muscle, the generation and functioning of which require half the genes of the whole genome and a majority of mitochondrial ones. Human being nervous system is sensitive to prenatal aggression, is particularly immature at birth and development may be affected by a whole range of age-dependent disorders distinct from those that occur in adults. Even diseases more often encountered in adulthood than childhood may have specific expression in the developing nervous system. The course of chronic neurological diseases beginning before adolescence remains distinct from that of adult pathology – not only from the cognitive but also motor perspective, right into adulthood, and a whole area is developing for adult neurologists to care for these children with persisting neurological diseases when they become adults. Just as pediatric neurology evolved as an identified specialty as the volume and complexity of data became too much for the general pediatician or the adult neurologist to master, the discipline has now continued to evolve into so many subspecialties, such as epilepsy, neuromuscular disease, stroke, malformations, neonatal neurology, metabolic diseases, etc., that the general pediatric neurologist no longer can reasonably possess in-depth expertise in all areas, particularly in dealing with complex cases. Subspecialty expertise thus is provided to some trainees through fellowship programmes following a general pediatric neurology residency and many of these fellowships include training in research. Since the infectious context, the genetic background and medical practice vary throughout the world, this diversity needs to be represented in a pediatric neurology textbook. Taken together, and although brain malformations (H. Sarnat & P. Curatolo, 2007) and oncology (W. Grisold & R. Soffietti) are covered in detail in other volumes of the same series and therefore only briefly addressed here, these considerations justify the number of volumes, and the number of authors who contributed from all over the world. Experts in the different subspecialties also contributed to design the general framework and contents of the book. Special emphasis is given to the developmental aspect, and normal development is reminded whenever needed – brain, muscle and the immune system. The course of chronic diseases into adulthood and ethical issues specific to the developing nervous system are also addressed. - A volume in the Handbook of Clinical Neurology series, which has an unparalleled reputation as the world's most comprehensive source of information in neurology - International list of contributors including the leading workers in the field - Describes the advances which have occurred in clinical neurology and the neurosciences, their impact on the understanding of neurological disorders and on patient care

SECTION 16: Inborn errors of metabolism and storage diseases

Chapter 160 Diagnostic work-up in acute conditions of inborn errors of metabolism and storage diseases

Chapter 161 Metabolic diagnostic work-up in chronic conditions

Chapter 162 Inborn errors of brain myelin formation

Chapter 163 Peroxisomal disorders

Chapter 164 Lysosomal leukodystrophies

Chapter 165 Leukodystrophies with astrocytic dysfunction

Chapter 166 Aicardi–Goutières syndrome

Chapter 167 Disorders of nucleotide excision repair

Chapter 168 Respiratory chain deficiencies

Chapter 169 Disorders of pyruvate metabolism

Chapter 170 Disorders of fatty acid oxidation

Chapter 171 Glucide metabolism disorders (excluding glycogen myopathies)

Chapter 172 Lysosomal diseases

Chapter 173 Neuronal ceroid lipofuscinoses

Chapter 174 Gangliosidoses

Chapter 175 Gaucher disease

Chapter 176 Niemann–Pick diseases

Chapter 177 Mucopolysaccharidoses and mucolipidoses

Chapter 178 Progressive myoclonus epilepsy

Chapter 179 Congenital disorders of glycosylation

Chapter 180 Inborn errors of copper metabolism

Chapter 181 Defects in amino acid catabolism and the urea cycle

Chapter 182 Amino acid synthesis deficiencies

Chapter 183 Epileptic encephalopathy with suppression-bursts and nonketotic hyperglycinemia

Chapter 184 Vitamin-responsive disorders

Chapter 185 Pyridoxine and pyridoxalphosphate-dependent epilepsies

Chapter 186 Monoamine neurotransmitter deficiencies

Chapter 187 Metabolic disorders of purine metabolism affecting the nervous system

Chapter 188 Creatine deficiency syndromes

Chapter 189 Cholesterol metabolism deficiency

Chapter 190 Enzyme replacement therapy and substrate reduction therapy in lysosomal storage disorders with neurological expression

Chapter 191 Gene therapy for disorders of the central nervous system

Chapter 160

Diagnostic work-up in acute conditions of inborn errors of metabolism and storage diseases

Valayannopoulos Vassili¹ * and Poll-The Bwee Tien², ¹Reference Center for Inherited Metabolic Disease of Children and Adults, Hôpital Universitaire Necker-Enfants Malades, Paris, France, ²Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, ^*Correspondence to: Dr Vassili Valayannopoulos, Centre de Référence des Maladies Héréditaires du Métabolisme de l’Enfant et de l’Adulte, Necker-Enfants Malades Hospital, 149 rue de Sevres, 75743 Paris Cedex 15, France. Tel: + 33-1-44-49-48-52/+ 33-1-44-49-48-58, Fax: + 33144494850, E-mail: [email protected]

Abstract

Inborn errors of metabolism may present with acute neurological symptoms at any age. However, especially in neonates and infants, these conditions may be acute and if untreated may lead to permanent cerebral lesions or to death. Knowledge of the main signs and symptoms of these conditions may be lifesaving, especially for conditions that are treatable. From the pathophysiological perspective, errors of metabolism can be divided into disorders causing “intoxication,” disorders impairing energy production, and disorders involving complex molecules. From the clinical perspective, errors of metabolism may present with acute symptoms in the neonatal period and early infancy; late-onset acute and recurrent attacks; chronic and progressive symptoms.

Nonspecific readily available biochemical markers may suggest the underlying condition but in most cases the choice of appropriate biochemical and molecular tests is required to establish the diagnosis.

Progress in the treatment of inborn errors of metabolism has been slower than progress in diagnostic methods and in understanding of the pathophysiology of these disorders. Nevertheless, outcomes are improving with the use of dialysis and drugs to promote the removal of toxic metabolites and measures to keep catabolism to a minimum. Early intervention is crucial when neurological sequelae could be avoided, which requires constant vigilance and routine measurement of diagnostic biochemical markers in suspected cases.

Introduction

Inborn errors of metabolism may present with acute neurological symptoms at any age. However, especially in neonates and infants these conditions may be acute, and, if untreated, may lead to permanent cerebral lesions or to death (Saudubray et al., 2002; Leonard and Morris, 2006). Knowledge of the main signs and symptoms of these conditions may be lifesaving, especially for conditions that are treatable.

Several clinical situations can be distinguished. From the pathophysiological perspective, inborn errors of metabolism can be divided in three groups: (1) disorders causing an “intoxication;” (2) disorders impairing energy production; and (3) disorders involving complex molecules.

From the clinical perspective, four distinct circumstances may be encountered: (1) acute symptoms in the neonatal period and early infancy (< 1 year); (2) late-onset acute and recurrent attacks; (3) chronic and progressive (nonspecific) symptoms; and (4) specific and permanent organ symptoms suggestive of an inborn error of metabolism.

Acute symptoms in the neonatal period and early infancy (< 1 year)

Coma, hypotonia, and seizures are the major clinical expressions of metabolic distress in the newborn.

The occurrence of lethargy or coma in a neonate after a free interval where the neonate appears to be normal is characteristic of “intoxication” disorders. Muscle tone changes and involuntary movements are important diagnostic hallmarks. Such conditions result from:

Aminoacidopathies: the clinical hallmark of maple syrup urine disease, the most common of these conditions, is coma associated with abnormal movements described as “boxing” or “pedaling” movements of the four limbs. Usually the neonate has a distinctive body and urine odor of maple syrup or burned sugar.

Organic acidurias (methylmalonic, propionic, isovaleric). Axial hypotonia contrasts with limb hypertonia associated with slow limb elevation, tremor, and involuntary movements of short amplitude. Superficial polypnea due to acidosis is common. In isovaleric acidemia, a sweaty-feet odor is usually present.

Urea cycle disorders. Axial hypotonia contrasts with limb hypertonia. However, there are usually no abnormal movements. Hepatomegaly may be present indicating hepatic dysfunction.

Ketolysis defects may display similar signs to organic acidurias, or mimic neonatal diabetes mellitus, due to the accumulation of massive amounts of ketone bodies and organic acids deriving from branched-chain amino acids.

In the absence of a specific treatment, all the above conditions may produce brain edema with increased intracranial pressure and seizures leading to death.

Coma with global hypotonia associated with specific organ symptoms (heart, liver, muscle, kidney) is characteristic of “energy deficiency” disorders. Lactic acidosis causing polypnea or symptoms related to brainstem dysfunction may occur (tachycardia or bradycardia, body temperature changes, respiratory irregularities). This group comprises: (1) respiratory chain defects; (2) pyruvate metabolism defects: pyruvate dehydrogenase and pyruvate carboxylase deficiencies, neonatal (“French”) type.

Coma may be associated with specific symptoms or organ manifestations:

• Coma with hypoglycemia may result from: (1) hyperinsulinism: hypoglycemia may occur independently of feeding or fasting and even in patients receiving intravenous glucose; (2) glycogen storage diseases: hypoglycemia occurs in the fasting state and in most cases there is an enlarged liver; (3) gluconeogenesis defects: hypoglycemia occurs in the fasting state, transient liver enlargement may be found during hypoglycemic episodes; (4) fatty acid β-oxidation defects: hypoglycemia occurs after prolonged fasting usually associated with other organ failure or impairment (liver, muscle, heart and kidney); (5) ketogenesis defects: the clinical presentation is similar to fatty acid oxidation defects.

• Coma with hepatic involvement may result from: (1) fatty acid β-oxidation defects; (2) urea cycle disorders; (3) respiratory chain disorders (Clayton, 2002).

Even though hypotonia is a common symptom in sick neonates and a hallmark of severe neuromuscular disorders, isolated severe hypotonia can be encountered in a few inborn errors of metabolism. The latter include amino acid metabolism disorders, energy deficiency disorders, peroxisomal disorders, lysosomal storage disease, and congenital disorders of glycosylation.

Amino acid disorders mainly consist of nonketotic hyperglycinemia and sulfite oxidase deficiency. Nonketotic hyperglycinemia causes global hypotonia associated with impaired consciousness and myoclonic jerks. Severe encephalopathy with epilepsy may occur. In the severe form of sulfite oxidase deficiency, hypotonia and seizures, mainly consisting of myoclonus, are the clinical hallmarks.

Energy deficiency disorders consist of respiratory chain disorders, pyruvate dehydrogenase and pyruvate carboxylase deficiencies, and fatty acid β-oxidation defects.

Peroxisomal disorders consist of defects either of single or multiple peroxisomal enzymes, or of peroxisomal biogenesis that are responsible for neonatal hypotonia associated with seizures, hepatomegaly, and dysmorphic features (high forehead, large fontanel, short limbs).

The main lysosomal storage disorder presenting with muscular hypotonia is acid maltase deficiency or Pompe disease; the disease presents with hypotonia (in general during the first months of life) associated with progressive hypertrophic cardiomyopathy.

Congenital disorders of glycosylation combine in neonates generalized hypotonia associated with strabismus, hyporeflexia, and dysmorphic features.

Seizures may occur in several inherited metabolic disorders where they may constitute an important revealing manifestation (De Vivo, 2002; Prietsch et al., 2002; Bahi-Buisson et al., 2006). The range of metabolic disorders that cause seizures in the neonatal period is very large. It includes all causes of hypoglycemia, vitamin-responsive conditions, aminoacidopathies, peroxisomal and lysosomal defects, neurotransmitter disorders, and congenital disorders of glycosylation, namely those involving O-glycosylation defects.

Vitamin-responsive seizures mainly consist of B₆-responsive seizures due to antiquitin deficiency, pyridoxamine phosphate oxidase deficiency responding to pyridoxal phosphate, and folinic acid-responsive seizures (for which the molecular basis is not completely elucidated even though some patients with antiquitin deficiency may respond to folinic acid).

Among aminoacidopathies, nonketotic hyperglycinemia, sulfite oxidase deficiency, and serine synthesis defects are the most epileptogenic. In the latter, severe congenital (or in some cases acquired) microcephaly associated with early spasticity and dystonia are characteristic.

Lysosomal disorders that cause seizures are mainly infantile neuronal ceroid lipofuscinoses.

Metabolic derangement and diagnostic tests

In most metabolic disorders presenting with coma, the clinical presentation, along with a few simple biochemical tests, may orient the diagnosis (Saudubray et al., 2002; Leonard and Morris, 2006). These include: acid–base balance (pH and bicarbonate), glucose in plasma and cerebrospinal fluid (CSF), ammonia and lactate in plasma, and ketone bodies in urine (urine dipstick). Body odor may be a diagnostic clue in maple syrup urine disease and in isovaleric aciduria, as mentioned above. Ketosis detected in urine by a dipstick is always abnormal in a newborn and a possible sign of metabolic disease. Dinitrophenylhydrazine is a specific solution detecting the presence of α-keto acids such as seen in maple syrup urine disease. F...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Handbook of Clinical Neurology 3rd Series
• Foreword
• Preface
• Contributors
• SECTION 14: Neuromuscular disorders
• SECTION 15: Cranial nerves and brainstem dysfunction
• SECTION 16: Inborn errors of metabolism and storage diseases
• SECTION 17: Heredodegenerative disorders
• SECTION 18: Postnatal toxic and induced disorders
• Index