3267 Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism CHAPTER 419

necessitating cardiac transplantation may be seen. Liver manifestations

have not been identified in patients with this disease.

GSD Mimicking Hypertrophic Cardiomyopathy Danon disease is an X-linked glycogen storage disorder caused by pathogenic

variants in the LAMP2 gene. This results in deficiency of lysosomalassociated membrane protein 2 (LAMP2), leading to defective

autophagosomal-lysosomal fusion and excessive accumulation of

autophagosomes in the heart and skeletal muscle. Patients present

primarily with hypertrophic cardiomyopathy but can be distinguished

from having the usual causes of hypertrophic cardiomyopathy by their

electrophysiologic abnormalities, particularly ventricular preexcitation

and conduction defects. In Danon disease, Wolff-Parkinson-White

(WPW) syndrome pattern is five times greater in prevalence than in

idiopathic and familial hypertrophic cardiomyopathy. Therefore, in a

young male with hypertrophic cardiomyopathy, the presence of WPW

pattern on electrocardiogram strongly suggests Danon disease. The

onset of cardiac symptoms such as chest pain, palpitations, syncope,

and cardiac arrest may occur between the ages of 8 and 15 years. Ocular manifestations are often underrecognized and include peripheral

pigmentary retinopathy, lens changes, and abnormal electroretinograms. Mild learning disability and cognitive deficits have been noted,

as well as speech and language delays, attention deficits, behavioral

problems, and dysmetria. The prognosis for LAMP2 deficiency is poor,

with progressive end-stage heart failure early in adulthood. Female

carriers can also be symptomatic. Although the disease is less severe in

females, cardiomyopathy, skeletal myopathy, retinopathy and cognitive

dysfunction have been described. Treatment is mainly symptomatic,

and involves management of heart failure, correction of conduction

abnormalities, and physical therapy, among others. Cardiac transplantation can be considered for refractory cases of heart failure. Neuropsychological evaluations and special education support may be required

for those with intellectual disabilities.

AMP-ACTIVATED PROTEIN KINASE GAMMA 2 DEFICIENCY (PRKAG2

DEFICIENCY) AMP-activated protein kinase gamma 2 (PRKAG2)

deficiency is caused by pathogenic variants in the PRKAG2 gene, which

is important in many cellular ATP metabolic pathways. Affected individuals present with cardiac abnormalities including hypertrophic cardiomyopathy and conduction system abnormalities, particularly WPW

syndrome. The extent of cardiac involvement is variable and includes

supraventricular tachycardia, sinus bradycardia, left ventricular dysfunction, or even sudden cardiac death in some cases. In addition to

cardiac involvement, there is a broad spectrum of phenotypic presentations including myalgia, myopathy, and seizures. Other manifestations

include developmental delays, hypotonia, areflexia, tremors, feeding

difficulties, frequent respiratory infections, and failure to thrive. Unlike

Danon disease, cardiomyopathy due to PRKAG2 pathogenic variants is

compatible with longer-term survival except for a congenital form that

presents in early infancy with a rapid fatal course. PRKAG2 syndrome

should be considered as a differential diagnosis in infants presenting

with severe hypertrophic cardiomyopathy. In rare instances, PRKAG2

patients may be misdiagnosed as having infantile Pompe disease due

to phenotypical similarity. Treatment is usually symptomatic and supportive, as in Danon disease. Heart transplantation has been suggested

as a preventive measure for noncongenital PRKAG2 deficiency.

SELECTED DISORDERS OF GALACTOSE

METABOLISM

“Classic” galactosemia is caused by galactose 1-phosphate uridyltransferase (GALT) deficiency with a GALT enzyme activity that is absent or

barely detectable. It is a serious disease with an incidence of 1 in 60,000

and an early onset of symptoms. The newborn infant normally receives

up to 40% of caloric intake as lactose (glucose + galactose). Without the

transferase, the infant is unable to metabolize galactose 1-phosphate

(Fig. 419-1), which consequently accumulates, resulting in injury to

parenchymal cells of the kidney, liver, and brain. After the first feeding,

infants can present with vomiting, diarrhea, hypotonia, jaundice, and

hepatomegaly. There is an increased risk for susceptibility to infection

with gram-negative organisms, such as Escherichia coli neonatal sepsis

in galactosemic infants, often with the onset of sepsis preceding the

diagnosis of galactosemia. Additional findings include hypoglycemia,

seizures, poor weight gain, cataracts, bleeding diathesis, renal failure,

cerebral edema, and neutropenia.

Widespread NBS for galactosemia has identified these infants early

and allowed them to be placed on dietary restriction. Elimination of

galactose from the diet reverses growth failure as well as renal and

hepatic dysfunction, improving the prognosis. However, long-term

developmental outcomes in classic galactosemia are poor, with a

majority of patients having speech delays and learning disabilities

that increase in severity with age. Impaired motor function and balance (with or without overt ataxia) is frequently seen. Ovarian failure

manifesting as primary or secondary amenorrhea is seen in females,

with 80–90% or more of women reporting hypergonadotropic hypogonadism. While most female patients are infertile when they reach

childbearing age, a few successful pregnancies have been reported.

Adults on dairy-free diets have developed cataracts, tremors, and low

bone density. The treatment of galactosemia to prevent long-term complications remains a challenge.

Genotype and phenotype relationship is well established in galactosemia with the Q188R mutation in homozygosity causing the above

described classical presentation. Several variants appear to be protective, particularly the Duarte variant (N314D) and the p.Ser135Leu

variant, which is more common in the African-American population.

In addition to cataract in neonatal or childhood period, galactokinase

deficiency may present with neonatal bleeding diathesis, encephalopathy and high levels of liver transaminases. Intellectual disabilities and

developmental delay have been described. Deficiency of uridine diphosphate galactose 4-epimerase can be benign when the enzyme deficiency

is limited to blood cells but can be as severe as classic galactosemia

when the enzyme deficiency is generalized.

SELECTED DISORDERS OF FRUCTOSE

METABOLISM

Fructokinase deficiency, or essential fructosemia (Fig. 419-1), causes a

benign condition that is incidentally diagnosed from the presence of

fructose as a reducing substance in the urine.

Deficiency of fructose 1,6-bisphosphate aldolase (aldolase B; hereditary fructose intolerance) is a serious disease in infants. These patients

are healthy and symptom-free until fructose or sucrose (table sugar) is

ingested (usually from fruit, sweetened cereal, or sucrose-containing

formula). Clinical manifestations may include jaundice, hepatomegaly,

vomiting, lethargy, irritability, and convulsions. The incidence of celiac

disease is higher among patients with hereditary fructose intolerance

(>10%) than in the general population (1–3%). Laboratory findings

show prolonged clotting time, hypoalbuminemia, elevation of bilirubin

and aminotransferase levels, and proximal renal tubular dysfunction. If

the disease goes undiagnosed and the deleterious intake of sugar continues, hypoglycemic episodes recur, and eventually death can occur

from progressive liver and renal failure. The mainstay of treatment is

the elimination of all sources of sucrose, fructose, and sorbitol from the

diet. Once dietary control is established, liver and kidney dysfunction

improve, and catch-up growth is common; intellectual development

is usually not affected. Over time, the patient’s symptom intensity

improves, even after fructose ingestion. The long-term prognosis is

good.

Fructose 1,6-diphosphatase deficiency is characterized by childhood

life-threatening episodes of hypoglycemia, acidosis, hyperventilation,

convulsions, and coma. These episodes are often triggered by foods

that contain fructose and include febrile infections and gastroenteritis

when oral food intake is low. Hypoglycemic episodes can occur in

neonatal period in nearly half of affected patients. Laboratory findings

include low blood glucose levels, high lactate, alanine and uric acid

levels, and metabolic acidosis. Renal tubular and liver functions are

normal, and aversion to sweets is usually not seen, unlike hereditary

fructose intolerance. Treatment of acute episodes requires the correction of hypoglycemia and acidosis by IV infusion of dextrose. Further

episodes can be prevented by avoidance of fasting and elimination