Despite the abundance of new case reports, there is considerable evidence that many inherited metabolic disorders remain undiagnosed or misdiagnosed. There are a number of reasons, the most important of which is the fact that many physicians are not aware of most of the highly specific symptoms or syndromes that are excellent keys to the diagnosis and consequently do not perform comprehensive examinations.
From a clinical point of view, all the inborn errors of metabolism can be divided into two large categories:
Category 1. Diseases that involve only one functional system or affect only one organ or anatomic system. Presenting symptoms are uniform, and diagnosis is usually easy even when the basic biochemical lesion gives rise to systemic consequences.
Category 2. Diseases in which the basic biochemical lesion either affects a metabolic pathway common to a large number of cells or organs or is restricted to one organ but gives rise to humoral and systemic consequences. Presenting symptoms are very diverse. The central nervous system is frequently involved in advanced disease, and diagnosis may be rendered difficult by the presence of secondary abnormalities. This category includes most inborn errors of intermediary metabolism, diseases of intracellular trafficking, and lysosomal disorders.
The second category can be subdivided on the basis of pathophysiology into three groups that are useful for diagnosis.
Group 1. Diseases that disturb the synthesis or catabolism of complex molecules (lysosomal and peroxisomal disorders; disturbances of intracellular trafficking and secretory protein processing). Clinical symptoms are permanent, progressive, independent of intercurrent events, and unrelated to food intake.
Group 2. Inborn errors of intermediary metabolism that lead to acute or progressive intoxication caused by accumulation of toxic compounds proximal to the metabolic block. The group includes aminoacidopathies, most organic acidurias, congenital urea cycle defects, and sugar intolerances. In these conditions, a symptom-free interval is followed by clinical signs of acute or chronic intoxication and by recurrent metabolic disturbances. Clinical expression is often late in onset and intermittent. Diagnosis is easy, relying mainly on chromatography of plasma and urine amino acids or organic acids. Treatment involves removing the toxin.
Group 3. “Energy deficiency” disorders, in which symptoms are caused at least partly by a deficiency in energy production or utilization resulting from an inborn error of intermediary metabolism in liver, myocardium, muscle, or brain. This group includes glycogenosis, gluconeogenesis defects, congenital lactic acidemias, fatty acid oxidation defects, and mitochondrial respiratory chain disorders. These diseases present an overlapping clinical spectrum, and manifestations sometimes result from accumulation of toxic compounds as well as from the deficiency in energy production. Common symptoms include hypoglycemia, hyperlactacidemia, severe generalized hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collapse, sudden infant death syndrome, and congenital malformations, the last suggesting that the abnormal process affected fetal energy pathways.
The clinical diagnostic circumstances observed in inborn errors of metabolism are divided in this chapter into eight categories: presentation in the neonatal period, intermittent late-onset acute presentation, progressive neurologic symptoms, ocular symptoms, skin symptoms, hematologic symptoms, visceral symptoms or syndromes, and endocrine symptoms. The following outline expands these categories and constitutes a “table of contents” for the chapter. The approach is developed in the text and tables.
Presentation in the Neonatal Period: “Neonatal Metabolic Distress”
Identification of children at risk
Type I: neurologic deterioration, intoxication type, with ketosis
Type II: neurologic deterioration, intoxication type, with ketoacidosis: organic acidurias
Type III: lactic acidosis with neurologic deterioration, “energy-deficiency” type: congenital lactic acidosis
Type IVa: neurologic deterioration, intoxication type, with hyperammonemia and without ketoacidosis: urea cycle defects
Type IVb: neurologic deterioration, energy-deficiency type, without ketoacidosis and without hyperammonemia
Type V: predominant liver presentation
Type Va: hypoglycemia with hepatomegaly
Type Vb: liver failure with hepatocellular necrosis
Type Vc: cholestatic jaundice
Type Vd: hepatosplenomegaly and storage signs
Intrauterine growth retardation
Babies born to mothers with acute fatty liver of pregnancy and HELLP syndrome
Intermittent Late-Onset Acute Presentation
Metabolic acidosis (Table 66-7)
Ketosis (Table 66-9)
Hyperlactacidemias (Table 66-10)
Hypoglycemia: general approach (Table 66-11)
Hypoketotic hypoglycemias due to inborn errors of ketogenesis (Fig. 66-1)
Sudden infant death syndrome (Table 66-14)
Recurrent attacks of dehydration (Table 66-15)
Exercise intolerance and recurrent myoglobinuria (Table 66-16)
Abdominal pain (recurrent attacks) (Table 66-17)
Cardiac disorders (acute cardiac failure, heartbeat disorders) (Table 66-18)
Bone crisis (Table 66-19)
Progressive Neurologic Symptoms
Progressive neurologic and mental deterioration
Part 4: onset in adulthood (15 years to more than 60 years) (Table 66-33)
Extrapyramidal signs (dyskinesia, dystonia, choreoathetosis, parkinsonism) (Table 66-34)
Deafness (Table 66-35)
Hypotonia in the neonatal period and in early infancy (Table 66-36) (see also I. “Acute Symptoms in the Neonatal Period: Neonatal Metabolic Distress”)
Hyperventilation attacks (Table 66-37)
Cataracts (Table 66-38)
Corneal opacity (Table 66-39)
Macular cherry red spot (Table 66-40)
Retinitis pigmentosa (Table 66-41)
Coarse facies (Table 66-42)
Angiokeratoma (Table 66-47)
Alopecia (Table 66-48)
Nonregenerative anemias (macrocytic) (Table 66-49)
Nonmacrocytic anemias (due to hemolysis or combined mechanisms) (Table 66-50)
Pancytopenia, neutropenia, thrombocytopenia (Table 66-51)
Increased neutrophil granulocytes
Bleeding tendency (Table 66-52)
Acanthocytosis (Table 66-53)
Visceral Symptoms or Syndromes (intestine, liver, heart, lung, kidney)
Chronic diarrhea (with failure to thrive, poor feeding, anorexia, hypotonia) (Table 66-54)
Hepatomegaly and hepatosplenomegaly (Table 66-55)
Liver failure, ascites, edema (Table 66-56)
Cardiomyopathy (Table 66-57)
Interstitial pulmonary infiltrates (Table 66-58)
Tubulopathy (renal Fanconi syndrome and tubular acidosis) (Table 66-59)
Renal symptoms (other than tubulopathy) (Table 66-60)
Primary adrenal insufficiency
Growth hormone deficiency
Hypogonadism and sterility