3265 Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism CHAPTER 419

attain normal adult stature. Fatty liver and liver fibrosis have been

identified in some patients, including children. Cholesterol, triglycerides, and liver enzymes levels are elevated. Fasting ketosis is a feature

of the disease, yet is not seen in all patients. Lactic and uric acid levels

are usually normal. Hypoglycemia may be mild in some but recurrent

in others. Phenotypic variability is being increasingly recognized,

with significant disease involvement in some cases of the X-linked

form. Liver histology shows distention of hepatocytes due to excess

glycogen accumulation; fibrosis is also noted. It is recommended that

patients be monitored for hepatic complications with regular CT or

MRI scans. Though previously thought to be a mild disease, a broad

clinical spectrum of presentations is now being recognized in GSD

IX, with more severe cases coming to light, even in the X-linked

form. Further research is needed to completely understand the natural history and long-term complications of the X-linked subtype of

liver GSD IX.

Treatment of liver GSD IX is symptom-based. Like in GSD III,

gluconeogenesis is intact in GSD IX. A high-protein diet with complex

carbohydrates in small, frequent feedings is effective in preventing

hypoglycemia. Blood ketones and glucose should be evaluated during

times of stress. Liver transplantation may be considered in those with

severe hepatic involvement.

Other subtypes of type IX liver GSD include GSD IX β and GSD IX

γ2. Additional subtypes, GSD IX α1 and IX γ1, affect only muscle and

are described in a later section. GSD IX β (GSD IXb) is an autosomal

recessive form of liver and muscle PhK deficiency caused by PHKB

pathogenic variants. Patients with GSD IX β typically present with

hepatomegaly. They exhibit a wide clinical spectrum and cannot be

distinguished based on clinical findings alone. GSD IX γ2 an autosomal recessive form of liver PhK deficiency, is due to PHKG2 pathogenic

variants. This is a severe form of GSD IX that often progresses to liver

cirrhosis. GSD IX γ2 typically is a more severe phenotype, when compared to GSD IX α2 and GSD IX β, with early liver cirrhosis and fibrosis. Previously, infants with severe isolated cardiomyopathy and low

PhK activity in the heart and muscle were considered to have a subtype

of GSD IX. However, there were no pathogenic variants in the genes

encoding for the PhK subunits. This presentation was later considered

to be a new syndrome, PRKAG2 syndrome, with a secondary decrease

in PhK activity. The condition can be lethal because of massive glycogen deposition in the myocardium. Details about this condition are

described under the section about PRKAG2 deficiency.

Type IV GSD (Branching Enzyme Deficiency, Amylopectinosis,

Polyglucosan Disease, or Andersen Disease) Type IV GSD

is caused by deficiency of branching enzyme leading to accumulation

of an abnormal glycogen with poor solubility. The disease is clinically

heterogeneous, with multisystem organ involvement, yet the primary

presentation may be characterized by manifestations in either liver or

muscle; thus two main types—hepatic and neuromuscular—are recognized. Individuals with the progressive hepatic form typically present

in the first 18 months of life with failure to thrive, hepatosplenomegaly,

and progressive liver cirrhosis leading to death in early childhood.

Hypoglycemia in GSD IV is secondary to advanced liver disease and

considered a late finding. Some patients may develop hepatocellular

carcinoma. These patients often have extrahepatic manifestations

involving the central and peripheral nervous system as well as cardiac

and skeletal muscles. The neuromuscular forms of the disease have

four recognized subtypes: perinatal, congenital, childhood, and adult

forms. The perinatal and congenital forms are lethal, and death occurs

in the neonatal period. The childhood form presents with myopathy

or cardiomyopathy, with typical systemic findings. The adult form is

known as adult polyglucosan body disease (APBD) and may present

with systemic involvement of the central and peripheral nervous system characterized by gait abnormalities due to spastic paraplegia neurogenic bladder, peripheral neuropathy, leukodystrophy, autonomic

dysfunction and cognitive impairment in the later stages of the disease.

Life expectancy is shortened in APBD patients, yet there is a paucity

of systematic long-term natural history studies. Definitive diagnosis of

GSD IV requires demonstration of pathogenic variants in the GBE1

gene or branching enzyme deficiency in liver, muscle, cultured skin

fibroblasts, or leukocytes.

Liver transplantation may be performed for progressive hepatic failure. Extrahepatic manifestations including cardiac and nervous system

involvement may occur after transplantation. Treatment for the adult

form of GSD IV includes symptomatic support for gait abnormalities

and bladder dysfunction, as well as periodic monitoring to uncover any

new neurologic deficits.

Other Liver Glycogenoses with Hepatomegaly and

Hypoglycemia These disorders include hepatic phosphorylase

deficiency (Hers disease, type VI) and hepatic glycogenosis with

Fanconi-Bickel syndrome. Patients with GSD type VI can have

growth retardation, hyperlipidemia, and hyperketosis in addition to

hepatomegaly and hypoglycemia. The clinical course can vary from

mild to severe. Fanconi-Bickel syndrome is caused by defects in the

facilitative glucose transporter 2 (GLUT-2), which transports glucose

and galactose in and out of hepatocytes, pancreatic cells, and the basolateral membranes of intestinal and renal epithelial cells. Patients with

Fanconi-Bickel syndrome have increased renal clearance of glucose,

amino acids, phosphate, and uric acid due to proximal renal tubular

dysfunction, impaired glucose and galactose utilization, and accumulation of glycogen in liver and kidney.

SELECTED MUSCLE GLYCOGENOSES

■ DISORDERS WITH MUSCLE-ENERGY

IMPAIRMENT

Type V GSD (Muscle Phosphorylase Deficiency, McArdle

Disease) Type V GSD is an autosomal recessive disorder caused by

deficiency of muscle phosphorylase. McArdle disease is a prototypical

muscle-energy disorder, as the enzyme deficiency limits ATP generation by glycogenolysis and results in glycogen accumulation.

CLINICAL AND LABORATORY FINDINGS There can be a broad, heterogeneous spectrum of clinical presentations with the neonatal form,

which is rapidly fatal at one extreme, and the classical form with myalgia, cramps, and myoglobinuria at the other. Symptom onset as late as

the eighth decade has been reported. Patients typically develop muscle

stiffness, pain, and weakness induced by exercise. The degree of muscle involvement is variable among the symptomatic patients; however,

the exercise intolerance typically worsens over time. Asymptomatic

individuals with absent muscle phosphorylase activity have also been

identified due to elevated serum CK.

Symptoms can be precipitated by (1) brief, high-intensity activity,

such as sprinting or carrying heavy loads; and/or (2) less intense but

sustained activity, such as climbing stairs or walking uphill. Most

patients can engage in moderate exercise, such as walking on level

ground, for long periods. Patients often exhibit the “second-wind”

phenomenon, in which, after a short break from the initiation of

strenuous physical effort, they are able to continue the activity without

pain. This phenomenon is unique to GSD V and is due to the increase

of blood glucose supply released from liver glycogen stores and fatty

acid oxidation as exercise progresses. Although most patients experience episodic muscle pain and cramping as a result of exercise, 35%

report permanent pain that seriously affects sleep and other activities.

Burgundy-colored urine is reported after exercise, resulting from myoglobinuria secondary to rhabdomyolysis. Acute renal failure can result

from intense myoglobinuria after vigorous exercise.

In rare cases, electromyographic findings may suggest inflammatory myopathy, a diagnosis that may be confused with polymyositis. These patients may be at risk for statin-induced myopathy and

rhabdomyolysis.

At rest, the serum CK level is usually elevated; after exercise, the

CK level increases even more. Exercise leads to an increase in levels of

blood ammonia, inosine, hypoxanthine, and uric acid; these abnormalities reflect residues of accelerated muscle purine nucleotide recycling

as a result of insufficient ATP production. NADH is underproduced

during physical exertion.

3266 PART 12 Endocrinology and Metabolism

DIAGNOSIS Lack of increase in blood lactate and exaggerated blood

ammonia elevations after an ischemic exercise test are indicative of a

muscle glycogenosis and suggest a defect in the conversion of glycogen

or glucose to lactate. This abnormal exercise response, however, can

also occur with other defects in glycogenolysis or glycolysis, such as

deficiency of muscle phosphofructokinase. A noninvasive, nonischemic forearm exercise test has been developed. Although this test has

high sensitivity, is easy to perform, and is cost-effective, the abnormal

exercise response does not exclude other muscle glycogenosis and

includes some risk. The cycle test detects the hallmark heart rate

observed during the second-wind phenomenon. A diagnostic confirmation is established by demonstration of pathogenic variants in the

myophosphorylase gene or by enzymatic assay in muscle tissue.

Treatment for muscle phosphorylase deficiency consists of preexercise consumption of simple carbohydrates (e.g., sucrose or sports

drinks) to protect muscles and improve exercise tolerance prior to the

onset of the second wind. Regular exercise at moderate intensity is

recommended to improve exercise capacity. Compared to patients who

are physically inactive, those who are physically active are known to

have improved cardiorespiratory fitness and a better long-term clinical

course. Additionally, poor bone health and significantly lower lean

mass have been observed in inactive patients.

Type IX GSD (Muscle Phosphorylase Kinase Deficiency)

GSD IX α1 and IX γ1 are muscle-specific PhK deficiency caused by

pathogenic variants in the PHKA1 and PHKG1 genes and are inherited

in an X-linked and autosomal recessive manner respectively. Patients

with muscle PhK deficiency present from childhood to adulthood with

symptoms including exercise intolerance, cramps and myoglobinuria

with exercise, fatigue, and progressive muscle weakness and atrophy.

Electromyographic and forearm ischemic exercise test findings are

typically normal. The heart and liver are not involved. Treatment for

muscle PhK deficiency may include physical therapy and nutritional

consultation to optimize glucose concentrations based on activity level.

■ DISORDERS WITH PROGRESSIVE SKELETAL

MUSCLE MYOPATHY AND/OR CARDIOMYOPATHY

Pompe Disease, Type II GSD (Acid α-1,4 Glucosidase

Deficiency) Pompe disease is an autosomal recessive disorder

caused by a deficiency of lysosomal acid α-glucosidase, an enzyme

responsible for the degradation of glycogen in the lysosomes. This disease is characterized by the accumulation of glycogen in the lysosomes

as opposed to accumulation in cytoplasm (as in the other glycogenoses).

CLINICAL AND LABORATORY FINDINGS The disorder encompasses

a range of phenotypes. Each includes myopathy but differs in the age

of onset, extent of organ involvement, and clinical severity. The most

severe is the classic infantile form, in which infants present with cardiomyopathy at birth and develop a generalized muscle weakness with

feeding difficulties, macroglossia, hepatomegaly, and congestive heart

failure due to the rapidly progressive hypertrophic cardiomyopathy.

Without treatment, patients with the classic infantile form do not

survive beyond 2 years of life. A variant form, known as nonclassic

infantile Pompe disease, also presents in the first year of life with less

severe cardiomyopathy and slower disease progression. All patients

with an absence of cardiomyopathy in the first year of life are considered to have the late-onset form. Young children with the late-onset

form have delayed motor milestones and difficulty in walking. With

disease progression, patients often develop proximal and later a distal

muscle weakness, swallowing difficulties, and respiratory insufficiency.

With the advent of newborn screening for Pompe disease, delayed

motor milestones and other musculoskeletal findings such as scapular

winging and pelvic girdle weakness are being recognized as early as the

first year of life in some babies with late-onset Pompe disease.

Adults typically present between the second and seventh decades

of life with slowly progressive myopathy without overt cardiac

involvement. The clinical picture is dominated by slowly progressive,

predominantly proximal limb girdle muscle weakness. The pelvic

girdle, paraspinal muscles, and diaphragm are most seriously affected.

Respiratory symptoms include sleep apnea, sleep disordered breathing, decreased forced vital capacity, somnolence, morning headache,

orthopnea, and exertional dyspnea. Respiratory failure causes significant morbidity and mortality in the late-onset form. In rare instances,

patients present with respiratory insufficiency as the initial symptom.

Basilar artery aneurysms and dilation of the ascending aorta have been

observed in patients with Pompe disease. Ptosis, lingual weakness,

hypernasality, speech difficulties, gastrointestinal dysmotility, and

incontinence due to poor sphincter tone are now being recognized as

part of the clinical spectrum. Small-fiber neuropathy, which presents

with painful paresthesia or pins-and-needles sensations, is also seen in

some patients with the late-onset form. Individuals with advanced disease often require some form of ventilatory support and are dependent

on a walking aid or wheelchair.

Laboratory findings include elevated levels of serum CK, aspartate

aminotransferase, alanine aminotransferase, and lactate dehydrogenase. Levels of urine glucose tetrasaccharide (Glc4

), a breakdown

product of glycogen, are elevated, especially on the severe end of the

disease spectrum, and can be used as a biomarker to monitor disease

progression and treatment responsiveness. In the infantile form of

the disease, chest x-ray shows massive cardiomegaly, echocardiogram

shows severely elevated left ventricular mass index, and electrocardiographic findings include a high-voltage QRS complex and a shortened

PR interval. Muscle biopsy shows vacuoles that stain positive for

glycogen; the muscle acid phosphatase level is increased, presumably

from a compensatory increase of lysosomal enzymes. Electromyography reveals myopathic features, with irritability of muscle fibers and

pseudomyotonic discharges, which appears early in the paraspinal

muscles. Serum CK is not always elevated in adults, and depending on

the muscle biopsied or tested, muscle histology or electromyography

may not be abnormal.

DIAGNOSIS The confirmatory step for a diagnosis of Pompe disease

is enzyme assay demonstrating deficient acid α-glucosidase or gene

sequencing with two pathogenic variants in the GAA gene. Enzyme

activity can be measured in muscle, cultured skin fibroblasts, or

blood. The latter is increasingly being used and is very reliable when

performed in laboratories with experience. Prenatal diagnosis using

variant analysis of DNA extracted from fetal cells obtained by amniocentesis or by measuring GAA enzyme activity in chorionic villi or

amniocytes is available.

The approval of enzyme replacement therapy (ERT) with alglucosidase alfa in 2006 has changed the natural history and clinical

course of Pompe disease. Children with the most severe, classic infantile form respond well to ERT and are living longer. Other adjunctive

treatment options include dietary modifications, submaximal aerobic

exercise, and respiratory muscle strength training. Early diagnosis with

early ERT initiation is the key to treatment efficacy. Gene therapy is

under early-phase clinical study as another treatment modality.

Pompe disease is now part of the recommended uniform screening

panel (RUSP) for newborns in the United States, and newborn screening (NBS) has been initiated in almost half of all states. In Taiwan,

where NBS for Pompe disease is performed routinely for all infants,

early disease detection and treatment initiation have led to better treatment outcomes in infantile Pompe patients. Similar evidence is also

emerging in the United States.

Polyglucosan Body Myopathy-2, Type XV GSD This is an

autosomal recessive, slowly progressive skeletal myopathy caused

by mutations in the GYG1 gene blocking glycogenin-1 biosynthesis.

GYG1 pathogenic variants result in a reduced or complete absence of

glyogenin-1, which impacts its autoglycosylation and/or its interaction

with glycogen synthase, resulting in impaired glycogen synthesis.

Affected individuals commonly present with adult-onset proximal

muscle weakness prominently affecting the hip and shoulder girdles.

The disease course is often progressive, with the most disabling muscle

weakness found at older age. Asymmetric muscle involvement has

been observed in patients with GSD XV. Individuals with pathogenic

variants in the GYG1 gene may also be identified without musculoskeletal manifestations. In these cases, cardiomyopathy and cardiac failure